Chapter 14 Cognitive Neuropsychology of Dementia Syndromes

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Cognitive Neuropsychology of Dementia Syndromes JASON D. WARREN • ELIZABETH K. WARRINGTON

Memory Episodic Memory Neural Correlates Paramnesias Short-Term Memory

Speech Single Word Processing Sentence Processing Prosody Neural Correlates

Perception Visual Objects Visual Space Nonvisual Sensory Information Hallucinations

Literacy and Numeracy Reading Spelling and Writing Calculation

Knowledge Words Visual Objects Faces Other Modalities The Organization of Knowledge Systems Neural Correlates Voluntary Action Unfamiliar Actions Familiar Actions Specific Forms of Apraxia Alien Limb Neural Correlates

Executive Functions Modulation of Cognitive Input Modulation of Cognitive Output The Supervisory System Neural Correlates Emotion Emotion Comprehension Emotional Expression Neural Correlates Paradoxes and Prospects

Central to our current understanding of the dementias is the concept that different brain regions are affected in a characteristic and nonuniform manner as disease evolves. This principle holds to a greater or lesser extent for all degenerative dementias and has important neurobiologic and clinical implications. Neurobiologically, mechanisms of regional neuronal vulnerability (which remain largely unknown) are likely to play a fundamental role in the pathogenesis of many

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dementias. Clinically, early identification of the “signature” of brain dysfunction has localizing and (to a more limited extent) diagnostic value. The discipline of neuropsychology is founded on the premise that cognition, like other aspects of human brain function, has a modular organization that allows a specific correspondence between anatomy and function to be established. Although applied historically to the study of focal brain lesions, the methods of neuropsychology have proved no less essential in elucidating the cognitive architecture of the dementias. Because the mapping between tissue pathology and clinical disease is imprecise and incomplete, a neuropsychological account of the core dementia syndromes provides a unique level of description that is complementary to other brain sciences. A number of caveats apply to the neuropsychological evaluation of individuals with dementia whether in the clinic or in research. The cognitive syndromes that characterize the dementias are necessarily transitional. The evolution of increasingly severe and widespread deficits is integral to the pathologic process, and a complete neuropsychological description of a particular individual or a particular disease entity therefore entails longitudinal study, typically over months or years. Indeed, the identification of an evolving rather than static pattern of deficits may be critical in establishing a clinical diagnosis of dementia. To assess the significance of apparently focal deficits (e.g., those involving literacy) in dementia syndromes, it is necessary to calibrate for premorbid general intellectual ability and attainments. Moreover, the distributed nature of the pathologic process in the dementias means that, even in the case of relatively focal syndromes such as the progressive aphasias, there may be evidence of additional neuropsychological deficits. In addition to their potential clinical role in guiding the diagnostic formulation in the individual patient, such subtle deficits may hold important clues to the pattern of disease spread in the brain. As is the case for other investigative modalities (e.g., structural brain imaging), the instruments of neuropsychology are not uniformly sensitive in the detection and quantification of disease affecting different anatomical regions and functional systems in the brain. Executive and emotional impairments, for example, are difficult to quantify, whereas other domains, such as early sensory processing, demand specialized psychophysical techniques. Such considerations impose certain biases in the interpretation of neuropsychological data. In this chapter, we aim to show that neuropsychology can contribute a comprehensive and coherent picture of diverse human cognitive functions using a common information processing approach. Our approach is based on core syndromes that arise from dysfunction in particular cognitive domains rather than disease phenotypes, because dysfunction in a cognitive domain is rarely, if ever, disease specific. Our focus is on clinical phenomenology, in keeping with the essentially empirical and descriptive nature of the field; however, we also indicate how clinical deficits may relate to macroscopic and microscopic brain architecture and theoretical models of brain function. Although the neuropsychological study of the dementias has broadly corroborated the picture of human brain organization derived from focal lesions and functional brain imaging studies in normal individuals, there are important differences of emphasis. Accordingly, we here restrict discussion of neural correlates to the evidence obtained in patients with degenerative disease. It is important to emphasize at the outset that any attempt to establish neuroanatomical correlates of cognitive deficits in the

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dementias is subject to a fundamental limitation: Diffuse pathologic processes produce widespread tissue damage, and the macroanatomical pattern of atrophy inevitably includes regions that are associated but not essentially involved with the production of a particular cognitive syndrome. It is rarely possible to draw precise conclusions regarding anatomical localization from the study of patients with degenerative disease.

Memory The complaint of poor memory is so common in patients with dementia that one might imagine it has limited value in the diagnosis or neurobiologic understanding of particular diseases. However, a number of lines of evidence from both the basic and clinical neurosciences suggest that memory, far from being an amorphous global function of the whole brain, is a multicomponent process supported by anatomically and functionally distinct brain networks.1–3 Neuropsychological evidence supports a fundamental dichotomy between “explicit” memory, the contents of which can be consciously accessed, and “implicit” memory, the contents of which are accessed automatically and do not depend on conscious mediation. The memory disturbances that are commonly observed in the dementias fall into the broad category of “explicit” memory. Although memory processes normally depend on the integrity of perceptual, attentional, and executive mechanisms,4 the brain systems that subserve memory are to some degree in parallel to those engaged in other cognitive operations.5–7 Explicit memory has “short-term” and “long-term” components. In the neuropsychological sense, “short-term” memory refers to the span for which information is retained for immediate repetition or reproduction, without rehearsal or other reinforcement (typically, less than a minute); information that is retained for longer periods constitutes “long-term” memory. These short-term and longterm memory systems have distinct functional roles3; the short-term store does not behave as a simple “gateway” to long-term storage. Long-term memory can be further subclassified into memory for episodes or events from the individual’s past experience (termed variously episodic, event, or autobiographical memory) and conceptual knowledge about the world (semantic memory, here considered on page 340). Although normal remembering depends on an intimate association between memory for events and memory for facts,5–7 these systems may be affected in comparative isolation in the dementias. EPISODIC MEMORY Patients with dementia who complain of their memory are usually describing impaired episodic memory: inefficiency or loss of the ability to remember the record of everyday experience. The paradigmatic illustration of the episodic memory syndrome is Alzheimer’s disease (AD); however, deficits of episodic memory are frequent across the spectrum of the dementias, even in diseases that traditionally have not been classified as amnesic disorders.8 The degenerative dementias rarely produce a pure amnesic deficit, nor do they produce the dramatic and almost complete loss of episodic memory observed in individuals with focal destruction

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of mesial temporal lobe or diencephalic structures. A relatively pure disorder of episodic memory characterizes the so-called amnesic variety of mild cognitive impairment, a putative precursor to AD (see Chapter 3).9 Episodic memory can itself be further fractionated into operationally distinct processes, namely the encoding and retrieval of events since the onset of the disease process (anterograde memory), retrieval of premorbid past events (retrograde memory), and memory for distinct classes of material (e.g., verbal material, faces, and topography). Anterograde Memory An impaired ability to establish new memories about the events of daily life (anterograde amnesia) underpins many of the symptoms that are commonly reported in the dementias. Anterograde amnesia has a number of possible functional bases that are difficult to dissect clinically: encoding, storage, and retrieval mechanisms interact with consolidation and forgetting processes, any or all of which may be affected to some degree by a diffuse pathologic process. A clinically useful distinction can be drawn between recognition (a judgment of familiarity) and recall (retrieval of information about a past experience). Recognition is typically more resilient than recall: Unlike recognition, recall is likely to depend on reconstitution or reanimation of the context in which material was learned. This can be exploited in assessing patients with psychiatric disease and frontal dementias, in whom recall is particularly vulnerable to poor attention and engagement with the task. Such patients may benefit from provision of cues to a greater extent than those with AD,10 arguing for a relatively greater deficit in retrieval than encoding, although this is by no means invariable.8 Relatively selective delayed recognition deficits or “false alarms” (identification of an item or event as familiar when in fact it is not) can occur with frontal lobe disease, possibly reflecting a loss of subjective familiarity.6,11 Retrograde Memory Impoverished recall of autobiographical episodes before the onset of the illness (retrograde amnesia) is common in dementias with prominent episodic memory loss. Patients may be able to give an outline of significant personal and public events but cannot evoke these events in all their rich detail. Remote episodes from early life are often claimed to be better recalled than recent events, suggesting that the vulnerability of episodic memory might depend on the recency of the event. Various accounts of this putative “temporal gradient” of episodic recall have been proposed,6 including impaired consolidation, “semanticization” of old memories, and the proliferation of stored memory traces by repeated reactivation.12 However, neuropsychological studies of retrograde memory in AD and other dementias indicate that the temporal gradient is variable and often mild.6,13,14 Frequent rehearsal of a limited repertoire of overlearned anecdotes may simulate a temporal gradient, and it is difficult to equate the saliency of remote versus recent events, a difficulty that is compounded by the phenomenon of normal forgetting. Autobiographical memory can be fractionated into memory for incidents and memory for “personal semantics” (e.g., the name of one’s school or an old address13), and the relation between these components has not been fully clarified.

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Material-Specific Memory Normal episodic memory is not unitary: The same event can be represented using memoranda in different modalities. Deficits of verbal, visual, and topographical memory are common early in the course of AD, dementia with Lewy bodies (DLB), vascular dementia (VaD), and other diseases, although they vary in their relative prominence. Patients frequently describe an inability to recall the details of conversations and messages and the names of acquaintances. Impaired verbal episodic memory, as indexed, for example, in tests of paired associate learning or recognition memory for words, is the most sensitive cognitive marker of early AD across studies,9 although it is not a specific deficit.8 There may be a true deficit of nonverbal memory for faces (“amnestic prosopagnosia”). Impaired topographical memory commonly presents initially as a difficulty with route finding and a tendency to become lost in unfamiliar locations. Patients may fail to recall familiar landmarks.15 NEURAL CORRELATES The anatomical and physiologic bases for episodic memory have been studied more intensively than any other neuropsychological function. The topographical pattern of disease in structural9,16,17 and histopathologic9,18 studies of early AD supports the critical involvement of the medial temporal lobe (hippocampal formation, parahippocampal gyrus, and entorhinal cortex) in episodic memory.4,9 However, episodic memory impairment is not related simply to medial temporal lobe atrophy,19 and indeed, abundant neuropsychological evidence implicates a distributed brain network that extends widely beyond the medial temporal lobes. The diencephalic system, comprising the thalamus and its limbic connections including the fornix and mamillary bodies, plays an important role.6 The basal forebrain, which is intimately related to the diencephalon and limbic circuit, is also implicated via at least two mechanisms. It is the origin of the ascending cholinergic projection pathways, which exert important modulatory and attentional influences on the medial temporal lobe and neocortex, that are disrupted in cholinergic-deficient disease states such as AD and DLB.20 In addition, the basal forebrain includes structures such as the ventral striatum, which may be damaged directly in conditions such as Huntington’s disease (HD).14 Posterior cortical areas including the posterior cingulate, retrosplenial, and temporoparietal association cortex are densely connected via the diencephalic system with the medial temporal lobes. Involvement of this posterior cortical network has been demonstrated in structural imaging studies of early AD.21 One might speculate that these diencephalic projection zones provide an interface between executive processes and medial temporal lobe storage mechanisms.17 Despite much interest in cognitive signatures that might differentiate memory disturbances produced by medial temporal lobe and diencephalic disease,6 the phenomenologic similarities outweigh the differences. Anatomical specificity for particular memory operations is difficult to determine in the dementias (or indeed, in human lesion studies generally) because of the rarity of highly selective strategic lesions. Both medial temporal lobe and neocortical networks are implicated in the organization and activation of elaborate multimodal schemata corresponding to the conscious experience of remembering autobiographical

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events, including the temporal and spatial context in which those events occurred.5,22 Impaired episodic memory may be an early and prominent feature in frontotemporal lobar degeneration (FTLD).8 Memory impairment in the setting of frontal lobe disease is likely to be heterogeneous and multifactorial. In principle, deficits could disrupt a number of different processes. These would include strategies for efficient memory encoding (e.g., sustained attention or context-dependent learning), editing of encoded material, organized search of memory stores, maintenance of an orderly timeline, attribution of the source of particular memories, and possibly emotional valence.6,8 The anatomical substrates for material-specificity within episodic memory have not been fully clarified in degenerative disease. Recognition memory tests that equate the relative difficulty of verbal and nonverbal recognition processes23 broadly implicate the left cerebral hemisphere in the processing of verbal material and the right hemisphere in the processing of nonverbal material. Asymmetric deficits of verbal or nonverbal episodic memory can occur in the setting of bilateral or generalized cerebral atrophy.23 In AD, right hippocampal and medial temporal lobe volumes have been correlated with visual memory measures and left hippocampal and medial temporal lobe volumes with verbal memory measures.16,24,25 However, these studies have not established a consistent correlation between material-specific memory deficits and tissue damage within the temporal lobe. Case studies of topographical memory have specifically implicated the right parahippocampal cortex,26 but further work is needed to relate topographical to other aspects of spatial memory. PARAMNESIAS In addition to the more usual clinical scenario in which there is a failure of episodic recall, certain dementia syndromes are characterized by false or distorted recall. These “paramnesias” include confabulation and reduplicative paramnesia. In the former case, the patient may describe events that never occurred when prompted to fill a gap in the record of everyday experience (“provoked” or “momentary” confabulation), or may spontaneously supply extended and detailed accounts of events that could not possibly have occurred (“fantastic confabulation”). Reduplicative paramnesias are characterized by the belief that particular places or persons have been transposed or duplicated: The patient may report that his or her house is an exact replica of the “real” one (topographical paramnesia) or that their spouse has been replaced by an impostor with identical appearance (the Capgras delusion). Confabulatory disturbances are most often observed in the setting of frontal lobe or fronto-limbic damage6,27,28 and may result from disruption of an executive process that normally underpins the active reconstruction of remembered material. This reconstruction process may involve re-creation of the “experience” of memory,6 including a sense of familiarity with the material. The Capgras delusion could plausibly arise from a disconnection between temporal lobe networks that normally link recognition and memory processes with limbic circuitry mediating the emotional response to familiar people or places.28,29 Deficiency in such experiential dimensions of memory, especially if coupled with impaired response monitoring and editing, might give rise to the sometimes bizarre misattributions found in the paramnesias.

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SHORT-TERM MEMORY The existence of separate short-term memory systems for the temporary storage of auditory verbal and visuospatial information is well established. Verbal shortterm memory is engaged by tasks such as digit span or word span that require short-term storage of verbally coded material (a string of numbers or syllables), whereas visuospatial span is engaged by tasks that require short-term storage of material (e.g., a sequence of spatial positions) that cannot be verbally recoded.30 The clinical significance of these short-term memory systems remains debatable. Short-term memory deficits frequently co-occur with other types of memory impairment, and reduced short-term memory for both verbal and visuospatial material has been documented in AD and DLB.31–33 However, short-term memory measures are not directly correlated with measures of episodic memory.13 Rather than being passively stored, information in short-term memory generally undergoes some form of cognitive manipulation: for example, when dialing a new telephone number, making sense of an ambiguous spoken message, or visualizing an unfamiliar route. These are active processes that are directed by executive systems. The interaction of executive systems with short-term memory stores constitutes “working memory.”3 Working memory can be considered an auxiliary resource that comes into play during active rehearsal or manipulation of verbal or visuospatial information in short-term storage. This interaction is illustrated in the distinction between forward digit span (passive storage of information) and backward digit span (active manipulation of on-line material). Breakdown in working memory may manifest as a dissociation between normal forward and impaired backward digit span. Working memory impairment frequently coexists with other executive deficits and has been documented in many degenerative disorders, including AD, DLB, VaD, FTLD, and HD.13,30,33,34 Short-term memory systems for verbal and visuospatial material have been conceptualized as the “phonologic loop” and the “visuospatial sketchpad,” respectively.3,31,32 The phonologic loop in turn comprises functionally dissociable subcomponents: a phonologic store and a subvocal rehearsal system.31 It is likely that the phonologic loop is supported by a frontoparietal network in the left cerebral hemisphere and the visuospatial sketchpad by a corresponding network in the right cerebral hemisphere. These short-term storage mechanisms can be regarded as “slave” systems under control of executive processes instantiated in fronto-subcortical networks and/or distributed cortico-cortical connections.3,31,34

Perception Perceptual analysis of the environment is a computationally demanding, multistage process that is vulnerable to the breakdown of distributed neural networks in the dementias. Contemporary models of perceptual processes have been heavily influenced both by neuroanatomical and electrophysiologic studies in nonhuman primates35 and by the theoretical algorithms of cognitive science.36 The processing of visual objects; complex sounds; and, less certainly, information in other sensory modalities conforms broadly to a hierarchical model with generic, dissociable stages of early sensory analysis, formation of structural

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representations, and the association of those representations with meaning. Objects in the visual scene exist in spatial relation to one another, and the perception of space requires specific computational mechanisms. The mechanisms that process visual objects and visual space can be damaged selectively, supporting a basic anatomical and physiologic distinction between ventral “what” and dorsal “where” cortical processing streams.35 However, anatomical involvement of both streams is usual as disease evolves,37–40 and the clinical picture is further modified by extensive functional interactions between the streams.41,42 Syndromes of progressive visual dysfunction are associated with relatively focal tissue loss and metabolic derangements involving the posterior cerebral hemispheres and are often classified together on anatomical grounds as posterior cortical atrophy (PCA). This is a clinically and pathologically diverse group of diseases. The most frequent tissue pathology is AD; however, a variety of others are represented, including corticobasal degeneration (CBD), DLB, and prion disease.40 VISUAL OBJECTS Early Visual Analysis Deficits of early visual sensory analysis may give rise to partial cortical blindness, affecting visual acuity, stereopsis, or the discrimination of elementary visual patterns (form, color, or motion).39,43,44 Clinically, such deficits may mimic peripheral visual loss; patients may complain of blurred vision, decreased acuity, or desaturation of hues. Patients may be unable to discriminate colors or patterns when choosing clothing. Letters of similar shape may be confused. Difficulties may be particularly apparent under conditions of reduced contrast or changing illumination. The patient may describe washes of color across the visual scene, with the features of abnormally prolonged complementary colored after-images.43 Misperceptions of visual information may occur; patterns on fabric or wallpaper may seem to shift and change. In more advanced disease, altered perception of visual size and form may lead to television images being mistaken for reality.45 Visual misperceptions of other kinds are also described and may be relatively more common in Creutzfeldt-Jakob disease.46,47 Objects in the environment or body parts (especially faces) may appear distorted (metamorphopsia), abnormally persistent or transposed (palinopsia), or multiply reduplicated (polyopia). Studies of early visual processing in AD and DLB have documented dissociable impairments of visual acuity, contrast sensitivity, stereopsis, color perception, size, shape, figure-ground discrimination, and perception of visual illusions.39,45,48–52 These processes are essential for parsing visual scenes and grouping of elementary visual features. This primitive organization of visual information is a prerequisite for the perception of objects.52 Object-Specific Perception Visual object identification may be impaired despite intact early visual processing, and indeed, this is the more usual scenario in the degenerative dementias. The patient may fail to recognize common household items or familiar people unless extra-visual cues are available; this may be evident first for drawings or photographs. There may be difficulty in distinguishing coins, bank notes, or playing

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cards. Patients are typically unable to identify fragmented, distorted, or overlapping pictures or letters, silhouettes, or unusual views or to match faces and other complex visual objects visually, despite having normal indices of early visual analysis.53 Such patients have apperceptive visual agnosia, a disorder of postsensory perceptual categorization corresponding to an inability to activate objectspecific structural representations: sets of distinctive geometric and volumetric features that enable object identity to be abstracted despite changing contexts and viewpoints.54 In contrast to disorders of early visual analysis, which impair the detection of perceptual differences, the core defect in visual apperceptive agnosia is impaired detection of perceptual similarities by recourse to stored object representations. Different perceptual categories (faces, inanimate objects, and twodimensional stimuli) may be differentially affected.42,53,55 Neural Correlates Isolated impairments of visual object perception are rare in degenerative disease, and opportunities to establish anatomical and physiologic correlations are limited. Although pathologic involvement of retinocalcarine visual pathways may contribute to early visual processing deficits in AD and certain other degenerative dementias,49,51 cortical dysfunction is likely to play the primary role. Early visual deficits are retinotopic,48 consistent with the involvement of visual cortex, and this is supported by available structural43,44 and metabolic43 brain imaging and neuropathologic39,43,56 evidence. However, defects of early visual processing commonly appear after the onset of apperceptive or visuospatial deficits, in the setting of more extensive tissue damage. The anatomical substrate of object-specific apperceptive deficits is likely to involve parieto-occipital association and parietal lobe areas. Pathologic studies in posterior variant AD suggest that projection neurons and long cortico-cortical connections are particularly vulnerable,44,56 consistent with the higher frequency of apperceptive than elementary visual disturbances. It is likely that early sensory analysis and the formation of object-level representations are organized at least partly in parallel, such that both can be used by knowledge systems to derive meaning about visual percepts, whereas object-specific mechanisms are specifically engaged under conditions of perceptual ambiguity.39 According to this formulation, early visual analysis is retinotopically organized in both cerebral hemispheres, whereas object-specific perception is mediated by the right hemisphere: a scheme consistent with available evidence in asymmetric posterior cortical atrophies.57 It has been proposed that identification of different perceptual categories may be differentially affected because of varying demands for configurational representation.55 Complex objects such as faces would place particular demands on such mechanisms, and apperceptive prosopagnosia has been correlated with atrophy predominantly involving the ventral “what” visual stream in the right inferior temporal lobe, including the “fusiform face area.”55,58,59 VISUAL SPACE Deficits in the perception of visual space are more common than disorders of visual object processing in the dementias. Visuospatial deficits are often especially prominent in AD and DLB and take a variety of forms. These can be broadly

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classified as visual disorientation, the impaired perception of space relative to self (egocentric space), and visuospatial agnosia, the impaired perception of spatial configurations that are not referenced to one’s own position (exocentric space). Both kinds of deficit frequently coexist in degenerative diseases involving the posterior hemispheres. Egocentric Space Patients who are deficient in their ability to localize points in space have visual disorientation. They may be unable to locate objects such as cutlery immediately after they are put down or when the item is in front of them and typically misreach for items. Threading a needle, reading lines of text, writing, using an index, or keeping within lanes when driving may become impossible; the localization of moving and static targets may be differentially affected. Accidents when walking or driving are common, resulting from loss of the ability to judge distances or motion. Ultimately, such individuals become functionally blind, groping their way in familiar surroundings, unable to negotiate obstacles or locate doorways. On examination, such individuals show components of Balint’s syndrome: fragmented perception of the visual field (simultanagnosia), inability to perform visually guided movements (optic ataxia), and/or inability to direct the eyes to a point in space (ocular apraxia). Because of the retinotopic encoding of egocentric space, these deficits frequently resemble hemi- or quadrantanopsic field defects. Optic ataxia arises from deficient visuomotor integration in programming a motor response rather than a primary defect of visual localization and may therefore be restricted to movements of a single arm within a single visual field. Impaired perception of optical flow (patterned visual motion, as during self-movement) has been correlated with navigational deficits in AD.60 Exocentric Space Patients who are deficient in their ability to perceive spatial relationships have visuospatial agnosia. They may be unable to orient clothing when dressing, a camera when taking a photograph, or an envelope when posting a letter. Loss of the ability to tell the time from clocks is characteristic. Patients are commonly unable to navigate familiar routes and become lost in the neighborhood or even within the house (topographical disorientation). Skills such as reading text or maps, writing, and calculation, which depend on accurate perception of spatial patterns, are often degraded. On examination, copying and constructional tasks are poorly performed and there may be specific deficits of spatial discrimination (position of dots in an array, line orientation) or spatial search (counting dots in an array, enumeration of cubes in a model). Neural Correlates Anatomically, the prominence of visuospatial deficits in PCA correlates with heavy involvement of the superior and posterior parietal lobes in structural and metabolic imaging and histopathologic studies.37,39,40,43,56,57,61,62 These regions are part of the putative dorsal cortical “where” visual processing stream. Findings in degenerative disease broadly indicate that visual localization is

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bilaterally mediated, whereas visuospatial analysis is a right hemisphere skill.57,62 These findings are in accord with focal lesion studies and suggest that visuospatial processing, like object processing, is hierarchically organized. However, this parallel raises unresolved theoretical difficulties. In general, accurate point localization is a prerequisite for the formation of a spatial representation. Exocentric spatial analysis would therefore depend on egocentric spatial encoding, just as the structural description of visual objects depends on elementary visual cues. This simple model is qualified by complex interactions with spatial attention mechanisms.60,63 Contemporary models of attention have been derived largely from the study of patients with acute focal cerebral lesions rather than dementia. Nevertheless, spatial attentional deficits may be observed in association with both visual disorientation and visuospatial agnosia in degenerative disease.41,60 These attentional deficits may correspond to distinct self- and object-centered attentional frames of reference, or a variably-sized attentional “spotlight.” There is some evidence that patients with AD have a restricted spatial attentional window, leading to difficulties in disengaging spatial attention from a target. However, “noisy” sensory processing is very likely to interact with any specific attentional deficit.63 NONVISUAL SENSORY INFORMATION Perceptual defects in the dementias are not restricted to the visual domain. Olfactory identification deficits may occur early in the course of AD, Parkinson’s disease, and other degenerative dementias and are likely to be at least partly central in origin.64 Auditory,65, gustatory,66 and somatosensory48 deficits have also been described. Pathophysiologic and anatomical information about the nonvisual modalities remains limited, and it is still to be determined whether deficits in other sensory modalities can be reconciled with models of perceptual analysis derived from the visual domain. The nonvisual modalities may constitute important test cases for the identification of modality-specific and modality-independent mechanisms of perceptual dysfunction in the dementias. HALLUCINATIONS In addition to deficits of perceptual analysis, the dementias may produce hallucinosis syndromes, representing an abnormal excess of perceptual content. These most commonly occur (and have been most adequately studied) in the visual domain. Visual hallucinations are particularly striking and complex in DLB but also occur in a range of other diseases (see Chapter 9). Descriptions of hallucinations are often remarkably stereotyped: The patient typically sees unfamiliar people (curiously, often soldiers in bright antique costumes) or animals (especially cats or other small creatures), mobile or stationary, often multiple, but generally silent. Hallucinations frequently appear in the evening or in darkness. They may be glimpsed transiently at the edge of view or emerge from an environmental feature such as a piece of furniture or a garden scene. Extracampine hallucinations, the sense of a presence beyond the field of view, are also common in DLB and have been proposed to arise from abnormal activation of the neural representation of a person.67 The “phantom boarder” delusion (the sense that there is another person in the house when there is not) may be a related phenomenon.68 The individual’s level of insight

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and response to hallucinatory experiences may vary, depending on attentional, cognitive, and affective resources and the context in which they occur. Complex visual hallucinations are qualitatively different from derangements of early visual processing (e.g., distortions or misperceptions) and from delusional misidentifications, but these phenomena commonly coexist and may lie on a neurobiologic continuum. Anatomical correlates of visual hallucinosis have been identified. The presence and duration of visual hallucinations has been correlated with histopathologic involvement of higher order cortices within the ventral visual stream (inferior temporal cortex and parahippocampal gyrus) in DLB.69 It is likely that the prominence of visual hallucinations is modulated by dysfunction of neurotransmitter pathways (in particular, deficiency of temporal lobe acetylcholine).

Knowledge The richness of our everyday experience is built not from percepts alone, but from percepts associated with meaning, and the attribution of meaning in turn depends on stored knowledge about the world. The brain mechanisms that mediate the storage and retrieval of knowledge constitute semantic memory.1,2 In contrast to episodic memory, the contents of semantic memory are not unique to the individual’s past experience: The memoranda are concepts and their relations, rather than events. Although the nature and extent of interaction between semantic and episodic memory systems remains contentious,6,22 it is clear that they are selectively vulnerable to particular degenerative pathologies. Although semantic impairment is well documented in AD,70–72 the most striking and selective deficits of semantic memory are produced by focal degeneration of the left temporal lobe. Recognition of this “semantic dementia” (SD) syndrome has placed the neural organization of human knowledge systems among the core theoretical issues confronting contemporary cognitive neuropsychology (see Chapter 5). Debate continues regarding the nature and significance of deficits that affect different modalities of knowledge acquisition (visual, verbal, nonverbal auditory, and so on), specific within-modality attributes (e.g., color), categories of knowledge (e.g., living things and inanimate objects), and the hierarchy of subcategories within each broad superordinate knowledge category (e.g., fruits and vegetables, body parts, countries). WORDS Words constitute a unique and highly specialized class of percepts linked to the knowledge stores built from spoken and written language. The disintegration of word knowledge in SD produces a progressive impairment of word-finding and word comprehension. This breakdown of language skills, which has the formal characteristics of a transcortical sensory aphasia, is generally the presenting and most prominent feature of the syndrome. Initially, there may be an inability to convey precise shades of meaning, difficulty in using and understanding specialized vocabulary or loss of facility with crossword puzzles. As the syndrome develops, conversation and written production becomes increasingly empty and circumlocutory and may ultimately be limited to a small stock of clichés or highfrequency words. Speech is typically fluent (although there may be word-finding

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pauses) and phonology, syntax, and prosody are well-preserved; indeed, the true extent of the patient’s difficulties may not be apparent to the casual listener. Naming deficits are characteristically early and prominent and are evident both in conversation and when the patient attempts to name items from a verbal description. Generic or superordinate terms are often used in place of the more specific designation (e.g., “bird” in place of “canary”), although alternative items from the same category may also be produced (e.g., “pigeon” in place of “canary”). Comprehension of syntactical constructions is typically intact within the limitations of reduced vocabulary. Single word repetition is generally preserved, although repetition of sentences is influenced by the level of comprehension; there may be “migration” of phonemes between words (e.g., “the flag was colored bright red” may become “the blag was fullered with a right breg”), consistent with the use of a phonologic rather than semantic code.73 Although naming deficits may initially appear relatively isolated, the definition and description of familiar words are generally also deficient and these deficits are influenced heavily by word frequency effects (e.g., “lion” may be retained, whereas “rhino” may not2). Defects in verbal knowledge can be probed by tasks that require the patient to classify items according to nominated criteria (e.g., “Is a tiger an animal?,” “Is a tiger bigger than a dog?”). Loss of word knowledge characteristically progresses from specific to superordinate categories (e.g., loss of knowledge about flowers might evolve in the sequence: damask—rose—flower— plant—living thing). Typically, meaning can still be assigned at the level of broad categories, even though more fine-grained classifications are impossible. Knowledge deficits may be largely restricted to the verbal domain with relative preservation of visual and nonverbal auditory modalities.2 Although rarely pure, category-specific effects within the verbal modality have also been documented in degenerative disease. There may be selective impairment of the ability to comprehend the names of living things74,75 or inanimate items76 or a selective deficit in the comprehension of concrete versus abstract words.2 Conversely, there may be relative preservation of the names of body parts,77 colors,78 or countries.79 One category effect is well established in degenerative disease: the dissociation between noun and verb knowledge. Impairments of noun retrieval and comprehension and selective deficits in the processing of nouns versus actions are well documented.80 Conversely, selective impairments of verb retrieval and comprehension have been demonstrated in patients with frontal dementia syndromes including motor neuron disease dementia.81 Such patients have agrammatic speech and difficulty in syntactic comprehension, with particular difficulty in the use of verb phrases and greater difficulty in naming actions than objects. There is some evidence that such patients rely more heavily on circumlocutions (noun phrases such as “laddering” for “climbing”) and “superordinate” verb forms (e.g., “being,” “making,” or “having”). VISUAL OBJECTS The spectrum of deficits produced by breakdown of brain knowledge systems is by no means confined to language. Indeed, deficits in other cognitive domains generally develop in the course of the illness and may dominate the clinical presentation. Vision has been the most widely studied of these nonverbal domains. The association of percepts with meaning represents a distinct stage

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in the recognition of visual objects that dissociates from the processes of early sensory analysis and perceptual categorization, and the selective inability to associate visual percepts with meaning constitutes an associative visual agnosia. Patients with SD may be unable to identify everyday objects, describe their function, or supply other information about them, despite accurate and detailed analysis of perceptual features and abstraction of structural descriptions (e.g., matching usual and unusual views of the object). This can be demonstrated within the visual domain by having the patient match pictures of objects according to semantic relatedness (e.g., Egyptian pyramid with camel rather than kangaroo), to classify pictures on the basis of semantic criteria (e.g., farm animals vs. wild animals), or to draw or color objects from memory. As in the case of word knowledge, loss of object-related knowledge characteristically progresses from object-specific to superordinate attributes and high-frequency items are less vulnerable than low-frequency items. Certain types of attribute (notably color) appear especially vulnerable. Individuals typically show high internal consistency in their repertoire of preserved versus degraded object knowledge. As is the case for verbal knowledge, visual semantic deficits can be relatively category- and/or modality-specific. Inanimate objects may be recognized more reliably than living things,82 and knowledge of maps or landmarks may be selectively impaired or selectively spared.15,79,83 A patient may not recognize an object by sight but may be able to define it from its spoken name.2,79 FACES The face is a key route to person-specific knowledge, and the processes that support face recognition have attracted considerable clinical and theoretical interest. The syndrome of progressive prosopagnosia illustrates the effects of the breakdown of face knowledge. Patients may lose the ability to recognize familiar faces, initially those of acquaintances, and later, famous people and close family members. The recognition deficit may be highly selective for faces, at least initially,84 and may occur despite intact perceptual analysis (as indexed, for example, by face-matching or age estimation tasks) and normal recognition of facial expressions. Patients with a primary defect of face knowledge may be unable explicitly to distinguish familiar or famous faces from unfamiliar ones. Face recognition may initially dissociate from other modalities of person knowledge, such as names,59,84 and from other categories of knowledge, including categories (e.g., buildings or countries83,84) that contain a large repertoire of unique exemplars. However, more widespread semantic deficits typically emerge and the perceptual analysis of faces may also become affected.58,59 OTHER MODALITIES Although the nonverbal auditory and other nonvisual sensory modalities have been studied less systematically, knowledge deficits also occur in these other modalities. Agnosia for environmental sounds has been described in SD.2,85 Impaired recognition of familiar voices is common later in the course of progressive prosopagnosia59 and may signal a more general defect in person knowledge. Agnosia for familiar odors has been described in association with prosopagnosia.86 Information about these modalities remains too limited to allow useful

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conclusions regarding modality-specific organizational properties or indeed the true extent of the analogy with visual objects. THE ORGANIZATION OF KNOWLEDGE SYSTEMS Evidence for category-specific semantic deficits in patients with dementia2,71,74,82 speaks to the broad issue of the organization of conceptual representations. It is unlikely that category-specific effects are attributable simply to frequency or familiarity confounds because they can be demonstrated even after such factors are carefully controlled.71 Accounts of category-specificity have focused on the distinction between living things and inanimate objects, although the basis even for this apparently fundamental dichotomy is far from clear. Considered ontogenetically, a fractionated knowledge store might be based on the distinctive sensory and functional properties87,88 that become incorporated into a given concept via different input channels (e.g., dogs and cats share many visual attributes but fewer auditory ones, whereas the converse would apply to canaries and whistles, and the latter also differ fundamentally with respect to their status as manipulable artefacts). Knowledge about superordinate categories is acquired before knowledge about specific categories during normal development, and this sequence is mirrored in degenerative disease.2 Furthermore, the sensory and functional properties associated with a given concept will vary in their relative salience and make a differential contribution to the multimodal representation of the concept (thus, color and shape are likely to be important in the conceptual representation of an apple or a banana, whereas auditory properties are probably more important in representing an oboe or a clarinet). This “multiple channels” account of the organization of brain knowledge systems has been challenged by alternative formulations that have variously emphasized the role of perceptual competition,89 correlation between conceptual features,90 evolutionary survival value,91 or the effects of individual differences.75 These different positions are of course not necessarily mutually exclusive: faces, for example, differ from other categories of visual objects both in their unique behavioral significance and their status as unique exemplars of a perceptually and semantically complex class of objects, and similar considerations may apply to proper nouns. It may be that certain categories of knowledge are in fact fundamentally distinct in computational terms. Knowledge about topography and places, for example, might involve spatial encoding mechanisms that do not depend on the sensory and motor associations that underpin other types of object knowledge.79 Evidence for modality-specific semantic deficits2,74,79 argues against a unitary “encyclopedic” knowledge store. Nevertheless, normal conceptual processing involves the binding of information obtained via different modalities to form a coherent multimodal representation. The neural mechanisms that support the assembly of such multimodal representations remain poorly understood. One influential model for the category of face knowledge was advanced by Bruce and Young.92 According to this model, face information initially undergoes structural encoding followed by a template-matching process at modality-specific face recognition units, and the output of these units becomes linked with other aspects of person knowledge at person identity nodes. Certain types of information (e.g., facial expressions) that are independent of personal identity are processed at least partly in parallel. This model may require some modification to account

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for the pattern and evolution of deficits affecting different modalities of person knowledge in progressive prosopagnosia.58,59,93 NEURAL CORRELATES The consistent and relatively focal involvement of the left temporal pole and anterolateral and inferior left temporal lobe in SD19,94 and broadly homologous right temporal lobe regions in progressive prosopagnosia59,84,95 suggests that neocortical regions in the anterolateral and inferior temporal lobe are critical for conceptual knowledge. Progressive prosopagnosia has been described much less frequently than SD. This is likely to be at least partly attributable to the clinical silence of the right temporal lobe relative to the eloquent left temporal lobe, and indeed patients may not present until bilateral disease supervenes.95 The degree of atrophy of anterolateral left temporal neocortical areas correlates with measures of semantic impairment in group studies.96 However, it must not be overlooked that anterolateral temporal neocortical regions are not affected in isolation. There is frequently atrophy of the hippocampal formation (albeit asymmetrically and predominantly anteriorly), amygdala, and entorhinal cortex,19,94 with variable extension into the posterior temporal lobe, inferior frontal lobe, and beyond.96 The development of profound language comprehension deficits in association with a disease process selectively striking the anterior temporal lobe poses difficulties for classical models of language processing. Disconnection from posterior and inferior regions that are distant from the site of maximal structural damage may play a role in the genesis of certain phenomena, such as naming deficits.97 However, the occurrence of category-specific deficits, the retention of partial knowledge, and the consistency of specific deficits argue that the knowledge system itself is involved. Progressive erosion of a distributed conceptual representation resulting from a diffuse degenerative process might plausibly manifest as a steady impoverishment of semantic associations,98 and evidence for graded activation of damaged conceptual representations has been presented in AD.72 In general, it is difficult to establish precise anatomical correlates for particular categories of knowledge in degenerative diseases. Categories of knowledge that are distant in psychological space need not, of course, be anatomically separate. However, it has been proposed that medial temporal lobe damage may predispose to deficits of animate knowledge and frontoparietal damage to deficits of inanimate knowledge, respectively.71,75 Person knowledge is likely to be asymmetrically distributed between the right and left anterior temporal lobes, the left anterior and inferolateral temporal lobe representing verbal information (e.g., personal names), and corresponding regions of the right temporal lobe representing familiar face information.93 In the case of words, verb knowledge is associated with pathologic involvement of inferior frontal areas: this may implicate dorsal motor pathways concerned with action processing.81

Voluntary Action Various motor disorders occur in patients with dementia, and many manifest as a deficiency or abnormal excess of elementary movements. The innumerable

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actions of everyday life, however, are the product of a complex interface between the motor apparatus proper and cognitive operations that plan, sculpt, and sequence individual movements according to the intent of the action, its effects, the context in which it occurs, and experience of past actions. Disease processes that damage these cognitive controls produce disorders of voluntary action, collectively labeled the apraxias. “Apraxia” designates a disturbance of voluntary movement that cannot be explained by elementary motor or sensory deficits.99 Disorders of elementary movement have widely accepted systems of classification and evaluation. No such consensus has been established for the apraxias, although these disorders have attracted the attention of neurologists for more than a century.100 A basic and empirically useful distinction can be drawn between disorders that affect unfamiliar actions (“ideomotor apraxia”), in which a novel motor program must be elaborated according to circumstance, and disorders that affect learned actions (“ideational apraxia”), in which a motor program established by past experience must be reactivated according to context. Apraxia in dementia generally occurs in association with more widespread deficits involving the dominant parietal or frontal lobes; however, cases of primary progressive apraxia have been described.101,102 UNFAMILIAR ACTIONS Apraxia for unfamiliar actions is a prominent feature of dementias such as AD that involve the posterior hemispheres, and in this setting there is often additional evidence of impaired visuospatial perception. Novel tasks requiring mechanical problem-solving (e.g., assembling prefabricated furniture or models) and learning new motor skills typically pose particular difficulties, whereas competence in the use of utensils and familiar gestures may initially be retained. The patient has difficulties in imitating the examiner’s meaningless hand positions and may perplexedly turn the hand this way and that while attempting to place it in the same orientation or the same location as the examiner’s. There may be particular difficulty when movements must be combined into a short sequence (Luria’s maneuver), and perseverative errors are common. Performance typically improves if the patient is able to enact the sequence with the examiner, suggesting that the demands of motor sequencing per se interact with the requirement to maintain a sequence of movements in visuospatial working memory; however, production of the individual actions in the sequence is generally also somewhat clumsy. FAMILIAR ACTIONS Less commonly, apraxia leads to impaired production of learned actions. Manual occupations and hobbies may be abandoned: The patient may be unable to use common household tools and utensils or attempt to use them inappropriately (e.g., attempting to write with scissors). Complex tasks requiring a specific sequence of actions (e.g., opening a tin with a can opener) are especially vulnerable. The assessment of learned actions usually is directed toward gestures involving the upper limbs. When instructed to perform a symbolic gesture (e.g., waving goodbye or saluting) or to pantomime the use of a tool (e.g., a screwdriver or hammer), an awkward or fragmentary approximation may be produced. Both the configuration of the fingers and the movements themselves are typically abnormal. The ability to imitate familiar and unfamiliar gestures, to use real

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objects, and to pantomime the corresponding actions are often comparably impaired in degenerative disease; however, dissociations have been described.99,101,103 Action production may be facilitated by holding the corresponding tool or other contextual cues.103 In addition, the patient may fail to recognize familiar gestures mimed by the examiner. However, the extent to which conceptual knowledge of actions and action production are dissociable has not been resolved.99,101,103–105 SPECIFIC FORMS OF APRAXIA Apraxias affecting specific parts of the body are well recognized in the dementias. Most reported cases of primary progressive apraxia have had asymmetric limb apraxia. Patients may complain initially of “clumsiness” involving one hand (more commonly the left), and more widespread praxic deficits commonly emerge as the illness evolves.101 Asymmetric limb apraxia is a cardinal presenting feature of CBD,106 and in this condition it is characteristically accompanied by asymmetric rigidity and other extrapyramidal or cortical sensory signs. Actions involving the affected limb are characterized by coarse, uncoordinated or “mutilated” constituent movements, and the hand appears “adexterous”: This pattern of abnormalities may constitute a distinct motor disorder that has been designated “limb-kinetic” apraxia, although its true nature is disputed.99,107 Progressive selective apraxia of gait associated with fear of falling represents a distinct clinical variant.108 There may be associated rigidity with the features of gegenhalten and initially few other neurologic signs, although upper limb apraxia may develop later in the course of the disease. However, gait abnormalities in the dementias may arise at various levels of the motor hierarchy and the status of gait apraxia as a disorder of voluntary action has been challenged.9 Impairments affecting the voluntary control of orofacial movements dissociate from disorders of limb praxis. Orofacial apraxia is most frequently observed in association with impaired speech production in the syndrome of primary progressive non-fluent aphasia (PNFA) (in particular, so-called “apraxia of speech”102) and in CBD.109 The patient may lose the ability to whistle and may later develop difficulty initiating chewing and swallowing. There may be a paucity of voluntary movements involving the lower face, mouth, and lips with retained reflexive and emotional brow and lid movements. When instructed to cough, yawn, or sigh the patient may produce an inadequate facsimile or simply repeat the instruction emphatically; however, these actions are typically normal when performed spontaneously and the examiner’s orofacial gestures may be imitated competently. The term constructional apraxia, widely used to describe the impaired ability to copy drawings of objects or designs, is problematic. It is observed in patients with degenerative diseases variously affecting visuospatial perception, spatial attention, and executive processes. Qualitatively, various types of error may be observed: These can be broadly classified as defects in reproducing spatial arrangements and defects of oversimplification. This breakdown is consistent with at least two dissociable cognitive operations, namely visuospatial analysis and the organization of actions for graphic production, both of which are relevant to constructional tasks.110 Particularly in more advanced disease, the patient’s attempt to copy a drawing may lie near or even overlap with the target: This “closing-in” phenomenon may be at least in part compensatory for praxic dysfunction.111

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Several other disorders are conventionally designated “apraxias,” although it is doubtful whether they should be regarded as primary disturbances of voluntary action. These include “dressing apraxia,” which is probably largely attributable to deficient visuospatial analysis, and “apraxia of eyelid opening,” which in many cases has the features of a focal dystonia.99 ALIEN LIMB Patients with asymmetric limb apraxia may have difficulty in making cooperative movements using both hands because the more affected hand tends to mirror the other or otherwise interferes with the action. Complaints that the affected limb is useless or seems not to belong to the patient are common; occasionally, this may be described as a loss of control over the actions of the limb. There may be involuntary tentacular movements of the fingers, or the arm may tend to levitate or assume other odd postures (especially when attention is diverted or during walking). Forced grasping or reaching for objects in the immediate environment may occur, or there may be more organized purposeless actions such as repeatedly removing and replacing spectacles.106 These strange phenomena have collectively been described as “alien limb” (or “alien hand” because the leg is less commonly affected). Among the dementias, the most characteristic association is CBD,106 although other pathologies have been described.112 NEURAL CORRELATES The identification of neural substrates for control of voluntary action is bedeviled by the intrinsic complexity of the component processes, by the lack of a widely accepted cognitive or physiologic model, and by terminologic confusion. An additional caveat is methodologic: The literature on the apraxias rests on parallel lines of evidence established by neurophysiologists, who have emphasized the detailed analysis of sensorimotor interactions, and neurologists and neuropsychologists, who have emphasized cognitive operations. These different levels of analysis may be reconciled if voluntary action is considered as essentially a problem of sensorimotor integration.107 According to this view, visual and somatosensory information are mapped onto stored visuo-kinesthetic representations of actions, and these representations are used to achieve specific on-line sensorimotor transformations during the control of action. These transformations would be mediated by multiple parallel parieto-frontal circuits that link a posterior (parieto-temporal) conceptual-recognition system with an anterior (frontosubcortical) production system. Although they are dissociable, disorders of voluntary action are frequently accompanied by visuospatial, executive, or other impairments in patients with degenerative dementia syndromes. Apraxia is a hallmark of the biparietal variant of AD,43 whereas imaging findings in asymmetric cortical degenerations have implicated both the dominant102–104 and nondominant101 parietal lobes. Conceptual knowledge of gestures is likely to be mediated at least in part by the dominant temporal lobe,105 whereas the left parietal lobe is likely to play a key role in the integration of sensory information in the organization of actions.103 If an anterior production system represents motor programs for action in each hemisphere,99,107 predominantly unilateral damage involving this system might lead to

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the development of asymmetric limb-kinetic apraxia involving either side.101 However, precise correlation is generally difficult in degenerative disease. Moreover, the control of actions depends on feed-forward and feedback sensorimotor loops.107 Patients with frontal-subcortical dementia syndromes may have particular difficulty with alternating or bimanual movements, and it is likely that interactions between cortex and basal ganglia are critical for scheduling sequences of actions and for tuning limb posture and orientation during voluntary actions of all kinds.99,107 Indeed, some of the most selective and striking praxic impairments occur in patients with CBD, in whom there is commonly evidence of frontosubcortical, as well as parietal, lobe damage.103 Alien limb phenomena in this condition may also be attributable to frontal lobe damage involving the supplementary motor area and/or anterior cingulate.113 Although orofacial apraxia is associated with asymmetric atrophy predominantly involving left inferior frontal and opercular regions,102,114 a distributed frontoparietal network of higher order controls has been proposed.109 The anatomical substrates for other forms of body-part-specific apraxia are also incompletely defined.

Speech The comprehension and production of speech are faculties unique to the human brain, and it is not surprising that they depend on complex and highly specialized cognitive systems. The recognition of focal syndromes of impaired speech perception and production115 has transformed our concept of the degenerative dementias as diseases in which particular brain regions and specific cognitive domains may be disproportionately vulnerable. SINGLE WORD PROCESSING Comprehension Comprehension of speech depends fundamentally on the accurate decoding of the acoustic signal at the level of the constituent sounds composing individual words. Selective impairments of speech perception manifesting as progressive word deafness have been described rarely in degenerative disease.115–118 In contrast to patients with SD who have a core defect of verbal knowledge, worddeaf patients have difficulty both in understanding and repeating spoken words despite normal comprehension of written material, and speech output is often loud and dysprosodic and may contain phonemic substitutions. Auditory temporal acuity and discrimination of speech sounds have been shown to be impaired disproportionately to any deficit of pure tone detection.118 A less severe impairment of environmental sound and/or music perception may also be present,116,118 although the patient may not volunteer this. Such observations argue for a more generalized apperceptive auditory agnosia rather than pure word deafness, the emphasis on speech perception reflecting the relatively greater salience and acoustic complexity of speech signals compared with other classes of complex sounds. Although in principle the perception of phonetic features and the perception of phonemes as categorical entities are operationally distinct, a clear dissociation

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between these levels of processing attributable to a degenerative cause remains to be demonstrated. Impaired comprehension of single words in the setting of intact acoustic analysis constitutes a transcortical sensory aphasia: This is a consequence of breakdown in verbal knowledge systems (discussed on page 340). Retrieval Word retrieval is a multicomponent and context-dependent process.119 Impaired word retrieval leads to word-finding pauses or circumlocutions in everyday conversation and a reduced ability to name (anomia). It is most often studied using confrontational naming tasks in which nouns (or less commonly, verbs81) must be produced in response to pictures or other stimuli. Failure of retrieval in this situation is characteristic of anomic aphasia, as observed in SD; however, naming (and more generally, word retrieval) deficits are observed in many dementias. In particular, naming difficulties may occur at an early stage in AD.120 Performance on naming tasks is strongly dependent on word frequency and the familiarity of the target item (thus, a cat or a chair may be named correctly, whereas a zebra or a scarecrow may not). Proper names may present particular difficulties: This is likely due both to semantic and phonologic factors.121 The multiple subprocesses involved in word retrieval are illustrated by the types of naming errors made by patients with different forms of dementia. Intact perceptual processing is a basic first requirement for confrontational naming, and once encoded, the sensory representation of the stimulus must activate the appropriate semantic links. Visual perceptual errors (e.g., a picture of a teapot may be described as a face) confound assessment of word retrieval and also interact with semantic deficits120,122: Patients may be able to name an object to definition or in the context of a sentence, although not to confrontation. Anomia is often attributable to a breakdown in verbal knowledge per se. Semantic errors may include superordinate and generic categorizations or circumlocutions (e.g., a picture of a squirrel may elicit “cat,” “animal,” or “they live in the garden, gray in color”); such errors are made by patients with AD and VaD as well as SD.122 However, these errors may be compensatory, resulting from a desire to communicate, rather than the direct result of a semantic deficit. Moreover, naming is not related simply to word comprehension. Word retrieval is an active process that demands that semantic and phonologic stores are searched efficiently and the appropriate items extracted.119 Anomia may arise from deficient access to phonologic codes (signaled by “tip-of-the-tongue” errors).121 Patients with PNFA characteristically make literal paraphasic errors (e.g., “stirel” for “squirrel”) consistent with a relatively greater difficulty in activating phonologic representations rather than a primary semantic defect.123 Neologisms are also observed in this population, although the overall frequency of such errors is substantially lower in degenerative diseases than in aphasic stroke. Naming deficits may be specific for output modality (speaking vs. writing in nonfluent FTLD syndromes124) or for a particular grammatical class (deficient spoken naming of verbs despite preserved verb comprehension and preserved noun naming in PNFA125; selective sparing of verb naming in AD126). Such dissociations suggest an important interaction between word retrieval and linguistic production processes and further suggest that neural representations of particular grammatical classes are distinct and specific for particular output channels.

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Production The translation of word representations into a spoken output involves a series of further operational stages.127 These can be broadly categorized as phonologic (selection and grouping of the appropriate syllable codes to compose a “phonologic score”) and articulatory (programming of the motor patterns corresponding to the phonologic score). Disturbances of both these stages typically coexist in patients with PNFA; however, it is not unusual for one component to dominate, and the potential for reciprocal interaction is clear.128 Considered together, dysfluent language output disturbances constitute a canonical subtype of FTLD; however, they are increasingly recognized as a presentation of related disorders in the non-Alzheimer spectrum, such as CBD129 and motor neuron disease dementia.81 In this regard, it is important to distinguish dysfluency resulting from a primary disorder of speech production from interrupted output resulting from prolonged word-finding pauses (so-called “logopenic” aphasia), which may occur in other dementias including AD.130 The disorder of speech timing that produces dysarthria in HD and other dementias with basal ganglia involvement131 should also be considered pathophysiologically distinct from PNFA. Phonemic paraphasias are a salient feature of PNFA, and particularly affect polysyllabic words. Some patients show a re-emergence of their childhood stutter. In addition, the kinetic program of speech may be distorted, with articulatory errors, speech apraxia, or aphemia (severe cortical dysarthria).114,128,132 Ultimately, there may be complete mutism. A phenotypic distinction can be drawn between patients with predominantly agrammatic and phonologic impairments and those with predominant apraxic and articulatory disturbances, although these two phenotypes often co-occur. Reduced phonologic working memory133 and defective articulatory rehearsal (e.g., as indexed by rhyming judgments that require recoding of graphemes to phonemes128) may contribute to errors in organizing and monitoring speech output. Anomia, although common, is seldom as severe in PNFA as in SD. Comprehension of words (including words that the patient cannot produce) is often preserved until a relatively advanced stage of the illness. Nevertheless, overlap syndromes with features of both PNFA and SD are not unusual. Relative selectivity for speech versus written output is not uncommon early in the course of PNFA, particularly in patients with prominent speech apraxia or dysarthria, but other language output channels generally become affected as the disease evolves. In general, different forms of speech output (spontaneous speech, repetition, reading aloud) are similarly affected in degenerative disease, although this is not invariable. Disproportionate impairment of repetition versus spontaneous speech (conduction aphasia134) and the converse pattern (transcortical motor aphasia135) have been described. SENTENCE PROCESSING Comprehension Under most circumstances in daily life, words must be processed not in isolation but when combined as sentences. The selective impairment of sentence comprehension is exemplified by patients with PNFA who have disturbed processing of grammatical structure. Comprehension of simple spoken commands may be

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impaired. Performance is poor on tasks requiring detection of grammatical violations or identification of agent and object from spoken sentences (of the type, “The dog that the boy chased is fast; who was chased?”).136,137 More subtle impairment of sentence comprehension has been documented in patients with AD. This impairment appears to be multifactorial in origin, including deficits in comprehension of pronouns,138 in processing the structural and semantic coherence of sentences,137 or in overriding canonical (first-noun-is-subject) sentence interpretations.139 However, other elements of grammar (e.g., gender, person, and tense inflections) may be comprehended normally.140 Such findings illustrate that the comprehension of grammar involves a number of different procedures (including determination of tense and number, interpretation of pronouns and prepositions, analysis of word order and subject-object relations, and parsing of clauses) that may be neurally, as well as operationally, distinct. These operations can be broadly classified as syntactical (relations between words) and morphologic (word modifications according to grammatical context). Syntactical operations often require that verbal information is maintained in working memory, and working memory capacity has been correlated with sentence repetition141 and pronoun comprehension138 in AD and sentence comprehension in PNFA.136 However, deficits in working memory and sentence processing are not causally linked.142 The comprehension of verb tense has attracted much recent interest because it speaks to a fundamental issue concerning the neural coding of language “rules.” Defective comprehension of irregular (“speak”-“spoke”) but not regular (“stop”“stopped”) verb morphology has been documented in SD143; however, the relationship may not be primarily semantic because comprehension of irregular past tense does not necessarily degrade in tandem with semantic knowledge.144 The reverse dissociation with disproportionately impaired comprehension of regular past tense has been described in Parkinson’s disease,145 although the significance of this deficit has been challenged.146 Syntactic properties of nouns, such as quantity (which determines plurality and quantifiers such as “some”), may also be processed separately from verbal semantics or working memory.147 Sentence Construction Normal propositional speech involves the construction of a sentence that conveys an idea or message. Disruption of the process of message generation produces dynamic aphasia. This language output disorder has characteristics similar to transcortical motor aphasia: a reduction in spontaneous propositional speech despite the ability to produce speech relatively normally in specific contexts such as naming, repetition, or reading. Dynamic aphasia has been documented in dementias that damage frontal or fronto-subcortical circuitry.148–150 The patient may appear to have “nothing to say,” with a striking paucity of spontaneous speech. That the deficit is a specific language disorder and not simply a consequence of abulia is demonstrated by a preserved ability to generate novel material fluently in other domains such as music.150 Word retrieval is generally preserved, and grammatical structure may be intact: These observations suggest that the defect in dynamic aphasia lies with the generation of a preverbal message.127,150 Sentence generation is influenced by context: Thus, a patient may be able to describe a simple picture showing a person reading but may not be able

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to generate a sentence incorporating the word book. Completion of sentences is also dependent on the requirement for generation of novel verbal material. Completions that require a phrase or a noun with many alternatives (“The man went to the shop to buy a ….”) typically pose difficulties, whereas completions that are dictated by the sentence context (“He posted the letter without a …”) are more successful.148,150 Once a sentence scheme is derived, it must be grammatically encoded. This process involves the combination of the constituent fragments of the sentence scheme according to the morphologic and syntactic rules appropriate to the language.127,151 The breakdown of grammatical output is a hallmark of PNFA and evident as effortful, dysfluent, and agrammatic speech with a disjointed and “telegraphic” quality resulting from omission of verbs, prepositions, and other function words.123,130,133,152 These features distinguish PNFA from the language output difficulties observed in patients with AD.123 The severity of agrammatism in many patients with PNFA has been an important stimulus to the investigation of speech comprehension in this group (see page 350). The qualitatively similar errors that characterize both expressive and receptive agrammatism suggest that the core deficit does indeed lie with the language system rather than motor or executive processes.81 PROSODY Prosody, the pattern of stress and timing that constitutes the melody of speech, is frequently abnormal in PNFA, but the selective disruption of speech prosody has been reported only rarely in dementia. Such patients may develop a monotonous voice with loss of the normal accents and rhythms of conversational speech. They may be unable to convey vocal emotions and linguistic intonation (e.g., to ask a question or convey emphasis), and the dynamic pitch shifts required when singing or reciting a poem, prayer, or story may become impossible.153,154 Other features of impaired speech production such as phonemic paraphasias may develop with progression of the illness. NEURAL CORRELATES Dementias that produce selective impairments of speech processing are associated with asymmetric atrophy predominantly involving the left peri-Sylvian region. The diffuse nature of the pathologic process and wide individual variation in the distribution of tissue damage favor the use of techniques such as voxel-based morphometry (VBM) to establish macroanatomical correlates of speech processing deficits. Certain broad patterns have emerged from both single-case and group studies in patients with focal dementia syndromes. These findings complement the large body of evidence derived from focal lesion studies and functional brain imaging. Deficits of speech perception are associated with atrophy involving the left posterior superior temporal gyrus, a region that includes early auditory areas.117,118 Word retrieval has been studied using VBM in PNFA, SD, frontotemporal dementia (FTD), CBD, and AD.119 The findings are consistent with multifocal interruption of a distributed, asymmetric (predominantly left-sided) brain network. Left lateral temporal cortex was involved in all disease groups, and the volume of this region correlated with naming accuracy. Additional

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correlations were observed specifically in left inferior and lateral frontal areas in PNFA, anterior cingulate in AD, and right inferior frontal-anterior temporal areas in CBD (the last was interpreted as a consequence of visual working memory processes that might be engaged during naming). Partially overlapping regions including the left frontal operculum and anterior insula have been identified in group and single-case studies of speech production breakdown in PNFA133 and cortical anarthria/speech apraxia,130 implicating these dominant anterior regions in the motor programming of speech. The region of metabolic abnormality extends widely beyond the relatively circumscribed tissue destruction detected on structural imaging.133,155 Sentence processing deficits are associated with tissue loss in similar regions of the dominant cerebral hemisphere. It is not possible to draw firm conclusions regarding the macroanatomical correlates of propositional speech failure in dynamic aphasia; however, it is likely that the syndrome results from damage involving a distributed left fronto-subcortical network.150 Deficits in both the comprehension and production of grammar are associated with atrophy involving the inferior frontal gyrus and insula,156 whereas impaired syntactic comprehension has been correlated specifically with involvement of the left posterior temporal-inferior parietal lobe.130 The insula may play a crucial role in linking grammatical, phonologic, and articulatory networks.156 It has been proposed that verb tense morphology is processed by dedicated rule-based and lexical-associative mechanisms instantiated in anatomically distinct fronto-subcortical and temporoparietal networks, respectively144,145; this remains unresolved. The anatomical basis of progressive dysprosody is even less secure, but individual cases have shown predominantly right-sided peri-Sylvian and frontal atrophy.153,154 Limited histopathologic evidence corroborates the role of left peri-Sylvian cortex in the pathogenesis of speech disorders in the dementias,117,132,152 albeit with widespread involvement of other cortical and subcortical regions in both cerebral hemispheres. Structural imaging and pathologic studies of patients with dementia share a common limitation in that they do not delineate the cognitive architecture of the distributed brain networks that process speech. Although detailed correlation of tissue damage with specific language functions can partially overcome such limitations,119 this issue underlines the need for complementary techniques such as longitudinal imaging to map the evolution of deficits157 and magnetic resonance spectroscopy to assess the integrity of axonal pathways linking cortical language areas.158

Literacy and Numeracy Reading, spelling, writing, and calculation are learned skills rather than innate capacities. This has both biologic and clinical implications. Biologically, neural mechanisms that sustain literacy and numeracy skills are likely to have been at least partly adapted from brain systems that support older and more elementary functions. Clinically, deficits of literacy and numeracy are often accompanied by or secondary to analogous deficits of visual perceptual, speech, or knowledge systems. An individual’s premorbid level of literacy and numeracy is heavily influenced by educational attainment and potentially by specific long-standing

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limitations such as developmental dyslexia or dyscalculia. Such factors must be taken into account when interpreting the effects of degenerative disease. Conversely, certain measures of literacy (e.g., reading vocabulary) are relatively resilient and can be used as an index of premorbid intellectual functioning.159 READING A basic distinction has been drawn by neurologists between reading disorders that occur without writing impairment (alexia without agraphia) and those that are accompanied by writing impairment (alexia with agraphia). This distinction maps only very loosely onto an information-processing model of the acquired dyslexias, in which disturbed visual analysis of written words produces a “peripheral” dyslexia (often leaving written output unscathed) and disturbed analysis of written words for sound or meaning produces a “central” dyslexia (often with associated deficits of written output). This model parallels the operational stages of nonlexical visual object processing (pages 336 and 341). Visual Analysis Impaired visual analysis of written words or peripheral dyslexia is often a prominent feature of PCA, and associated visuoperceptual and visuospatial impairments are common.37,38,39,40,43,48,160,161 Less severe forms of peripheral dyslexia may be relatively common in unselected patients with AD.162 Many patients with PCA have a core defect in recognition of visual word-forms. These individuals typically read letter-by-letter, and words written in script or with missing or distorted letters present particular difficulties. Musical notation reading may be especially vulnerable.161 Patients may spell words or even write cogent sentences that they are subsequently unable to read. Visual paralexias (e.g., mistaking “K” for “X” or “R” for “P”) are common. Initially a word-length effect on reading rate and accuracy can be demonstrated, consistent with a letter-byletter reading strategy. However, recognition even of individual letters may eventually become impossible. There may be evidence of asymmetrical spatial analysis of written words. Erroneous completions of a word based on its stem or ending (e.g., “wish” for “dish” or “room” for “root”) suggest misreading of the left or right portion of the word, respectively (“neglect dyslexia”). There may be particular difficulty reading text versus words in isolation,38,39 consistent with an interference effect from other similar stimuli in the visual field (“attentional dyslexia”). Analysis for Sound and Meaning “Central” deficits of written word processing beyond the stage of visual wordform analysis fall into two general categories: These correspond to two parallel routes to reading, based on analysis for sound (the phonologic encoding of printto-sound correspondences) and analysis of meaning (sight vocabulary). Features of these different forms of central dyslexia may coexist in patients with dementia. If reading by sound is damaged, there is a failure to use the general rules of phonologic encoding (“phonologic” dyslexia). These patients often have remarkably intact sight vocabulary but have particular difficulty reading “meaningless”

14 • Cognitive Neuropsychology of Dementia Syndromes

grammatical function words (“and,” “if,” “for,” etc.) and morphologic features such as tense or plurals. There may be difficulties producing individual letter sounds or making rhyme judgments. Difficulty reading nonwords, which relies entirely on phonologic encoding, is characteristic: Reading of nonwords is influenced by similarity to real words, and meaningless letter strings may be “lexicalized” (e.g., “kisp” may be read as “kiss”). Both regular and irregular words are read correctly, consistent with the use of a sight vocabulary (the semantic route to pronunciation163,164). Impaired reading by sound has been demonstrated in AD165 and PNFA.123 If reading by sight vocabulary is damaged, there is reliance on reading by sound. Patients typically have difficulty in reading irregular (exception) words because these rely on a stored knowledge of words as distinct entities. Irregular words are incorrectly regularized according to surface orthographic features (e.g., “yacht” may be pronounced “yached”), whereas regular words are read correctly (“surface” dyslexia). Performance on irregular words is further influenced by word frequency and the consistency of the variant pronunciation among orthographically similar words (e.g., the irregular sounding of “-ind” in “bind,” “hind,” or “kind” is consistently used for many similar words, whereas the irregular sounding of “-ome” in “come” is highly unusual166). Impaired reading by sight vocabulary is a frequent feature of the SD syndrome in English-speaking individuals. Analogous effects have been described in other languages: for example, a Japanese patient with SD developed selective dyslexia for kanji script (for which pronunciation is constrained by semantic context) but not phonetically regular kana.167 Patients with impaired sight vocabulary (unlike individuals with peripheral dyslexia) often read long regular words and nonwords at normal speed and may be able to segment extended letter strings into the constituent words even if those words are not comprehended.168 Such observations indicate that the core defect lies beyond the stage of visual word-form analysis. Evidence of an additional partial impairment of sight vocabulary is found in some patients with impaired reading by sound. This is illustrated by word class effects, with better performance reading nouns and adjectives than inflected verbs and better performance reading concrete nouns with high visual imageability (e.g., “tulip”) than low-imageability abstract nouns (e.g., “justice”).163 This syndrome with combined deficits of reading by sight and reading by sound has been termed “deep dyslexia.” Reading by sound and reading by sight vocabulary, the phonologic and semantic routes to reading, must interact under normal circumstances. The basis for this interaction has not been fully defined. Occasionally, patients with SD continue to read competently irregular words that they cannot comprehend.169 In principle, this might indicate “summation” of intact phonology with impaired semantics, direct visual access to a phonologic lexicon independently of semantics, or the use of print-to-sound correspondences for orthographic units of different sizes up to and including whole words. Neural Correlates Considering the diverse subprocesses involved in reading (visual analysis, phonologic, and semantic computations, overt or covert speech), it is not surprising that widely distributed cortical networks have been implicated in the dyslexias.

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Peripheral dyslexias are associated with bilateral or predominantly left-sided occipito-temporo-parietal atrophy and/or hypometabolism37,38,39,43,160,161 and histopathologic involvement of the ventral visual pathway.39 Impaired reading by sight vocabulary is associated with predominantly left-sided anterior temporal atrophy,166,167 in common with other components of the SD syndrome. In contrast, impaired reading by sound has been associated with generalized or minimal atrophy on brain imaging 163,164 and tissue pathology predominantly affecting left peri-Sylvian language regions.156 SPELLING AND WRITING Spelling and writing are both highly developed literacy skills and intimately related, in that efficient written expression depends on a capacity to spell. The dysgraphias can be broadly classified according to whether the core defect lies with spelling processes (“central” dysgraphias) or the motor programing and execution of writing (“peripheral” or output dysgraphias). The dysgraphias have empirical and theoretical correspondences with the dyslexias (crudely, writing can be regarded as the operational “reverse” of reading) and can be interpreted using an analogous information-processing framework. As is the case for the dyslexias, mixed forms are common. Spelling As is the case for reading, spelling can proceed via separable sound-based (phonologic) and vocabulary-based routes, and central dysgraphias affecting each route have been described in patients with dementia. Impaired spelling by sound (“phonologic” dysgraphia) is associated with particular difficulty writing grammatical function words and word endings despite competent rendering of nouns, attributable to a breakdown in sound-to-print transcoding; it has been observed in patients with AD170 and PNFA.171 The production of phonologically implausible spelling errors and an inability to spell nonwords (e.g., “nolder” may be spelled “nibar”) are characteristic. Some patients make letter substitution, omission, and transposition errors that are related to word length but not to linguistic properties. This disorder of spelling assembly has been interpreted as evidence of a defective “graphemic buffer,” with impaired storage of orthographic codes for translation to the corresponding physical letter codes. The breakdown of vocabulary-based spelling (“surface” dysgraphia) manifests as phonologically plausible renderings of “exception” words (which have an unconventional sound-to-print mapping; e.g., “juice” may be spelled “juse”), and ambiguous phonemes (which have several plausible sound-to-print mappings; e.g., the sound “ur” in “burn” could be alternatively rendered as “ir,” “er,” or “ear”).172 A word frequency effect is generally, although not invariably, observed.172 Phonologically regular, unambiguous words (e.g., “splash”) and nonwords are spelled correctly. Equivalent abnormalities have been described in other languages (e.g., inappropriate apostrophe use in Italian173). Impaired spelling vocabulary is a common feature of the SD syndrome174 but occurs in other settings; indeed, it is probably the commonest writing disorder in AD.171 In patients with a disorder of written spelling, the capacity to spell aloud (although it is infrequently called on) is in general comparably affected. However,

14 • Cognitive Neuropsychology of Dementia Syndromes

relatively selective impairment of oral spelling has been described in patients with AD175 and the reverse dissociation in VaD,176 indicating that there are distinct graphemic buffers for these different output channels. Writing The various stages of letter shape selection, formation, placement, and sequencing that underpin the motor output process of writing may be deranged in dementias that disrupt visuospatial analysis or voluntary action. These peripheral dysgraphias take several different forms. Effortful, impoverished, or inconstant letter formation, sometimes with mixing of upper and lower case, has been described in VaD177 and as a presentation of CBD.178 Such “ideational dysgraphia” may be attributable to defective retrieval of the motor routines corresponding to letter codes. A qualitatively similar disturbance of writing may accompany apraxia in CBD or AD. However, “apraxic dysgraphia” in such cases is sometimes highly selective (e.g., it may be restricted to transcription or production of letters in upper versus lower case or print versus cursive style).171,179 Conversely, writing may be relatively spared in the presence of apraxia for other voluntary actions.101,103 A general decline in legibility with reduplication of letter strokes, poor spacing and placement of letters on the page, and skewed or undulating lines of script is characteristic of spatial dysgraphia: This disorder is observed particularly in PCA37,39,61 and also occurs in typical AD, often (although not invariably) appearing later than linguistically based disturbances of writing.171 Neural Correlates The neural correlates of the dysgraphias overlap but are separable from those of dyslexia. Dysgraphia is generally associated with bilateral or predominantly left-sided parietal43,61,180 or frontoparietal103,178,179 atrophy and hypometabolism. Although detailed analyses are relatively few, the complexities of dysgraphia in such cases collectively implicate both “central” processes, involved in soundbased and vocabulary-based spelling and phoneme-to-grapheme conversion, and “peripheral” operations required for the planning and organization of the motor act of writing. The precise anatomical bases for defects in each of these various operations remain elusive. Although surface dysgraphia is associated with surface dyslexia and other features of SD in the setting of left temporal lobe atrophy, spelling appears to be more vulnerable than reading to semantic deterioration.174 This suggests that the transcoding of phonology to orthography requires specific computational resources, although these are difficult to establish using macroanatomical indices of tissue damage. CALCULATION Disorders of calculation can be classified according to whether the core defect lies with the computation itself or with the procedures required to process written and spoken numbers. Both types of defect have been described in the dementias. Patients typically complain of a loss of facility in handling change or household accounts and may have relinquished these responsibilities to others. There may

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be specific difficulties in adding scores and calculating totals in games, in using measuring instruments, or in reading and writing numerals and number words (e.g., when issuing a check). Dyscalculia is a prominent feature of diseases affecting the posterior hemispheres.37,38,40,181 Occasionally, progressive dyscalculia may be the presenting feature of a focal degeneration.182 Numerical Facts and Procedures Disorders of computation affect knowledge of number magnitude and numerical expressions (e.g., 9 is greater than 6; 9 > 6), arithmetical facts (e.g., 4 × 6 = 24), quantity facts (e.g., how many days in a year?), and arithmetical procedures (of the type required to solve 25% of 80 = ?). A basic distinction can be drawn between impaired knowledge of arithmetical procedures and number facts: Although both can be considered domains of semantic (numerical) knowledge, degenerative diseases may produce dissociations between these two numerical domains and also with respect to non-numerical knowledge categories. Selective impairment of quantity facts alone has been demonstrated in SD, whereas selective preservation of quantity and arithmetical facts has been shown in AD, FTLD, and VaD.183 Knowledge of arithmetical facts (in particular, multiplication tables) dissociates both from other aspects of number knowledge and from arithmetical procedures: Selective impairment of arithmetical facts has been documented in familial AD, whereas selective preservation of arithmetical facts has been demonstrated in sporadic AD and FTLD.183 Magnitude comprehension, arithmetical procedural skills, and even complex problem-solving skills may be retained despite the loss of basic arithmetical (multiplication) and number fact knowledge and disintegration of other semantic domains in SD.184,185 Selective impairment of numerical semantics sparing other semantic domains and fine-grained dissociations affecting specific arithmetical operations (intact multiplication and addition versus impaired division and subtraction) have been described in PCA.181 Number Reading and Writing Number reading and writing and transcoding between Arabic numerals and number words are commonly impaired in patients with dyscalculia181,182,184,185,186; many of these cases have other features of the SD syndrome. However, selective preservation of number reading and writing has been described in SD,187 lending further support to the view that numerical knowledge has neural substrates that are at least partially independent of other semantic categories. Spatial acalculia, attributable to spatial disorganization of written calculations, has been described in AD presenting with prominent visuospatial deficits.188 Neural Correlates In diverse conditions including AD, PCA, and FTLD,38,157,182,189 dyscalculia is consistently associated with bilateral or predominantly left-sided parietal atrophy and hypometabolism. Calculation performance in AD has been correlated with regional left inferior parietal metabolism independently of disease severity.189 The inferolateral left temporal lobe is implicated in aspects of number knowledge and binding of number words with numerical meaning.186 Although these regions

14 • Cognitive Neuropsychology of Dementia Syndromes

overlap extensively with the parieto-temporal networks implicated in dyslexia and dysgraphia, the many well-documented instances of dissociated numerical and language abilities indicate that calculation is not simply dependent on verbal mediation.

Executive Functions The generation of complex behavior demands that many cognitive operations are combined, coordinated, adapted to different contexts, and directed to relevant goals. The regulatory and supervisory brain mechanisms that achieve this together constitute the cognitive executive, and these mechanisms are instantiated chiefly in the frontal lobe cortex and its subcortical connections. However, it has proved problematic to incorporate executive brain functions within a modular information processing framework and the precise role played by the frontal lobes in human mental life has been hotly debated. The core functions of the cognitive executive (reviewed in references 190–192) have been characterized variously as programming, regulation and verification of behavior (Luria), coordination of multiple “slave” systems,3 goal-directed behavioral sequencing (Jouandet and Gazzaniga), modulation of central “set” (Milner), formation of temporal structures (Fuster), coherent organization of mental contents (Damasio), weighting of candidate behavioral goals (Duncan), contention scheduling, construction and verification of mental schemata (Shallice and Norman), and a cognitive “gateway” between stimulus-dependent and stimulus-independent thought (Burgess). A central feature of these and other accounts is a supervisory system or “buffer”: This buffer is proposed to hold information on-line for evaluation, allowing the behavioral “default mode” of automatic, obligatory stimulus-response associations to be transcended and modified.191,193 The operation of the cognitive executive is directly reflected in a complex behavioral output. Although any cognitive operation can only be assessed in terms of some behavioral index, elaborate purposeful behavior is the very raison d’être of executive processing. Any information-processing account of the cognitive executive that ignores complex behavior must be a very impoverished one. However, complex behaviors often appear superficially to have little kinship with the traditional subject matter of cognitive neuropsychology and resist reduction to simple theoretical algorithms and quantitative procedures.194 Furthermore, precise anatomical correlations are often difficult to establish. Although many dementias produce executive dysfunction, executive impairments are particularly closely associated with FTLD (see Chapter 5). It is important to acknowledge at the outset, however, that a too literal equation of executive with frontal lobe processes raises both theoretical and practical issues. Rather than “frontal lobe syndromes,” impairments of executive function are more appropriately considered as “dysexecutive syndromes” with a range of anatomical associations. Here we consider a set of core executive functions that might be disrupted in various dysexecutive syndromes. These are adapted from the supervisory and gateway models of Shallice and Burgess,190–192 which suggest operational analogies with other cognitive functions reviewed in this chapter. In practice, dysexecutive syndromes overlap extensively, and mixed or fragmentary forms are common.

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MODULATION OF COGNITIVE INPUT The input to the cognitive executive comprises the raw material of mental life, whether sensory data, images, or memoranda. These inputs are normally evaluated and weighted by the executive prior to the generation of behavioral responses.192 Perhaps the most striking syndrome of FTD is characterized by loss of this capacity to “gate” or modulate the effects of cognitive inputs according to the overall sensory or cognitive context. Affected individuals almost invariably lack insight into their difficulties, but a change in the patient’s personality is all too evident to others, and poor social judgment and inappropriate behavior or insensitive remarks are frequent presenting features. Disinhibition and impulsivity may wreak havoc with personal and occupational relationships, not uncommonly leading to loss of a job or marriage, estrangements from family members, legal infringements, traffic accidents, or ill-advised business or financial transactions. Inability to extract higher order patterns from sensory stimuli or memoranda is likely to contribute to a reduced capacity for abstract thought. Defective processing of social signals may contribute to impaired understanding of the mental states of self and others (“theory of mind”).195 Patients typically display an inflexible and concrete approach to occupational and daily life tasks. Checking or counting routines, ritualized daily routes, and schedules and clock-watching are common. Analogies and similarities may not be recognized (“a table and a chair are both in the kitchen”), and proverbs may be interpreted literally (“people in glass houses shouldn’t throw stones or the glass will break”). The ability to formulate a strategy for “searching” cognitive or sensory inputs is often compromised: This commonly manifests as reduced verbal fluency (the number of words generated in 1 minute according to a specified criterion, usually semantic category or initial letter). There is often evidence of altered processing of sensory signals. Narrowing of food preference in favor of sweet or strongly flavored foods is characteristic: The patient may steal sweets or demand ice cream at every meal. Dysregulation of other physiologic drives (e.g., decreased libido and insomnia196) and abnormally enhanced or blunted responses to pain or temperature197 may also be evident. Patients with impaired response modulation have particular difficulty in taking account of feedback or assessing the consequences of their own behavior; for example, they may continue to offer the same solution on a card-sorting task even when told repeatedly that the solution is wrong, a form of “conceptual” perseveration. This may contribute to risk-taking behavior.198 More dramatic instances of perseveration may emerge as context-irrelevant verbal fragments, gestures, or other motor patterns. In daily life, this tendency may extend to complex behaviors, such as hoarding; the patient may accumulate hundreds of cans of pet food, newspapers, or useless trinkets. Compulsive writing (hypergraphia) is another perseverative phenomenon. MODULATION OF COGNITIVE OUTPUT The output of the cognitive executive is the almost infinite repertoire of behavioral programs that underpin conscious thought and voluntary action. An impaired ability to generate this output leads to a loss of autonomy and increasing dependency on environmental cues and events to initiate behavioral subroutines.

14 • Cognitive Neuropsychology of Dementia Syndromes

Apathy (abulia), inertia, passivity, perseveration, and motor and verbal stereotypies are common features of this syndrome. Left undisturbed, patients may contentedly spend all day watching television or absorbed in jigsaw puzzles or word-games, and they may be disengaged from these activities only with difficulty. Loss of initiative commonly extends to household tasks and personal hygiene, which may fall into disarray unless others intervene. There may be utilization behavior (e.g., the patient may don spectacles or peel a piece of fruit unquestioningly when the item is placed before them), hyperorality (sometimes including mouthing of inedible items), compulsive reading aloud of signs and other written material, or mimicry of others’ speech (echolalia) or actions (echopraxia). Ultimately, a state of akinetic mutism may supervene. There are typically impairments both on word and gesture generation tasks. Dynamic aphasia may be regarded as a domain-specific deficit of this kind.150 To achieve behavioral goals, behavioral subroutines must be triggered appropriately and switching between different components of the behavioral repertoire must be possible. These operations depend in turn on mechanisms that control the timing and speed of executive processing. Patients with fronto-subcortical dementias often have slowness of thought (“bradyphrenia”) and difficulty in switching between behavioral subroutines or “sets” spontaneously or according to context. There may be perseverative errors on attempting to draw a sequence of alternating shapes or produce a sequence of alternating hand movements. Palilalia (repetition of the patient’s own words or terminal phrases) also occurs in dementias with fronto-subcortical involvement.199 THE SUPERVISORY SYSTEM The “default mode” of human behavior is governed by a large number of behavioral subroutines on the basis of automatic input-output associations.190,191 However, many executive operations, such as sustained attention and monitoring, formulation of a problem-solving strategy, or mental rehearsal, depend on the capacity to suppress, modify, or select alternative behavioral subroutines (the way out of a maze is rarely the most direct). One important stage in formulating a solution to a problem is likely to involve the construction of a cognitive “model” or schema about internal, external, and remembered events in relation to future goals. Such a model would enable hypotheses and potential responses to be tested mentally prior to the generation of an actual response. Operations of this kind require a supervisory system that manipulates information in parallel to inputoutput circuits. Many patients with FTD show evidence of degradation of this supervisory system. Poor concentration, distractibility, and restlessness often lead to deterioration in work performance, and reading for pleasure and other hobbies requiring sustained attention may be abandoned. Although routine or simple tasks may still be performed competently, the patient is often unable to cope with novel or multistep tasks, unexpected contingencies or conflicting task demands. An inefficient approach to problems and difficulty in taking even simple decisions may lead to a relegation of occupational and personal responsibilities. The patient may take days to prepare a straightforward report or arrange a family outing. There may be a preoccupation with detail and failure to grasp the essentials of work-related tasks or social situations.

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Deficient attention may disrupt performance on a range of psychometric tasks or lead to apparent inconsistencies. However, executive difficulties are exposed par excellence by tasks that demand planning, abstract thought, flexibility, and consideration of alternative solutions. There is often little consistency between tests or even between testing sessions in an individual case. Characteristic features include implausible but overprecise estimates (distance from London to New York is “266 miles”), impaired performance on dual tasks (e.g., tracking a visual target while reciting a list of numbers), and difficulty grasping simple rules (sorting multidimensional items by size, shape, or color) or in devising a problemsolving strategy (e.g., the “Tower of London” puzzle). NEURAL CORRELATES The anatomy and pathophysiology of executive dysfunction in degenerative disease remains poorly understood, and there is little consensus regarding the neural correlates of core executive functions such as those proposed here. A similar pattern of cognitive and behavioral impairments may be associated with variable findings on structural and metabolic brain imaging.198,200 Disinhibition, sociopathic behavior, and altered physiologic drives broadly correlate with predominantly right-sided anterior temporal and inferior frontal lobe atrophy and hypometabolism and abulia with dorsolateral frontal and anterior cingulate involvement.196,200–203 Disinhibition, impaired theory of mind, and disturbed modulation of sensory inputs are associated particularly with orbitofrontal and ventromedial frontal atrophy.195,200 Anosognosia (impaired awareness of deficits) has been correlated with right inferior frontal hypoperfusion.204 Predominantly left-sided anterior temporal lobe atrophy in SD is associated with various behavioral abnormalities196,202; however, these are qualitatively somewhat different from those observed with primary FTD (e.g., repetitive-compulsive behavior may be more common in SD202). The complex circuitry linking frontal cortex with subcortical structures such as the basal ganglia and thalamus is clearly implicated in a range of executive syndromes131,205; however, detailed clinicoanatomical and functional correlations have not been established. Bradyphrenia and executive deficits are salient features of the “subcortical” dementia syndrome.131,206 Although it is theoretically problematic (and certainly lacks anatomical and pathologic specificity), the concept of subcortical dementia remains clinically useful, designating a syndrome of cognitive slowing, attentional and motivational impairments, and affective blunting with relative preservation of many cognitive skills. The concept reflects a growing appreciation of the cognitive functions of subcortical pathways and nuclei, notably the thalamus and basal ganglia, and the role played by parallel re-entrant cortico-subcortical circuits in diverse cognitive operations.131,205,207 The separation of functions conventionally regarded as “cortical” and “subcortical” is clearly not absolute131: for example, rule application in the “cortical” domains of language and arithmetic may be affected by striatal damage in HD.208 Slowness of cognitive processing may be task specific,209 consistent with parallel fronto-subcortical circuits mediating different executive functions. The frontal lobes are targets of multiple distributed neurotransmitter projection pathways ascending from the brainstem, and abnormalities of neurotransmitter function are likely to be involved in the pathogenesis of dysexecutive

14 • Cognitive Neuropsychology of Dementia Syndromes

syndromes. Serotonergic defects have been described in FTLD syndromes.198 Multiple neurotransmitter systems have been implicated in the subcortical dementias, notably dopaminergic deficiency in Parkinson’s disease.131 However, work in this field remains too preliminary for any clear conclusions to be drawn.

Emotion Emotion is the mainspring of most complex human behavior, and the incorporation of emotion processing in testable models of human brain function is a major challenge confronting contemporary cognitive neuropsychology. Disturbances of emotion comprehension and expression are often closely associated with executive impairments in FTLD and other dementias. Disturbances of mood (in particular, depression) are common in AD and other degenerative disorders210 and are likely to be due at least in part to damage involving limbic circuits and their neocortical projections. The most dramatic disorders of emotion processing, however, are seen in patients with FTD and focal right temporal degeneration. Phenomenologically, disorders of emotion processing can be considered as disturbances of emotion comprehension and emotional expression. In general, however, these disturbances are intimately inter-related. EMOTION COMPREHENSION Defective comprehension of the emotions of others is a major factor in the social difficulties experienced by patients with FTLD. Poor understanding of the emotional states of people and animals may be interpreted as coldness and lack of affection. Patients may have a sound intellectual grasp of a situation (e.g., an accident or domestic altercation) but fail utterly to comprehend its emotional significance.211 An individual’s sense of humor may become more childlike (there may be a preference for cartoons and slapstick and loss of appreciation of irony). Specific deficits of emotion comprehension have been documented in FTLD and other dementias. Recognition of facial expressions has been the most widely studied modality. Defective recognition of negative emotions has been described in FTLD and may dissociate from other aspects of face processing.212,213 A relatively selective deficit affecting recognition of disgust occurs in HD and may be a sensitive marker of disease.214 Nonverbal vocal sounds and other channels of emotional expression may be similarly affected.211,212,214,215 Defective comprehension of affective prosody has been described in FTLD,211 AD,216 Parkinson’s disease,217 and HD.218 EMOTIONAL EXPRESSION Although the expression of emotion is difficult to assess objectively, patients with FTD often show impoverished emotional reactivity and loss of empathy. Blunting of emotional responses is commonly associated with an impassive, rather hostile facial expression211 that is at odds with the person’s state of mind; this may reflect a loss of the normal moment-to-moment reactivity to changes in others’ facial expressions during everyday social exchanges. Many patients with FTD display fatuous and puerile emotional responses, often with empty jocularity and

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childlike excitability (moria) and sometimes a tendency for rhyming or punning (Witzelsucht). A relatively selective loss of the capacity to show fear has been reported in SD.202 NEURAL CORRELATES The neuroanatomical substrates of emotion processing are of considerable theoretical and clinical interest. The attribution of emotional value to stimuli and behavioral responses is essential to adapt successfully to different environments and to set and achieve behavioral goals. A distributed predominantly right-sided frontotemporal network including the amygdala and orbitofrontal cortex has been implicated in brain imaging studies of FTLD212,219: This network is a plausible interface between primitive emotional states linked to biologic drives and the neocortical cognitive machinery of complex goal-directed behaviors.220 Preferential involvement of the basolateral nuclei of the amygdala in FTLD has been proposed to underpin the particular difficulties with emotion processing in FTLD versus other diseases that involve the amygdala.213 A further issue concerns the neuroanatomical bases for specific “canonical” emotions (disgust, fear, anger, sadness, surprise, joy221). Limited evidence supports the involvement of striatal and limbic structures in processing the negative emotions of disgust and fear, respectively.202,214,215

Paradoxes and Prospects Cognitive neuropsychology has helped to overturn the traditional notion that dementias are necessarily global brain diseases, and the study of patients with dementia has reaffirmed the essentially modular architecture of human cognitive processes (Fig. 14-1 and Table 14-1). The development of similar cognitive syndromes in different diseases (Table 14-1 and Fig. 14-2) argues that these syndromes primarily reflect the topography rather than the histopathology of brain damage. A complete neuropsychological phenotype is constructed from a combination of core deficits determined by the topography of the disease process in the brain (Fig. 14-2). That cognitive syndromes in dementia should so often mirror the effects of focal lesions is remarkable. Nevertheless, the diffuse nature of neurodegenerative processes means that precise correlations between behavior and anatomy are only rarely possible in the dementias, and it would be equally remarkable if the nature of the pathologic process did not influence the cognitive phenotype. This is underlined by examples of syndromes (neglect, conduction and jargon aphasia, semantic category effects) that are more often associated with acute lesions than degenerative disease affecting similar parts of the brain. Dementias disrupt neural systems (particular cell types, subcellular structures, proteins, neurotransmitters), and the cognitive consequences of system failure are very likely to be complementary to the effects of focal tissue destruction. A theoretical framework is needed if the cognitive neuropsychology of dementia syndromes is to complete the transition from taxonomy to hypothesis testing, and computational and neural network models may contribute to this transition.98 Model making, however, should be regularly refreshed by clinical observation, which

14 • Cognitive Neuropsychology of Dementia Syndromes

L

R

Parietal

Frontal

Temporal

Parietal

Occipital

Occipital

Episodic memory

Frontal

Temporal

Episodic memory

Action

Calculation

Literacy

Space

Executive

Speech

Knowledge

Sensory analysis

Object representation

Emotion

Figure 14-1 A modular view of cognitive syndromes. The schematic represents the anatomical localization of core cognitive domains in the left (L) and right (R) cerebral hemispheres. In the context of the dementias, the proposed localization indicates local neural networks that are disrupted by a diffuse or multifocal pathological process involving that region. Episodic memory is represented “in parallel” to other cognitive operations because the systems subserving memory are widely distributed within each hemisphere and dysfunction of these systems may dissociate from other cognitive deficits implicating these regions (see text). The localizationist perspective adopted here should be qualified: Connections between local networks (not illustrated in the diagram) are also vulnerable in the dementias.

will continue to confront us with the unexpected and the counterintuitive. The concern of the clinician is generally to link cognitive architecture to the architecture of the physical brain. In an era that emphasizes the group study and the meta-analysis, it is salutary to recall that many conceptual and clinical advances have originated as observations made in individual patients.2,115 With the advent of increasingly sophisticated brain imaging and molecular biologic techniques, it is reasonable to ask what cognitive neuropsychology can contribute to the study of the dementias. Degenerative diseases illustrate the effects of multifocal breakdown, “noise” and redundancy in distributed neural networks, and how these effects evolve in time and space within the brain. The information processing approach of cognitive neuropsychology provides both theoretical and practical tools for probing neural network dysfunction. Modular cognitive functions are normally integrated in complex behavior: Degenerative diseases demonstrate the breakdown in these integrative mechanisms, no less than the failure of individual cognitive functions themselves. It is difficult to see how candidate integrative systems, such as cortico-subcortical circuits, ascending neurotransmitter projection pathways and limbic mechanisms, could be fully

365

Short-term/working Verbal Visuospatial PERCEPTION Visual objects Sensory analysis Structural description Visual space Egocentric Exocentric KNOWLEDGE Words Visual objects Faces (persons) L IPL, L FL R IPL, R FL

Visual cortex Visual association cortex Bilat SPL R PL L ant, inf TL L ant, inf TL R > L ant, inf TL

Partial cortical blindness Visual apperceptive agnosia

Visual, auditory disorientation Visuospatial agnosia

Transcortical sensory aphasia Visual associative agnosia Prosopagnosia

L med TL + limbic/ neocortical connections R med TL + limbic/ neocortical connections Bilat (inf) FL, temporolimbic connections

Neuroanatomical Correlates

?Impaired syntax analysis ?Impaired imagery

Paramnesias: confabulation, topographical reduplicative paramnesia, misidentifications

Anterograde, retrograde autobiographical amnesia

Neurologic Disorder

Cognitive Syndromes in the Dementias

Experiential dimensions (editing, temporal sequence, familiarity)

Nonverbal

MEMORY Episodic/event Verbal

Cognitive Domain

TABLE 14–1

SD, AD

PCA, AD, DLB PCA, AD, DLB

PCA, CJD PCA, AD, DLB, CBD, CJD

AD, DLB, VaD, FTLD AD, DLB, VaD

FTLD, DLB, AD

AD, DLB, VaD

AD, DLB, VaD

Major Disease Associations

2, 75, 76, 79–81, 94, 96 2, 82, 83, 94, 96 59, 84, 93, 95

33, 37, 39, 40, 43, 57, 61, 62

39, 43–52 42, 53, 55, 57

3, 13, 30–34

6, 8, 28

7, 9, 14–16, 23–25, 33

References

366 The Dementias 2

Spatial analysis (neglect dyslexia, attentional dyslexia)

Prosody LITERACY AND NUMERACY Reading Peripheral Word-form

Grammatical encoding

Sentences Comprehension Message generation

Retrieval Production

L post-inf TL

Alexia without agraphia

L post TL / IPL

?R or L peri-Sylvian

L peri-Sylvian

L peri-Sylvian L dorsolat FL

Dysprosodia

Nonfluent aphasia Dynamic aphasia; transcortical motor aphasia Agrammatism

L ant TL, L FL L peri-Sylvian, L IFG, insula

Bilat auditory cortex L ant, inf TL

Word deafness Transcortical sensory aphasia

Anomia Nonfluent aphasia; speech apraxia, cortical anarthria

L FL/SPL/IPL L FL/SPL/IPL, L ant TL L inf FL, frontal operculum

Neuroanatomical Correlates

Ideomotor apraxia Ideational apraxia Orofacial apraxia

Neurologic Disorder

Cognitive Syndromes in the Dementias—cont’d

VOLUNTARY ACTIONS Unfamiliar Familiar Facial movements SPEECH Words Perception Comprehension

Cognitive Domain

TABLE 14–1

PCA, AD

PCA, AD

FTLD

FTLD, MNDD

FTLD, MNDD FTLD, CBD, PSP

AD, FTLD PNFA, CBD

FTLD, CBD SD

AD, CBD, PCA AD, CBD, FTLD, SD FTLD, CBD

Major Disease Associations

37–40, 43, 48, 160–162 38, 39

81, 123, 130, 133, 152, 155 153, 154

136, 137 148–150

115–118 2, 75, 76, 79–81, 94, 96 119-122 81, 115, 123, 128–130, 132, 155

99, 101–103, 105, 107 102, 109, 114

References

14 • Cognitive Neuropsychology of Dementia Syndromes

367

L peri-Sylvian, L IFG, insula L ant, inf TL

L IPL

L IPL/L FL

Agraphia

Apraxic agraphia

Neuroanatomical Correlates

Alexia with agraphia

Neurologic Disorder

Cognitive Syndromes in the Dementias—cont’d

Central Reading by sound (phonologic dyslexia) Reading by sight vocabulary (surface dyslexia) Spelling (central dysgraphias) Spelling by sound (phonologic dysgraphia, spelling assembly dysgraphia) Spelling by vocabulary (surface dysgraphia) Writing (peripheral dysgraphias) Spatial planning (spatial dysgraphia) Letter form selection (ideational dysgraphia) Motor act

Cognitive Domain

TABLE 14–1

171–174 37, 39, 61, 171 171, 177–179

SD PCA, AD CBD CBD, FTLD

170, 171

166–168

SD

AD, PNFA

123, 156, 163–165

References

AD, PNFA

Major Disease Associations

368 The Dementias 2

Timing and speed

Bilat inf FL, (especially orbitofrontal), ant TL, R>L

Bilat FL/frontosubcortical connections

Disinhibition, impulsivity, concreteness, perseveration, rituals/rigidity, hoarding, sweet tooth, altered response to pain/temperature Decreased verbal and nonverbal fluency ?Sociopathy

Abulia, perseveration, stereotypies, utilization behavior, hyperorality, echolalia, echopraxia Bradyphrenia, “subcortical dementia” Fronto-subcortical connections

SD

L IPL

Neuroanatomical Correlates

L TL

Acalculia

Calculation Procedures

Facts Number reading / writing EXECUTIVE FUNCTIONS* Modulation of input Inputs from sense data, memoranda Abstraction Feedback of own behavior “Search” of cognitive or sensory inputs “Theory of mind” Modulation of output Generation

Neurologic Disorder

Cognitive Syndromes in the Dementias—cont’d

Cognitive Domain

TABLE 14–1

PSP, VaD, DLB, PD

FTLD, PSP

FTLD

184–188

AD, PCA

Major Disease Associations

131, 206, 209

193, 197, 199, 200, 202, 203

193, 195–198, 200–203

37, 38, 40, 181–183, 189

References

14 • Cognitive Neuropsychology of Dementia Syndromes

369

R FL, ant TL, insula, amygdala

Bilat FL/fronto-subcortical connections

Neuroanatomical Correlates

FTLD, HD

FTLD, PSP, DLB, VaD

Major Disease Associations

202, 211

211–219

190, 191, 193, 206

References

AD, Alzheimer’s disease; ant, anterior; CBD, corticobasal degeneration; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies; FL, frontal lobe; FTLD, frontotemporal lobar degeneration; HD, Huntington’s disease; IFG, inferior frontal gyrus; inf, inferior; IPL, inferior parietal lobe; L, left; lat, lateral; med, medial; MNDD, motor neuron disease-dementia; PCA, posterior cortical atrophy; PD, Parkinson’s disease; PL, parietal lobe; PNFA, progressive non-fluent aphasia; post, posterior; PSP, progressive supranuclear palsy; R right; SD, semantic dementia; TL, temporal lobe; VaD, vascular dementia. *Speculative classification (see text).

Production

Loss of empathy, altered sense of humor Impassivity, fatuity

Distractibility Impaired problem solving

Supervisory system Attention Strategy

EMOTION Comprehension

Neurologic Disorder

Cognitive Syndromes in the Dementias—cont’d

Cognitive Domain

TABLE 14–1

370 The Dementias 2

14 • Cognitive Neuropsychology of Dementia Syndromes

AD

SD

Verbal memory

Executive

Speech Verbal knowledge Action Literacy Calculation

Nonverbal memory Emotion Nonverbal knowledge

PNFA

Space Object representation

FTD

Figure 14-2 Neuropsychological signatures of disease. The target diagrams illustrate neuropsychological profiles in a healthy individual (left) and in patients (right) with Alzheimer’s disease (AD), semantic dementia (SD), progressive nonfluent aphasia (PNFA), and frontotemporal dementia (FTD). These are representative or “typical” profiles that might be observed in an individual patient, rather than composite profiles applicable to the entire disease group. Each sector of the target represents a particular cognitive domain as shown (color code as in Fig. 14-1). Distance along the radial dimension represents level of functioning, and concentric lines represent percentile scores relative to a healthy age-matched population. Normal function in a cognitive domain is represented by color extending to the perimeter of the target; loss of function is represented by reduction of the colored sector corresponding to that cognitive domain. The neuropsychological profile of a particular disease is evident in the pattern of “erosion” of cognitive functions: the differential loss of function across cognitive domains. Comparing Figures 14-1 and 14-2, the cognitive signatures of disease are largely determined by the topographical pattern of tissue damage in the brain. (Target diagrams modified from McFie J: Assessment of Organic Intellectual Impairment. London, Academic Press, 1975.)

characterized without regard for their neuropsychological effects. Techniques such as functional brain imaging and VBM can delineate entire dysfunctional brain networks (including compensatory and abnormal activity26,222) and identify functional and anatomical patterns that are common across disease populations. These brain imaging techniques are complementary to cognitive neuropsychology: The brain areas that are critical for specific cognitive operations can only be

371

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