Clinical symptoms in Alzheimer's disease

Handbook of Clinical Neurology, Vol. 89 (3rd series) Dementias C. Duyckaerts, I. Litvan, Editors # 2008 Elsevier B.V. All rights reserved

Alzheimer’s disease Chapter 19

Clinical symptoms in Alzheimer’s disease ´ PEZ AND STEVEN T. DEKOSKY * OSCAR L. LO Departments of Neurology, Psychiatry, Neurobiology and Alzheimer’s Disease Research Center, University of Pittsburgh School of Medicine, Pittsburgh PA, USA

19.1. Introduction Alzheimer’s disease (AD) is the most prevalent form of dementia in individuals age 65 and older (Jorm and Jolley, 1998). The pathological substrate of the dementia is felt to be altered metabolism of amyloid precursor protein (APP) resulting in formation of amyloid (neuritic or senile) plaques in the cortex and limbic system, and altered process of the microtubuleassociated protein tau, which leads to the formation of neurofibrillary tangles (NFT). The pathological hallmarks were described by Alzheimer in his seminal paper (Alzheimer, 1907). Significant loss of synapses (DeKosky and Scheff, 1990), and of cholinergic, serotonergic, and noradrenergic function, as well as glutamatergic dysfunction, contribute to the cognitive and behavioral symptoms (Perry, 1980; Bowen et al., 1983; Palmer et al., 1987, 1988). Amyloid deposition occurs early in the disease, especially in heteromodal association areas (Selkoe, 1994; Klunk et al., 2004). However, memory decline points to the toxic effects of soluble amyloid and its oligomers on the pathological cascade directly and interfering with cognitive function (Cleary et al., 2005). The NFT pathological process usually starts in the mesial temporal areas, continuing to the allocortex and neocortex (Pearson et al., 1985; Braak and Braak, 1991; Delacourte et al., 1999). Clinically, AD starts with deficits in recent (short-term) memory, wordfinding, and language difficulties, and gradually progresses to global cognitive impairment (Becker et al., 1994a). The cognitive deficits are accompanied by a variety of abnormal neurological and psychiatric symptoms that increase in frequency and severity as

the disease progresses; some of these have been associated with a more rapid cognitive and functional decline. In this chapter we examine the clinical presentation of AD, and the factors that can influence its progression. In addition, we discuss current controversies in AD and call for reconsideration of the definition of dementia, and their implications for the diagnosis of AD.

19.2. Clinical criteria for dementia and Alzheimer’s disease The clinical diagnosis of AD is based on the presence of a dementia syndrome. Standardized consensus criteria for dementia agreed that the essential feature of the syndrome is the loss of intellectual abilities of sufficient severity to interfere with occupational or social functioning (WHO, 1993; APA, 1994). However, current clinical criteria for dementia differ in the extent and severity of the cognitive deficits that are required to define dementia. For example, the Diagnostic and Statistic Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for dementia require the presence of memory deficits and impairments in at least one other cognitive domain (i.e., aphasia, apraxia, agnosia, disturbance in executive function), while the International Classification of Diseases–10 (ICD-10) (WHO, 1993) requires that memory should be associated with impairments in at least two other cognitive domains. Another difficulty with current criteria for dementia is that they are based on the assumption that memory must be impaired for the diagnosis of dementia. It is now clear that patients can have cognitive deficits that significantly affect their activities of daily living with

*Correspondence to: Steven T. DeKosky, M.D., Professor and Chair, Department of Neurology, Director, Alzheimer’s Disease Research Center, University of Pittsburgh, 3471 Fifth Avenue, Suite 811, Pittsburgh, PA 15213, USA. E-mail: DekoskySt @upmc.edu.

208

´ PEZ AND S.T. DEKOSKY O.L. LO

relative preservation of memory performance. For example, subjects with an angular gyrus syndrome (i.e., receptive language deficits, alexia without agraphia, anomia, acalculia, constructional deficits, digital agnosia) secondary to vascular lesions (Benson et al., 1982), frontal lobe dementia (Lopez et al., 1999a), or an atypical onset of AD (e.g., “posterior” presentation) (Hof et al., 1993) can present with normal memory function. The Neurological Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) criteria for AD proposed a more practical approach to this issue, requiring impairment in at least two cognitive domains, although they stated that memory deficits must be progressive (McKhann et al., 1984). All of the criteria are silent in the severity of memory impairment required, or whether verbal and visuospatial memory must be affected. Although the NINCDS/ADRDA criteria require some (even simple) neuropsychological testing, no specific cognitive tests are specified or recommended. From the perspective of the clinician, the diagnosis and classification of any dementia syndrome must follow four steps: (1) establish a decline in cognitive function from a previous level of functioning; (2) establish that the cognitive deficits interfere with the subject’s work functioning, social interaction, or activities of daily living; (3) establish the presence of cognitive deficits in at least two cognitive domains; and (4) establish with some level of confidence the disease or the factors involved in the etiology of dementia (Becker et al., 1994b). Clinicians should also weigh the importance of disruptive behaviors in the diagnosis of dementia, although psychiatric symptoms are not part of any dementia criteria. New onset of aggression, disinhibition, agitation, or psychosis may provide further support for the clinical diagnosis of dementia, and it may also aid in specifying the diagnosis. 19.2.1. The NINDS/ADRDA criteria for AD The NINCDS/ADRDA (McKhann et al., 1984) are the most frequently used criteria for AD. These criteria classify AD based on the degree of certainty of the diagnosis, and whether AD is associated with other disease processes (i.e., Probable vs. Possible AD). The criteria for Probable AD require meeting the AD clinical criteria and that other conditions that may explain cognitive deficits have been excluded. By contrast, the diagnosis of Possible AD requires a history and progression of dementia consistent with AD, but in which clinical evidence of some other disease pro-

cess(es) is present, which might have contributed to the patient’s cognitive symptomatology. Such other disorders might include severe cerebrovascular disease (CVD) or stroke; head injury; depression; alcoholism; hypothyroidism; vitamin B12 deficiency; or other diseases that may have affected cognition (e.g., history of encephalitis, history of CO2 intoxication, history of primary hypercalcemia). Determining how such factors that can cause cognitive impairment affect the progression of AD is extremely important, having implications for both research studies and clinical practice.

19.3. Cognitive symptoms Impaired memory is the hallmark of the cognitive presentation of AD. The initial phase is characterized by subtle memory deficits (e.g., misplacing objects, forgetting conversations, problems remembering names, and missing appointments). However, AD patients usually have a global cognitive impairment (Becker et al., 1994a; Cahn et al., 1997). A study conducted to identify the best predictors of AD found that auditory verbal and visual delayed recall (with intrusions and perseverative errors), confrontation naming, and cognitive flexibility/divided attention tests were the best predictors of AD in a group of highly educated subjects (Cahn et al., 1997). AD does not always present as a neuropsychologically homogeneous entity with an initial memory deficit followed by subsequent impairments in other cognitive functions. Some patients can have prominent deficits in multiple cognitive domains other than memory, especially in early stages of the disease (Becker, 1994b). Frontal (Johnson et al., 1999) and occipital (Hof et al., 1993) lobe, or executive function (Baddeley et al., 1997) deficits can be the most relevant initial symptom in AD. In addition, it is important to note that memory can be preserved in a small number of AD patients. A study conducted on 191 Probable AD subjects showed that 79% of the patients had both verbal and visual memory deficits at baseline examination, 6% had only visual memory deficits, and 7% had only verbal memory affected. Interestingly, 7% of the patients had normal memory performance, although all these subjects progressed to have both types of memory involved after 1-year follow-up (Becker et al., 1992). When confronted with a subject with Alzheimer-like symptoms but relatively intact memory, careful monitoring of the patient is advised; memory will decline. Language deficits are the second most prominent cognitive manifestation of AD (Faber-Langendoen

CLINICAL SYMPTOMS IN ALZHEIMER’S DISEASE et al., 1988; Huff et al., 1988; Boller et al., 1991; Price et al., 1993; Becker et al., 1994a). Dysnomia, verbal paraphasias, and word-finding difficulty are the most salient features of the language problems in AD, and in some cases they can be the initial clinical symptom. Category fluency (animals, vegetables, and fruits) deficits showed a sensitivity of 100% and specificity of 92.5% for AD (Cahn et al., 1997). The gradual loss of category fluency in AD has been attributed to deterioration in the structure of lexical-semantic knowledge (Huff et al., 1988; Martin, 1992). Both fluency and, to a lesser degree, auditory comprehension are usually impaired in AD (Becker et al., 1994a). However, although language comprehension tends to deteriorate in more advance stages of the disease, the understanding of figurative expressions (expressions whose meaning differs from the literal meaning of the words, such as proverbs, metaphors, hyperbole, idioms) is affected in early stages (Papagno et al., 2003). Importantly, language deficits have been reported to be the most important cognitive predictor of rapid decline in AD (Boller et al., 1991). Visuoconstructional/visuospatial drawing (e.g., clock drawing, and copying of geometric figures) abilities are impaired in AD subjects in the early stages of AD (Becker, 1994; Cahn et al., 1997; Saxton et al., 2003). Similarly, problem-solving, concept formation, and cognitive flexibility deficits (Becker, 1994; Cahn et al., 1997) as well as ideational apraxia are common in these patients, although some patients can also manifest ideomotor apraxia (Della Sala et al., 1987; DeRenzi and Lucchelli, 1988). Importantly, most AD patients are either unaware of their cognitive deficits, or are unable to recognize the magnitude of these deficits (Starkstein et al., 1993; Lopez et al., 1994; Marshall et al., 2004). This lack of awareness of cognitive deficits (anosoagnosia) worsens as the disease progresses, and presents difficulties for caregivers, especially regarding such issues as the patient’s driving, managing finances, willingness to sign power of attorney over to a relative, and similar issues.

19.4. Neurological signs The general neurological examination in AD, especially early in the course, is normal. In fact, localizing signs should prompt a careful search for other etiologies. Localizing signs in the presence of a clinical picture that looks much like AD suggest that two processes are extant. Non-specific neurological signs (e.g., frontal release signs), cranial nerve abnormalities (e.g., diminished upward gaze), and gait abnormalities are more frequent in AD than in normal aging (Becker et al., 1994a). However, the most frequent neurological signs

209

associated with AD are myoclonic movements, and extrapyramidal signs (EPS), and their presence affects the clinical progression of the disease (Stern et al., 1994; Heyman et al., 1996; Lopez et al., 1997b). Many studies have focused on EPS, since these can be present in early stages of the disease. Myoclonic movements tend to occur more frequently in the evening or while sleeping. They are seen in rapidly progressive AD and are common in later stages (Benesch et al., 1993; Tschampa et al., 2001). 19.4.1. Extrapyramidal signs EPS are common in AD patients, and more prevalent as the disease progresses (Lopez et al., 1997b; Scarmeas et al., 2004). Cross-sectional studies have shown that bradykinesia and rigidity are the most frequent EPS in AD, while tremors are uncommon. AD patients with EPS are generally more cognitively impaired than those without EPS. However, the neuropathological substrates of the increase in EPS in AD are not clear. AD patients with EPS can have no neuronal loss or Lewy bodies in the substantia nigra and locus ceruleus, and it has been suggested that extranigral lesions involving the mesocortical dopaminergic pathways play a role in the development of EPS in AD (Morris et al., 1989). Furthermore, positron emission tomography (PET) studies have found that striatal dopamine metabolism in AD correlates with global measures of cognitive impairment, suggesting that severity of the cortical pathology can affect dopamine subcortical pathways (Meguro et al., 1997). Others have reported that AD patients with EPS had more neurofibrillary tangles in the substantia nigra than those without EPS, and greater neuronal loss than non-demented controls (Liu et al., 1997), raising the possibility that the presence of EPS was secondary to an early nigral dysfunction (e.g., cytoskeletal abnormalities, altered synapses). However, the severity of neuronal loss in the substantia nigra did not explain the presence of EPS. In addition, EPS are one of the three cardinal features of dementia with Lewy bodies ( DLB) (McKeith et al., 2005), which, whether alone or accompanying AD, is characterized by mild EPS, gait abnormalities, psychiatric symptoms, and rapid progression of the illness (McKeith et al., 2005). The time of onset of the EPS in AD has implications for diagnosis. AD patients who have EPS early in the disease (i.e., at time of diagnosis) appear to deteriorate faster both cognitively and functionally (Stern et al., 1994; Lopez et al., 1997b) than those who do not present with EPS. EPS have also been found to be predictors of death and institutionalization in AD (Stern et al., 1994; Lopez et al., 1997b). There appears

210

´ PEZ AND S.T. DEKOSKY O.L. LO

to be a subgroup of AD patients with EPS in whom tremors and rigidity are major clinical features (Lopez et al., 1997b). These patients have a worse outcome, and possibly greater neuropathological changes. EPS can also affect the progression of the disease by imposing a greater physical limitation on patients, with subsequent functional decline (Lopez et al., 1997b). 19.4.2. Alzheimer’s disease and dementia with Lewy bodies Neuropathological series have found that 20–30% of the patients with dementia have Lewy bodies (LB) in the neocortex and brainstem (Hansen et al., 1990; Lopez et al., 2000a), when ubiquitin-based methods were used, and approximately 60% with a-synucleinbased methods (Hamilton, 2000). The majority of cases with LB which have come to autopsy have concomitant AD pathology; those with “pure” LB are less frequent (Cercy and Bylsma, 1997; White et al., 2002; Tsuang et al., 2005). There is debate concerning how these patients should be classified. Some researchers have used more liberal criteria, classifying these patients as having “Dementia with Lewy Bodies” (DLB), regardless of the presence of AD pathology; others have made the distinction between cases with pure LB, and those with LB associated with AD (Gibb, 1990; Hansen and Samuel, 1997). The Third Report of the DLB Consortium proposed a probabilistic approach that takes into account both AD and Lewy body pathology. The likelihood that a DLB-related clinical symptom is explained by the presence of Lewy bodies is inversely related to the severity of AD pathology (McKeith et al., 2005). That is, a patient with abundant cortical Lewy bodies with minimal AD pathology will most likely be classified as DLB. Dementia with Lewy bodies requires the clinical syndrome of dementia and at least one of the three cardinal symptoms: the presence of fluctuating cognition with pronounced variations in alertness, visual hallucinations, and EPS (McKeith et al., 2005). Other reported features are auditory/olfactory hallucinations, delusions, hypersomnia, frequent falls, syncope, transient loss of consciousness, neuroleptic sensitivity (McKeith et al., 1996), major depression (Klatka et al., 1996), REM sleep behavior disorder (Boeve et al., 2003), abnormal EEG (Tschampa et al., 2001), myoclonus (Tschampa et al., 2001), and urinary incontinence (Del-Ser et al., 1996). The Third Report of the DLB Consortium proposed that in addition to the cardinal symptoms, certain features are suggestive of the diagnosis of DLB (i.e., REM sleep behavior disorder, severe neuroleptic sensitivity, low dopamine transporter uptake in the basal ganglia demonstrated by SPECT

or PET), and others are supportive of the diagnosis (i.e., frequent falls and syncope, transient episodes of loss of consciousness, severe autonomic dysfunction, hallucinations in other sensory modalities, depression, atrophy of the medial temporal lobe structures in CT/ MRI scans, systematized delusions, reduced occipital lobe metabolism in PET/SPECT scans, abnormal MIBG myocardial scintigraphy, slow waves in the EEG with temporal sharp waves) (McKeith et al., 2005). It is quite difficult to specify symptoms related to Lewy bodies when they occur in the context of AD (i.e., ADþLB) (Forstl et al., 1993; Mega et al., 1996; Papka et al., 1998; Lopez et al., 1999a). Retrospective studies have found that EPS are the core symptoms of ADþLB (Forstl et al., 1993; Heyman et al., 1999; Lopez et al., 2000a), while others found that psychosis (delusions þ hallucinations) (Weiner et al., 1996), and depression (Papka et al., 1998) were more frequent in ADþLB than in AD, and did not find any relationship between ADþLB and EPS. Other studies have found that cogwheel rigidity was the only EPS that could discriminate between AD and ADþLB subjects (Lopez et al., 2000a). Finally, longitudinal studies have noted that patients with ADþLB developed EPS and diurnal hypersomnia earlier, and had shorter time to institutionalization than patients with AD alone (Lopez et al., 2000b). Neuropsychological studies have suggested that memory functions are somewhat less impaired in subjects with DLB compared to those with “pure” AD. However, identification of a specific pattern of the neuropsychological deficits in DLB remains unsettled. While some studies found that DLB patients had worse executive/attentional functions than those with AD (Kraybill et al., 2005; Calderon et al., 2001), others reported worse visuospatial/visuoconstructional deficits in DLB subjects (Shimomura et al., 1998). Other studies have found that working memory (Calderon et al., 2001), and praxis (Walker et al., 1997) were worse in DLB than in AD subjects. In general, executive and visual-spatial functions are worse in DLB or DLBþAD than in AD alone, similar to the pattern of findings in patients with Parkinson’s disease and Parkinson’s disease with dementia.

19.5. Behavioral and psychological symptoms Psychotic symptoms (e.g., delusions, hallucinations), and disruptive behaviors (e.g., aggressive behavior, psychomotor agitation, wandering) are common in AD patients (Becker et al., 1994a; Aarsland et al., 1996; Devanand et al., 1997; Lopez et al., 2003). These may represent specific phenotypes with different natural

CLINICAL SYMPTOMS IN ALZHEIMER’S DISEASE histories. Psychotic symptoms are among the most disturbing behavioral symptoms in AD. AD patients are frequently suspicious that somebody is stealing things from them, or that there are people in the house (phantom boarder). Other delusions include the false belief that their spouses are unfaithful, or they are about to be abandoned, that a family member has been replaced by an identical-appearing impostor (Capgras syndrome), or that his/her house is somewhere else (reduplicative paramnesia) (Migliorelli et al., 1995a; Mack et al., 1999). Visual hallucinations are more frequent than auditory or other sensory hallucinations. The psychotic episodes in AD tend to be less structured than those seen in schizophrenia or in DLB (Lopez et al., 2000a). Neuropathological and neuroimaging studies have found that patients with psychosis have greater involvement of the temporal and frontal lobes. Subjects with AD with psychosis had lower cerebral glucose metabolism in the left dorsolateral prefrontal cortex and anterior temporal lobe on PET imaging (Hirono et al., 1998b; Mega et al., 2000; Lopez et al., 2001), while patients with aggression had lower metabolism in the orbitofrontal cortex (Hirono et al., 2000; Lopez et al., 2001). Neuropathological studies have found greater AD pathology in the frontal-temporal areas in patients with psychosis (Zubenko et al., 1991), and aggression (Palmer et al., 1988), and genetic studies suggest there are genetic influences associated with this behavioral phenotype. Indeed, some authors have proposed that there is a familial trait in AD patients with psychotic symptoms. A study conducted in 461 AD siblings from 371 AD subjects (probands), enrolled as part of the National Institute of Mental Heath Alzheimer’s Disease Genetic Initiative, found the rate of psychosis was increased in the siblings with AD of the AD probands with psychosis (Bacanu et al., 2002, 2005). In addition, the estimated heritability for psychosis was up to 60% when the probands had multiple and persistent psychotic symptomatology (Bacanu et al., 2005). Genetic studies of behavioral manifestations in AD are an active area of research, as are those possible risk alleles that would increase susceptibility or provide protection against AD. Few longitudinal studies have assessed the effect of behavioral problems on progression of the disease. Studies conducted in unselected samples of AD patients (Probable þ Possible AD) found that wandering, agitation, and behavioral problems were associated with shorter physical survival (Walsh et al., 1990; Moritz et al., 1997). Not surprisingly, agitation and aggression are associated with institutionalization in demented individuals (Ryden, 1988; Hamel et al., 1990; Lieberman and Kramer, 1991) and specifically in AD patients (Steele et al., 1990; Lopez et al., 1999b; Gilley et al., 2004).

211

The presence of psychosis (Drevets and Rubin, 1989; Stern et al., 1994; Lopez et al., 1997a) and disruptive behaviors (Walsh et al., 1990; Moritz et al., 1997) are associated with cognitive decline and institutionalization in AD. However, although AD patients with these behaviors have increased use of psychiatric medications, few studies have assessed psychiatric symptoms as predictors of progression in AD while taking into account the medication used to control these symptoms. A study that controlled for the use of sedatives, antidepressants, and neuroleptics found that psychotic symptoms remained important predictors of institutionalization and functional decline (Lopez et al., 1999b). Depressive symptoms can occur in up to 86% of the patients with AD (Wragg and Jeste, 1989), although the frequency of major depressive episodes is estimated to be between 12% and 30% of the patients at any time during the course of the disease (Migliorelli et al., 1995b; Lopez et al., 2003). Indeed, the frequency of depressive symptoms in AD is recognized by a subtype of AD in the DSM-IV criteria, AD with depression (APA, 1994). Neuropathological and neuroradiological studies have found that these patients have a greater compromise of frontotemporal–subcortical (e.g., aminergic nuclei) structures (Zubenko and Moossy, 1988; Chan-Palay, 1991; Hirono et al., 1998a). The effect of depression on the clinical course of AD remains controversial. Some studies have found that major depression, when it occurs after the onset of dementia symptoms, increases the risk of death in AD patients (Burns et al., 1991), while others have not (Walsh et al., 1990; Jagger et al., 1995; Lopez et al., 1999b). Interestingly, several epidemiological studies have shown that late-life depressive symptomatology increases the risk of subsequent AD (Devanand et al., 1996; Geerlings et al., 2000; Ganguli et al., 2006). Therefore, the identification of an incipient AD in the context of major depression is extremely important. These are usually patients with cognitive deficits and depression, whose mood-related symptoms improve with antidepressant therapy, but their cognitive dysfunction remains. A major difficulty in correlating behavioral symptoms in life with neuropathological findings is the usually long duration between diagnosis and characterization of the behavioral disturbances and death. Early depression, anxiety, or psychosis, or agitation/aggression in the midcourse of AD can be carefully defined. However, symptoms wax and wane over time, and patients’ language skills deteriorate such that they cannot verbalize their depression, psychotic ideation, or reasons for agitation. Finally, patients may spend years after their evaluations in chronic care facilities, where pathology worsens and

´ PEZ AND S.T. DEKOSKY O.L. LO

212 Table 19.1

Cognitive, behavioral, and neurological signs and symptoms in different stages of AD Stage by MMSE scores

Cognitive

Behavioral

Neurological

Mild (Score 20)

Relative preservation of some cognitive functions. Cognitive deficits affect IADL, but not ADL

Apathy may be present. Major depression can be the initial symptom. Psychosis, aggression and agitation are rare

Moderate (Score 19–10)

All cognitive domains are affected. Impairments in all IADL, and in some ADLs

Apathy is prominent. Depression is less frequent than in the mild stages. Psychosis, aggression, and agitation are more frequent

The neurological exam is usually normal Mild parkinsonism in some patients Myoclonic movements are uncommon The neurological exam can be normal More parkinsonism in some patients Myoclonic movements are more frequent, especially at night Paratonia (Gegenhalten or Mitghem) The neurological exam is nonfocal, but mild to moderate parkinsonism can be present in the majority of the patients Myoclonic movements can be observed during the day

Severe (Score 9)

Severe deterioration of all cognitive domains. May need help with all ADLs

Apathy is prominent. Major depression is less frequent than in other stages. Psychosis, aggression, and agitation are more frequent

IADL, instrumental activities of daily living (e.g., job performance, managing finances); ADL, activities of daily living (e.g., getting dressed, control of sphincters).

post mortem correlations with mid-disease course symptoms are diminished. Table 19.1 shows a relationship among the cognitive behavioral, and neurological signs and symptoms in different stages of the disease based on the Mini-Mental State Examination scores (Folstein et al., 1975). This test, while not perfect for dementia screening (for instance, it has little assessment of executive functions), has the advantage of being widely known, widely available, and it has been translated into many languages.

19.6. Atypical presentations AD can present as a frontal lobe syndrome, with significant behavioral abnormalities (Johnson et al., 1999) or circumscribed to an executive function deficit (Baddeley et al., 1997). The “posterior variant” of AD involves bilateral occipital and parietal lobe deficits (Berthier et al., 1991; Hof et al., 1993). These patients usually have Balint’s syndrome, which involves a reduction of visual attention, with subsequent

simultagnosia (an inability to perceive more than one object at a time), and optic ataxia (the inability to reach accurately toward an object). Because these symptoms are usually attributed to a visual problem, these patients are often seen first by ophthalmologists. A profound language disturbance can be the initial manifestation of AD, resembling primary progressive aphasia (expressive language deficit, reduced speech fluency, anomia, with preserved language comprehension and other cognitive functions) (Karbe et al., 1993; Wicklund et al., 2004). Other cases can present with a corticobasal syndrome (e.g., left hemi-parkinsonism, alien hand syndrome) (Chand et al., 2006). The diagnosis of AD in the context of other neurodegenerative disease is difficult; some patients can start with clear manifestations of other disease processes (e.g., progressive supranuclear palsy), and later develop AD (Urasaki et al., 2000), or vice versa. Detailed neurological, neuropsychological and neuroimaging studies (MRI, PET, SPECT), and lumbar puncture with analysis of specific pathological proteins can help to

CLINICAL SYMPTOMS IN ALZHEIMER’S DISEASE identify two concomitant disease processes, or an atypical form of AD.

19.7. Conclusion AD is characterized by gradually progressive neuropsychological deficits, which involve all cognitive domains, including memory, language, attention/executive functions, visuospatial/visuoconstructional, problem-solving, and conceptualization. Although memory deficit is the classic initial cognitive symptom, these patients can present with disproportionate language, executive, or visuospatial/visuoconstructional deficits. In addition, memory problems can be absent in a small subgroup of AD patients, in the early stages. Ideational and ideomotor apraxia are present in AD, especially in late stages. Many if not most AD patients are unaware of their cognitive problems or the severity of their deficits. The clinical characteristics of AD are well defined, such that it is now a specific diagnosis of inclusion, rather than of exclusion of all other causes. The next frontier in advances in diagnosis and correlation of clinical status or progression will probably be with utilization of biomarkers. Volumetric assessment with MRI in longitudinal and cross-sectional studies will define regional and global changes in brain structures and aid with differential diagnosis (Thompson et al., 2001). CSF markers, especially b-amyloid and tau and its metabolites, are already used as an aid for diagnosis (Galasko et al., 1998; Andreasen et al., 2001). Although the sensitivity and specificity of the CSF findings are not better than the diagnostic acumen of a skilled clinician (Mayeux, 1998), they are useful in confirming the diagnosis. CSF findings of an “Alzheimer-like” profile of low b-amyloid and elevated tau or phospho-tau in subjects with mild cognitive impairment are highly predictive of development of AD (Hansson et al., 2006). New PET techniques assessing the specific pathological proteins involved in neurodegenerative dementias (Klunk et al., 2004; Small et al., 2006) should increase both diagnostic accuracy and clinical–pathological correlation, as well as providing an objective measure of therapeutic interventions directed at slowing or reversing the accumulation of abnormal proteins. Assessment of changes in the amounts of abnormal proteins could then be correlated with clinical status and response to therapeutic interventions.

Acknowledgments This study was supported by grants AG05133, AG14449, AG03705, AG20098, and AG14449 from the National Institute on Aging.

213

References Aarsland D, Cummings JL, Yenner G, et al. (1996). Relationship of aggressive behavior to other neuropsychiatric symptoms in patients with Alzheimer’s disease. Am J Psychiatry 153: 243–247. Alzheimer A (1907). Uber eine eigenartige Erkrankung der Hirnrinde. Allg Zeits f Psychiat 64: 146–148. American Psychiatric Association (1994). DSM-IV: Diagnostic and Statistic Manual of Mental Disorders, 4th edn. American Psychiatric Association, Washington, DC. Andreasen N, Minthon L, Davidson P, et al. (2001). Evaluation of CSF-tau and CSF-alpha beta 42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 58: 373–379. Bacanu SA, Devlin B, Chowdari KV, et al. (2002). Linkage anlysis of Alzheimer disease with psychosis. Neurology 59: 11–12. Bacanu SA, Devlin B, Chowdari KV, et al. (2005). Heritability of psychosis in Alzheimer disease. Am J Geriatr Psychiatry 13: 624–627. Baddeley AD, Della Sala S, Papagno C, et al. (1997). Dual task performance in dysexecutive and non-dysexecutive patients with a frontal lesion. Neuropsychology 11: 187–194. Becker JT (1994). In: L Cermak (Ed.), Neuropsychological Explorations of Memory and Cognition: Essays in Honor of Nelson Butters. Plenum Press, New York, pp. 103–116. Becker JT, Lopez OL, Wess J (1992). Material specific memory loss in probable Alzheimer’s disease. Jour Neurol Neurosurg Psych 55: 1177–1181. Becker JT, Boller F, Lopez OL, et al. (1994a). The natural history of Alzheimer’s disease: Description of study cohort and accuracy of diagnosis. Arch Neurol 51: 585–594. Becker JT, Martin A, Lopez OL (1994b). In: I Grant, A Martin (Eds.), Neuropsychology of HIV Infection. Oxford University Press, New York, pp. 133–145. Benesch CG, McDaniel KD, Cox C, et al. (1993). End-stage Alzheimer’s disease. Glasgow Coma Scale and the neurologic examination. Arch Neurol 50: 1309–1315. Benson DF, Cummings JL, Tsai SY (1982). Angular gyrus syndrome simulating Alzheimer’s disease. Arch Neurol 39: 616–620. Berthier ML, Leiguarda R, Starkstein SE, et al. (1991). Alzheimer’s disease in a patient with posterior cortical atrophy. J Neurol Neurosurg Psychiatry 54: 1110–1111. Boeve BF, Silber MH, Parisi JE, et al. (2003). Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 61: 40–45. Boller F, Becker JT, Holland AL, et al. (1991). Predictors of decline in Alzheimer’s disease. Cortex 27: 9–17. Bowen DM, Allen SJ, Benton JS (1983). Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer’s disease. J Neurochem 41: 266–272. Braak H, Braak E (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82: 239–259.

214

´ PEZ AND S.T. DEKOSKY O.L. LO

Burns A, Lewis G, Jacoby R, et al. (1991). Factors affecting survival in Alzheimer’s disease. Psychol Med 21: 363–370. Cahn DA, Salmon DP, Bondi MW, et al. (1997). A populationbased analysis of qualitative features of the neuropsychological test performance of individuals with dementia of the Alzheimer type: implications for individuals with questionable dementia. J Int Neuropsychol Soc 3: 387–393. Calderon J, Perry RJ, Erzinclioglu SW, et al. (2001). Perception, attention, and working memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 70: 157–164. Cercy SP, Bylsma FW (1997). Lewy bodies and progressive dementia: a critical review and meta-analysis. J Int Neuropsychol Soc 3: 179–194. Chand P, Grafman J, Dickson DW, et al. (2006). Alzheimer’s disease presenting as corticobasal syndrome. Mov Disord 21: 2018–2022. Chan-Palay V (1991). Depression and dementia in Parkinson’s disease: Catecholamine changes in the Locus coeruleus - Basis for therapy. Dementia 2: 7–17. Cleary JP, Walsh DM, Hofmeister JJ, et al. (2005). Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 8: 79–84. DeKosky ST, Scheff SW (1990). Synapse loss in frontal cortex biopsies in Alzheimer’s Disease: Correlations with cognitive severity. Ann Neurol 27: 457–464. Delacourte A, David JP, Sergeant N, et al. (1999). The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology 52: 1158–1165. Della Sala S, Lucchelli F, Spinnler H (1987). Ideomotor apraxia in patients with dementia of Alzheimer type. J Neurol 234: 91–93. Del-Ser T, Munoz DG, Hachinski V (1996). Temporal pattern of cognitive decline and incontinence is different in Alzheimer’s disease and diffuse Lewy body disease. Neurology 46: 682–686. DeRenzi E, Lucchelli F (1988). Ideational apraxia. Brain 111: 1173–1185. Devanand DP, Sano M, Tang MX, et al. (1996). Depressed mood and the incidence of Alzheimer’s disease in the elderly living in the community. Arch Gen Psychiatry 53: 175–182. Devanand DP, Jacobs DM, Tang M, et al. (1997). The course of psychopathologic features in mild to moderate Alzheimer disease. Arch Gen Psychiat 54: 257–263. Drevets WC, Rubin EH (1989). Psychotic symptoms and the longitudinal course of senile dementia of the Alzheimer type. Biol Psychiatry 25: 39–48. Faber-Langendoen K, Morris JC, Knesevich JW, et al. (1988). Aphasia in senile dementia of the Alzheimer type. Ann Neurol 23: 365–370. Folstein MF, Folstein SE, McHugh PR (1975). Mini-mental state: A practical method grading the cognitive state of patients for the clinician. J Psychiatr Research 12: 189–198. Forstl H, Burns A, Luthert P, et al. (1993). The Lewy-body variant of Alzheimer’s disease: Clinical and pathological findings. Br J Psychiatry 162: 385–392.

Galasko D, Chang L, Motter R, et al. (1998). High cerebrospinal fluid tau and low amyloid B42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 55: 937–945. Ganguli M, Du Y, Dodge HH, et al. (2006). Depressive symptoms and cognitive decline in late lfie. Arch Gen Psychiatry 63: 153–160. Geerlings MI, Schoevers RA, Beekman AT, et al. (2000). Depression and risk of cognitive decline and Alzheimer disease. Results of two prosepective community-based studies in The Netherlands. Br J Psychiatry 176: 568–575. Gibb WRG (1990). Cortical Lewy body dementia. Behav Neurol 3: 189–196. Gilley DW, Bienias IL, Wilson RS, et al. (2004). Influence of behavioral symptoms on rates of institutionalization for persons with Alzheimer’s disease. Psychol Med 34: 1129–1135. Hamel M, Gold DP, Andres D, et al. (1990). Predictors and consequences of aggressive behavior by community-based dementia patients. Gerontologist 30: 206–211. Hamilton RL (2000). Lewy bodies in Alzheimer’s disease: A neuropathological review of 145 cases using alphasynuclein immunohistochemistry. Brain Pathol 10: 378–384. Hansen LA, Samuel W (1997). Criteria for Alzheimer’s disease and the nosology of dementia with Lewy bodies. Neurology 48: 126–132. Hansen L, Salmon D, Galasko D, et al. (1990). The Lewy body variant of Alzheimer’s disease: A clinical and pathologic entity. Neurology 40: 1–8. Hansson O, Zetterberg H, Buchhave P, et al. (2006). Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 5: 228–234. Heyman A, Peterson P, Fillenbaum G, et al. (1996). The consortium to establish a registry for Alzheimer’s disease (CERAD). Part XIV: Demographic and clinical predictors of survival in patients with Alzheimer’s disease. Neurology 46: 656–660. Heyman A, Fillenbaum GG, Gearing M, et al. (1999). Comparison of Lewy body variant of Alzheimer’s disease with pure Alzheimer’s disease: Consortium to Establish a Registry for Alzheimer’s Disease, Part XIX. Neurology 52: 1839–1844. Hirono N, Mori E, Ishii K, et al. (1998a). Frontal lobe hypometabolism and depression in Alzheimer’s disease. Neurology 50: 380–383. Hirono N, Mori E, Ishii K, et al. (1998b). Alteration of regional cerebral glucose utilization with delusions in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 10: 433–439. Hirono N, Mega MS, Dinov ID, et al. (2000). Left frontotemporal hypoperfusion is associated with aggression in patients with dementia. Arch Neurol 57: 861–866. Hof PR, Archin N, Osmand AP, et al. (1993). Posterior cortical atrophy in Alzheimer’s disease: analysis of a new case and re-evaluation of a historical report. Acta Neuropathol (Berl) 86: 215–223. Huff MJ, Mack L, Mahlmann J, et al. (1988). A comparison of lexical-semantic impairments in left-hemisphere stroke and Alzheimer’s disease. Brain Lang 34: 262–278.

CLINICAL SYMPTOMS IN ALZHEIMER’S DISEASE Jagger C, Clarke M, Stone A (1995). Predictors of survival with Alzheimer’s disease: A community-based study. Psychol Med 25: 171–177. Johnson JK, Head E, Kim R, et al. (1999). Clinical and pathological evidence for a frontal variant of Alzheimer disease. Arch Neurol 56: 1233–1239. Jorm AF, Jolley D (1998). The incidence of dementia: a meta-analysis. Neurology 51: 728–733. Karbe H, Kertesz A, Polk M (1993). Profiles of language impairment in primary progressive aphasia. Arch Neurol 50: 193–201. Klatka LA, Louis ED, Schiffer RB (1996). Psychiatric features in diffuse Lewy body disease: A clinicopathologic study using Alzheimer’s disease and Parkinson’s disease comparison groups. Neurology 47: 1148–1152. Klunk WE, Engler H, Nordberg A, et al. (2004). Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55: 306–319. Kraybill ML, Larson EB, Tsuang DW, et al. (2005). Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both. Neurology 64: 2069–2073. Lieberman MA, Kramer JH (1991). Factors affecting decisions to institutionalize demented elderly. Gerontologist 31: 371–374. Liu Y, Stern Y, Chun MR, et al. (1997). Pathological correlates of extrapyramidal signs in Alzheimer’s disease. Ann Neurol 41: 368–374. Lopez OL, Becker JT, Somsak D, et al. (1994). Awareness of cognitive deficits and anosoagnosia in Probable Alzheimer’s disease. Eur Neurol 34: 277–282. Lopez OL, Brenner RP, Becker JT, et al. (1997a). EEG spectral abnormalities and psychosis as predictors of cognitive and functiional decline in probable Alzheimer’s disease. Neurology 48: 1521–1525. Lopez OL, Wisnieski SR, Becker JT, et al. (1997b). Extrapyramidal signs in patients with probable Alzheimer’s disease. Arch Neurol 54: 969–975. Lopez OL, Litvan I, Catt KE, et al. (1999a). Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias. Neurology 53: 1292–1299. Lopez OL, Wisniewski SR, Becker JT, et al. (1999b). Psychiatric medication and abnormal behavior as predictors of progression in probable Alzheimer’s disease. Arch Neurol 56: 1266–1272. Lopez OL, Hamilton RL, Becker JT, et al. (2000a). Severity of cognitive impairment and the clinical diagnosis of Alzheimer’s disease with Lewy bodies. Neurology 54: 1780–1787. Lopez OL, Wisniewski S, Hamilton RL, et al. (2000b). Predictors of progression in patients with Alzheimer’s disease and Lewy bodies. Neurology 54: 1774–1779. Lopez OL, Smith G, Becker JT, et al. (2001). The psychotic phenomenon in probable Alzheimer’s disease: A positron emission tomographic study. J Neuropsychit Clin Neurosci 13: 50–55. Lopez OL, Becker JT, Sweet RA, et al. (2003). Psychiatric symptoms vary with the severity of dementia in probable Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 15: 346–353.

215

Mack JL, Patterson MB, Tariot PN (1999). Behavior rating scale for dementia: Development of test scales and presentation of data for 555 individuals with Alzheimer’s disease. J Geriatr Psychiatry Neurol 12: 211–223. Marshall GA, Kaufer DI, Lopez OL, et al. (2004). Right prosubiculum amyloid plague density correlates with anosognosia in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 75: 1396–1400. Martin A (1992). In: L Backman (Ed.), Memory Functioning in Dementia. North-Holland, Amsterdam, pp. 119–134. Mayeux R (1998). Evaluation and use of diagnostic tests in Alzheimer’s disease. Neurobiol Aging 19: 139–143. McKeith IG, Dickson DW, Loew J, et al. (2005). Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65: 1863–1872. McKhann G, Drachman DA, Folstein MF, et al. (1984). Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34: 939–944. Mega MS, Masterman DL, Benson F, et al. (1996). Dementia with Lewy bodies: Reliability and validity of clinical and pathologic criteria. Neurology 47: 1403–1409. Mega MS, Lee L, Dinov ID, et al. (2000). Cerebral correlates of psychotic symptoms in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 69: 148–149. Meguro K, Yamaguchi S, Itoh M, et al. (1997). Striatal dopamine metabolism correlated with frontotemporal glucose utilization in Alzheimer’s disease: A double-tracer PET study. Neurology 49: 941–945. Migliorelli R, Petracca G, Teson A, et al. (1995a). Neuropsychiatric and neuropsychological correlates of delusions in Alzheimer’s disease. Psychol Med 25: 505–513. Migliorelli R, Teson A, Sabe L, et al. (1995b). Prevalence and correlates of dysthymia and major depression among patients with Alzheimer’s disease. Am J Psychiatry 152: 37–44. Moritz DJ, Fox PJ, Luscombe FA, et al. (1997). Neurological and psychiatric predictors of mortality in patients with Alzheimer disease in California. Arch Neurol 54: 878–885. Morris JC, Drazner M, Fulling K, et al. (1989). Clinical and pathological aspects of parkinsonism in Alzheimer’s disease: A role for extranigral factors?. Arch Neurol 46: 651–657. Palmer AM, Francis PT, Bowen DM (1987). Catechlaminergic neurones assessed antemortem in Alzhiemer’s disease. Brain Res 414: 365–375. Palmer AM, Stratmann GC, Procter AW, et al. (1988). Possible neurotransmitter basis of behavioral changes in Alzheimer’s disease. Ann Neurol 23: 616–620. Papagno C, Lucchelli F, Muggia S, et al. (2003). Idiom comprehension in Alzheimer’s disease: the role of the central executive. Brain 126: 2419–2430. Papka M, Rubio A, Schiffer RB, et al. (1998). Lewy body disease: can we diagnose it? J Neuropsychiatry Clin Neurosci 10: 405–412. Pearson RCA, Esiri MM, Hiorns RW, et al. (1985). Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer’s disease. Proc Natl Acad Sci USA 82: 4531–4534.

216

´ PEZ AND S.T. DEKOSKY O.L. LO

Perry EK (1980). The cholinergic system in old age and Alzheimer’s disease. Age Aging 9: 1–8. Price BH, Gurvit H, Weintraub S, et al. (1993). Neuropsychological patterns and language deficits in 20 consecutive cases of autopsy-confirmed Alzheimer’s disease. Arch Neurol 50: 931–937. Ryden MB (1988). Aggressive behavior in persons with dementia who live in the community. Alzheimer Dis Assoc Disord 2: 342–355. Saxton JA, Becker JT, Wisniewski S (2003). In: JA Knight (Ed.), The Handbook of Rey-Osterrieth Complex Figure Usage: Clinical and Research Applications. Psychological Assessment Resources, Lutz, FL, pp. 569–582. Scarmeas N, Hadjugeorgiou GM, Papadimitriou A, et al. (2004). Motor signs during the course of alzheimer disease. Neurology 63: 975–982. Selkoe DJ (1994). Alzheimer’s disease: a central role for the amyloid. J Neuropathol Exp Neurol 53: 438–447. Shimomura T, Mori E, Yamashita H, et al. (1998). Cognitive loss in dementia with lewy bodies and Alzheimer’s disease. Arch Neurol 55: 1547–1552. Small GW, Kepe V, Ercoli LM, et al. (2006). PET of brain amyloid and tau in mild cognitive impairment. N Eng J Med 355: 2652–2663. Starkstein S, Fedoroff JP, Price TR, et al. (1993). Neuropsychological deficits in patients with anosoagnosia. Neuropsychiat Neuropsychol Behav Neurol 6: 43–48. Steele C, Rovner B, Chase GA, et al. (1990). Psychiatric symptoms and nursing home placement of patients with Alzheimer’s disease. Am J Psychiatry 147: 1049–1051. Stern Y, Albert M, Brandt J, et al. (1994). Utility of extrapyramindal signs and psychosis as predictors of cognitive and functional decline, nursing home admission, and death in Alzheimer’s disease: Prospective analyses from the Predictors Study. Neurology 44: 2300–2307. Thompson PA, Mega MS, Woods RP, et al. (2001). Cortical change in Alzheimer’s disease detected with a diseasespecific population-based brain atlas. Cerebral Cortex 11: 1–16.

Tschampa HJ, Neumann M, Zerr I, et al. (2001). Patients with Alzheimer’s disease and dementia with Lewy bodies mistaken for Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 71: 33–39. Tsuang D, Simpson KL, Li G, et al. (2005). Evaluation of selection bias in an incident-based dementia autopsy case series. Alzheimer Dis Assoc Disord 19: 67–73. Urasaki K, Kuriki K, Namerikawa M, et al. (2000). An autopsy case of Alzheimer’s disease with a progressive supranuclear palsy overlap. Neuropathology 20: 233–238. Walker Z, Allen RL, Shergill S, et al. (1997). Neuropsychological performance in Lewy body dementia and Alzheimer’s disease. Br J Psychiatry 170: 156–158. Walsh JS, Welch HG, Larson EB (1990). Survival of outpatients with Alzheimer-type dementia. Ann Intern Med 113: 429–434. Weiner MF, Risser RC, Cullum M, et al. (1996). Alzheimer’s disease and its Lewy body variant: a clinical analysis of postmortem verified cases. Am J Psychiatry 153: 1269–1273. White L, Petrovich H, Hardman J, et al. (2002). Cerebrovascular pathology and dementia in autopsied HonoluluAsia Aging Study participants. Ann NY Acad Sci 977: 9–23. Wicklund AH, Johnson N, Weintraub S (2004). Preservation of reasoning in primary progressive aphasia: further differentiation from Alzheimer’s disease and the behavioral presentation of frontotemporal dementia. J Clin Exp Neuropsychol 26: 347–355. World Health Organization (1993). The ICD-10 classification of mental and behavioral disorders: diagnostic criteria for research. WHO, Geneva. Wragg RE, Jeste DV (1989). Overview of depression and psychosis in Alzheimer’s disease. Am J Psychiat 146: 577–587. Zubenko G, Moossy J (1988). Major depression in primary dementia: clinical and neuropathological correlates. Arch Neurol 45: 1182–1186. Zubenko GS, Moossey J, Martinez J (1991). Neuropathologic and neurochemical correlates of psychosis in primary dementia. Arch Neurol 48: 619–624.