Neural substrates of cognitive and behavioral deficits in atypical Alzheimer's disease

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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v

Review

Neural substrates of cognitive and behavioral deficits in atypical Alzheimer's disease Armin von Gunten a,⁎, Constantin Bouras b , Enikö Kövari b , Panteleimon Giannakopoulos a,b , Patrick R. Hof c,d a

Division of Old Age Psychiatry, Department of Psychiatry-CHUV, Route du Mont, 1008 Prilly-Lausanne, Switzerland Department of Psychiatry, HUG Belle-Idée, 2 ch. du Petit-Bel-Air, 1225 Chêne-Bourg, Switzerland c Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA d Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA b

A R T I C LE I N FO

AB S T R A C T

Article history:

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive

Accepted 11 November 2005

cognitive decline that typically affects first memory and later executive functions, language,

Available online 18 January 2006

and visuospatial skills. This sequence of cognitive deterioration is thought to reflect the progressive invasion of the cerebral cortex by the two major pathological hallmarks of AD,

Keywords:

neurofibrillary tangles (NFT) and senile plaques (SP), as well as degree of neuronal and

Atypical

synaptic loss. In atypical AD, prominent and early deficits are found in language, motor

Focal

abilities, frontal and executive capacities, or visuospatial skills. These atypical clinical

Alzheimer's disease

features are associated with an unusual pattern of NFT or SP formation that predominantly

Neuropathology

involves cortical areas usually spared in the course of the degenerative process. In an

Neurodegeneration

attempt to classify this highly heterogeneous subgroup, the present article provides an overview of clinicopathological analyses in patients with atypical progression of AD symptomatology with special reference to the relationship between specific cognitive and behavioral deficits and hierarchical patterns of AD lesion distribution within the cerebral cortex. On the basis of these representative examples of a cortical circuit-based approach to explore the mechanisms giving rise to AD neuropsychological expression, we also critically discuss the possibility to develop a matrix linking clinical presentations to degeneration of forward and backward long corticocortical pathways in this disorder. © 2005 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinicopathological correlations in typical Alzheimer's disease . . . . . . . . . . Atypical AD syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Posterior or parieto-temporo-occipital variants of AD . . . . . . . . . . . . 3.1.1. Primary progressive predominantly occipitotemporal syndromes. 3.1.2. Primary progressive predominantly parieto-occipital syndromes .

⁎ Corresponding author. Fax: +41 21 643 62 38. E-mail address: [email protected] (A. von Gunten). 0165-0173/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2005.11.003

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3.1.3.

Hierarchical patterns of AD lesion distribution and neuronal loss in predominantly posterior parieto-temporo-occipital variants of AD: comparisons with typical AD . . . . . . . . . . . . 3.2. Anterior or frontotemporal variants of AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Primary progressive predominantly motor syndromes . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Primary progressive aphasias and related syndromes . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Primary progressive predominantly dysexecutive and behavioral syndromes . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.

Introduction

Cognition in typical AD is characterized by a progressive decline that affects first memory and later executive functions, language, and visuospatial skills. This sequence of cognitive deterioration is thought to reflect the progressive invasion of the cerebral cortex by the two major pathological hallmarks of AD, neurofibrillary tangles (NFT) and senile plaques (SP), as well as neuronal and synaptic loss (Arnold et al., 1991; Braak and Braak, 1991; Cragg, 1975; Flood et al., 1987; Gomez-Isla et al., 1996a, 1997; Husain and Stein, 1988; Lezak, 1995; Mapstone et al., 2003; Terry et al., 1987). Detailed analyses of AD lesion regional distribution have demonstrated that certain components of the neocortical and hippocampal circuits within the medial temporal lobe are particularly prone to degeneration (Arnold et al., 1991; Braak and Braak, 1991; Cragg, 1975; Crystal et al., 1988; Flood et al., 1987; Giannakopoulos et al., 1997; Gomez-Isla et al., 1996a, 1997; Hof et al., 1992; Hyman, 1997; Lezak, 1995; Mapstone et al., 2003; Morris et al., 1996; Price et al., 2001; Terry et al., 1987). The diagnostic criteria for AD are, however, heavily weighted towards memory impairment as the central deficit and may, therefore, prevent inclusion of cases with other patterns of cognitive decline (Galton et al., 2000). However, it is now well documented that certain cases of dementia do not meet the accepted clinical and neuropathologic criteria for the definition of AD, yet, they show the same histopathologic features (Engel et al., 1992). They are referred to as atypical AD cases and may represent examples of clinicopathologic subtypes of AD. The clinical heterogeneity of AD patients has long been recognized (Shuttleworth, 1984; Wertheimer et al., 1977). Although AD is usually associated with early and prominent memory impairment (Diagnostic and statistical manual of mental disorders, 1994; World Health Organization, 1993), patients with neuropathologically confirmed AD may also display early deficits in language, musical skills and prosody, motor abilities, frontal and executive capacities, as well as visuospatial skills (Aharon-Peretz et al., 1999; Broussolle et al., 1996; Confavreux et al., 1992). These early reports have now been expanded to include cases with atypical clinical presentation which may also not fit into traditional neuropathological classification systems for AD (Braak and Braak, 1991). In these cases, atypical clinical features are associated with unusual patterns of NFT or SP invasion of the cerebral cortex. Importantly, these clinicopathologic case studies have been able to establish strong relationships between the regional distribution of AD lesions and both neuropsychological and behavioral deficits (Braak and Braak, 1991; Ceccaldi et al., 1995;

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Hof et al., 1990a, 1992, 1993; Hudson and Grace, 2000; Levy et al., 1997; Rossor et al., 2000; Vogt et al., 1990). Most of the reported patients with clinically atypical AD died at an advanced stage of the disorder (Galton et al., 2000; Hof et al., 1997). Nevertheless, the atypical AD lesion distribution was still related to the clinical features observed (Vogt et al., 1990), supporting the validity of clinicopathological analyses even in cases characterized by the spreading of AD lesions throughout the entire cerebral cortex (Hof et al., 1997). Consequently, atypical AD cases have been considered as prototypical examples of correlations between the degeneration of selective sets of corticocortical projections and patterns of cognitive decline (Duyckaerts et al., 1986; Hof et al., 1990a, 1997; Hudson and Grace, 2000; Lewis et al., 1987; Petersen, 1998; Rosen et al., 2002). After providing a brief summary of changes found in typical AD, we provide here a detailed review of atypical variants of AD and discuss clinicopathologic correlations in these cases within the framework of the corticocortical disconnection theory.

2. Clinicopathological correlations in typical Alzheimer's disease While the definite diagnosis of AD is based on neuropathological criteria, the clinical diagnosis of probable and possible AD in clinical settings is usually made according to the NINCDS-ADRDA criteria. Probable AD corresponds to a typical clinical syndrome, whereas possible AD is suggested when the observed clinical features are at odds with the typical syndrome (McKhann et al., 1984). Typical AD has been originally thought as an early and progressive amnestic syndrome mainly involving episodic memory which is accompanied by non-cognitive features (i.e., depression, anxiety, psychotic signs and symptoms, as well as behavioral disturbances) in more advanced stages of the disease (Kennedy et al., 2001; Petersen, 1998; Reisberg et al., 1982). Variations, however, occur mainly in late-onset forms and may be more pronounced than those suggested by early epidemiological studies (Cummings, 2000; Scheltens et al., 1993; Wertheimer et al., 1977). In fact, AD cases with disproportionate visual constructive impairment (Boxer et al., 2003), dissociations of linguistic abilities (Harasty et al., 2001), or severe behavioral and personality changes accompanying memory disorders have been recently reported. Examples of unusual evolution in typical AD cases have been also described in rare patients with asymmetric cortical atrophy who presented with unusually rapid progressive

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language or behavioral impairment and better preservation of praxis and gnosis (Giannakopoulos et al., 1994). The first cited diagnostic criteria for AD were elaborated by a National Institute on Aging (NIA) workshop (Consensus recommendations for the postmortem diagnosis of Alzheimer's disease, 1997) and described by Khachaturian (1985). These criteria were intended to aid in the development of uniform procedures by proposing minimal SP densities as a function of age. Although this method may appear arbitrary, it was justified by the assumption that SP formation may be partly a benign age-related phenomenon. Implicitly, these criteria recognize that SP formation is not sufficient to cause dementia as SP densities associated with AD at younger ages are unrelated to clinical symptoms at older ages. It is thus surprising that the presence of NFT is not considered for cases over 50 years of age. Several other criticisms of Khachaturian's criteria have been formulated: the type of SP is not specified; precise quantification of SP may be technically difficult and, most importantly, could change in function of the apolipoprotein E genotype; only neocortical areas were taken into account; and the role of the clinical history remains vague (Gomez-Isla et al., 1996b; Hyman, 1997; Markesbery, 1997; Schmechel et al., 1993). Khachaturian's recommendations were not broadly accepted, and their validity has been questioned. Subsequent to the 1985 workshop, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (Mirra et al., 1991) proposed another set of standardized neuropathological criteria. These semiquantitative criteria were determined as a function of the development of neuritic plaques in three age groups (less than 50, 50 to 75, and over 75). The diagnosis was based on a combination of clinical information and an “age-related plaque score” that reflected the maximal neocortical involvement, and a level of diagnostic certainty was assessed (i.e., definite, probable, or possible AD). These criteria are uncomplicated, limit the sensitivity and specificity problems related to quantitative criteria, and do not require extensive training. The combined CERAD categories of possible, probable, and definite AD correspond closely to cases fulfilling Khachaturian's criteria for AD (Nagy et al., 1998). As in these latter criteria, the hippocampal formation is ignored, despite its involvement in the pathogenesis of AD. However, the major weakness of CERAD criteria resides in that they have been inspired somewhat unilaterally by the amyloid cascade hypothesis and do not consider NFT densities in the neocortex, even though these correlate strongly with the severity of dementia. In 1997, the NIA-Reagan Consensus conference attempted to integrate the experience of neuropathologists from the United States and Europe in a comprehensive set of criteria for AD (Consensus recommendations for the postmortem diagnosis of Alzheimer's disease, 1997). In contrast to CERAD criteria which incorporate clinical data to provide a neuropathological diagnosis, these new criteria aim to define the likelihood that a clinically overt dementia is due to AD lesions and can thus guarantee the role of the neuropathological diagnosis as a “gold standard”. The procedures take into account both the CERAD criteria and Braak staging system. The use of CERAD protocols for tissue processing was adopted, but semiquantitative assessment of

AD lesions must be made in several neocortical areas, hippocampal formation, substantia nigra, and locus coeruleus. Conceptually, the merit of these criteria is their attempt to conciliate the amyloid cascade hypothesis with the major role of NFT in clinicopathological correlations. In terms of clinicopathological correlations, several lines of evidence indicate that the primary progressive amnestic syndrome so characteristic of the initial stages of typical AD is the consequence of the neuropathological changes in the medial temporal structures, in particular, the entorhinal cortex and the hippocampus. The initial stages of AD are characterized by NFT spread from the entorhinal cortex to the hippocampus, corresponding to Braak and Braak stages 1 and 2, which precedes the progressive invasion of the allocortex and isocortex (Braak and Braak, 1991). Previous clinicopathological studies also revealed strong relationships between the patterns of NFT distribution and cognitive deficits in typical AD cases. For instance, constructional apraxia correlated with NFT densities in Brodmann areas 7 and 18 (Nielson et al., 1996), associative visual agnosia with NFT densities in Brodmann areas 18, 19, and 37 (Giannakopoulos et al., 1999), and naming and identification of famous faces deficits with NFT densities in Brodmann areas 9 and 24 (Giannakopoulos et al., 2000a). Spatial disorientation was related to the disruption of corticocortical circuits between right areas 7 and 23 and the CA1 field of the hippocampus (Giannakopoulos et al., 2000b). In the domain of behavioral disorders, typical AD with positive psychotic phenomena (delusions or hallucinations or both) had a 2- to 3-fold increase in NFT counts in the middle frontal, the anterior third of the superior temporal, and the inferior parietal cortex (Farber et al., 2000). In contrast to NFT, several earlier and more recent clinicopathological studies showed that SP correlated less well with clinical features, and their presence may be associated with no or only minimal intellectual changes in the elderly (Delaère et al., 1990; Dickson et al., 1992; Morris et al., 1996). Similarly, there were no correlations between the development of psychotic features and SP regional distribution in typical AD (Farber et al., 2000). The NFT distribution is not only area-specific but also cell-specific. In the hippocampus, particularly in the CA1 and CA2 regions, pyramidal cells are selectively damaged, whereas glutamatergic cells degenerate in the entorhinal cortex presumably interrupting complex neuronal circuits in the medial temporal lobe that are indispensable for encoding new information (Price, 2000; Squire, 1986, 2004; Squire et al., 2004) (Figs. 1 and 2).

3.

Atypical AD syndromes

Focal degenerative syndromes were described long ago (Franceschi, 1908; Marie and Leri, 1904; Mingazzini, 1902, 1914; Pick, 1892; Veraguth, 1900). In 1892, A. Pick reported a 71year-old man with severe progressive aphasia and more general mental deterioration associated with marked left temporal lobe atrophy. Thus, A. Pick was the first to emphasize that the clinical presentation of classical neurodegenerative disorders may often include focal symptoms (Pick,

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Fig. 1 – Lateral view of the human brain illustrating the cortical areas involved in atypical AD cases according to Brodmann classification. 1892). However, little attention was given to reports of focal or lobar atrophy until Mesulam's report on primary progressive aphasia in 1982 (Mesulam, 1982). This author stressed certain features of primary progressive aphasia including his observation that it was not associated with a progression to global dementia or only after 7 years of progressive and debilitating aphasia. Other cognitive functions were relatively spared. The syndrome was associated with focal degeneration of the left perisylvian structures. Later, Mesulam added that, in primary

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progressive aphasia, all repercussions in daily living should be attributed to language impairment, at least during the first 2 years of illness (Mesulam, 2001). The first attempt to classify these syndromes has been also made by Mesulam who proposed to divide them into primary progressive amnesia, primary progressive aphasia, progressive visuospatial dysfunction, and primary behavioral dysfunction (Mesulam and Weintraub, 1992). Other, albeit similar, classifications included primary progressive aphasia/posterior cortical atrophy/ progressive apraxia (Black, 1996), primary progressive aphasia/posterior cortical atrophy/frontotemporal variants (Kramer and Miller, 2000), and progressive aphasia/perceptual– motor syndrome/frontal and temporal lobe syndromes (Caselli, 1996). The terminology remains confusing since it hesitates between clinically defined syndromes (i.e., aphasia) and anatomically defined ones (i.e., biparietal atrophy). In fact, AD does not necessarily respect macroscopic brain boundaries, and some degree of spread of AD lesions to adjacent regions is frequently observed. Furthermore, an overlap between different syndromes is likely to occur in most cases of atypical AD. As an example, aphasia syndromes may occur as a consequence of lesions bridging widespread anterior and posterior brain areas, particularly those around the parietotemporo-occipital junction. We decided to discuss clinical syndromes by dividing them into those linked to clinical features suggestive of posterior or parieto-temporo-occipital and those suggestive of anterior or frontotemporal lesion locations thus following the logical thread of a posteroanterior gradient from predominantly perceptive and sensory

Fig. 2 – Macroscopic (a) and histological (b–d) findings in a typical AD case. Note the massive atrophy of neocortical association areas (a). Note also the preferential NFT formation in both CA1 field of the hippocampus (b) and area 20 (c) compared to their relative rarity in area 9 (d). Scale bar: 250 μm.

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association cortices and their subcortical connections to cortices subserving motor and executive abilities.

3.1.

Posterior or parieto-temporo-occipital variants of AD

Deficits suggestive of posterior brain involvement independent of the aging process are quite common in typical AD, and the original early-onset case described by Alzheimer (1907) also had perceptual impairment and visual hallucinations. A variety of clinically heterogeneous syndromes including apraxia and visuoperceptive deficits are likely to reflect posterior brain involvement. Most of the syndromes described in this chapter have been referred to as posterior cortical atrophy (PCA) or Benson's syndrome (Benson et al., 1988; Berthier et al., 1991; Graff-Radford et al., 1993; Hof and Bouras, 1991; Hof and Morrison, 1990; Hof et al., 1989, 1993, 1997; Jacquet et al., 1990; Levine et al., 1993; Levy et al., 1997; Magnani et al., 1982; Mendez et al., 1990a,b,c, 2002; Nagaratnam et al., 2001; Nissen et al., 1985; Pietrini et al., 1996; Victoroff et al., 1994). In PCA, sensory aphasic features can be associated with partial Bálint's syndrome, visual associative agnosia, and visuospatial deficits presumably depending on the regional distribution of AD-related lesions in posterior cortical areas. Diagnostic criteria for PCA were recently described (Mendez et al., 2002). The distinction of an occipitotemporal and a biparietal form of PCA has been proposed, although in many patients features of both can coexist. The occipitotemporal variant combines visual distortion, difficulty with object recognition, topographic agnosia, and alexia. Clinical examination typically reveals restricted visual fields or unilateral extinction on bilateral stimulation, impaired color vision and stereopsis, deficits in object recognition, prosopagnosia, and alexia (either letter-by-letter reading or attentional alexia). In the biparietal variant, visuospatial problems, agraphia, and dyspraxia concur. They may manifest themselves as a full blown Bálint's syndrome, yet, visual fields, basic perceptual abilities, object recognition, and reading are usually preserved (Ross et al., 1996). Primary progressive posterior cortical dysfunction in the elderly is often due to AD and more rarely to the Lewy body variant of AD, Creutzfeldt–Jakob disease, progressive subcortical gliosis of Neumann, fatal familial insomnia, or corticobasal degeneration (Benson et al., 1988). In AD/PCA cases and related syndromes, both structural and functional alterations predominate in the parieto-temporo-occipital junction and occipital cortex (Benson et al., 1988; Berthier et al., 1991; GraffRadford et al., 1993; Hof and Bouras, 1991; Hof and Morrison, 1990; Hof et al., 1989, 1993, 1997; Jacquet et al., 1990; Levine et al., 1993; Levy et al., 1997; Magnani et al., 1982; Mendez et al., 1990a,b,c, 2002; Nagaratnam et al., 2001; Nissen et al., 1985; Pietrini et al., 1996; Victoroff et al., 1994). Predominant apraxia in primary progressive biparietal syndrome was related to various SPECT patterns including bilateral hypoperfusion in superior and posterior parietal lobes, focal hypoperfusion in left temporoparietal areas (with only mild reduction in the right parietal areas), and even bilateral hypoperfusion in temporal lobes (Ross et al., 1996). Likewise, MRI in these patients showed a bilateral parietal atrophy out of proportion to that seen elsewhere in the brain which was more pronounced in the left hemisphere. Temporal structures

appeared to be preserved in some of these patients (Mizuno et al., 1996; Ross et al., 1996). However, on standard CT and MRI scans, patients with posterior cortical dysfunction may often fail to show posterior cortical atrophy (Benson et al., 1988).

3.1.1. Primary progressive predominantly occipitotemporal syndromes In typical AD, visual impairment mainly includes reading difficulties, visual agnosia, and impaired processing of famous faces, but problems in more basic sensory processing such as in shape and color discrimination, deficient contrast sensitivity, and movement detection, as well as visual field deficits have been also described (Armstrong, 1996; Cohen et al., 1993; Cormack et al., 2000; Cronin-Golomb et al., 1991, 2000; Duffy et al., 2000; Fujimori et al., 1997; Giannakopoulos et al., 1998, 2000a; Gilmore et al., 1994; Hill et al., 1995; Mendez et al., 1990a; Parasuraman et al., 1995; Rosler et al., 2000; Trick and Silverman, 1991). The possible causal relationship between lesions in the retina, visual pathways, and subcortical visual centers, such as the lateral geniculate nucleus, lateral inferior pulvinar, and superior colliculus, and visual disturbances in typical AD remains controversial. Impairment of retinal or retinocortical functioning has been suggested by some (Kergoat et al., 2002; Parisi et al., 2001) but not all clinical studies (Justino et al., 2001). Similarly, reduction in the number of retinal ganglion cells and their axons has been found in some neuropathological studies (Blanks et al., 1996a,b; Sadun et al., 1987), but others have not confirmed these data (Curcio and Drucker, 1993). SP but no NFT were found in lateral geniculate nucleus, whereas both SP and NFT were encountered in the superior colliculus (Leuba and Saini, 1995). Likewise, SP, NFT, neuritic plaques, and neuropil threads have been found in the pulvinar (Kuljis, 1994) and neuropil threads and NFT in the Edinger–Westphal nucleus (Valenti, 2004). However, basic sensory deficits are rarely isolated in primary progressive degenerative syndromes. When achromatopsia, hemiachromatopsia, or other impairments of color perception, deficient contrast sensitivity, ocular dysmetria, and hemianopsia occur early in the course of a primary progressive syndrome, they generally do so in the realm of more complex visuospatial syndromes (Aharon-Peretz et al., 1999; Ardila et al., 1997; Bartolomeo et al., 1998; Bashir et al., 1998; Beversdorf and Heilman, 1998; Chan et al., 2001; CroninGolomb et al., 2000; Delamont et al., 1989; Filoteo et al., 2002; Jarry et al., 1999; Mendez and Cherrier, 1998; Mendez et al., 2002; Sereno et al., 1995). Patients with these deficits display complex disturbances of visual function that include alexia both for words and music, anomia, agraphia, transcortical sensory aphasia, complete or partial Bálint's syndrome (see below) and Gerstmann's syndrome (left–right disorientation, finger agnosia, agraphia, acalculia), as well as cortical blindness, prosopagnosia, achromatopsia or hemiachromatopsia, or other impairments of color perception, deficient contrast sensitivity, ocular dysmetria, and left or right hemineglect, apraxia, hemianopsia, or dissociation between normal explicit and altered implicit processing of global visual information (Aharon-Peretz et al., 1999; Ardila et al., 1997; Armstrong, 1996; Bartolomeo et al., 1998; Bashir et al., 1998; Beversdorf and Heilman, 1998; Chan et al., 2001; Contant et al., 1993; Cormack et al., 2000; Cronin-Golomb et al., 1991, 2000;

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Delamont et al., 1989; Duffy et al., 2000; Filoteo et al., 2002; Fujimori et al., 1997; Giannakopoulos et al., 1999, 2000a; Gilmore et al., 1994; Hill et al., 1995; Jarry et al., 1999; Mendez and Cherrier, 1998; Mendez et al., 1990a, 2002; Parasuraman et al., 1995; Rosler et al., 2000; Sereno et al., 1995; Trick and Silverman, 1991). Several studies have shown that prominent visual and visuospatial symptoms are not rare in atypical AD (Benson et al., 1988; Cogan, 1985; Croisile et al., 1991; Fletcher and Sharpe, 1988; Magnani et al., 1982). A particularly prominent feature in these cases with early visual deficits is a severe impairment in motion perception and target tracing (Butter et al., 1996; Cronin-Golomb et al., 1993; Duffy et al., 2000; Fletcher and Sharpe, 1988; Furey-Kurkjian et al., 1996; Katz and Rimmer, 1989; Kiyosawa et al., 1989; Kurylo et al., 1994; Leuba and Kraftsik, 1994; Mentis et al., 1996; Neary and Snowden, 1987; Sadun et al., 1987; Silverman et al., 1994). The clinical symptomatology of AD patients with PCA suggests that subsets of cortical pathways linking the primary occipital cortex to the posterior parietal and cingulate visual association cortex are affected in the early stages of the dementia (Hof and Bouras, 1991; Hof et al., 1989, 1990b, 1993, 1997) whereas anterior spread may occur at later stages of the disease (Goethals and Santens, 2001). Spatial disorientation in these cases was related to a selective incapacity to link a visual percept with a location in a cognitive map with memory mechanisms playing a lesser role (Benson et al., 1988; Cogan, 1985). Similarly to AD, a visuospatial variant of mild cognitive impairment has been recently described suggesting that visuospatial impairment may develop as an independent precursor sign of neurodegeneration (Mapstone et al., 2003). Several of the AD patients showing predominantly visual function impairment have symptoms comparable to the observation made in 1909 by the Hungarian physician Rezsö Bálint of a complex visual syndrome characterized by simultagnosia, cortical paralysis of visual fixation associated with optic ataxia, and severe disturbance of visual attention in patients with large bilateral watershed infarcts in the parietooccipital region (Bálint, 1909; Husain and Stein, 1988). The occurrence of a Bálint's-like syndrome in AD patients was first documented by Ernst Grünthal in 1928 (Grünthal, 1928) and subsequently by Ferdinand Morel in 1945 (Morel, 1945). Quantitatively, inordinately high densities of AD lesions are observed in the occipital regions of AD/PCA cases and visuomotor impairment similar to Bálint's syndrome with a gradient in NFT densities from area 17 to the visual association area 19 and parietal cortex (area 7b), as well as in the posterior cingulate cortex (area 23) (Berthier et al., 1991; Graff-Radford et al., 1993; Hof and Bouras, 1991; Hof et al., 1989, 1990a, 1993, 1997; Jacquet et al., 1990; Kaida et al., 1998; Levine et al., 1993; Mendez and Cherrier, 1998; Mendez et al., 1990a,b; Victoroff et al., 1994). The division of these cases into dorsal parieto-occipital and ventral temporo-occipital subtypes has been suggested, but not all of them may fit into these two categories (Confavreux et al., 1992; Galton et al., 2000; Mendez et al., 2002). Patients with primary progressive prosopagnosia and primary progressive visual agnosia have been also reported (Evans et al., 1995; Freedman and Costa, 1992; Mendez et al., 2002; Mizuno et al., 1996; Nagaratnam et al., 2001). Prosopagnosia has been associated with progressive

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right temporal atrophy (Evans et al., 1995), but neuropathologically confirmed AD cases with these disorders are rare. One such study showed an occipital displacement of AD lesion distribution with a preferential localization in mid- and inferior temporal cortex (areas 37, 20, and 21) instead of the inferior parietal and posterior cingulate cortex, demonstrating the specific involvement of the occipitotemporal visual pathway (Hof and Bouras, 1991). Not only defective symptoms and signs but also release phenomena may occur. Visual hallucinations are a frequent concomitant of both typical AD and AD/PCA, but some of the patients reported may have suffered from diffuse Lewy body dementia (Cogan, 1985; Pearson et al., 1985). Although structural imaging studies suggest that visual hallucinations in AD may be caused by the development of AD neuropathology within the visual cortex (Holroyd et al., 2000; Scepkowski et al., 2003), there is no definite neuropathological demonstration of this relationship. In contrast, a predominant NFT formation in middle frontal gyrus, superior temporal cortex, and inferior parietal lobule has been described in AD patients with visual hallucinations (Farber et al., 2000), while a striking association has been found between high densities of Lewy bodies in amygdala and parahippocampal cortex in patients with Lewy body dementia and severe visual hallucinations (Harding et al., 2002).

3.1.2. Primary progressive predominantly parieto-occipital syndromes The complexity of the clinical presentations in the beginning of some primary progressive syndromes has prompted many authors to define some of them according to the presumed cortical localization of the disease process rather than a specific clinical manifestation. Thus, the triad of progressive visuospatial problems, dyspraxia, and dysgraphia has been associated with progressive biparietal atrophy (Ross et al., 1996). However, one should keep in mind that a substantial degree of overlap still exists between this syndrome and the above described occipitotemporal syndromes (Benson et al., 1988; Berthier et al., 1991; Crystal et al., 1982; Golaz et al., 1992; Graff-Radford et al., 1993; Green et al., 1995; Hof and Bouras, 1991; Hof and Morrison, 1990; Hof et al., 1989, 1993, 1997; Jacquet et al., 1990; Jagust et al., 1990; Kaida et al., 1998; Levine et al., 1993; Levy et al., 1997; Lleo et al., 2002; Magnani et al., 1982; Mendez et al., 1990a,b,c, 2002; Nagaratnam et al., 2001; Nissen et al., 1985; Pietrini et al., 1996; Ross et al., 1996; Rossor et al., 1999; Victoroff et al., 1994). Patients with typical AD often have various forms of apraxia, but they appear later in the course of the disease when memory impairment has become evident. In some patients, AD may mimic corticobasal degeneration or occurs in combination with this latter condition (Ball et al., 1993; Cogan, 1985; Jagust et al., 1990; Lleo et al., 2002). A few pathologically documented cases of atypical AD with primary progressive apraxia have been reported (Lleo et al., 2002). A substantial neuritic plaque and NFT formation has been observed in the parietal lobes of a patient with dyspraxia and related difficulties in writing as well as extremely poor performance on visuospatial tests and transitive and intransitive hand gestures (Ross et al., 1996). An AD case with parietal involvement confined to the right hemisphere

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showed unskillful movements that were accompanied by hemineglect, incomplete Bálint's syndrome, environmental agnosia, as well as left-sided motor symptoms, including dystonic postures and myoclonus (Kaida et al., 1998). A 60year-old man presented with problems driving his car and slowly progressive apraxia. The alien hand sign, writing and calculation difficulties, and mild left hand agraphesthesia and astereognosis followed. At autopsy, he had marked right hemisphere atrophy. NFT and SP were preferentially localized in the prefrontal, temporal, and posterior parietal cortices in both hemispheres, whereas the hippocampal formation displayed lower lesion densities than neocortical areas; significantly higher lesion densities were found in the more atrophic side, with a regional topography matching the clinical symptoms (Green et al., 1995). Some of the clinical features in these patients cannot be explained by apraxia and must be attributed to other deficits such as motor and memory impairment or specific language deficits. For instance, some patients had impairment of auditory–verbal short-term memory, phonological aspects of language, or visuoperceptive deficits (Ross et al., 1996). The memory and language deficits seemed to appear later in the course than dyspraxia and may be due to the spread of the disease from parietal areas to other areas, particularly to the superior temporal lobe (Benson et al., 1988; Cogan, 1985; Hof et al., 1990a). Neglect and right hemisphere syndromes have rarely been reported in atypical AD. Primary progressive neglect is unusual as the slow progression of the degenerative process may allow for adaptive changes which prevent neglect

syndromes. However, it should be considered that neglect syndromes are rarely investigated in degenerative diseases, and they may be more frequent than expected. Thus, akinesia is often seen in degenerative diseases and may be due to bilateral neglect similar to what occurs in akinetic mutism (Heilman et al., 1985). Predominant right-side neglect was reported in probable AD associated with hypoperfusion in the left posterior and right parietal regions, but no neuropathological assessment was available for this patient (Bartolomeo et al., 1998). Another patient with primary progressive apraxia also showed hemineglect among other features including incomplete Bálint's syndrome, environmental agnosia, as well as left-sided motor symptoms. The biopsy revealed numerous neuritic plaques and mild NFT formation in occipitoparietal association (Kaida et al., 1998) (Fig. 3).

3.1.3. Hierarchical patterns of AD lesion distribution and neuronal loss in predominantly posterior or parieto-temporo-occipital variants of AD: comparisons with typical AD While the visual association cortex contains high densities of SP and NFT in typical AD, area 17 usually contains numerous SP, but relatively few NFT even at advanced stages of the disease (Arnold et al., 1991; Braak and Braak, 1991; Hof and Morrison, 1990; Hof et al., 1989, 1990a; Lewis et al., 1987; Pearson et al., 1985; Rogers and Morrison, 1985). In nonagenarians and centenarians with either no dementia or very mild cognitive impairment (Levine et al., 1993), NFT were scarce in area 17, indicating that aging per se had no major influence on

Fig. 3 – Macroscopic (a) and histological (b–d) findings in an AD/PCA case. Note the striking atrophy of the visual association areas (a). Substantial NFT formation is present in the CA1 field of the hippocampus (b) and area 9 (c). Note also the massive NFT and neuritic plaque formation in area 17 (d). Scale bar: 250 μm.

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NFT formation in the primary visual cortex. In typical AD, NFT are present in area 18, but their laminar distribution differs from that in temporal, parietal, and frontal cortices as they are predominantly located within layer III, as opposed to layers IV–VI, and are far less numerous (Hof and Morrison, 1990; Hof et al., 1989, 1990a; Lewis et al., 1987). Based on NFT distribution, areas 17 and 18 are relatively spared in typical AD as it usually presents, suggesting that the clinicopathologic outflow from area 17 to area 18 is far less affected than it is among temporal or parietal visual association areas, early in the course of the disease (Hof and Morrison, 1990; Hof et al., 1989, 1990, 1993, 1997). The increase of neuropathologic involvement along visual cortical hierarchies from the primary visual areas to the parietal and temporal cortex corresponds to the marked complexity of visual dysfunctions in AD (Benson et al., 1988; Cogan, 1985; Cronin-Golomb et al., 1993; Curcio and Drucker, 1993; Hinton et al., 1986; Kurylo et al., 1994, 1996; Mentis et al., 1996; Neary and Snowden, 1987; Parasuraman et al., 1995; Pietrini et al., 1996). Data regarding neuronal loss are scarce and did not include stereological analyses. Density analyses showed that, in contrast to frontal, parietal, and temporal areas (Mountjoy et al., 1983), total neuron counts in area 17 do not differ between typical AD and control brains. However, a 30% neuronal loss has been reported in the primary area 17 (Leuba and Saini, 1995) sparing, however, calcium-binding-positive interneurons (Leuba et al., 2001). Our previous neuropathological work revealed striking differences in AD lesion distribution between conventional AD and AD/PCA cases. As a rule, areas 17, 18, and 19 contain a much higher density of NFT in AD/PCA cases. Differences are most marked in the occipital areas and were predominant in areas 17 and 18 with increases over conventional AD cases as high as 35-fold (Hof et al., 1989, 1990a, 1993, 1997). Smaller differences exist in areas 19, 7b/7m, and 23. NFT counts in areas 37, 20, and 21 do not differ significantly between typical AD and AD/PCA cases with the marked exception of AD cases with early visual agnosia characterized by an increased AD lesion density in inferior temporal cortex and occipitotemporal junction. In prefrontal areas 9, 45, and 46, NFT densities are consistently lower in AD/PCA cases compared to conventional AD cases, supporting the notion of a shift of the lesion distribution into occipital regions that are usually not severely involved in AD (Arnold et al., 1991; Hof and Bouras, 1991; Hof and Morrison, 1990; Hof et al., 1989, 1990a,b, 1993, 1997). SP are also much more numerous in the occipital cortex of AD/PCA cases than usually seen in AD cases. Depending on the area, up to five-fold increases in SP density occur in AD/PCA cases, the largest differences being observed in areas 17 and 18. Area 9 has slightly higher SP counts in AD/PCA, whereas no differences are observed in areas 45 and 46. These observations demonstrate the specific involvement of the cortical pathways linking the primary visual occipital regions to the posterior parietal and cingulate visual association cortex in early stages of AD/PCA cases. The distribution of NFT and SP in AD/PCA cases suggests that specific elements of visual corticocortical circuits are severely disrupted. In 1945, Morel reported that AD-type changes (i.e., NFT) in his case of visual AD affected predominantly layer III followed by layer V and VI, while these

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alterations were not seen in layer II and IV (Morel, 1945). According to more recent studies, the high density of NFT in layer III of area 17 indicates that projections to area 18 are affected, and the high density of NFT in layer III of areas 18 and 19 similarly suggests that there is a disruption of feedforward projections to higher-order visual association areas in the occipitoparietal junction. The high numbers of NFT in layers V and VI of area 18 indicate that feedback projections to area 17 are also affected. The disruption of feedback projections, which terminate in both supra- and infragranular layers, is well correlated to the high SP densities in all layers of area 17 in these cases. Furthermore, increases in SP density in area 18 suggest an involvement of feedback projections from the area 19 complex and feedforward projections from area 17. The same logic can be applied to the very high SP densities in areas 7b/7m and 23, which may reflect the degeneration of feedforward connections from area 19 as well as to the prefrontal areas 9 and 46 that receive projections from the parietal visual areas (Wilson et al., 1993). Taken together, these data reveal the pertinence of the corticocortical disconnection hypothesis to interpret the progressive involvement of cortical networks linking the parietal, cingulate, and occipital regions in AD/PCA cases (Minoshima et al., 1994; Reiman et al., 1996; Vogt et al., 1990, 1992, 1997). In reference to cortical parcellation schemes obtained in macaque monkeys as well as from neuropathological and functional imaging studies in humans, it is possible that these particular areas of the occipital cortex represent the human equivalent of areas V4 and MT in the intraparietal sulcus of monkeys which are known to be involved in visuomotor and visuospatial tasks (Clarke, 1993, 1994, 1995; Clarke and Miklossy, 1990; DeYoe et al., 1996; Engel et al., 1997; Felleman and Van Essen, 1991; McCarthy et al., 1995; Miklossy, 1993; Orban et al., 1995; Sereno et al., 1995; Tootell and Taylor, 1995; Tootell et al., 1995; Watson et al., 1993). The human area MT consistently contains higher NFT and SP densities than the surrounding occipital fields (Hof et al., 1997). In addition, the loss of Meynert cells in layer VI of area 17 observed in AD/PCA cases with Bálint-like syndrome suggests that long forward projections from this area to area MT are affected (Hof et al., 1989, 1990a). Interestingly, the existence of a separate region involved in kinetic contour detection has also been reported in humans (Orban et al., 1995). The inferoposterior and medial parietal areas 7b/7m that are generally considered to be involved in several aspects of motion processing and are severely affected in PCA cases may include this region, which is distinct from area MT, and the consistent and severe involvement of area 23 in the posterior cortical atrophy cases is particularly relevant since this cortical area is in fact an important component of the visuomotor system (Olson and Musil, 1992a,b; Olson et al., 1993; Vogt et al., 1997).

3.2.

Anterior or frontotemporal variants of AD

Cognitive and behavioral deficits related to anterior brain damage independent of the aging process are quite common in typical AD. Speech, various motor and language disorders as well as changes in executive functions and social abilities occur at different stages of AD usually once the typical memory impairment has become obvious. Predominance of these

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symptoms is often seen in atypical AD cases, although they are usually more suggestive of other degenerative brain disorders, in particular, frontotemporal dementia (FTD) (Fig. 4).

3.2.1.

Primary progressive predominantly motor syndromes

Dysarthria or impaired speech articulation may be a sign of neurodegenerative disease (Broussolle et al., 1996; Cohen et al., 1993; Heston et al., 1966; Matsuoka et al., 1967; Miwa et al., 1995; Soliveri et al., 2003). It can accompany a variety of motor, cognitive, or non-cognitive symptoms (Cohen et al., 1993; Miwa et al., 1995; Soliveri et al., 2003). Articulatory impairment often accompanies primary progressive aphasia, but it can also precede speech impairment (Broussolle et al., 1996; Doran et al., 1995; Rosen et al., 2002). In most cases of primary progressive dysarthria, no definite histological diagnosis is available. In some families, dysarthria with other motor signs as initial manifestations could be attributed to AD (Heston et al., 1966; Lüers, 1945). In addition, early dysarthria was observed in patients with both AD-type and amyotrophic lateral sclerosistype lesions, amyotrophic lateral sclerosis/parkinsonism– dementia complex of Guam (Matsuoka et al., 1967), kuru-like features (Ishino et al., 1983), as well as in patients with rapidly progressive aphasia and bulbar motor neuron disease due to an atypical distribution of neuropil threads and NFT in AD (Doran et al., 1995). Familial early-onset AD seems quite often characterized by initial dysarthria and gait disorder, but it may be difficult to identify which of the two occurs first (Heston et al., 1966; Lüers, 1945). In these cases, largely disseminated SP

and NFT in the cortex and CA suggested no clear-cut focal degeneration (Lüers, 1945). However, although there was a widespread cortical atrophy, a predominance of SP in frontal, hippocampal, and parahippocampal regions was described in one of these cases (Heston et al., 1966). In a neuropathologically heterogeneous case combining lesions found in AD, the amyotrophic lateral sclerosis/parkinsonism/dementia complex of Guam and Kuru who had presented with slurred speech and gait disorder, there was bilateral frontal and basis pontis atrophy with moderate ventricular dilation. Numerous SP were found in the cerebral and cerebellar cortices, basal ganglia, brainstem, spinal cord with substantial NFT formation in the cerebral cortex, substantia innominata, substantia nigra, locus coeruleus, and Edinger–Westphal nucleus. In addition, there were histological changes characteristic of amyotrophic lateral sclerosis and spinocerebellar degeneration as well as amyloid angiopathy (Matsuoka et al., 1967). In another case with mixed dysarthric and motor signs, SP were widespread in the frontal cortex and NFT were dispersed throughout the cerebral cortex. Granuovacuolar degeneration, kuru-like plaques, as well as amyloid angiopathy were found in particular in the dentate nucleus (Ishino et al., 1983). Finally, in rare earlyonset AD cases, predominant dysarthria was associated with a preferential NFT involvement of the caudate nucleus, thalamus, hypothalamus, nucleus Meynert, cranial nerve nuclei, substantia nigra, and locus coeruleus (Aikawa et al., 1985). Besides dysarthria, various motor signs are often present in typical AD. Primary progressive motor features may be isolated at early stages and comprise spastic paraparesis or

Fig. 4 – Macroscopic (a) and histological (b–d) findings in an AD/PPA case. Note the focal atrophy of the frontal cortex (a). Mild NFT formation was evident in CA1 field of the hippocampus (b). Note also the minimal NFT counts in area 20 (c) in contrast to the severe NFT invasion of the area 9 (d). Scale bar: 250 μm.

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paraplegia, hemiparesis, parkinsonian features, akinesia, myoclonus, the alien hand sign, or motor neuron disease (Aikawa et al., 1985; Ball et al., 1993; Crook et al., 1998; Doody and Jankovic, 1992; Doran et al., 1995; Engel and Grunnet, 2000; Heilman et al., 1985; Heston et al., 1966; Ishino et al., 1983; Jagust et al., 1990; Kempler et al., 1990; Kennedy et al., 2001; Lüers, 1945; Scepkowski et al., 2003; Worster-Drought et al., 1940). Motor signs can be concomitant with various cognitive or non-cognitive features at early stages or represent subsequent symptoms associated with the evolution of the dementing process (Aikawa et al., 1985; Barrett, 1913; Crook et al., 1998; Engel and Grunnet, 2000; Fukatsu et al., 1980; Ishino et al., 1983; Jagust et al., 1990; Lüers, 1945; Matsuoka et al., 1967; Sakurai et al., 1998; van Bogaert et al., 1940; WorsterDrought et al., 1940). A pyramidal syndrome as an initial manifestation has been reported both in sporadic AD with or without parkinsonian features and early-onset familial AD (Aikawa et al., 1985; Barrett, 1913; Crook et al., 1998; Engel and Grunnet, 2000; Heston et al., 1966; Jagust et al., 1990; Lüers, 1945; van Bogaert et al., 1940). Two cases with early-onset spastic paralysis had AD-type brain lesions, but the authors challenged the diagnosis since the lesion load was low, SP morphology was different from that observed in AD and NFT were absent (Worster-Drought et al., 1940, 1944). Myoclonus in combination or not with the alien hand sign was also described in a neuropathologically confirmed case of AD (Ball et al., 1993; Wojcieszek et al., 1994) but seems to be more frequent in familial early-onset AD with APP, PS1, and PS2 mutations (Kennedy et al., 2001). Seizures are more common than generally thought in the late stages of typical AD and may occur early in the course of the disease in earlyonset familial AD (Kennedy et al., 2001). Importantly, the motor signs observed in AD can often mimic corticobasal degeneration (Ball et al., 1993; Boeve et al., 1996; Carrilho et al., 2001; Doody and Jankovic, 1992; Riley, 1996), and brains of patients with neuropathologically confirmed corticobasal degeneration can also show lesions evoking either AD, progressive supranuclear palsy, or Parkinson's disease (Eberhard et al., 1996; Ozsancak et al., 1999; Schneider et al., 1997). Clinicopathological correlations focusing on motor symptoms in AD are still very rare partly reflecting the frequent coexistence of other neurological conditions (i.e., corticobasal degeneration, amyotrophic lateral sclerosis) but also the difficulty to draw the line between a primary motor disorder and apraxia. However, in a case of early-onset AD with an initial left progressive hemiparesis, there was a severe atrophy more pronounced on the right than left side. Neuropil threads and NFT were found throughout the neocortex, but neuron loss and gliosis was particularly severe in layer II and III in the right somatosensory cortex (Jagust et al., 1990). Another patient with early-onset AD developed signs of motor dysfunction early in the clinical course. A quantitative neuropathologic analysis revealed much higher densities of NFT and neuritic plaques in the primary motor cortex than is usually observed in AD (Benson et al., 1988). Moreover, two familial AD cases with progressive spastic paraparesis exhibited numerous SP and NFT and particularly pronounced amyloid angiopathy in the precentral cortex with mild to severe degeneration of the lateral corticospinal tracts (Benson et al., 1988). It is thus possible in these cases to establish correlations between the

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progressive damage of motor cortices and early development of motor symptoms in typical AD.

3.2.2.

Primary progressive aphasias and related syndromes

Aphasia or language impairment in typical AD is almost invariably fluent with naming difficulties in the context of the anomic, transcortical sensory, or Wernicke's-type aphasias (Greene et al., 1996; Weintraub et al., 1990). This contrasts with the initial descriptions of primary progressive aphasia (PPA) (Mesulam, 1982) and the three major subtypes of this condition which has been recently proposed: non-fluent PPA characterized by apraxia of speech and deficits in processing complex syntax, semantic dementia characterized by fluent speech and semantic memory deficits, and logopenic progressive aphasia characterized by slow speech and impaired syntactic comprehension and naming (Gorno-Tempini et al., 2004). In the last years, many such cases of PPA as well as other less frequent variants have been reported and their progression characterized (Bianchetti et al., 1996; Cohen et al., 1993; Déruaz et al., 1993; Doran et al., 1995; Fuh et al., 1994; Ghacibeh and Heilman, 2003; Graham and Hodges, 1997; Hillis et al., 2002; Hodges and Miller, 2001; Holland et al., 1985; Karbe et al., 1993; Kempler et al., 1990; Lippa et al., 1991; Mehler et al., 1986; Mendez and Zander, 1991; Mesulam, 2001; Mingazzini, 1902; Poeck and Luzzatti, 1988; Polk and Kertesz, 1993; Rosen et al., 2002; Turner et al., 1996; Wagner and Bachman, 1996; Warren et al., 2003; Wechsler, 1977). Patients with PPA may be devoid of concomitant clinical features at least for some time (Déruaz et al., 1993; Engel and Fleming, 1997; Greene et al., 1996; Holland et al., 1985; Kirshner et al., 1987; Li et al., 2000; Wechsler, 1977), although their clinical manifestations usually evolve to dementia later on (Déruaz et al., 1993; Engel and Fleming, 1997; Greene et al., 1996; Kirshner et al., 1987; Mehler et al., 1986; Mesulam, 2001; Papagno and Capitani, 2001). These patients may live independently for many years and make use of compensatory strategies (Beland and Skat, 1992; Engel and Fleming, 1997; Weintraub et al., 1990). Other cognitive deficits such as slight motor symptoms or apraxia, visuospatial impairment, as well as memory and dysexecutive disabilities may complete the clinical findings (Fuh et al., 1994; GornoTempini et al., 2004; Goulding et al., 1989; Graham and Hodges, 1997; Hodges and Graham, 1998; Hodges and Miller, 2001; Kempler et al., 1990; Mesulam, 2001; Rosen et al., 2002). However, many neuropsychological domains are difficult to test and hamper detection of cognitive impairment in nonlinguistic domains (Foster and Chase, 1983). Likewise, noncognitive changes such as depression and obsessionality can occur (Mesulam, 2001; Mingazzini, 1902; Rosen et al., 2002). Some features may be dependent on the aphasia subtype as patients with the non-fluent type of PPA may have right-sided decrease of dexterity, while those with semantic dementia may have extrapyramidal features (Gorno-Tempini et al., 2004) and evolve to FTD (Hodges and Miller, 2001). Functional neuroimaging reveals metabolic changes in specific brain regions that correlate with specific language impairment. In contrast to FTD characterized by language deficits related to impaired grammatical analysis and hypoperfusion in frontal and anterior temporal areas, in typical AD, language comprehension difficulties are usually the consequence of

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impaired semantic processing which correlates with hypoperfusion in temporoparietal areas (Grossman et al., 1998). In contrast to that originally thought, almost 20% of PPA cases displayed substantial AD pathology (Mendez and Zander, 1991; Mesulam, 2001). In a review of 112 patients, 3 (19%) out of 16 PPA patients had neuropathologically confirmed AD (Westbury and Bub, 1997). Moreover, some PPA cases due to atypical AD have been reported (Table 1). A few additional cases have been also described, but the diagnosis of pure PPA was not evident, or the postmortem analysis revealed concomitant disorders, or no individual case descriptions were available to establish possible clinicopathologic correlations (Caselli et al., 2002; Doran et al., 1995; Greene et al., 1996; Kertesz and Munoz, 2002; Westbury and Bub, 1997). In order to illustrate the complexity of the clinicopathological correlations in this field, we summarize below some case reports of atypical AD with predominant fluent or non-fluent aphasia. A 56-year-old man with subsequently confirmed atypical AD started having word-finding difficulties with subsequent deterioration of prepositional speech and writing. Twelve months later, he had dressing difficulties. Both EEG and CT pointed to a predominant involvement of the left frontal and temporal regions. At 16 months after onset, fluent aphasia with poor reading comprehension, agraphia, acalculia, left– right confusion, difficulties in copying, and inability to button clothes and identify famous persons was diagnosed. These clinical features were compatible with an angular gyrus syndrome. Over the following 3 months, clumsiness of his right arm and myoclonus occurred with further progression towards ataxia, seizures, and death after 6 years. Macroscopic atrophy was more pronounced in left temporal pole. Neuropil threads and NFT as well as widespread neuronal loss and reactive gliosis were found predominantly in temporal and parietal (layers II and III) and to a lesser degree frontal and occipital lobes. Strikingly, no neuronal loss was observed in hippocampus and subiculum. In this case, there was at least some degree of correspondence between the angular gyrus syndrome and neuronal loss in parietal cortex (Pogacar and Williams, 1984). In an early-onset case of AD starting with fluent aphasia initially marked by word-finding difficulties, moderate symmetrical dilation of the third and lateral ventricles with numerous neuropil threads spread diffusely throughout the cortex was found. However, neuropil threads were most numerous in the temporal lobes, and the plaque density was considerably greater in the left superior temporal cortex consistent with the predominance of fluent aphasia. Neuropil threads density was also higher in the left calcarine cortex. NFT were far less numerous and equally distributed. Neuropil threads rather than NFT pathology parallel the clinical features in this patient (Benson and Zaias, 1991). Another man with moderate global brain atrophy displayed widespread diffuse neuronal cell loss, gliosis, and very high densities of SP and NFT. The latter were frequent in all examined neocortical (frontal, temporal, parietal, and occipital cortex) and subcortical (basal ganglia, thalamus, hypothalamus, hippocampus) areas. However, they were most abundant in the left middle frontal gyrus, thus possibly correlating with the patient's PPA (Karbe et al., 1993).

A woman of 59 years had slight word-finding and articulatory difficulties that progressed towards dementia about 10 years later. Atrophy was severer on the left hemisphere mainly in anterior perisylvian and frontal regions. Although neuronal loss was severe, there were only a few NFT in temporal lobes bilaterally, nucleus Meynert, and frontal and left occipital lobes. Though few, neuropil threads were more frequent in temporal than frontal and occipital lobes (Déruaz et al., 1993). A man of 70 years presented with amnestic aphasia and paraphasias evolving towards comprehension and speech difficulties associated with pica and collectomania. Neuronal loss and gliosis were severe in temporal and frontal cortices, moderate in hippocampus, amygdala, Meynert nucleus, hypothalamus, medial thalamic nucleus, and caudate nucleus and mild in parietal and occipital cortices. Pathological changes were superior on the left side consistent with the marked asymmetrical temporal lobe atrophy and dilation of inferior horns of the lateral ventricle. NFT were numerous in CA1–4, subiculum, entorhinal, insular, and cingulate cortex. There were few NFT in other regions of the temporal, frontal, precentral and postcentral cortex, amygdala, medial thalamic nuclei, periaqueductal gray, striatum, hypothalamus, substantia nigra, and locus coeruleus. SP were abundant throughout the cerebral cortex. In this case, PPA was more likely to be related to cell death in left frontal and temporal lobes than AD lesions (Li et al., 2000). A 63-year-old woman had anomia and paraphasias, but early difficulties with activities of daily living and emotional lability developed while her speech disorder evolved towards a global aphasia within 2 years. At that time, she also had orofacial and limb apraxia and motor neuron disease. While the EEG was normal, a CT at 65 years of age showed atrophy of the left temporal lobe. Mild neuronal loss occurred in CA1 in the absence of NFT neither in the hippocampus nor in entorhinal or parahippocampal regions. However, NFT and neuropil threads were numerous in temporal isocortex, while neuropil threads were also abundant in frontal, parietal, and occipital cortices. Severe AD lesion formation within the left frontoparietal sulci may have caused the aphasia syndrome (Doran et al., 1995). A patient with early-onset AD and fluent paraphasic speech had macroscopically insignificant atrophy and no asymmetry. Abundant neuropil threads and NFT were diffusely spread throughout the cerebral cortex. Thus, there was no preferential localization of AD lesions, although cortical atrophy was more marked in left perisylvian area, and PET showed left temporal hypoperfusion extending towards the left frontal areas and the thalamus (Kurylo et al., 1994). In a 61year-old man who had developed non-fluent PPA, gyral atrophy was moderate with moderate neuronal loss and severe NFT, SP, and neuropil thread formation in Brodmann areas 4 and 6, 1, 2, 3, 5, 40, and 44/45, the middle to posterior thirds of the superior and middle temporal gyri. High NFT densities without neuropil threads were also present in Brodmann area 39. Likewise, PET revealed no focal metabolic deficits, further pointing to the absence of a clear correlation between structural/functional patterns of cortical involvement and PPA (Greene et al., 1996). In a 66-year-old man with word-finding and comprehension difficulties and phonemic paraphasias, the postmortem

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analysis revealed both Pick and AD pathology. Focal atrophy was more accentuated on the left hemisphere. Pick cells and relatively fewer NFT were found in all cortical layers, mainly, in the frontal and temporal cortices, predominantly on the left side. NFT were seen in hippocampus, amygdala, thalamus, and pigmented nuclei of the brainstem, but there were no SP. PPA was thought to be primarily related to Pick's disease rather than AD (Holland et al., 1985). In summary, the scarce neuropathological studies in clinically documented PPA cases revealed an overall weak correlation between the development of degenerative lesions and the aphasia syndrome. Although this phenomenon can partly reflect the severe involvement of most neocortical areas at late stages of dementia, it is noteworthy that none of the previously mentioned case reports used stereological estimates which make possible the accurate assessment of total neuron and lesion numbers within a given area. Rare cognitive deficits such as aprosodia, agraphia, acalculia, and amusia may coexist with language disorders in PPA. Aprosodia or dysprosodia is the difficulty or incapacity to modulate speech melody or to understand someone's speech melody on a semantic and emotional level. It can be a part of slowly progressive anarthria and secondary or concomitant to speech apraxia and dysarthria (Broussolle et al., 1996; Cohen et al., 1993). For instance, a case of progressive affective aprosodia and prosoplegia (inability to make emotional facial expressions) was described in which normal prepositional speech but lost ability to use automatic speech were combined with expressive amusia, drawing dysfluency, directional visual impersistence, and an asymmetrical right visual grasp. This 49-year-old woman with progressive automatic speech disorder had predominant right frontal lobe atrophy on an MRI scan (Ghacibeh and Heilman, 2003). The writing deficits characteristic of agraphia may represent the initial presentation of primary progressive apraxia, AD/PCA, primary progressive aphasia, or frontal agraphia (frequent duplication of letters and down-strokes) (Broussolle et al., 1996; Mendez and Zander, 1991; Mizuno et al., 1996; Pogacar and Williams, 1984; Ross et al., 1996; Turner et al., 1996). Similarly, reading deficits or alexia can be part of AD/PCA or PPA (Mingazzini, 1914; Pogacar and Williams, 1984). Acalculia can be seen with a primary progressive biparietal syndrome (Ball et al., 1993). In this case, it takes the form of spatial acalculia. As acalculia is also part of the Gerstmann syndrome, it is also typically found in cases with PCA mainly affecting the right hemisphere (Leger et al., 1991; Mizuno et al., 1996). However, difficulty in calculating may also accompany PPA (Kempler et al., 1990; Kirshner et al., 1987; Pogacar and Williams, 1984).

3.2.3. Primary progressive predominantly dysexecutive and behavioral syndromes Prefrontal syndromes include dysexecutive, amotivational, and behavioral disturbances, the first usually being linked to dorsolateral, the second to median, and the third to orbitofrontal regions and their connections with specific subcortical structures such as the basal ganglia (Alexander et al., 1990; Sarazin et al., 1998). The term “dysexecutive” refers to the breakdown of a variety of higher cognitive functions that enable us to logically and temporarily coordinate and sequence actions,

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to inhibit inadequate and to trigger appropriate actions in a given context, as well as to plan ahead and to determine our actions according to future or expected contingencies. The transition towards socially inappropriate behaviors is vague, and many patients with dysexecutive syndromes have some degree of socially inadequate behaviors (Danek, 2002; Mitchell, 2004). Dysexecutive features are often part of typical AD, but primary progressive dysexecutive syndromes have been mainly reported in the realm of FTD with or without tau pathology (Mann, 1998; Rahman et al., 1999; Tanabe, 2000; Tolnay and Probst, 2002). Importantly, although the differential diagnosis between FTD and AD in the elderly is sometimes considered an easy task, certain late-onset FTD cases must be distinguished from atypical AD (Derouesne, 2003; von Gunten et al., 2005) as several recent contributions demonstrated that patients with AD may have early dysexecutive features which accompany memory impairment (Johnson et al., 1999; von Gunten et al., 2005). In these patients, NFT load was substantially higher in the frontal lobes than in other cortical areas (Johnson et al., 1999; von Gunten et al., 2005). Atypical AD may also be associated with amotivational or behavioral syndromes (Beland and Skat, 1992; Mesulam, 1982; Rosen et al., 2002). However, it is noteworthy that most reports on this dimension of AD contained neither premorbid nor current psychiatric assessments. Depressive symptoms or concern have been often considered an adequate reaction in the context of the early phases of AD (Déruaz et al., 1993; Mesulam, 1982). Other psychiatric symptoms frequently observed in PPA and AD/PCA, including anxiety, obsessive ideation and compulsions, hyperorality with weight gain, paranoid ideation, decreased capacity of judgment, inappropriate joviality, poor hygiene, alimentary habits change, neglect of grooming, coprolalia, emotional lability, pathological crying, impulsivity, disinhibition, restlessness, wandering, hoarding, childishness, antisocial attitudes, violent behavior, have all been described in early and more recent case reports (Bak et al., 2001; Bianchetti et al., 1996; Lüers, 1945; Mizuno et al., 1996; Rosen et al., 2002; Snowden et al., 1992; van Bogaert et al., 1940; Wechsler, 1977). Whether these symptoms reveal a premorbid psychiatric disorder or are consecutive to the brain pathology per se is a matter of debate (Lüers, 1945; van Bogaert et al., 1940). This ambiguity is illustrated in a case report of a patient with de Clérambault syndrome or erotomania (i.e., the delusional belief held by a person that another person is in love with him/her) and increasing suspiciousness compatible with a schizophrenia spectrum disorder in whom dementia was documented 4 years after the onset of the psychiatric symptoms. The patient died at 69 years after a disease course of 17 years. An orbitofrontal variant of AD was neuropathologically confirmed (Rothschild and Kasanin, 1936). As a rule, AD cases with concomitant psychiatric and behavioral deficits differ from those in which these features are the initial and most outstanding clinical symptoms related to an atypical lesion distribution. Whether or not psychiatric symptoms precede memory impairment in typical AD is difficult to ascertain as these patients are usually seen when they already have memory impairment (Copeland et al., 2003). In particular, it is unclear whether an elderly individual who becomes peculiar and excitable over the year preceding his

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Table 1 – Cases of neuropathologically confirmed primary progressive focal syndromes with AD lesions Reference

Patients described 1

Rothschild and Kasanin, 1936

1

van Bogaert et al., 1940

5

Category

Cortical pathology

Histological preparation

Particularities/ Comments

Woman; 33 years; careless wandering; rigidity, paresis, spasticity of all members, hand ataxia; when first seen at 35 years, disorientation, euphoria alternating with depression, convulsions, gradual mental deterioration with death at 42 years Woman; 52 years at onset; infatuation with young man living nearby, erotomanic syndromes, increasing suspiciousness and mood variations; when first examined at 56 years, fantastic delusions complete disorientation, very defective memory, poor judgment and anosognosia; stable for 4 years, then progression and death at 69 years

Behavioral/ motor

Numerous SP and NFT in all cortical regions. Plaques in optic thalamus, striatum, cerebellum, brainstem, and spinal pyramidal tract

Nissl, Bielschowsky, Simchovwicz

Unclear whether or not the patient had early cognitive impairment

Behavioral

Nissl, Bielschowsky, Dieterle–Neumann modification of del Rio Hortega method

Clinical features suggest that this patient may have had premorbid schizophrenia

Man; 30 years at onset; memory deficits and severe personality disorder (violence, jealousy, alimentary disturbance) followed by spastic paraplegia; dementia

Behavioral

Nissl, Spielmeyer, Scharlach, Holzer, von Braunmühl

Familial young-onset AD

Woman; 26 years at onset; fatigue and character changes with querulous and violent behavior; 2 years later, spastic paraplegia; dementia Man; 26 years at onset; behavioral changes (carelessness, violence, judgment); 1 year later, beginning quadriplegia; dementia

Behavioral

AD Macroscopically, generalized cortical atrophy. Microscopically, diffuse neuronal loss in particular parietal, temporal, anterior frontal parts, and CA; disturbed cytoarchitecture (schizophrenia?); great numbers of plaques in parietal lobes N hippocampus, CA, temporal lobes (more abundant in III layer); abundant NFT in same regions as plaques, but less evenly distributed AD—familial form Slight macroscopic frontal atrophy; Pronounced gliosis and neuronal loss; dense SP, numerous NFT; degeneration in basal ganglia, substantia nigra and of pyramidal tracts mostly with SP and NFT As above; sister of previous case

Behavioral

As above; brother of previous cases

As above

As above

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Barrett, 1913

Clinical features

Heston et al., 1966

2

2

Behavioral

AD—familial form, no link with patients above Description of nephew: numerous SP and NFT throughout cortex, in particular, in fronto-parietal areas with fewer lesions in motor and temporo-occipital regions, as well as basal ganglia and subcortical regions As above; sister of previous patient

As above

Motor

AD—familial form Numerous and largely disseminated SP; NFT in cortex and CA; amyloid angiopathy

Silver impregnation, Nissl, Alzheimer–Mann; van Gieson

Motor

As above; sister of previous patient

As above

Motor

AD—familial form Moderate neuronal loss, SPs, and rare NFT

PAS, not otherwise specified

Biopsy in right frontal lobe EEGs normal

Motor

AD—familial form Mild generalized cortical atrophy; SPs in all cortical areas, most prominently in frontal and temporal (hippocampus and parahippocampus) regions; NFT not well demonstrated

PAS, Congo red, Thioflavine T

2 more cases of very young onset familial AD with early motor involvement are described, but the initial symptomatology was mixed

Behavioral

Familial young-onset AD; Two further members of the subsequent generation of this family also had clinically similar AD, but their disorder started with episodic memory problems

As above

Father may have had the same disorder

189

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Lüers, 1945

Man; age of onset unclear, around 32 years; behavioral and functional disorder (carelessness, irritability, querulousness, suspiciousness); later memory and speech problems; followed by seizures, ataxia, dementia Woman; 35 years at onset; carelessness, jealousy, querulous, anxiety; later, memory and speech disorder; seizures, rigidity, dementia Man; 26 years at onset; speech and gait disturbance; progressive deterioration with incontinence, crying and shouting (clinical diagnosis: MS) Woman; age unclear; pain and stiffness in right leg, reduced mobility; spastic paraparesis; euphoria, dysarthria; progressive dementia (clinical diagnosis: MS) Man; 47 years at onset; progressive weakness and clumsiness in right hand and leg with handwriting difficulties and dysarthria; when examined 8 months after onset, dysphasia, apathy, memory deficits, right predominant spastic paresis Man; 33 years at onset; increasing stiffness and tremor in left extremities, dysphagia, dysarthria, emotional lability; when seen at 36 years left spastic paresis, myoclonus, tremor, only slight forgetfulness; death from renal failure at 36 1/2 years

190

Table 1 (continued ) Reference

Patients described

Clinical features

Category

1

Woman; 28 years at onset; gradually slurred speech and gait disturbance; then personality change and increasing dementia

Motor

Fukatsu et al., 1980

1

Man; 39 years at onset; low back and leg pain, difficulty in walking; then depressive mood and personality change; increasing dementia; death in apallic state 2 years after onset

Motor

Crystal et al., 1982

1

Motor

Ishino et al., 1983

1

Woman; 51 years at onset; initially, numbness in left hand, difficulty in knowing arm position in space; later, astereognosis, agraphaestesia, of left hand; difficulty in figure construction; gegenhalten, choreoathetoid movements followed by progressive dementia Gender and age (about 30–35 years) unclear; motor features with myoclonic jerks, generalized convulsions, dysarthria, ataxic symptoms

Motor

AD + amyotrophic lateral sclerosis/parkinsonism– dementia complex of Guam + Kuru disease Bilateral frontal and basis pontis atrophy, moderate ventricular dilation; Numerous SP in cerebral and cerebellar cortex, basal ganglia, brainstem, spinal cord; widespread NFT in cerebral cortex, substantia innominata, substantia nigra, locus coeruleus, Edinger– Westphal; Arterial changes; ALS-like and spinocerebellar degeneration AD Slight generalized atrophy and ventricular dilation; Numerous argentophilic plaques in cerebral cortex and senile plaques especially in cerebellum; presence of NFT; widespread amyloid angiopathy Numerous SP; scattered NFT; mild reactive astrocytosis; focal amyloid angiopathy in right frontal lobe

AD + kuru-like SP widespread in frontal cortex; NFT in cerebral cortex; SP, NFT, granuovacuolar degeneration, kuru-like plaques, amyloid angiopathy, grumose alteration in particular in the dentate nucleus

Histological preparation

Particularities/ Comments

Sudan, Sudan black, Scarlet red, CopperPhthelocyanin, PAS, Best Carmin, Alcian blue, Congo red, Bennhold, Mayer, Lendrum, Jod reaction, Feyrter, Toluidine blue, coupled tetrazolium

Article in Japanese; abstract available; Twin suffering from clinically identical disease

Not mentioned in abstract

Article in Japanese; abstract available

Biopsy-proven AD; biopsy in right frontal lobe

PAS, Bodian, Hirano, Nissl, HE

Article in Japanese; abstract available CT: cerebral atrophy and basal ganglia calcification

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Matsuoka et al., 1967

Cortical pathology

1

Woman, 63 years at onset; motor vehicle accidents, problems with judgment and coordination; 5 years after onset, loss of use of left hand (pyramidal syndrome and parkinsonian features) and mild/moderate dementia (aphasia, visuospatial deficits, impaired memory); increasing deficits to severe dementia by 72 years

Motor

Ball et al., 1993

1

Man; 66 years old at onset; difficulty dressing, using knife and fork; myoclonus, pout and left grasp reflex; incomplete left homonymous hemianopsia; dystonic posturing of the left hand; alien hand sign left; visuoperceptive and memory impairment; general deterioration with relatively preserved language function until death 4 years after onset

Motor/Apraxia

Wojcieszek et al., 1994

1

Motor

Riley, 1996

1

Man; 61 years old at onset; progressive speech disturbance, right hand incoordination, poor balance, and intellectual decline; a few months later, forgetfulness; progressive motor (with myoclonus being the predominant movement disorder) and cognitive deterioration Man; 59 years at onset; motor learning difficulties; stops using right arm, gait deterioration; at 64 years, poor memory and abstract thinking; left arm action tremor and decreased sensation; at 65 years, myoclonic jerking in left arm and leg; at 66 years, left arm neglect, severe apraxia, rigidity, pyramidal signs; further deterioration, total dependence, died of pulmonary embolism

Motor

AD Macroscopically severe atrophy right N left; Neuritic plaques and NFT throughout the neocortex, and hippocampus, numerous Hirano bodies; In right somatosensory cortex (Brodmann 3, 2, 1), severe nerve cell loss (layer II and III), marked spongiosis, mild superficial gliosis; normal striatum and substantia nigra AD Widened sulci and narrowed gyri throughout cerebral hemispheres, most obviously in the temporal lobes. Many NFT, senile plaques in hippocampus and throughout the neocortex, also in deep grey matter. Granulovacuoles and a few Hirano bodies in hippocampus. A few large, pale chromatolytic neurons in neocortex not sufficient for corticobasal degeneration Moderate atrophy Numerous neuritic plaques, sometimes with amyloid cores, and NFT in all cortical areas; slight nerve cell loss and gloss; similar changes in hippocampus, amygdala; fewer NFT in striatum

AD Numerous SP and NFT in most hippocampus; no achromatic cells; loss of cerebellar Purkinje cells (possible independent cerebellar degeneration)

HE, Bielschowsky, stain for glial fibrillary acidic protein

CT: generalized atrophy EEG: occasional bihemispheric, periodic sharp discharges

HE, Luxol-fast blue, cresyl violet, Congo red, silver impregnation according to Marsland and Glees. IHC for glial fibrillary acidic protein A4 protein, neurofibrillary protein, and ubiquitin

Cortical atrophy and ventricular enlargement more pronounced on the left than right side

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Jagust et al., 1990

No precision, no stainings mentioned

191

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192

Table 1 (continued ) Reference

Clinical features

Category

Cortical pathology

Histological preparation

Bashir et al., 1998

1

Woman; 66 years old at onset; initially, motor signs; 8 months later, left homonymous hemianopsia, gradual deterioration including confusion, agitation, depression, and visual hallucinations

Motor

Crook et al., 1998

3

Man and woman in a family of 12 affected individuals with onset between 45 and 57 years; typical AD with progressive spastic paraparesis Woman unrelated to previous two cases

Motor

Boeve et al., 1996

1

Aikawa et al., 1985

1

Petersen, 1998

1

No individual case description: Motor clinically definite case of corticobasal degeneration: progressive asymmetric rigidity and/or apraxia Motor/Behavioral AD HE, Nissl, Bodian, Woman; 27 at onset; difficulty Diffuse symmetrical atrophy, Holzer, Congo red concentrating and with predominantly frontal and household chores, irritability; temporal lobes. Markedly gradual forgetfulness and slurred enlarged lateral ventricles. speech; at 29 progressive rightMany NFT and neuritic plaques sided weakness, then ataxia and particularly prominent in falls; at 30 years: moderated hippocampus and the frontal and impairment of recent memory, temporal cortices. NFT also in slight depression, cerebellar caudate nucleus, thalamus, dysarthria, spastic right hypothalamus, nucleus Meynert, hemiparesis/hyperreflexia/ some cranial nerve nuclei, Babinski's sign, ataxia; gradual substantia nigra, and locus deterioration, mutism, patient coeruleus; bedridden, death 6 years after Degeneration of corticospinal onset from bronchopneumonia tracts. Neuritic plaques with amyloid cores in the cerebellum Woman; 60 years at onset; Motor/apraxia AD difficulty driving, then buttoning Asymmetric distribution of

Mild atrophy of temporal lobes; Mild to moderate neuronal loss, gliosis, diffuse plaques, neuriticcored plaques; Lewy bodies in cortex; Far more NFT in right superior and inferior temporal and right striate and peristriate cortices AD HE, Bielschowsky, Large plaques like loosely packed IHC for tau and ubiquitin cotton wool balls (absence of congophilic cores) Numerous intraneuronal NFT, only little neuritic pathology; particularly pronounced amyloid angiopathy in precentral cortex and mild degeneration of lateral corticospinal tracts in one patient (severe in the 3rd patient) AD Widespread NFT and senile plaques

Particularities/ Comments Right parietal–occipital and inferior temporal hypoperfusion [SPECT]; Diffuse Lewy body disease and possible AD; however, NFT pathology correlated with hemianopsia Presenile familial AD due to deletion of exon 9 of presenilin 1

EEG at age 32: irregular frontal slow waves

MRI: generalized atrophy more prominent on right side

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Patients described

1

Grünthal, 1928

1

Morel, 1945

1

Corsellis and Brierley, 1954

1

Brain MRI normal at age 62

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Engel and Grunnet, 2000

Ventricular dilation [encephalography] (see also Hof et al., 1993

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193

clothes and tying shoes left neuritic plaques and NFT upper extremity N right; meeting however criteria for intermittent jerking of her limb; AD over next year, memory impairment and some spelling difficulties; on examination, apraxia, increased tone, reduced arm swing, pronator drift of left arm. Gradually also in right arm; another year later, hypokinetic dysarthria, asymmetric apraxia, rigidity, myoclonus, impaired joint position sense in left N right arm; generalized cognitive dysfunction with relative sparing of verbal intelligence and naming (=corticobasal degeneration syndrome) Woman; 57 years at onset; death Motor/Behavioral AD and PLS HE; Thioflavin stain; Mildly atrophic brain; primary Bielschowsky silver stain after 12-year evolution; primary lateral sclerosis (PLS) beginning lateral sclerosis; NFT in hippocampus and clustered in with heaviness/weakness in left leg; at 62, clearly spastic gait; parahippocampal gyrus; retirement and difficulty granulovacuolar degeneration managing personal affairs; and Hirano bodies; cortex: mild cognition corresponding to a mild neuron loss and astrocytosis in frontal systems dementia stable; particular in orbitofrontal and at 67, wheelchair-bound; major parahippocampal gyri; decline of cognitive function numerous SP in orbitofrontal, during the 6 months before death frontal, occipital, and temporal cortex; infrequent NFT in cortex Woman; 53 years old at onset; PCA The highest amounts of SP and initially, forgetfulness; spatial above all NFT in parietodisorientation and Bálint occipital cortex, much less in syndrome; left–right occipital, frontal, and temporal disorientation, autotopoagnosia, cortex reading difficulties Man; 55 years at onset; initially, PCA Brain atrophy more pronounced rapidly progressive memory in both posterior segments; impairment and dyslexia; motor AD changes in “optopsychic” disorders of vision, psychic area N “optomotor” paralysis of gaze, cortical area N “optosensorial” area; blindness Layer III N V/VI; II/IV not affected Woman; 56 years old at onset; PCA Severe amyloid vascular change; initially, “vacant air about her”, NFT most marked in occipital

194

Table 1 (continued ) Reference

Patients described

1

Cogan, 1985

1

Kobayashi et al., 1987

1

Hof et al., 1989

6

Kiyosawa et al., 1989

2

difficulty recognizing people; 6 years later, memory problems, wandering about at night, dementia with spastic paralysis and paresis Man; 69 years old at onset; progressive visual loss within 4 months to total cortical blindness; then progressive memory loss, myoclonus, disorientation, confusion, jargon aphasia First attended at 65 years; visuospatial disorientation, difficulty driving [poor vision], reading; left hemineglect; dressing difficulties, motor eye disturbance, visual and topographic agnosia, optic ataxia, left hemianopsia, prosopagnosia Man; 55 years old at onset; initially, forgetfulness, disorientation for time and space; then gradually progressive dementia; when first seen at 60 years of age severe Bálint's syndrome, constructional apraxia, myoclonus, muscle rigidity and hyperreflexia; paraphasia and logoclonia, perseverations Mean age 78 years at autopsy; Bálint's syndrome; presence of memory defects and intellectual impairment

Simultagnosia, environmental visual agnosia, dyslexia, dysphasia with dysgraphia

Category

Cortical pathology

Histological preparation

Particularities/ Comments

cortex, absent in frontal cortex; SP apparently abundant and severe in all cortices

PCA

Minimal cerebral atrophy; Diffuse neuronal loss; numerous SP and many NFT throughout cortex

PCA

Abundant NFT and plaques

Most parts of brain were discarded; only cortex material for electron microscopy research of slow virus was kept

PCA

Diffuse atrophy of cerebrum most severe in occipital and temporal lobes; Moderate to severe neuron loss and glial proliferation; many NFT in cortex and numerous SP throughout the cortex

Diffuse brain atrophy [CT] AD in an Al-refiner; increased Al content in tangle-bearing neurons as compared with usual AD

PCA

Very high amount of NFT in area 17 that further increased in area 18, substantially lower densities in superior frontal cortex, approximately equal densities in parietal cortex as compared to typical AD cases; neuritic plaques more numerous in area 17/18 and inferior parietal cortex as compared to typical AD Biopsy-proven AD with no specification

No individual case histories

PCA

Biopsy-proven AD cases without specification which 2 of the 8 patients described

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Faden and Townsend, 1976

Clinical features

8

Mean age 80 years at autopsy; Bálint's syndrome

PCA

Jacquet et al., 1990

1

Woman; 58 years at onset, initially, difficulty reading and visual impairment; later, difficulty executing manual tasks, linguistic impairment, spatial disorientation, prosopagnosia; progressive more general cognitive decline

PCA

Ross et al., 1990

1

PCA

Berthier et al., 1991

1

Hof and Bouras, 1991

1

Initial alexia and visual agnosia; subsequently, Bálint's and Gerstmann's syndrome, and transcortical sensory aphasia Woman; 45 years old at onset; initially, slowly progressive visual loss with piecemeal perception and writing difficulties; later, reading and calculation deficits, spatial disorientation, decreased manual skills Woman; 78 years old at onset; initially, aperceptive visual agnosia; slight memory

PCA

PCA

Strikingly higher NFT counts in occipital visual areas 17/18/19 and superior colliculus, lower counts in frontal areas 9 and 45, equal in posterior parietal cortex 7b as compared with typical AD; much higher incidence of neuritic plaques in visual occipital cortex and higher incidence in posterior parietal [area 7b] and posterior cingulate [area 23] as compared to typical AD; similar profiles in atypical and typical AD in the inferior temporal gyrus Cerebral atrophy predominant in parieto-occipital regions; Substantial neuron loss in occipital cortex, very high number of SP, few NFT but many neuropil threads; some SP but many NFT in frontal cortex; high numbers of both SP and NFT in temporal cortex; globally, predominance of AD lesions in occipital lobe Many NFT and SP strongly concentrated in the occipital and parietal lobes; congophilic arteriopathy Right parietal biopsy showing mild neuronal loss and lipofuscin accumulation; abundant neuritic plaques, some immature neuropil threads, and occasional NFT

Cortical atrophy predominant in occipital and partly parietal regions [CT]

2 non-AD patients with posterior cortical atrophy are also reported Abstract available only Biopsy-proven AD

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Hof et al., 1990a,b

underwent a biopsy; Reduced glucose metabolism in visual association cortex and inferior parietal cortex; cortical atrophy restricted to parietooccipital areas [MRI] No individual case histories

Cortical atrophy predominant in temporal and occipital lobes; Dramatic increase of NFT and

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196

Table 1 (continued ) Reference

Patients described

Clinical features

Category

impairment and disorientation; 2 years later, prosopagnosia, tactile agnosia; progressive evolution towards dementia over the following 9 years

Hof et al., 1993

2

1

Victoroff et al., 1994

1

Man; 55 years old at onset; rapidly progressive visual impairment, increasing difficulties in reading, progressive memory impairment Man; approximately 57 years old at onset; reading and driving difficulties; visual agnosia; calculation impairment; steady decline over 12 years with appearance of more generalized cognitive impairment

Man; 58 years old at onset; progressive difficulty in reading, calculating, and finding his way

PCA

PCA

PCA

neuritic plaques in visual occipital areas 17/18/19 and visual temporal association area 21, lower NFT densities in frontal areas [9/45/46] and posterior parietal cortex [7b] as compared with typical AD Cortical atrophy predominating in posterior parietal cortex and occipital lobe; Numerous NFT and SP throughout cortex; high densities of NFT in visual cortex increasing from area 17 through 18 and 19/ 7b/23 both in supra- and infragranular layers. Area 20 had lower NFT densities than areas 19/7b/23 As above, but highest NFT densities in area 7b

Marked cerebral atrophy, particularly in parieto-occipital regions; Abundant NFT and SP; NFT density was higher in the parietooccipital areas [18/19 N 17], posterior cingulate, and temporal lobes than in the frontal areas; SP density was higher in visual association and frontal cortex than in primary visual cortex, plaques with amyloid cores and neuritic change were very high in both primary and association cortex and very low in frontal cortex Cerebral atrophy slightly more prominent in the occipital lobes; Many NFT and neuritic plaques

Histological preparation

Particularities/ Comments

Mild cerebral atrophy [CT]

This second patient is identical to the one Morel had reported

Mild diffuse atrophy [MRI]

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Levine et al., 1993

Woman; 50 years old at onset; complaint of visual impairment; difficulty reading and identifying objects; probable Bálint's syndrome limited and infrequent eye movements; modest memory deficit on formal testing; progressive decline

Cortical pathology

while driving, no memory impairment; subsequent development of full Gerstmann's and Bálint's syndrome

Ceccaldi et al., 1995

2

1

Levy et al., 1995

1

Ross et al., 1996

1

PCA

Man; 60 years old at onset; problems driving car, slowly progressive apraxia; features of alien hand sign; then writing and calculation difficulties, mild left hand agraphesthesia and astereognosis Woman; 65 years old; slowly progressive loss of visual acuity and field; trouble playing golf and reading; later, relative left homonymous visual field defect

PCA

Woman; 54 years old at onset; dyspraxia and related difficulty in writing, then severe visual disorientation, simultagnosia, extremely poor performances on visuospatial tests and both transitive and intransitive hand gestures; later, rapid and global decline in cognitive functioning

PCA/Apraxia

PCA

Diffuse moderate cerebral atrophy, more pronounced in retrorolandic regions, especially the parietal areas Diffuse neocortical neuron loss; numerous SP [mostly neuritic] in pyramidal layer of hippocampus and all associative cortices; numerous NFT all over the cortex, especially in the superior parietal cortex bilaterally Numerous predominantly neuritic plaques and NFT in right middle and inferior temporal lobe

Right occipital biopsy Large quantities of NFT and neuritic plaques; amyloid angiopathy

Cortico-subcortical atrophy predominant in retrorolandic areas [CT]; right retrorolandic hypoperfusion [SPECT]

Biopsy-proven AD case; Generalized atrophy [MRI]; Hypoperfusion in right frontal, parietal, temporal, and occipital regions [SPECT]

Biopsy-proven AD case Normal CT scan, subsequently bilateral parietal and occipital lobe atrophy [MRI]; a vascular zone in distal right calcarine segment [arteriography] Greatly decreased perfusion in superior parietal lobes bilaterally [SPECT]

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197

AD Moderate generalized atrophy with particular emphasis on both superior parietal lobules; Severe nerve cell loss in parietal cortex, less in medial temporal areas; Extensive neuritic plaques and NFT in archi- and neocortex with particularly severe parietal involvement

Biopsy-proven AD; Cortical atrophy predominant in retrorolandic regions [CT and MRI]

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Green et al., 1995

Man; 50 years old at onset; left hand apraxia, topographical difficulties and visuoconstructive impairment, spatial dysgraphia, mild left hemineglect; evolving slowly towards dementia Woman; 60 years old at onset; left hand apraxia, spatial dysgraphia and dyscalculia, constructive apraxia, severe left hemineglect

throughout the cortex; however, lowest densities in area 17 and anterior cingulate, intermediate densities in area 18 and parietal and temporal cortex, and highest densities in posterior cingulated, inferior frontal, and especially postcentral gyrus Right frontal biopsy showing SP and NFT

198

Table 1 (continued ) Reference Rogelet et al., 1996

Clinical features

Category

Cortical pathology

2

Man; 59 years old at onset; initially, slight memory impairment spatial disorientation with environmental agnosia, agraphia, alexia; 2 years after onset, prosopagnosia, color agnosia; over the following years, progressive deterioration of his mental state, Bálint's syndrome and Gerstmann's syndrome Woman; 51 years old at onset; initially, complaint of memory difficulties; over following 4 years, progressive impairment of visuospatial and perceptual capacities, alexia, environmental agnosia; then, Bálint's syndrome, components of Gerstmann's syndrome, worsening of memory and linguistic abilities 2 early-onset cases; 6 patients presenting with partial or complete Bálint's syndrome and 5 cases developing this syndrome during their dementia; all cases eventually developed severe AD clinically

PCA

Right frontal lobe biopsy showing abundant neuritic plaques and NFT; mild neuronal loss and gliosis

Mild atrophy, most pronounced in parieto-occipital areas on initial CT; 2 years after 1st examination, marked hypoperfusion in right parietotemporal region [SPECT]

PCA

Right frontal lobe biopsy showing abundant neuritic plaques and NFT; slight neuronal loss and reactive gliosis

Initial CT normal; CT 4 years after 1st examination: bilateral symmetrical atrophy prominent in parieto-occipital regions

PCA

One of the cases corresponds to Morel's patient

Woman; 46 years old at onset; mild forgetfulness remaining stable; at 52 years, clumsiness and myoclonus in left upper limb; severe visuo-constructional impairment, partial Bálint's, dressing apraxia, left hemineglect, environmental agnosia Woman; 77 years at 1st

PCA

Marked posterior cortical atrophy; numerous NFT and SP throughout the cortical mantle; clear gradient of NFT densities from area V1 to visual parietal association cortex, posterior cingulate cortex, and area MT; much fewer NFT in frontal areas [9/45/46]; intermediate densities in inferior temporal cortex Right parietal and occipitoparietal biopsy showing numerous neuritic plaques and infrequent NFT

11

Kaida et al., 1998

1

Petersen, 1998

1

PCA

AD

Histological preparation

Particularities/ Comments

Needle biopsy from right parietal and parieto-occipital cortices; Severe hypoperfusion in parieto-occipital regions, more marked on the right [SPECT]; generalized mild cortical atrophy, accentuated in right parieto-occipital area [MRI] EEG: right hemisphere delta

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Hof et al., 1997

Patients described

Galton et al., 2000

1

PCA

Man; 63 years old at onset; difficulties performing manual tasks and writing, visual disorientation; later generalized intellectual impairment, extreme impairment on all visuospatial tasks and severe apraxia. Further decline also of language

PCA

Woman; 58 years old at presentation; dyspraxia, dysgraphia, and simultagnosia; severe visuospatial deficits on testing; moderate episodic memory impairment

PCA

Progressive ideomotor apraxia, hemi-inattention, unilateral limb dystonia, myoclonus

PCA

Neuropathological changes of AD with a predominance of neuropathological markers in the right parietal region

focus MRI: relative right hemisphere atrophy

Moderate neuronal loss in hippocampus [CA1 pyramidal layer]; high amount of SP in hippocampus, entorhinal cortex; high amount of NFT visual and parietal cortex, CA1, and entorhinal cortex, moderate amount in temporal, frontal, and primary motor and sensory cortex Moderate cortical atrophy more so in the superior parietal lobules; Severe neuron loss in hippocampus [CA1 pyramidal layer], entorhinal cortex, and area 7; high amount of SP in hippocampus, entorhinal cortex, parietal and occipital cortex, moderate amounts in temporal and frontal cortex; high amount of NFT in visual and parietal cortex, CA1, and entorhinal cortex, moderate amount in temporal, frontal, and primary motor and sensory cortex Severe neuron loss in hippocampus [CA1 pyramidal layer] and entorhinal cortex; high amount of SP in hippocampus, parietal, occipital, and frontal cortex; high amount of NFT in CA1, parietal, temporal, and frontal cortex Abundant amyloid deposits and phosphorylated tau accumulation in NFT and neuropil threads

Bilateral reduction in occipital lobe perfusion [SPECT]; enlarged calcarine fissure with posterior brain atrophy [CT]

Reported clinically as case 3 in Cogan, 1985 Biparietal reduction in perfusion [SPECT], gross posterior cortical atrophy especially of left parietal and temporal lobes

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Lleo et al., 2002

3

assessment; frequently getting lost in familiar surroundings; difficulty navigating while driving; over time, difficulty aligning her body in space; later, dressing difficulties with memory and language relatively spared; PIQ 30 below VIQ. Death after 5 years of evolution Woman; 65 years old at onset; poor vision, perceptual problems, severe visual disorientation; attention and severe episodic memory impairment

Biparietal hypoperfusion [SPECT]

Abstract available only

199

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200

Table 1 (continued ) Reference Renner et al., 2004

Patients described 14

Clinical features

Cortical pathology

Men and women with variable features of primary progressive posterior dysfunction

PCA

A preliminary analysis of 5 subjects (1 with concomitant Parkinson's disease) showed equal burden of cored and total SP and NFT in the parietal lobes as typical AD 7 cases of AD and 2 cases with AD + LBD; moderate to severe parieto-temporo-occipital atrophy; greatest SP and NFT densities in BA 17/18; sparing of hippocampus in 3 patients Atrophy especially in left frontal gyri, especially the superior as well as left superior temporal gyrus AD Macroscopic atrophy especially of temporal poles, left N right; abnormally thin cortical layer Widespread neuronal loss and reactive gliosis especially in temporal and parietal lobes (layers II–III), less in frontal/ occipital, not in hippocampus/ subiculum Neuritic plaques and NFT parallel neuron loss

Tang-Wai et al., 2004

9

Men and women with a variety of visual symptoms, aphasic, and apraxic signs

PCA

Mingazzini, 1914

1

Man; 57 years at onset; difficulty speaking and understanding, impulsive actions, irritability

PPA

Pogacar and Williams, 1984

1

PPA/PCA

Holland et al., 1985

1

Man; 56 at onset; word-finding deficits with subsequent deterioration of prepositional speech and writing; after 12 months, dressing difficulties; at 16 months, fluent aphasia, poor reading comprehension, agraphia, acalculia, left–right confusion, difficulties copying, unable to button clothes, could not identify famous persons (mimics angular gyrus syndrome); over 3 m clumsiness of right arm, myoclonus; further progression with ataxia, seizures, and death 6 years after onset Man; 66 years at onset; wordfinding difficulties and phonemic paraphasia, comprehension difficulties; mutism at 73 years with no evidence of memory loss; still good reading comprehension, writing still possible, possibly word deafness; after 9 years, irritability and later flattened affect; subsequent personality deterioration and incontinence, bulimia, and PICA. Death after 12 years of evolution

PPA/Behavioral

Pick (and AD) Focally accentuated atrophy, left more than right; Pick cells and (fewer) NFT in all cortical layers (but mainly lower levels) mainly in cortex of frontal and temporal lobes more on left than right side; NFT in hippocampus, amygdala, thalamus, and the pigmented nuclei of brainstem, but no SP

Histological preparation

Particularities/ Comments

HE, Luxol Fast Blue/PAS, Thioflavine S, Bielschowsky silver, various IHC

Only 2 patients had prominent posterior atrophy on CT or MRI

Thioflavine S, HE, Bielschowsky silver; various IHC

Occipitoparietal atrophy on CT or MRI or posterior hypoperfusion or hypometabolism on SPECT/PET were an inclusion criterion

Weigert–Pal's hematoxylin; HE

HE, cresyl-violet, Weil, Luxol, Holzer, Bielschowsky

EEG at 12 months: normal, at 19 months: delta/theta over frontotemporal regions, left N right CT at 12 months: mild atrophy of left temporal lobe and enlargement of left lateral ventricle

HE, Bielschowsky, Bodian, EEG: 6–7 cps left Thioflavin S, Masson's trichrome, PPA was felt to be rather due to PAS, Wilder's method for PD than to AD reticulin

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Category

1

Man, 58 years at onset; complaint of word-finding difficulties; at 63 years: fluent but paraphasic speech including repetition and naming with relative sparing of comprehension, agraphia, mild impairment in block design and rhythm discrimination, nonverbal intelligence and memory were good

PPA

Benson and Zaias, 1991

1

Man, 57 years at onset; increasing word-finding difficulties; mild fluent aphasia 4–5 years after onset, limited confrontation naming and repetition, acalculia; at 63 years, aphasia; subsequent progression of aphasia over 1 year with semantic paraphasias, agraphia, alexia; memory remained relatively intact; progressive physical and mental deterioration during 8 months preceding death 8 years after onset

PPA

Déruaz et al., 1993

1

PPA

Karbe et al., 1993

1

Woman; 59 years at onset; slight word-finding and articulatory difficulties at 61 years; at 63 years, concerned by her difficulties, phonetic disintegration, severe anomia, understanding satisfactory, agraphia, calculation preserved, goes on working; worsening when 68 years old and progression towards dementia; death at 72 years Man; 55 years old at onset; primary progressive aphasia; global dementia present 3 years after onset and death at 58 years of age

PPA

AD Macroscopically neither significant atrophy nor asymmetry. Microscopically abundant neuritic plaques and NFT spread diffusely throughout cerebral cortex (15–35 plaques per 10× field in frontal cortices). NFT present in most cortical areas but less numerous AD (though authors say: nondiagnostic since atypical) Moderate symmetrical dilation of 3rd and lateral ventricles Numerous neuritic plaques spread diffusely throughout cortex most numerous in temporal lobes; plaque density considerably greater in left N right superior temporal and calcarine cortex; NFT far less numerous but equally distributed; granulovacuolar degeneration and few Hirano bodies; nonsignificant neuronal loss and gliosis AD (Khachaturian criteria for AD not fulfilled) Severe neuron loss (especially layer III and V) and gliosis in cortex; few NFT in both temporal lobes (in particular CA), nucleus Meynert, both frontal and left occipital lobes; few neuritic plaques in temporal lobes N frontal and occipital lobes

HE, cresyl violet, Bodian, Hirano–Zimmerman

CT and MRI normal at 4–5 years of evolution; CT 1 year later: mild non-focal atrophy; PET: decreased left temporoparietal hypometabolism

HE, Bodian, Congo red; Luxol fast CT 2 years after onset: normal blue; IHC for GFAP, tau, and Macroscopically severe atrophy ubiquitin on left N right side, particularly in anterior perisylvian and frontal regions; MRI 4 years after onset: atrophy left N right side NB. Khachaturian criteria for AD not fulfilled!

Not specified

(continued on next page)

201

AD Moderate global brain atrophy Widespread diffuse neuronal cell loss, gliosis, very high density of SP and NFT. NFT in all examined neocortical (frontal, temporal, parietal, and occipital cortex) and subcortical (basal ganglia,

CT initially normal CT at 63 years: mild–moderate generalized atrophy, greatest in left perisylvian area PET: left temporal hypoperfusion extending towards left frontal areas and thalamus

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Kempler et al., 1990

202

Reference

Doran et al., 1995

Greene et al., 1996

Patients described

1

1

Clinical features

Category

Woman; 63 years old at onset; word-finding difficulties and paraphasia, ADL difficulties, emotional lability; when 65, global aphasia, orobuccal and limb apraxia, motor neuron disease

PPA/motor

Man; 61 years at onset; at 66 years, non-fluent speech with phonemic paraphasias and syntactic omissions, severe anomia; over next 12 months: lack of concern about hygiene; global cognitive decline

PPA/Behavioral

Cortical pathology thalamus, hypothalamus, hippocampus) areas, e.g. left middle frontal gyrus +++ (not otherwise specified) AD

Histological preparation

HE, cresyl-violet. Luxol fast blue, modified Bielschowsky, IHC for tau protein, neurofilament, and ubiquitin

Mild neuron loss in CA1 without NFT neither in hippocampus nor entorhinal or parahippocampal regions; Numerous NFT and neuropil threads in temporal isocortex, neuropil threads also in frontal, parietal, and occipital cortices; IHC profiles of neuropil threads and NFT as in AD AD HE, Congo red, IHC for tau and Moderate gyral atrophy in medial amyloid β proteins parts of cortex with moderate neuronal loss and frequent NFT, SP equally severe in Brodmannʼs areas 1–6, 40, 44, 45, middle/ posterior thirds of superior/ middle temporal gyri; higher NFT densities without neuropil threads in Brodmann area 39.

Particularities/ Comments

CT at 65 years: atrophy of left temporal lobe and increased widening of left frontoparietal sulci; EEG normal

PET: no focal defect; MRI: mild general cerebral atrophy, more in left perisylvian region; LP normal

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Table 1 (continued )

Westbury and Bub, 1997 Li et al., 2000

3 (2) 1

No case reports Man; 70 years at onset; death 6 years after onset; amnestic aphasia and paraphasia at onset; 2 years later, comprehension and speech difficult, pica, and collectomania; pulsion and rigidity; evolving to generalized dementia

PPA PPA/Behavioral

Similar but fewer lesions in occipital cortex; mild NFT changes only in CA1; occasional NFT in medial thalamus AD

Cases are reported according to their category (determined by the presenting symptom) and, within each category, according to the year of publication. IHC = Immunohistochemistry; HE = Hematoxylin– Eosin; PCA = posterior cortical atrophy; PPA = primary progressive aphasia.

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AD HE, Klüver–Barrera; IHC for tau, Severe neuron loss and gliosis in ubiquitin, amyloid β and human temporal and frontal cortices, collagen IV antibodies mild in parietal and occipital cortices, moderate in hippocampus, amygdala, Meynert nucleus, hypothalamus, medial thalamic nucleus, and caudate nucleus. Left much more than right. Many NFT in CA1–4, subiculum, entorhinal, insular, and cingulated cortices; some NFT in other temporal, frontal, and postcentral cortices, amygdala, medial thalamic nuclei, periaqueductal gray; few NFT in precentral cortex, striatum, hypothalamus, substantia nigra, locus coeruleus abundant throughout cerebral cortex

No case reports (case of Benson and Zaias Marked asymmetrical temporal lobe atrophy and dilation of inferior horns of lateral ventricle predominantly left (CT and MRI)

203

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memory decline should be considered as a typical or an atypical AD case (Lowenberg and Waggoner, 1934). When these symptoms are secondary to focal degenerative disorders, they fall into the vague diagnostic group referred to as primary behavioral dysfunction (Mesulam and Weintraub, 1992). For instance, psychosis, obsessions and compulsions, behavioral disinhibition, and profound disruption of social conduct were predominant features of progressive right frontotemporal degeneration in five patients who ultimately progressed to dementia. They had hypoperfusion in the frontal and anterior temporal lobes, more pronounced on the right side (Miller et al., 1993). A number of patients with probable primary progressive behavioral syndrome have, in fact, AD. Two cases with a frontal lobe variant of AD have been described by Brun and Gustafson in their magistral publications on frontal lobe dementia of the non-AD nonPick type, but no detailed case descriptions were given (Brun, 1987; Gustafson, 1987). In AD cases with prominent aberrant behaviors, predominant damage of the frontal lobes has been reported. In some cases, the frontal atrophy is more marked macroscopically, but NFT and SP loads can also be higher in frontal regions as compared to other cortical areas (van Bogaert et al., 1940). Similarly, cases with combined primary progressive motor or aphasic syndromes and early behavioral features showed pronounced frontal and temporal AD lesion involvement (Aikawa et al., 1985; Holland et al., 1985). We recently reported a patient whose main clinical features were the early development of cognitive and behavioral frontal lobe-like symptoms and the presence of environmental reduplicative paramnesia. These unusual clinical features were associated with an atypical distribution of NFT that predominated in the frontal (areas 8 and 9) and anterior cingulate (area 24) and, to a lesser extent, the temporal association cortices (areas 20 and 21) (von Gunten et al., 2005). In agreement with several recent studies showing poor relationships between amyloid deposition and cognitive deficits in AD (for a review, see Giannakopoulos et al., 2003), there was no relationship between the pattern of SP distribution and evolution of the clinical symptoms in this case.

4.

Conclusion

Focal, lobar, and gyral degeneration are terms used to qualify primary progressive syndromes (Harasty et al., 1996) for which no consensual classification exists due to their clinical and neuropathological heterogeneity (Black, 1996; Caselli, 1995; Gorno-Tempini et al., 2004; Kramer and Miller, 2000; Mesulam, 2001; Mesulam and Weintraub, 1992; Ross et al., 1996). The clinical expression of these conditions is likely to correspond more closely to the functional anatomy of the affected brain areas than to the underlying pathology. The complex constellations of symptoms described in this review display variable probabilities of being associated with AD pathology. Symptoms associated with posterior cortical degeneration are more likely due to an atypical distribution of AD neuropathological changes which affect preferentially three distinct cortical sites leading to the progressive and frequently heterogeneous disruption of ventral and dorsal visual proces-

sing streams: the extrastriate visual association cortex related to complex visual representations, the posterior parietal cortex which subserves spatial localization, and the inferior temporal cortex which is the main locus of object recognition. In contrast, clinical features suggestive of anterior brain involvement are less likely to be secondary to AD lesions with the exception of a small and poorly defined subgroup showing predominant frontal glucose hypometabolism and early deficits on social cognition. Anterior temporal loberelated cognitive deficits occupy an intermediate place in this spectrum, reflecting the multiple functions of this complex lobe. Frequently affected in FTD group, it may also exhibit a particular pattern of AD lesion distribution mainly in cases with AD and PPA. Besides these three main groups of atypical AD cases, a careful review of the literature reveals the existence of several individual AD cases with highly specific patterns of cognitive deficits and lesion distribution in usually preserved cortical and subcortical areas (i.e., motor cortex, somatosensory cortex, subcortical nuclei) pointing to the substantial inter-individual variability which characterizes this heterogeneous disorder. From a classical neuropathological viewpoint, it is clear that certain of the above reported cases do not meet the accepted clinical and neuropathological criteria for the definition of AD, yet they display the same histopathologic features. The particular clinical expression in these cases reflects the breakdown of specific subsets of corticocortical projections. Although the origin of this phenomenon is still unclear, genetic determinants may play a crucial role in some phenotypes of pathologically confirmed atypical AD. Consistent with this possibility, specific motor disorders including paraplegia, myoclonus, and early seizures as well as early predominantly behavioral features have been reported in familial early-onset AD due to amyloid precursor protein and presenilin gene mutations (Aikawa et al., 1985; Crook et al., 1998; Heston et al., 1966; Kennedy et al., 2001; Lüers, 1945; van Bogaert et al., 1940). The variants of AD described in this review should thus be considered not only as rare exceptions of the usual pathogenetic course but also as representative examples of a corticalcircuit-based approach to explore the mechanisms giving rise to its neuropsychological expression (Price, 2000). The currently available data support a continuum between typical and atypical AD cases and indicate that it would be possible to establish links between specific clinical AD presentations and degeneration of specific forward and feedback projections of the long corticocortical pathways. This perspective stresses the necessity for detailed and accurate cognitive, behavioral, psychopathological, and functional testing, including premorbid cognitive or personality features that are neglected aspects in most studies, as well as for meticulous neuropathologic assessment of dementing syndromes with extensive sampling of the cerebral cortex.

Acknowledgments This work was supported by grant from Lausanne University School of Medicine (to AvG), NIH grants AG02219 and AG05138 (to PRH), and the Jérôme Tissières Foundation (to PG).

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