Brain, Vol. 123, No. 3, 484-498,
March 2000
© 2000 Oxford University Press
Invited review |
Atypical and typical presentations of Alzheimer's disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases
1 University Neurology Unit, 2 The Cambridge Brain Bank Laboratory, Department of Histopathology, Addenbrooke's Hospital, 3 MRC Cognition and Brain Sciences Unit and 4 University Department of Pathology, Cambridge, UK
Correspondence to:
John R. Hodges, MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 2EF, UK E-mail: John.hodges{at}mrc-cbu.ac.uk
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Abstract |
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There has been increasing awareness that some slowly progressive focal cortical syndromes can be the presenting features of Alzheimer's disease, but pathological evidence has been sparse. This clinico-pathological series presents our experience with pathologically proven atypical as well as typical Alzheimer's disease presentations. We report and compare four patterns of presentation: a typical pattern with initial amnesic syndrome (n = 4 cases), progressive visual dysfunction (n = 1), progressive biparietal syndrome (n = 2) and progressive aphasia (n = 6). The aphasic presentations include both fluent and non-fluent aphasic syndromes. The neuropsychological profiles and neuroimaging clearly reflect the presenting clinical features, and show a close relationship to the distribution of pathology in these cases. Of note was the sparing of medial temporal structures (hippocampus and/or entorhinal cortex) in several aphasic cases and the severe occipito-parietal involvement in those with prominent visuospatial disorders at presentation. Our data demonstrate the wide spectrum of Alzheimer's disease presentations. The recognition of atypical presentations of Alzheimer's disease is important when attempting to make an early accurate pre-morbid diagnosis of neurodegenerative disease.
Alzheimer's disease; atypical presentations of Alzheimer's disease; progressive aphasia; posterior cortical atrophy
BA = Brodmann area
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Introduction |
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TopAbstractIntroductionPatients and methodsIllustrative casesDiscussionReferences |
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Alzheimer's disease is widely considered to be clinically homogeneous with a characteristic profile of neuropsychological deficits (McKhann et al., 1984
; Morris et al., 1989; Locascio et al., 1995). It is true that, using histological diagnosis as the gold standard, current research criteria (McKhann et al., 1984) are accurate in up to 90% of cases. Such criteria, however, are heavily weighted towards memory impairment as the central deficit and may, therefore, exclude atypical cases. A means for early accurate diagnosis is the aim of much research, as treatment interventions would be most likely to benefit patients in the earliest disease stages (Hodges, 1998). It is important, therefore, to identify the complete spectrum of clinical presentations of histologically proven Alzheimer's disease.
In group studies of patients with Alzheimer's disease, the most prominent and earliest neuropsychological impairment is of anterograde episodic memory (Grady et al., 1988; Welsh et al., 1991; Greene et al., 1996b). After the prodromal phase of amnesic problems, which may last a number of years (Linn et al., 1995), inevitable progression of the disease leads to involvement of attentional and executive processes, semantic memory, praxis and visuoperceptual abilities (Grady et al., 1988; Mendez et al., 1990; Greene et al., 1995; Hodges and Patterson, 1995; Locascio et al., 1995; Binetti et al., 1998; Perry and Hodges, 1999). This pattern of neuropsychological changes reflects the current view regarding the progression of pathology which is thought to involve initially the transentorhinal (or perirhinal) region before spreading into the hippocampal complex proper in the medial temporal lobe structures and thereafter the temporal lobes and basal forebrain (Hyman et al., 1986, 1990; Braak and Braak, 1991; Van Hoesen et al., 1991; Van Hoesen, 1997). It is clear from neuropathological studies that while this classic staging may fit the majority of cases, a significant proportion do not adhere to this orderly pattern (Gertz et al., 1998). This conclusion raises the further question of just how commonly patients with Alzheimer's disease might have atypical presentations with prominent early deficits other than episodic memory.
Over the past 15 years, there has been increasing awareness of slowly progressive focal cortical syndromes in which memory impairment is not a prominent feature and other symptoms predominate. These include progressive aphasia (Chawluk et al., 1986; Snowden et al., 1989; Hodges et al., 1992) and visuoperceptual or spatial syndromes (Cogan, 1985; De Renzi, 1986; Benson et al., 1988; Freedman et al., 1991; Ross et al., 1996). Whether these cases are due to Alzheimer's disease pathology or to other, non-Alzheimer pathology such as spongiform change with or without Pick bodies, is often unconfirmed and therefore controversial. Benson and colleagues, for example, suggested that in their five cases, of what was named posterior cortical atrophy, the long progressive decline and relative preservation of memory argued against Alzheimer's disease; but lacking pathological evidence, this view remains speculative (Benson et al., 1988). Similarly, Chawluk and colleagues hypothesized that it was highly unlikely that Alzheimer's disease was the underlying cause of progressive aphasia in their patients, on the basis of the long course of the disease and sparing of memory, plus evidence from a biopsy of one of their original six cases (Chawluk et al., 1986). Since Chawluk and colleagues' report in 1986, it has become clear that although the language syndrome in progressive aphasia is heterogeneous, two main patterns can be identified: progressive non-fluent aphasia and progressive fluent aphasia. In the latter syndrome, the linguistic deficit reflects a breakdown in the conceptual knowledge base for language comprehension and production as well as other cognitive capacities requiring semantic memory. This has led to adoption of the term semantic dementia to describe this syndrome (Snowden et al., 1989; Hodges et al., 1992; Hodges and Patterson, 1996).
Despite definitive documentation of non-Alzheimer's disease pathology in some cases within this spectrum of disorders, it is also now clear that pathologically proven Alzheimer's disease can present with a focal cortical syndrome. Cases with progressive occipitoparietal atrophy, causing either visual agnosia and alexia, a biparietal syndrome with symptoms of Balint's syndrome (Kobayashi et al., 1987; Hof et al., 1989, 1990; Berthier et al., 1991; Levine et al., 1993; Victoroff et al., 1994; Ross et al., 1996) or a right parietal syndrome (Crystal et al., 1982; Ball et al., 1993), have revealed clear Alzheimer's disease pathology at post-mortem. Review of the literature concerning the pathological basis of progressive aphasia also indicates that, while the majority of cases have had non-Alzheimer's disease pathology, there are at least four well documented cases of progressive aphasia with Alzheimer's disease pathology (Pogacar and Williams, 1984; Green et al., 1990; Benson and Zaias, 1991; Greene et al., 1996a); these included both fluent and non-fluent aphasic syndromes.
To our knowledge, there have only been three longitudinal clinico-pathological series examining the neuropsychological patterns in Alzheimer's disease. Neary and colleagues prospectively studied 24 patients with presenile dementia who had a temporal or frontal cerebral biopsy, which revealed Alzheimer's disease pathology in 75% of the cases (Neary et al., 1986). Neuropsychologically, the Alzheimer's disease patients presented with selective amnesia in two cases, amnesia, anomia and visuoperceptual impairment in 11 patients, amnesia and severe visuoperceptual impairment in three patients, and amnesia, dyspraxia and executive difficulties in two patients. These findings clearly demonstrate heterogeneous patterns of cognitive decline in Alzheimer's disease. In a retrospective study, Price and colleagues documented the neuropsychological profiles of 20 patients with autopsy-proven Alzheimer's disease (Price et al., 1993). Again there was heterogeneity within the group regarding the presenting cognitive syndrome. Although episodic memory was affected in all patients, the memory disorder was mild by comparison with language disorders in two patients and with visuospatial problems in two further cases. Interestingly, in the majority of cases, the aphasia was anomic, with late effects on language comprehension. Non-fluent aphasia was not observed, even in the last stages of the disease.
In the most recent study, Kanne and colleagues investigated the relationship between initial presentation and pathology in 41 patients (Kanne et al., 1998). Having established three principal cognitive factors corresponding to executive, memory and visuospatial functions, in a larger clinical cohort they then documented a significant correlation between these factors and the relative burden of pathology in frontal, temporal and parietal regions, respectively. This indicates that, as one would predict, the heterogeneity in earliest clinical presentation relates to the underlying distribution of Alzheimer's disease pathology. It should be noted that the patients studied by Kanne et al. died on average 5 years after their last cognitive assessment, and that their neuropyschological evaluation was limited and did not, for example, include a comprehensive language assessment.
Despite the accruing evidence of atypical presentations of Alzheimer's disease, a number of issues remain unresolved. For instance, why do some areas not usually affected early in the disease become affected preferentially in specific patients? What is the range of atypical presentations particularly with respect to the profile of aphasic and visual symptoms? How precise is the correspondence between clinical phenotype, neuroradiological findings and distribution of pathological changes? Are atypical cases under-diagnosed, or diagnosed later than typical presentations? Some authors have argued that patients with progressive focal atypical cortical syndromes due to Alzheimer's disease are impaired additionally in episodic memory and general intellectual function at the time of initial diagnosis, and that the differentiation between Alzheimer's disease and other progressive focal cortical syndromes is not a clinical dilemma (De Renzi, 1986).
In this study, we attempt to address some of these questions. We present the neuropsychological profiles, neuroimaging and neuropathological data of a group of nine patients with pathologically proven Alzheimer's disease who presented with atypical patterns of deficit. We contrast them with four pathologically proven Alzheimer's disease patients with classical initial memory dysfunction. To our knowledge, this is the first pathologically proven cohort of atypical Alzheimer's disease patients investigated with both a comprehensive battery of neuropsychological tests and parallel neuroimaging.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsIllustrative casesDiscussionReferences |
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Patients
The 13 patients, who all presented to the Memory Clinic at Addenbrooke's Hospital, Cambridge, between 1990 and 1995, were all fully investigated with a standard neurological examination and blood investigations. They underwent, as far as possible, extensive neuropsychological examination, with longitudinal follow-up in many cases, and neuroimaging. All had post-mortem examinations performed by the same neuropathologist (J.H.X.). Table 1
provides demographic details. The four patients with typical Alzheimer's disease represent the first four cases who have come to autopsy of the cohort of 52 cases followed longitudinally by our group (Hodges and Patterson, 1995). The nine atypical cases all came to autopsy over the period 1994–1997 and represent 50% of cases seen in Cambridge with a focal dementia syndrome who have had autopsies (the remainder had non-Alzheimer forms of dementia).
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Neuropsychological tests
The neuropsychological tests detailed below were administered to all of the patients where possible. Table 2
displays the results of neuropsychological assessment for all patients except C.M.
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The Mini Mental State Examination (Folstein et al., 1975
) was used as a general measurement. Memory tests included: (i) digit span; (ii) logical memory [immediate and delayed story recall from the Wechsler Memory Scale—Revised (Wechsler, 1987)]; (iii) recognition memory test for words and faces, 50 item versions (Warrington, 1984); and (iv) recall of the Rey Complex Figure.
Perceptual tests included: (i) fragmented letters, dot counting and cube analysis subtests from the Visual Object and Space Perceptual Battery (Warrington and James, 1991); (ii) object matching (unusual views test) (Humphreys and Riddoch, 1984); and (iii) Benton's Judgement of Line Orientation Test (Benton et al., 1983). Language tests included: (i) letter fluency for words beginning with F, A and S; (ii) reading of 126 pairs of regular and exception words varying in frequency (Patterson and Hodges, 1992); (iii) writing or oral spelling of 36 words (Patterson and Hodges, 1992); and (iv) Test for the Reception of Grammar (Bishop, 1989). The semantic tests included: (i) category fluency for three categories each of living and man made items; (ii) picture naming and word–picture comprehension tests (n = 48 for each) from the semantic battery of Hodges and Patterson (Hodges and Patterson, 1995); and (iii) pyramids and palm trees test [three picture version (Howard and Patterson, 1992)].
Neuroimaging
Imaging for all patients was carried out in the Department of Radiology, Addenbrooke's Hospital, Cambridge. CT and MRI scans were reported by senior neuroradiologists and SPECT (single photon emission computed tomography) scans by a nuclear medicine consultant. Eleven patients had a CT scan of the brain, six had MRI of the brain, with 3D set acquisition in the coronal plane using an SPGR (spin gradient echo) T1-weighted sequence, and a T2-weighted axial sequence, and 12 (i.e. all except one case) had a 99mTc-HMPAO SPECT scan.
Neuropathology
All 13 cases were examined neuropathologically after death in the Pathology Department, University of Cambridge by a senior neuropathologist (J.H.X.). J.H.X. was blinded to the clinical diagnosis, although he was aware that the cases were those of possible Alzheimer's disease patients. At the time of autopsy, the brain was weighed, and the brainstem and attached cerebellum were separated from the cerebral hemispheres by a horizontal incision at the diencephalo-mesencephalic junction. The cerebral hemispheres were separated by an incision through the length of the corpus callosum. The left cerebral hemisphere and the attached half of the midbrain were immersed in formol saline. The left half of the brainstem and the right cerebellar hemisphere were fixed in formalin with the left cerebral hemisphere. The right cerebral hemisphere, right hemi-brainstem and left cerebellar hemisphere were then prepared for rapid freezing, but only after sampling of the right cerebral cortex. Small blocks of fresh tissue from the cortex of the right cerebral hemisphere were removed from Brodmann areas (BAs) 8, 24, 44, 45, 47, 20, 21, 22, 41, 42, 37 and 40; these were put into cassettes and fixed in formol saline. They were used to provide neuroanatomical data for the non-dominant hemisphere to complement the morphometric studies on the left hemisphere (see below). Horizontal slices through the left half of the brainstem and a vertical slice through the right cerebellar hemisphere were also frozen rapidly. These frozen slices of brain were stored at –70°C.
After fixation, the left cerebral hemisphere, left hemi-brainstem and the right cerebellar hemisphere were photographed and subsequently cut into slices 0.5 cm (cerebrum) and 0.3 cm (brainstem and cerebellum) thick. The slices were photographed.
After neuropathological examination, blocks of fixed tissue were sampled according to the CERAD (Consortium to Establish a Registry of Alzheimer's Disease) protocol (Mirra et al., 1991). Additional blocks were taken from the BAs noted above, from lateral and medial occipital cortex to allow application of Braak and Braak's staging for Alzheimer-type pathology (Braak and Braak, 1991) and from the basal ganglia at the level of the subthalamic nucleus, including putamen, globus pallidus, dorsal thalamus, subthalamic nucleus and insular cortex. Apart from routine haematoxylin and eosin staining on all blocks, immunohistochemical techniques were used for the assessment of neurodegenerative changes. The immunohistochemical panel of antibodies included those against abnormal tau, A4 ß-peptide and ubiquitin, which were used to assess the presence and extent of neurofibrillary inclusions, neuropil threads, Pick bodies, cortical Lewy bodies, total (pre-amyloid and amyloid) plaque load, neuritic plaques and cerebral amyloid angiopathy. Nerve cell loss, spongiosis and gliosis were assessed on the haematoxylin and eosin and GFAP (glial fibrillary acidic protein) preparations. All these parameters were assessed semi-quantitatively according to CERAD criteria.
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Illustrative cases |
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TopAbstractIntroductionPatients and methodsIllustrative casesDiscussionReferences |
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Progressive visual dysfunction
A.P.
This 69-year-old retired medical secretary presented with a 4 year history of poor vision. She was referred initially to an ophthalmologist who found no retinal or ocular problems to account for her extreme difficulty in reading. At this stage, A.P. was living alone without evidence of memory or other cognitive deficits. One year before assessment by our clinic, memory problems developed although perceptual problems still predominated. She was unable to read or watch television. She had to dress herself by feel and had difficulty using a knife and fork. She continued to enjoy listening to the radio although other pastimes were no longer possible. She had suffered one episode of formed visual hallucinations when she saw swarms of insects inside her house. Her mobility was affected by her visual problems and she had sustained a fractured neck of femur after a fall 3 years before.
On examination, her visual fields were severely restricted and visual acuity was 6/18 bilaterally. Fundoscopy revealed normal discs, lenses and maculae. She had normal pupillary reflexes and her eye movements appeared full. She was partially orientated. Her severe visual disorientation and perceptual deficits meant that only verbal formal neuropsychological tests were administered. On general intellectual tasks, A.P. achieved high average scores on comprehension and vocabulary. She obtained low average scores on information and digit span, and mental arithmetic was very poor. Free recall of a prose passage was severely impaired, as was verbal paired associate learning, and she had a very reduced verbal fluency score. She was not willing to undergo more extensive neuropsychological assessment, but the results obtained demonstrate impairments of attention and memory in addition to her visual deficit. A SPECT scan demonstrated marked bilateral reduction in occipital lobe perfusion, and a CT scan showed an enlarged calcarine fissure with posterior brain atrophy. Continued deterioration meant that A.P. was soon unable to live independently and moved into a nursing home; she died 2 years after presentation to our clinic. Neuropathological examination after death demonstrated established Alzheimer's disease (CERAD definite, Braak stage VI) with particularly severe involvement of the occipital visual cortex.
In summary, this patient presented with primary visual malfunction followed by memory impairment and more global cognitive decline. The pathological diagnosis was of visual variant Alzheimer's disease.
Progressive biparietal syndrome
J.M.
A 63-year-old right-handed ex-lecturer (first reported as case 3 in Ross et al., 1996) complained in 1987 of problems in performing manual tasks and an inability to write. He had particular difficulties tying his shoelaces, dressing and performing bimanual tasks such as washing up, peeling vegetables or gardening. He was only able to sign his name and was otherwise unable to write. At this stage, his memory was reported as normal by relatives and there was no personality change. Over the next 5 years, J.M. progressed from the initial biparietal syndrome to a more global dementia. By 1992, when he first underwent neuropsychological assessment, he had evidence of generalized intellectual impairment. He was extremely impaired on all visuospatial tasks and grossly apraxic. Language assessment demonstrated impairment of syntactic comprehension as well as semantic knowledge. Oral spelling was also severely impaired (only 1/36 items correct) which, together with the almost total inability to write, indicated both a central and a peripheral agraphia. He also performed poorly on tests of phonological competence including a rhyme production task and phoneme blending. SPECT scanning revealed biparietal reduction in perfusion, and MRI showed gross posterior cortical atrophy especially of the left parietal and temporal lobes (Fig. 1) (see Ross et al., 1996). J.M. continued to deteriorate in language and reading tasks and died aged 73. Neuropathological examination confirmed the pre-morbid diagnosis of Alzheimer's disease (CERAD definite, Braak stage VI) with a single small incidental microscopic infarct in the hippocampus. There was moderate cortical atrophy with discernible emphasis on the superior parietal lobules. Microscopically, neuronal loss was most severe in BA 7.
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In summary, this case presented atypically with severe difficulties in writing, poor hand coordination and impaired visuospatial skills. There was biparietal hypoperfusion on SPECT, and MRI revealed left parietal and temporal atrophy. Neuropathologically, the parietal lobes, particularly superiorly, were most affected.
Progressive aphasia syndromes
Non-fluent aphasia: P.G.
This 74-year-old right-handed ex-secretary (reported as case 1 in Hodges and Patterson, 1996; also Croot et al., 1998) presented in 1991 with a 2 year history of progressive loss of speech fluency. She complained of an inability to converse due to hesitancy, word finding difficulties and speech distortion. Her reading, writing and memory were unaffected and she was living independently and able to drive. Spontaneous speech was poorly articulated, with abnormal prosody and frequent phonemic errors, mild word finding difficulty and abnormally short phrase length. Comprehension of single words was normal, but she had difficulty understanding syntactically complex sentences. Repetition of short words was good, but the requirement to repeat multisyllabic words and phrases produced frank phonological errors. Visuospatial abilities were very well preserved.
Neuroimaging revealed minimal left cerebral atrophy with widening of the sylvian fissure on MRI and a normal SPECT image. Over the subsequent 3 years, P.G.'s language abilities continued to decline dramatically, in stark contrast to no deterioration in general cognitive abilities or in her ability to live independently. By this time, she had almost no spontaneous speech; although she was sometimes able to give appropriate 1–2 word answers to direct questioning, many of her utterances were incomprehensible. It is notable that at this stage her visuospatial abilities and non-verbal memory remained normal. Comprehension also became severely impaired and she had difficulty understanding even single words. A repeat MRI scan of her brain revealed a more obvious degree of generalized atrophy involving both frontal lobes with more marked widening of the left sylvian fissure (Fig. 2) (see Hodges and Patterson, 1996).
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The clinical diagnosis was progressive non-fluent aphasia. We confidently predicted that this syndrome was unlikely to be due to Alzheimer's disease (Hodges and Patterson, 1996
; Croot et al., 1998) as P.G.'s language deficit was the only impairment for 3 years, with little change in her general cognitive abilities or activities of daily living over this time. She died aged 78, four years after initial presentation. Neuropathological examination, contrary to pre-morbid expectations, demonstrated features of Alzheimer's disease (Braak stage IV, CERAD probable Alzheimer's disease), but with unusual features: the entorhinal cortex was relatively spared, with only a few tangles in the entorhinal cortex proper; there were, however, moderate numbers of tangles in CA1 and the transentorhinal cortex. Well defined plaques were not a feature of this case. In summary, this case presented with a non-fluent aphasic pattern, including difficulties in communicating due to hesitant, distorted speech with syntactic abnormalities and some word finding difficulties. MRI demonstrated some mild left cerebral atrophy around the perisylvian region without obvious hippocampal atrophy. Pathologically, there was relative sparing of the medial temporal lobe structures and severe involvement of superiolateral temporal lobe areas.
Mixed aphasia: P.B.
This 65-year-old right-handed man first sought medical advice in 1984 because of speech difficulties that had progressed slowly since his retirement from being a senior business manager in 1981. He complained of difficulty in finding the right words, in putting words in the correct order and in following conversations and books. His non-verbal memory and practical skills were very well preserved, and he continued to enjoy driving, cycling, fishing and golf. When he was first assessed by us in 1990, P.B. had a severe impairment in naming and comprehension, and disruption to semantic memory. He also made some phonological errors and stuttered in spontaneous speech. His oral reading of single words showed a striking pattern of surface alexia, which has been reported in two publications (reading performance at presentation, Patterson and Hodges, 1992; longitudinal decline in reading, Patterson et al., 1996); his writing also showed clear surface dysgraphia. He had no visuospatial deficits and, although his non-verbal reasoning was outside the normal range, it was relatively well preserved 6 years after initial presentation. The clinical diagnosis was of progressive aphasia (mixed type). He had a family history of dementia in that his mother had been demented in her late life. CT scans performed in 1984 and 1988 were normal, but a SPECT scan in 1991 revealed some left temporoparietal hypoperfusion.
For some time, P.B. maintained an impressive ability to find his own way around by either bicycle or car; but from 1991 his other abilities (as well as his willingness to be tested) gradually deteriorated. Language impairment was, however, always the prominent feature. By 1994, he had become virtually mute and required institutionalized care. He died in 1995.
Pathological examination revealed severe atrophy of the left temporal lobe and mild generalized cerebral atrophy (Fig. 3). Microscopically, there was extensive Alzheimer-type pathology throughout the cerebral cortex, particularly in the temporal association cortex and perisylvian cortex. There was marked cell loss in the temporal cortex and no evidence of Pick's pathology. The lesions were typical of Alzheimer's disease but the distribution was very atypical. There were a few isolated Lewy bodies in the cortex with insignificant brainstem involvement. The pathological diagnosis was Alzheimer's disease (Braak Stage V, CERAD definite) with incidental Lewy body disease.
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This case illustrates a mixed aphasic presentation with initial problems in both semantic aspects of language (naming and word comprehension) and syntactic features (impairments both in expressive and receptive grammar), plus some phonological errors in spontaneous speech. Neuropathologically, there was a highly atypical distribution of Alzheimer's disease-type pathology, principally involving the temporal poles.
Fluent aphasia: O.M.
This 67-year-old lady presented with a 2–3 year history of insidious decline in language abilities affecting both production and comprehension. She more recently had developed difficulties using objects and preparing meals. At presentation, her day-to-day memory was poor. On neuropsychological assessment, her language skills were globally disrupted, with impairments in receptive as well as expressive vocabulary. She had difficulties understanding all but the most common words and made numerous errors on a sentence comprehension task. Her speech was fluent but with a very limited vocabulary, and she was unable to perform on a test of word definitions, or to name pictures of common objects. She made some errors in repetition, but this simple aspect of language was relatively well preserved. Although in the context of such profound language impairments it was difficult to assess other cognitive functions, there was evidence of some impairment in non-verbal skills. For instance, on Ravens Coloured Matrices, a relatively easy test of non-verbal reasoning, she performed in the low average range. She also scored outside normal limits on a short, easy test of recognition memory for faces (17/25). Although her dot counting and cube analysis scores were normal, she did show some impairment of perceptual analysis of incomplete drawings and fragmented letters. Thus the patient had a severe progressive fluent aphasia and semantic impairment with evidence of a more general deterioration of memory and visuoperceptual skills. In view of these non-semantic deficits, we had not characterized her as a case of semantic dementia, but instead favoured a diagnosis of probable Alzheimer's disease with profound aphasia.
MRI showed very striking left temporal atrophy. A SPECT scan demonstrated bilateral reduction of uptake in the frontotemporal regions, which were more marked on the left.
The pathological diagnosis was of CERAD definite, Braak stage V Alzheimer's disease. There was moderate cerebral gyral atrophy with emphasis on the frontal lobe (pole and superomedial portions), temporal pole and medial temporal lobes. Microscopically, there was no asymmetry in the cerebral cortical Alzheimer-type pathology between the right and left hemispheres, and in the left hemisphere there was no apparent difference in the severity of Alzheimer-type change between primary language areas and association cortex. There was some evidence of incidental meningeal cerebral amyloid angiopathy.
In summary, this case presented with fluent progressive aphasia, characterized by severe anomia and word comprehension problems. There was involvement of other cognitive domains at presentation, especially non-verbal memory, and these showed a fairly rapid deterioration. Structural imaging demonstrated left temporal atrophy in this and the two other fluent cases, and functional imaging showed bitemporal hypoperfusion in all cases, with more extensive cortical involvement in two patients. Pathologically, the temporal lobes were severely affected.
Illustrative typical presentation of Alzheimer's disease
G.W.
This 69-year-old man, a retired antiques dealer, was referred to the Memory Clinic in July 1992 with a 12 month history of episodic memory problems. Both the patient and his wife described his difficulty in remembering recent events such as conversations, television programmes and family news. He had become repetitive but was able to continue to enjoy his hobbies (writing poetry and articles), collecting antiques and followed current events. Language and spatial abilities were intact. He had a medical history of ischaemic heart disease. A SPECT scan was unremarkable. On initial presentation, his neuropsychological profile demonstrated only a mild amnesic syndrome which was particularly marked for non-verbal material as evidenced by his poor performance on recall of the Rey figure (Table 3). Over the next 2 years, his amnesia worsened as measured by logical memory delayed recall, but his semantic memory, language, attention, visuospatial and perceptual abilities all remained intact (Table 3). He died of acute cardiac failure in 1996. The pathological picture was one of relatively early Alzheimer's disease (Braak stage IV). The hippocampus and parahippocampal gyrus showed numerous neurofibrillary tangles in neurons from the CA1 pyramidal cell layer, and there were numerous tangles in the entorhinal cortical neurons. There was also some involvement of BA 38 (the temporal pole).
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Discussion |
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TopAbstractIntroductionPatients and methodsIllustrative casesDiscussionReferences |
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It is clear from this study that pathologically proven Alzheimer's disease can present with a range of cognitive symptoms. Although there may be more, we have identified three main patterns: posterior cortical atrophy with either major visual deficits or a predominantly biparietal syndrome; progressive aphasia which may be fluent, non-fluent or mixed; and the typical amnesic prodrome. All of these are followed by global impairment. We will now discuss each of these patterns.
Typical cases
The clinical presentation of our four typical patients supports the current view of both the standard initial neuropsychological profile and the nature of its progression. Episodic memory complaints were the primary feature, with subsequent involvement of attentional, language, semantic and visuospatial abilities in most cases. Biparietal hypoperfusion on SPECT scanning was seen in some, but not all, of the typical cases, as is well described in the literature (Testa et al., 1988; Holman et al., 1992; Greene et al., 1996c). Brain CT scans (without temporal orientated alignment) were normal or demonstrated mild generalized atrophy (Table 1
).
Our pathological data documenting the distribution of disease in the typical cases are concordant with descriptions of Alzheimer's disease pathology throughout the literature, namely the early and severe involvement of the transentorhinal region, the hippocampal complex spreading to the temporal neocortex, and association neocortex affecting particularly the frontal and parietal association areas (Table 4) (Hyman et al., 1990; Braak and Braak, 1991; Van Hoesen et al., 1991; Van Hoesen, 1997).
Of particular interest is the patient (G.W.) who died at an early stage of the disease. This patient's only significant abnormality at presentation was amnesia. Longitudinal neuropyschological data showed a hint of decline in category fluency but an impressively stable performance (and sometimes even improvement, perhaps attributable to familiarity with the tests) across other cognitive domains (Table 3). Of note was his poor non-verbal and verbal recall, as measured by reproduction of the Complex Rey Figure after a delay and by logical memory. He exhibited a relatively better performance on the recognition memory test for faces and words (Table 3). Pathologically, disease was limited to the temporal lobe with severe involvement of the entorhinal cortical neurons and hippocampus, which would explain the neuropsychological profile of poor recall (Aggleton and Shaw, 1996). Preservation of recognition memory would not be predicted with the marked involvement of the perirhinal cortex (Suzuki, 1996); but G.W.'s recognition memory performance was only relatively preserved, not flawless and we suggest that his relatively good scores may be due in part to insensitivity of the tests.
Progressive aphasic cases
Mesulam argued that primary progressive aphasia represents a distinct syndrome which can be distinguished from the aphasic presentation of Alzheimer's disease by the clinical profile, and suggested that this syndrome had a high likelihood of being associated with a non-Alzheimer's disease degenerative process (Mesulam, 1987). In differentiating the two syndromes, he offered preserved insight, social skills and episodic memory as features of primary progressive aphasia, in contrast to the aphasia secondary to Alzheimer's disease, which was associated with early loss of insight and rapid deterioration in memory and other cognitive functions. Several of our patients also had a long history of aphasia prior to general cognitive decline. One patient, P.G., had a non-fluent progressive aphasia without other cognitive difficulties which persisted for 5 years. Another, P.B., with a more mixed aphasic syndrome, also had normal episodic memory for at least 6 years as judged by performance on non-verbal tasks, thus fulfilling even very strict criteria for a diagnosis of primary progressive aphasia (Chawluk et al., 1986). All other aphasic cases had a definite informant-confirmed history of a selective aphasic syndrome as the original symptom, followed by a phase of more rapid progression with severe memory and visuospatial problems. In these cases, a diagnosis of Alzheimer's disease was suspected at presentation despite the prominent aphasic component.
The range of language disorders in our cases is worthy of comment. Two patients presented with non-fluent, agrammatic aphasia with relative preservation of single-word comprehension. Only three previous cases of non-fluent aphasia in Alzheimer's disease have been reported in the literature (Pogacar and Williams, 1984; Green et al., 1990; Benson and Zaias, 1991). Three of our cases presented with fluent aphasia with semantic impairments leading to anomia and impaired comprehension. O.M. had severe involvement of semantic memory (Table 2), while C.T. and C.M. had a more anomic presentation. The pattern of language impairments in these patients is similar to the pattern seen later in the clinical course in typical Alzheimer's disease (Price et al., 1993) with severe anomia and comprehension becoming progressively impaired. It is interesting to note, however, that although these patients had impairments in semantic memory, they also had evidence of impairments in episodic and working memory, and deficits in visuospatial function, such that none met criteria for semantic dementia (Hodges et al., 1992). Moreover, a meta-analysis of 13 cases of semantic dementia with post-mortem pathology revealed non-Alzheimer's disease pathology in all cases (Hodges et al., 1998). It seems, therefore, that although both fluent and non-fluent aphasia can be the initial presentation of Alzheimer's disease, cases rarely, if ever, have the characteristics of semantic dementia. One patient, P.B., had a more mixed presentation, with marked semantic anomia and a deficit in single word comprehension, as well as phonological errors and grammatical problems.
On structural imaging, five of the six progressive aphasia cases demonstrated striking left temporal or more general asymmetrical left hemispheric atrophy, while on functional imaging, temporal hypoperfusion (with more extensive cortical hypoperfusion) was seen in four cases.
Pathologically, there was widespread involvement of the temporal lobe (Table 4A and B), with all patients having severe involvement of the temporal neocortex. Interestingly, in the two non-fluent aphasia cases (P.G. and A.S.), there was relative sparing of the hippocampus and entorhinal cortex with regard to neuronal loss and plaque formation. These areas, as mentioned above, are usually affected early and severely in the disease. P.B. also had a highly atypical distribution of pathology with severe anterior temporal atrophy. The fluent cases (O.M., C.T. and C.M.) had severe involvement of the medial temporal lobe and temporal neocortex. Thus the spectrum of language impairments of these atypical Alzheimer's disease patients is wide and suggests that both non-fluent and fluent aphasic presentations are more common than previously recognized as initial features of Alzheimer's disease. Occasionally, the patients who fulfil stringent criteria for primary progressive aphasia and language impairment may remain isolated for many years.
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Posterior cortical cases
The posterior cortical cases in the literature with progressive occipitoparietal atrophy have presented with either visual agnosias (alexia, achromatopsia and aperceptual object agnosia), features of Balint's syndrome (optic ataxia, visual disorientation and simultanagnosia) or apraxic disorders (Cogan, 1985
; De Renzi, 1986; Benson et al., 1988; Berthier et al., 1991; Freedman et al., 1991; Victoroff et al., 1994; Ross et al., 1996). Although these patients have been grouped together throughout the literature under the name posterior cortical atrophy (as termed by Benson et al., 1988), a more differentiated classification was suggested by Ross and colleagues (Ross et al., 1996). They noted that there were two broad groups of presentations reflecting the predominant site of pathology, namely either occipitotemporal or biparietal. Those with predominant occipitotemporal pathology [disrupting the ventral (`what') visual processing stream that is important for object, face and written word recognition (Ungerleider and Mishkin, 1982)] suffer from visual distortion, apperceptive object agnosia, topographical agnosia and alexia. The biparietal patients have predominant pathology in the region of the dorsal or `where' stream (which is important for object location, visually guided motor movements and motor planning) and suffer initial visuospatial problems, agraphia and dyspraxia, which may progress to Balint's syndrome, but with preserved visual fields, basic perceptual abilities, object recognition and reading. The initially sharp distinctions between these two presentations undoubtedly become less clear as the pathological process advances. The clinical presentations of our two progressive biparietal cases (J.M. and N.K.) were in keeping with the biparietal variant in this classification, with initial dyspraxic difficulties, poor visuospatial abilities and difficulty writing, progressing in the case of N.K. to simultanagnosia, but with preserved basic visual abilities. Although there was evidence of other cognitive impairments at the time of the first neuropsychological assessment, both J.M. and N.K. had a definite history of a selective biparietal syndrome at presentation. The finding of biparieto-occipital hypoperfusion on SPECT imaging in these patients also concurs with previous findings (Freedman et al., 1991; Pietrini et al., 1996) although these studies used [18F]fluorodeoxyglucose PET.
Primary visual failure appears to be even rarer than occipitotemporal or biparietal syndromes as a presenting feature of Alzheimer's disease, with only one previous pathologically proven case in the literature (Levine et al., 1993). This patient with the so-called visual variant of Alzheimer's disease was a 59-year-old man with initial problems in reading, identifying objects by sight and locating objects. Although visual acuity was normal and colour identification preserved, peripheral fields were constricted, contrast sensitivity was severely impaired and flicker fusion frequencies were depressed peripherally. He also developed widespread visuospatial abnormalities. Over a 12 year follow-up, his visual symptoms progressively worsened, and his memory and language abilities, which were mildly impaired at presentation, also deteriorated. Autopsy examination demonstrated marked atrophy of the parieto-occipital region and mild atrophy of the hippocampus. Microscopically, gliosis was more prominent posteriorly and neurofibrillary tangle density was greatest in the posterior cingulate cortex (area 23), the visual cortex (area 17) and association cortex (areas 18 and 20) compared with the frontal lobes. The percentage of plaques (with amyloid cores and neuritic change) was very high in the primary and association visual cortex, and very low in the frontal cortex (Levine et al., 1993). Our case, A.P., had a similar unusual presentation with impairment of basic perceptual abilities which was reflected by both her neuroimaging (a SPECT scan demonstrated bioccipital hypoperfusion, and a CT scan showed posterior cortical atrophy), and the distribution of pathology, where there was particularly severe involvement of the primary visual cortex (Table 4B).
With regard to the dichotomy in posterior cortical cases suggested by Ross et al. (Ross et al., 1996), the case of Levine et al. was assigned to the occipitotemporal subgroup. With the additional and congruent evidence from our case A.P., we now suggest that there are three broad groups of posterior cortical presentations reflecting the cortical areas of most severe pathological involvement: occipitotemporal, biparietal and primary visual. The occipitotemporal and biparietal presentations may be more common than the primary visual variant, as these former syndromes would suggest early involvement of association cortex which is generally more susceptible to Alzheimer's disease pathology (Pearson et al., 1985). Primary visual cortex, if affected, is usually involved late in the disease process (Braak and Braak, 1991). The distribution of pathology in our cases supports this description, with severe parietal involvement in the biparietal cases and severe involvement of the primary visual cortex in the visual variant case (Table 4) (see also Hof et al., 1989, 1990, 1997; Hof and Bouras, 1991).
A recent review of the literature indicated that the vast majority of patients with this presentation who have been examined pathologically have histological features of Alzheimer's disease (Pantel and Schroder, 1996), suggesting that posterior cortical atrophy is primarily an atypical pattern of Alzheimer's disease presentation. These cases are different from typical Alzheimer's disease cases in both the time course and relative severity of perceptual and visuospatial impairments
General comments
This series of patients and the detailed neuropyschology, neuroimaging and neuropathology enable us to comment on the range of Alzheimer's disease presentations. All our patients presented with slowly progressive insidious initial symptoms. There were no differences between the typical and atypical presentations with respect to age at presentation (age range 58–84 years), length of illness (3–10 years) or in the length of time that the symptoms were reported before presentation at the memory clinic (1–5 years). By the time of neuropsychological assessment, most but not all of our patients, in both the atypical and typical groups, had evidence of a more global cognitive impairment (Table 2). Although the majority of patients had deficits in episodic memory, this was not a universal feature. Thus, the contention of both De Renzi and Mesulam that focal cortical syndromes without episodic memory impairment are not likely to be due to Alzheimer's disease (De Renzi, 1986; Mesulam, 1987) is largely substantiated; but our series draws attention to the fact that there are exceptions to this rule, and that occasional patients such as P.G. and P.B. do present without episodic memory impairment and go on to have pathologically proven Alzheimer's disease.
The absolute and relative frequencies of these different presentations of Alzheimer's disease are not known, and the specialist clinic-based nature of our sample makes it difficult to draw firm conclusions. We estimate that 180 patients with probable Alzheimer's disease were seen in our memory clinic from 1990 to 1995 and that 26 had atypical presentations (six visuospatial and perceptual and 20 aphasic), although only nine of these have come to post-mortem. An approximate estimate of atypical presentations is therefore 14%. In a previous clinico-pathological study, prominent aphasic and visuoperceptual presentations occurred in a fifth of the series of 20 consecutive post-mortem Alzheimer's disease cases (Price et al., 1993). Obviously selection bias may affect these results, but atypical presentations may be more common than previously described. The neuropsychological profiles and neuroimaging clearly reflect the clinical syndrome, and have a close relationship with the distribution of the pathology. The pathology of the typical and atypical cases was otherwise indistinguishable. Our series demonstrates that the underlying pathological process is difficult to predict pre-mortem: Alzheimer's disease should be clinically considered in a wide spectrum of focal cortical syndromes. Advances in the understanding of the molecular pathology in Alzheimer's disease and of specific neuronal sensitivities to the pathological process may, in the future, be able to explain this heterogeneity.
A point worthy of comment is the number of our atypical cases that had additional incidental pathology. Three atypical cases had incidental cerebral amyloid angiopathy ranging in severity from mild to moderate. Two cases had cortical Lewy bodies present. This raises the question of whether a functional or structural interaction between different disease processes may alter the involvement of different cortical areas. The proportion of cases with secondary pathology was similar to that found in other series (Mirra et al., 1991).
Our data clearly demonstrate the heterogeneity of Alzheimer's disease presentations. An obvious point, but one that is frequently overlooked, is that it is the distribution of pathology rather than the nature of the disease that is reflected in the clinical syndrome. The profiles of both atypical and typical presentations can appear focal in nature for many years before inevitable deterioration. Although certain distributions of pathology are typical in Alzheimer's disease, further characterization of the range and frequency of atypical presentations is important in order to improve the diagnosis of cortical dementia syndromes.
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Acknowledgments |
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We thank Naida Graham, Elaine Giles, Lindsay Stuart-Green, John Greene, Karen Croot and Sarah Ross for help with data collection. C.J.G. is supported by an MRC-link project grant to J.R.H. and Barbara Sahakian, and this research has been supported by MRC research project grants to J.R.H. and the Cambridge Brain Bank.
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