Focal cortical presentations of Alzheimer’s diseaseS. Alladi,1 J. Xuereb,2 T. Bak,1 P. Nestor,1 J. Knibb,1 K. Patterson3 and J. R. Hodges1,3

1Department of Clinical Neurosciences, 2Department of Histopathology, Addenbrooke’s Hospital, Hills Road, CambridgeCB2 2QQ and 3MRC ^ Cognition and brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 7EF, UK

Correspondence to: Professor John R. Hodges, MRC-Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge,CB2 7EF, UKE-mail: john.hodges@mrc-cbu.cam.ac.uk

To determine the frequency of Alzheimer’s disease (AD) pathology in patients presenting with progressivefocal cortical syndromes, notably posterior cortical atrophy (PCA), corticobasal syndrome (CBS), behaviouralvariant frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA) (or a mixed aphasia) andsemantic dementia (SD); and to compare the age of onset, evolution and prognosis in patients with focal corticalpresentations of AD versus more typical AD and those with non AD pathology. From a total of 200 patientswith comprehensive prospective clinical and pathological data we selected 120 :100 consecutive cases with focalcortical syndromes and 20 with clinically typical AD.Clinical files were reviewed blind to pathological diagnosis.Of the 100 patients with focal syndromes, 34 had AD as the primary pathological diagnosis with the followingdistribution across clinical subtypes: all 7 of the PCA (100%); 6 of 12 with CBS (50%); 2 of 28 with bvFTD (7.1%);12 of 26 with PNFA (44.1%); 5 of 7 with mixed aphasia (71.4%) and 2 of 20 with SD (10%). Of 20 with clinicallytypical AD, 19 had pathological AD. Age at both onset and death was greater in the atypical AD cases thanthose with non-AD pathology, although survival was equivalent. AD is a much commoner cause of focal corticalsyndromes than previously recognised, particularly in PCA, PNFA and CBS, but rarely causes SD or bvFTD.The focal syndrome may remain pure for many years. Patients with atypical AD tend to be older than thosewith non-AD pathology.

Keywords: Alzheimer’s disease; frontotemporal dementia; posterior cortical atrophy; corticobasal syndrome;progressive aphasia

Abbreviations: PCA=posterior cortical atrophy; CBS=corticobasal syndrome; PNFA=progressive non-fluent aphasia;FTD= frontotemporal dementia; FTLD= frontotemporal lobar degeneration; SD=semantic dementia

Received April 24, 2007. Revised July 3, 2007. Accepted August 10, 2007

IntroductionIn the absence of an accurate biomarker, the in vivodiagnosis of Alzheimer’s disease (AD), in common withother neurodegenerative disorders, rests very largely onthe characterization of the presenting cognitive profilesupported by neuroimaging (Nestor et al., 2004; Hodges,2006). AD is regarded as an essentially amnestic syndrome,whereas frontotemporal dementia (FTD) and corticobasalsyndrome (CBS) are the overarching labels for patientswith prominent behavioural deficits, aphasia or apraxia(Neary et al., 1998; Hodges and Miller, 2001; Hodges, 2006;Josephs et al., 2006a, b). The gold standard, however,remains neuropathological examination with the demon-stration of characteristic histological changes (Blennowet al., 2006). Comprehensive unbiased clinicopathologicalstudies are limited; but recent single, and multi-centre,surveys suggest that AD pathology—in cases presentingwith focal syndromes not involving prominent

amnesia—may be more common than previously recog-nised (Forman et al., 2006; Hodges, 2006; von Guntenet al., 2006). Moreover, amnesia may be prominent inpathologically verified FTD, which further clouds the issue(Graham et al., 2005).

In this study, typical AD refers to a pattern characterizedby early episodic memory loss followed by various com-binations of attention-executive, language and visuospatialimpairment, thought to reflect the spread of pathologyfrom the medial temporal lobe to other neocorticalareas (Brun and Englund, 1981; Braak and Braak, 1991;Van Hoesen, 1997; Price and Morris, 1999; Tiraboschiet al., 2004; Hodges, 2006). In contrast to this typicalprofile, there are a growing number of reports of atypicalfocal cortical presentations of AD. It is well established thatmost patients with a progressive disturbance of aspects ofvisuo-perceptual and spatial abilities, often referred to as

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posterior cortical atrophy, have underlying AD pathology(Benson et al., 1988; Hof et al., 1993; Mackenzie-Ross et al.,1996; Hof et al., 1997; Galton et al., 2000; von Guntenet al., 2006). In addition, it is now clear that a proportionof patients with progressive aphasia, of both fluent andnon-fluent type, can have AD as the primary pathology(Galton et al., 2000; Knibb et al., 2006; von Gunten et al.,2006). Recently, cases of CBS secondary to AD pathologyhave also been reported (Boeve et al., 1999; Lleo et al.,2002; Doran et al., 2003). The existence of a frontalpresentation is more controversial: patients with familialAD secondary to presenilin 1 mutations may have abehavioural onset (Portet et al., 2003; Mendez andMcMurtray, 2006) and there are isolated reports of sporadicAD resembling FTD (Johnson et al., 1999; von Guntenet al., 2006).Several issues remain unresolved. First, the frequency at

which focal dementias are secondary to AD pathology hasnot been established. An earlier case series from Cambridgereported on 13 patients with atypical and typical presenta-tions of AD from a total of 50 patients reaching autopsybut did not attempt to estimate the frequency at whichsuch syndromes are due to AD versus other pathologies(Galton et al., 2000). Second is the related question ofwhether focal dementia secondary to AD pathology differsfrom more typical AD, and from focal dementia due toother pathologies, in age of onset, disease duration andsurvival. FTD is usually associated with an early onset(Ratnavalli et al., 2002; Harvey et al., 2003) and a morerapid progression of disease than in AD (Raskovsky et al.,2005; Roberson et al., 2005). Third, do atypical AD casesremain focal for a short or long time? There has been anassumption that focal cortical syndromes that remainwithout significant memory impairment are unlikely to bedue to AD (Mesulam, 2001). The evolution of deficitsrequires further systematic study to address this importantquestion. In this large clinicopathological series from asingle centre, our aims were

(1) To determine the frequency of AD pathology inclinically typical AD versus progressive focalcortical syndromes, notably PCA, CBS, bvFTD, PNFAand SD.

(2) To compare the age of onset, evolution and pro-gnosis of patients with focal presentations and moretypical AD.

MethodsA total of 120 cases with a clinical diagnosis of either (i) typicalAD (n=20) or (ii) a focal cortical syndrome (n= 100) wereselected from 200 consecutive patients seen in the Memoryand Cognitive Disorders Clinic at Addenbrooke’s Hospital,Cambridge during the period 1990–2007 on whom detailedclinical, neuropsychological and post-mortem neuropathologicaldata were available. All 120 had been seen by the senior author(JH). Cases with an in vivo diagnosis of an alternative

neurodegenerative disease including Progressive SupranuclearPalsy, Huntington’s disease, Dementia with Lewy bodies, fronto-temporal dementia with motor neuron disease were excluded(n=50). Cases were also excluded if they had a non-degenerativediagnosis such as leukodystrophy, tumour or vascular pathology(n=20). A small number with inadequate clinical and neuro-psychological data were also excluded (n=10). Typical AD wasdiagnosed clinically in cases presenting with progressive andpredominant amnesia associated with other cognitive deficits.Focal cortical syndromes consisted of one of the followingsubtypes: progressive aphasia (non-fluent, fluent or mixed),progressive social-dysexecutive syndrome (behavioural variantFTD), posterior cortical atrophy (PCA) or corticobasal syndrome(CBS) (see later for criteria). All cases were classified on the basisof clinical features at first presentation. Over this time periodevery effort was made to enrol all patients with a focal corticalsyndrome into the brain donor programme, with a greater than90% success rate in brain retrieval post-mortem. Of the 100 focalcortical presentation cases, 30 were included in the earliercombined Cambridge–Sydney series (Hodges et al., 2003, 2004)essentially comprising all of the FTLD pathology cases who diedprior to 2002. More typical AD patients were enrolled as part ofa longitudinal study of cognition in AD undertaken on a cohortassessed between 1992 and 1995 (Greene et al., 1995; Hodges andPatterson, 1995; Greene et al., 1996; Greene and Hodges, 1996;Lambon-Ralph et al., 2003; Hodges et al., 2006). Pathologicaldiagnoses were all made by the same senior neuropathologist(JHX) who was blind to the clinical information. Althoughall patients underwent imaging, variable methods were usedduring the 15-year period which precluded an informativecomparison or interpretation of these results. The work wasapproved by the Cambridge Local Research Ethics Committee.Declarations of intent for post-mortem brain donation wereobtained from next of kin with subsequent consent for participa-tion after death.Clinic records of the 120 patients were reviewed by a researcher

blind to pathological diagnosis (SA), looking for a range ofcognitive, behavioural and neurological features either reported tobe present at onset or recorded at first presentation to the clinic(Table 1). Formal neuropsychological evaluation was conducted inall cases but a wide variety of tasks were used during the studyperiod. Assessments always included tests of episodic and semanticmemory, language, visuospatial and executive function. Follow-updata were evaluated for development of new cognitive deficits withtime. Since focal cortical syndrome patients did not have memoryloss as the first and predominant complaint, particular attentionwas paid to later development of amnesia.

Typical AD (McKhann et al., 1984, 2001)

(1) Memory loss as the first and predominant complaint.(2) Associated with at least one of the following—language

disorder (e.g. anomia), visuospatial impairment, attentionaldeficit or apraxia.

(3) Neuropsychological evaluation showing deficits in memoryand one another cognitive domain.

(4) Absence of early motor features.

Progressive aphasia (Mesulam et al., 2003; Knibb et al., 2006)

(1) The primary complaint, and the predominant featureon clinical assessment, was of gradual-onset languagedisturbance.

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(2) Activities of daily living were not affected by any deficit otherthan language disturbance (for example, episodic memoryimpairment or visuospatial impairment).

Progressive non-fluent aphasia (PNFA) was diagnosed in thepresence of effortful or distorted speech output with phonologicaland/or syntactic errors. Semantic dementia (SD) was defined asfluent speech, marked anomia, impaired word comprehension anddeficits in non-verbal semantic association tasks (Adlam et al.,2006). Patients with features not typical of non-fluent aphasia orsemantic dementia or with some features of each were consideredto have mixed aphasia.

Behavioural variant FTD (Neary et al., 1998; Rahman et al., 1999;Torralva et al., 2007)

(1) Change in personality and social behaviour as the firstand prominent symptom, notably apathy, reduced empathy,disinhibition, stereotypic behaviours, alterations in foodpreference and poor self-care.

(2) Diagnosis supported by the presence of dysexecutivesymptoms.

(3) Mild or later onset of memory loss.

Corticobasal syndrome (Litvan et al., 1997)

(1) Asymmetric apraxia and extrapyramidal syndrome (rigidity,bradykinesia, tremor).

(2) Cortical involvement suggested by alien limb phenomena,cortical sensory loss, hemisensory neglect, visuo-spatialdeficits or myoclonus.

Posterior cortical atrophy (McMonagle et al., 2006)

(1) Presentation with progressive visual or visuospatial impair-ment in the absence of ophthalmologic impairment.

(2) Evidence of complex visual disorder on examination:elements of Balint’s syndrome, visual agnosia, dressingapraxia or environmental disorientation.

(3) Proportionately less memory loss or reduced verbal fluency.

PCA patients were further divided into three broad sub-groups:

(1) Biparietal syndrome: apraxia, visuospatial problems, agraphia,Balint’s syndrome with preserved basic perceptual abilities,object recognition and reading.

(2) Occipitotemporal syndrome: alexia, apperceptive agnosiaand/or prosopagnosia.

(3) Visual variant: primary visual failure and impairment of basicperceptual abilities.

Pathological criteriaAutopsies were performed within 48 h, and the cerebrum wasbisected with the left half fixed in formalin and the right halffrozen. Tissue samples were taken from the frontal (Brodmannarea 9), temporal (area 20), parietal (area 39), occipital (areas17 and 18) and anterior cingulate (area 24) cortices, as well asfrom the hippocampus at the level of the lateral geniculatenucleus, amygdala, anterior and posterior basal ganglia (includingthe basal forebrain), thalamus, hypothalamus, midbrain, pons,medulla oblongata and cerebellum. Sections from all regions werestained for routine screening using currently recommendeddiagnostic protocols for AD (Mirra et al., 1997; Knibb et al.,2006). Non-AD pathologies were diagnosed according to standardcriteria used in previous clinicopathologic studies (Galton et al.,2000) as follows: frontotemporal lobar degeneration (FTLD) witheither tau-positive, tau-negative or ubiquitin-positive inclusions(FTLD-U), corticobasal degeneration (Hodges et al., 2004),dementia with Lewy bodies (McKeith et al., 1996; Knibb et al.,2006), progressive supranuclear palsy (Dickson, 1999; Knibbet al., 2006). Standard stains used included haematoxylin andeosin, Congo red, and the modified Bielschowsky silver stain.Immunohistochemistry was performed using antibodies againstubiquitin (Z0458 diluted 1:200; Dako, Glostrup, Denmark), tau(T5530 diluted 1:10 000; Sigma, St Louis, MO or mAb 11.57courtesy of Laboratory of Molecular Biology, Cambridge, UK),bA4 peptide (M872 DAKO UK, diluted 1:50 using ABC formatwith 5min pre-treatment in formic acid) and synuclein (18-0215,Zymed Laboratories, San Francisco, CA; or SA3400 diluted 1:200,Affiniti Research Products, Mamhead, Exeter, UK). A diagnosisof AD was made only in cases reaching Braak stage 4 or greater(Braak and Braak, 1991) and required the presence of bothneuritic plaques and neurofibrillary tangles with involvement ofthe isocortex.

ResultsClinically typical ADOf the 20 patients selected with clinical features typical forAD in life, 19 had pathological confirmation of AD and onehad a diagnosis of FTD with ubiquitin-positive inclusions[as previously reported (Graham et al., 2005)].

Focal cortical syndromesOf the 100 patients with focal cortical syndromes, AD wasthe primary pathological diagnosis in just over a third(34 of 100, 34%): of these 34, 19 presented with progressiveaphasia, two with behavioural variant FTD, 6 with CBSand 7 with PCA (Fig. 1). Specifically with regard to the53 patients with progressive aphasia, AD pathology was

Table 1 Definition of clinical features extracted frompatient files

1. Amnesia; forgetting events and/or conversations; repetitivequestioning and/or misplacing objects; deficit confirmed byepisodic memory tests.

2. Aphasia; word finding difficulty, reduced speech output,anomia, semantic or phonetic paraphasias, impaired compre-hension or repetition, dyslexia and dysgraphia.

3. Visuospatial deficits; spatial disorientation, impaired visuocon-struction or visuoperception on neuropsychological tests,hemineglect, Balint’s syndrome (optic ataxia, visual disorien-tation, simultagnosia), visual failure not due to primary oculardisease.

4. Apraxia; difficulty in performingmanual tasks in the absence ofsignificant sensory or motor deficits.

5. Dyscalculia, dysgraphia, alexia, as prominent features.6. Frontal behavioural symptoms; changes in personality and

social behavior, specifically apathy, disinhibition, stereotypicbehaviors, alterations in food preference, and poor self-care.

7. Other neuropsychiatric features; delusions, hallucinations,agitation and depression.

8. Motor signs; extrapyramidal features that include rigidity,bradykinesia, tremors and postural instability, myoclonus,bulbar involvement, early urinary incontinence, gait disorder.

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found in 19 (36%) including 12 of 26 with PNFA (46%),2 of 20 with SD (10%) and 5 of 7 with mixed aphasia(71%). Of 28 with bvFTD only 2 (7.1%) had AD pathology.A half of those with CBS had AD pathology (6 of 12, 50%)while all seven cases (100%) with PCA were found to haveAD pathology. None of the progressive aphasia or CBS orPCA patients with AD pathology had evidence of classiccorticobasal type pathology or concurrent cortical Lewybody inclusions.The remaining 66 cases had one of the pathological

variants of FTLD, as shown in Table 2. In line with ourearlier report concerning a smaller combined Cambridge–Sydney series (Hodges et al., 2003, 2004), the PNFApatients had predominant tau-positive pathology with twoshowing classic corticobasal degeneration and three Pickbody positive, four had progressive supranuclear palsy andtangle-only dementia (AD type but without amyloidplaques). Only 4 of the 26 had FTD-U. In contrast, thevast majority of the semantic dementia patients (14 of 20;70%) had ubiquitin positive inclusions (FTLD-U). Themixed aphasia group (n= 7) had predominantly ADpathology (5 of 7): the remaining two cases were brothers

with a unique combination of tau-positive and a synucleinpositive inclusions (Yancopoulou et al., 2005). The bvFTDshowed the widest spectrum of pathologies: 16 had tau-positive forms of FTLD (nine classic Pick bodies, fourcorticobasal degeneration, two familial tauopathies and onePSP), 6 had FTLD-U and 4 lacked any distinctive inclusionpathology. All 12 CBS patients had either AD (6; 50%) orclassic corticobasal tau-positive pathology (6; 50%).

SurvivalTable 3 compares the demographic profile, disease courseand survival of patients with pathologically confirmedtypical AD (n= 19), focal AD (n= 34) and focal dementiasdue to non-AD pathology (n= 66). Patients with focaldementias due to AD were significantly (P< 0.05) olderthan those non-AD pathology at presentation (68.4 versus62.8 years) and at death (73.5 versus 67.3 years P< 0.05).Average survival from presentation was 5 years in bothgroups with an overall disease duration from symptomonset of 9.7 years versus 8.1 years in the AD versus non-ADgroups. Age at onset, presentation and death was virtuallyidentical in the typical and atypical AD groups. KaplanMeier survival analysis failed to reveal significant differencesin median survival between the typical AD, focal AD andnon-AD groups suggesting that prognosis is equivalent.

Clinical characteristics of focal corticalsyndromes

Progressive aphasia (Table 4)Of the 19 cases with progressive aphasia secondary toAD pathology, 12 fulfilled criteria for PNFA, 2 for SDand 5 had a mixed aphasia syndrome. Only one hadprominent behavioural symptoms, one had apraxia and twohad visuospatial problems on neuropsychological examina-tion. On follow-up, 10 of the 19 subsequently developed

Table 2 Distribution of pathologies according to clinical diagnosis

Progressive Aphasia bvFTD CBS PCA Total

PNFA Semantic Dementia Mixed

FTLD SubtypesTau-positiveClassic Pick bodies 3 3 0 9 0 0 15Familial 0 1 0 2 0 0 3Corticobasal degeneration 2 0 0 4 6 0 12Other 5a 0 2b 1c 0 0 8

Tau-negativeUbiquitin-positive 4 14 0 6 0 0 24DLDH 0 0 0 4 0 0 4

Alzheimers Disease 12 2 5 2 6 7 34

Total 26 20 7 28 12 7 100

a1 tangle only dementia, 4 PSP; bfamilial cases with a synuclein and tau pathology; cPSP.DLDH=Dementia lacking distinctive histology.

Spectrum of focal cortical syndromes secondary to AD pathology

0

20

40

60

80

100

120

PCA Mixedaphasic

CBS PNFA bv FTD SD

Patient groups

% w

ith

AD

pat

ho

log

y

Fig. 1 Spectrum of focal cortical syndromes secondary to ADpathology (n=29).

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prominent memory loss after 2 to 8 years (mean 4.5 years)from the onset of aphasia. The remaining nine patientsretained a pattern of remarkably pure aphasia at least to thestage at which they were no longer able to attend the clinic.The clinical profiles of many of these patients have beenpreviously reported (Knibb et al., 2006). The mixed caseswere of particular interest. There was considerable hetero-geneity, but of the five with AD pathology, two resembledsemantic dementia but with additional phonological deficits(see Galton et al., 2000). Three conformed to what has beenreferred to as logopenic aphasia with reduced speech outputand anomia and impaired sentence repitition, but withoutphonological errors (Gorno-Tempini et al., 2004). The twonon-AD cases were brothers with mixed semantic andphonological deficits extensively documented by Crootet al. (1999) and later shown to have a uniqueneuropathological profile characterized by both tau and asynuclein inclusions (Yancopoulou et al., 2005).

Behavioural variant FTDIn two AD patients the history was dominated bybehavioural symptoms. Both presented with disinhibition,apathy and personality change, one had a prominent dys-executive syndrome. Both developed memory symptomsbetween 1 and 3 years after onset. There was a degree ofaphasia at presentation in both although behaviouralchanges predominated.

Illustrative bvFTD case with AD pathology. A 56-year-oldwoman had become argumentative, garrulous and disin-hibited for 2 years. One year later her practicalskills, including cooking and dressmaking, declined.At the memory clinic in 1991, she was found to haveprominent perseveration, utilization behaviour, impulsivity,confabulation and forgetfulness. There were marked deficitson a range of frontal executive tests. Language skills werepreserved. She scored 13/30 on the MMSE. A clinicaldiagnosis of bvFTD was made. Assessment 2 years latershowed severe anomia, poor language comprehension,impaired day-to-day memory and deficits on visuopercep-tual tasks. She died at the age of 66 years, 10 years afterdisease onset.

Corticobasal syndrome (Table 5)All six patients with AD pathology and CBS presented withsevere asymmetric upper limb apraxia and extrapyramidalfeatures. Three had alien limb phenomenon and myoclo-nus. All had a degree of generalized cognitive impairmentcharacterized by mild memory loss and four had prominentvisuospatial problems (visuoperceptual and constructiveimpairment in two, visuoconstructive and hemineglectin two).

Illustrative CBS case with AD pathology. A 70-year-oldwoman presented in 1995 with 3 years of difficulty incontrol of her right arm, causing problems with writing anddressing. One year later memory problems and wordfinding deficits appeared. Cognitive examination showeddyspraxia, dyscalculia, severe dysgraphia, mild word findingdifficulty and poor executive function. Physical examinationrevealed slow saccades, myoclonic finger jerks, rigidity, alienhand phenomena and a tendency for the arms to adoptawkward positions while walking. Her MMSE was 15/30and ACE 51/100. CT scan showed generalized cerebralatrophy. A diagnosis of CBD was made. During the next2 years, she developed complete loss of function of bothhands and progressive memory impairment. Her lastassessment in 1998 was dominated by severe bilateralapraxia. She died aged 79 years, 9 years post onset.

Posterior cortical atrophy (Table 6)Of the seven patients with PCA, all of whom had ADpathology, two had progressive visual failure and five hadbiparietal syndrome. Six of seven patients developedmemory impairment 1–3 years (mean 2 years) after onsetof visuospatial symptoms. On follow-up, six patientsbecame severely amnesic, four developed aphasia whilenone demonstrated prominent behavioural symptoms.

DiscussionSeveral insights emerge from this large clinicopathologicalstudy of typical AD and focal cortical syndromes. The mostsignificant is that a high proportion (i.e. just over a third)of focal cortical dementia syndromes are associated with

Table 3 Demography and survival of typical and focal cortical syndromes due to AD pathology

Typical AD(n=19)

Focal cortical syndromesdue to AD (n=34)

Focal cortical syndromesdue to non-AD (n=66)

P-valuea

Sex (M:F) 11:8 16:18 42:24Age of onset 64.3 (9.7) 63.8 (8.6) 59.2 (7.6) nsAge at presentation 67.8 (9.1) 68.4 (8.3) 62.8 (7.4) 50.05Age at death 72.5 (8.9) 73.5 (9.0) 67.3 (7.5) 50.05Duration of illness at presentation 3.5 (2.4) 4.6 (1.8) 3.6 (2.7) nsTotal duration 8.2 (3.6) 9.7 (3.3) 8.1 (4.1) ns

aOne-way ANOVA.Values are in years, expressed as mean (SD).

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Table 4 Summary of clinical features of progressive aphasia cases with AD pathology

Patient Age ofonset

Duration of symptomsat presentation (years)

Total durationof symptoms(years)

Clinical syndromeat presentation

Amnesia Apraxia Visuospatiala Frontalbehavior

Duration offollowup(years)

Deficits on follow up withinthree years of presentation

Onset of amnesiaafter aphasia (years)

1 77 4 8 PNFA N N N N 3 None N2 72 2 6 PNFA N N N N 2 None N3 71 1 8 PNFA N N N N 6 Apraxia N4 63 4 5 PNFA N N N N 1 Disinhibition, Apraxia N5 64 2 8 PNFA N Y Y N 2 Amnesia 26 64 1 6 PNFA N N Y N 2 Amnesia 37 58 2 5 PNFA N N N Y 2 Apraxia, Amnesia, Visuospatial 38 67 4 8 PNFA N N N N 4 Amnesia, apraxia, stereotypic behavior 59 63 5 10 PNFA N N N N 3 Amnesia, Visuospatial 810 76 1 3 PNFA N N N N 3 Amnesia, Visuospatial 111 79 2 5 PNFA N N N N 3 Amnesia, Visuospatial 212 60 2 7 PNFA N N N N 3 Amnesia, Apraxia, Disinhibited 113 60 2 6 SD N N N N 3 Ritualistic behaviour N14 51 8 12 SD N N N N 2 None N15 62 9 14 Mixed N N N N 1 Irritability N16 70 1 12 Mixed N N N N 4 Amnesia, Apraxia, visuospatial 417 74 5 9 Mixed N N N N 1 Amnesia 618 67 2 4 Mixed N N Y N 2 Amnesia 119 50 1 5 Mixed N N Y Y 4 Amnesia 1

Y=yes; N=no.aVisuopatial problems detected only on neuropsychological assessment.

Table 5 Summary of clinical features of CBS with AD pathology

Patient Age ofonset

Duration atpresentation(years)

Totalduration(years)

Asymmetricapraxia

Extrapyramidalfeatures

Visuospatialdeficits

Gerstmann’ssyndrome

Amnesia Aphasia FrontalBehavior

Deficits onfollow upwithin threeyears ofpresentation

Onset ofamnesia afterapraxia(years)

1 78 5 5 Y Y Y Y Y N N N 32 81 10 13 Y Y Y N Y Y N Hemineglect 53 70 3 9 Y Y Y Y Y Y N Cortical sensory loss 14 60 2 3 Y Y Y Y Y Y N N 05 70 2 13 Y Y Y N N N N Amnesia, Aphasia 36 74 3 10 Y Y Y N Y Y N Behavioural 0

Y=yes; N=no.

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AD pathology, with the association strongest for PCA.A surprisingly high proportion, a half, of those with CBSand with progressive non-fluent aphasia also had ADpathology. Patients with behavioural variant FTD and SDonly rarely (one-tenth in our series) demonstrated ADpathology. Another major finding was the late onset, orabsence, of significant amnesia even in advanced stages,suggesting sparing of the medial temporal lobe by ADpathology until very late. Survival of patients with typicalAD did not differ from those with focal dementias with ADpathology, although cases with non-AD pathology weresignificantly younger at presentation and diagnosis. Survivalin the atypical AD cases and the non-AD cases was verysimilar (9.7 versus 8.1 years from reported symptom onset).All of the focal AD patients had advanced Alzheimerpathology (at least Braak stage 4) and lacked otherexplanatory neuropathological changes. In this series,a diagnosis of clinically typical AD almost always predictedAD pathology.

Increased interest in the clinical manifestations ofneurodegenerative disorders over the past decade has ledto the realization that focal dementia syndromes represent amuch higher proportion of cases than previously recog-nized. For instance, two epidemiological studies showedthat FTD was the second most common form of dementiain the age group less than 65 years (Ratnavalli et al., 2002;Harvey et al., 2003). In a large clinic-based series fromJapan involving 330 dementia patients, 13% were diagnosedin life as FTD (Ikeda et al., 2004). The unique clinicalfeatures of each of the focal cortical syndromes clearlyreflect the locus of pathology and not necessarily itshistological nature. The assumption, so far, has been thatclinical variants of FTD (bvFTD, SD and PNFA) and CBSare generally not due to AD pathology, although studiescorrelating clinical diagnosis and pathology in focaldementias have been few and have consisted mainly ofeither single case reports or relatively small series withparticular cortical syndromes (Boeve et al., 1999; Galtonet al., 2000; Knibb et al., 2006; von Gunten et al., 2006).Taking neuropathology as a starting point, Forman et al.(2006) compared 90 cases with a pathological diagnosis ofFTLD and 24 additional cases with a clinical diagnosisof FTD but with alternative pathology including 19 withAD: of these 19 cases approximately half had a languagepresentation. Our findings concur with those of Formanet al. Since the present study was longitudinal in nature,with 200 consecutive autopsies, including 100 with focalcortical dementias, evaluated over a period of 17 years in asingle centre, the high frequency of AD pathology in thisgroup (one-third) assumes considerable significance.

Turning to individual cortical syndromes, our findingssupport a growing literature suggesting that progressiveaphasia is probably the commonest atypical presentationof AD and that a higher proportion of cases have ADpathology than previously recognized (Forman et al., 2006;Knibb et al., 2006; von Gunten et al., 2006). AmongTa

ble6

Summaryof

clinicalfeatures

ofpo

steriorcorticalatrophywithAD

patholog

y

PtAge

ofon

set

Durationat

presentatio

n(years)

Total

duratio

n(years)

Clinical

syndrome

Prim

ary

visual

failure

Com

plex

visual

disorder

Apraxia

Dysgraphia/

Dyscalulia

Amnesia

Aph

asia

Fron

tal

Behavior

Deficitson

follow

upwithin

threeyearsof

presentatio

n

Onset

ofam

nesia

after

visuospatial

symptom

s(years)

153

13

Biparietal

NY

YN

YN

NAph

asia

12

535

8Biparietal

NY

YY

YN

NAph

asia

33

635

10Biparietal

NY

YY

YY

NMyoclon

us,eye

movem

entabno

rmality

34

514

9Biparietal

NY

YN

NN

Amnesia

,Aph

asia,apathy

25

693

13Biparietal

NY

YY

NN

NN

N6

574

12Visual

YY

NY

YN

NN

07

654

6Visual

YNT

NY

YN

NAph

asia

3

Y=yes,N=no

,NT=no

ttested.

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the aphasia subtypes, PNFA accounted for the majorityof AD cases. In a few cases, unusual mixed aphasiaappeared to be a clinical clue suggestive of AD pathology.Some of these cases conform to what has been termedlogopenic progressive aphasia (Gorno-Tempini et al., 2004)which has been previously suggested to be associated withAD pathology. Further work is required to establishpremorbid markers of different pathologies. In terms ofthe spectrum of FTLD pathologies present in the progres-sive aphasic cases, the findings support our earlier workfrom Cambridge and Sydney which took as a starting pointa positive pathological diagnosis and looked back at thediagnosis. It should be noted that 30 of 100 cases from thepresent series were included in the joint Cambridge–Sydneyinitiative study (Hodges et al., 2003, 2004). Patients withPNFA had a very high rate of tau-positive pathology witheither AD (46%), classic Pick body FTD (11%), corticobasaldegeneration (7%) or PSP (15%). Only 4 of the 26 cases(15%) had FTLD-U. Clinical features that might discrimi-nate between underlying pathologies were explored in detailby Knibb et al. (2006) who found the AD cases to be older,but no other distinguishing factors. Apraxia of speech hasbeen suggested to be a marker of non-AD forms oftauopathy in PNFA (Josephs et al., 2006a, b). We were notable to explore this hypothesis since our patients were notassessed for this specific language output disorder, manyhaving presented to the clinic before we routinely evaluatedmotor speech. Earlier work has established that, by contrastto PNFA, semantic dementia is very predictably associatedwith FTLD-U type pathology, but without the intraneur-onal Lentiform inclusions that characterize familial ubiqui-tinopathies (Davies et al., 2005). In this series of 20 cases,14 (70%) had FTLD-U. Interestingly, although semanticmemory problems are prominent in AD, semantic dementiaas a focal manifestation of AD appears to be very rare. Theoccasional case with AD or Pick body positive FTLDpathology appears clinically indistinguishable from thosewith FTLD-U.The concept of frontal variant AD has been somewhat

controversial. Prominent and early behavioural problems andexecutive dysfunction in AD have occasionally been reportedgiving rise to the label of frontal variant AD (Johnson et al.,1999; von Gunten et al., 2006). In these cases, however,frontal involvement typically occurred on the background ofan otherwise typical amnestic syndrome. In our series, bvFTDsecondary to AD pathology was present in 2 of 28 casescoming to autopsy (7%). While none of them had amnesia atonset, in both diffuse cognitive dysfunction developed within3 years of symptom onset. Our findings are thus compatiblewith the existence of a behavioural variant of AD, but incontrast to patients with non-AD pathology, the diseaseprocess does not appear to remain restricted to the frontallobes for very long. The other 26 cases had a wide spectrum ofFTLD pathologies with a slight prepondence of tau-positivecases (nine classic Pick body inclusions, four corticobasaldegeneration and two familial tauopathies) compared to

tau-negative (six FTLD-U and four lacking distinctivehistopathology). As in a prior study, there were no clearmarkers which distinguished subgroups (Hodges et al., 2003,2004) but further longitudinal analysis of bvFTD cases isrequired to establish markers of AD versus other pathology.

The corticobasal syndrome (CBS) is now known todemonstrate considerable pathologic heterogeneity (Boeveet al., 1999; Mathuranath et al., 2000). Our findingsconfirm a strong association between CBS and ADpathology. Clinical manifestations of CBS due to ADpathology in our series ranged from typical asymmetricapraxia, extrapyramidal syndrome and late cognitiveimpairment to a disorder characterized by severe cognitivedysfunction with apraxia and extrapyramidal features.Further work is required to determine in vivo markers ofAD pathology in CBS.

Posterior cortical atrophy (PCA) is now a well-recognized focal dementia syndrome which appears to benearly always due to AD pathology (Benson et al., 1988;Hof et al., 1993; Mackenzie-Ross et al., 1996; Hof et al.,1997; Galton et al., 2000; von Gunten et al., 2006). In ourseries, all seven cases with PCA had AD pathology andother pathologies, notably cortical Lewy bodies and cortico-basal changes, were absent. Presentation as biparietalsyndrome was more common than primary visual failure.All seven cases had normal or only mildly impairedmemory at presentation. Additionally, there was relativepreservation of behaviour and language. This suggests thatAD pathology remains restricted to the posterior regionsof the brain with sparing of temporal and frontal lobes tilllate in the disease. Another interesting finding was theoverlap of cognitive features between PCA and CBS. Bothsyndromes are characterized by apraxia and prominentvisuospatial features: visual neglect, optic ataxia andGerstmann’s syndrome (Mendez, 2004; Bak et al., 2005,2006). Case descriptions of clinical CBD with AD pathologyalso have supported this clinical overlap (Boeve et al., 1999;Lleo et al., 2002; Doran et al., 2003). Involvement ofparietal cortex asymmetrically in both clinical variants is thelikely explanation for the difficulty in clinically distinguish-ing CBS from PCA in certain cases.

Our study has significant implications for early diagnosisof AD at the stage of mild cognitive impairment (MCI).The original concept of MCI arose from the assumptionthat amnesia is the prominent early feature of AD (Petersenet al., 1999, 2001a, b) although the label has been extendedto patients with so-called non-amnestic MCI (Gautier et al.,2006). Our study confirms that non-amnestic presentationsof AD occur more often than previously recognized (Boeveet al., 1999; Galton et al., 2000; Mendez, 2004; Knibb et al.,2006). Wider inclusion criteria for MCI and longitudinalfollow-up of patients with non-amnestic MCI will revealwhether it is possible to make a diagnosis of focal atypicalAD at a preclinical stage.

Certain limitations surface in this study. First, ourstudy does not address the actual prevalence or incidence

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of atypical AD due to the specialist clinic-based nature ofthe sample. Future community-based clinicopathologicalstudies that include both typical and focal dementias arerequired to establish how common focal AD is in thepopulation. Secondly, the lack of uniform imaging dataprecluded us from determining whether focal AD isassociated with characteristic patterns of brain atrophy. Itremains to be established whether imaging data iscomplementary to clinical features in making a moreaccurate ante-mortem diagnosis. It seems unlikely thatstructural imaging will discriminate between pathologiessince symptoms reflect the location of disease regardless ofthe exact histological type, although it is possible thatmore systematic evaluation of the medical temporal lobescan provide clues as to the presence of underlying ADpathology (Likeman et al., 2005). In contrast, modernfunctional imaging such as the amyloid binding ligand PIB(Klunk et al., 2004; Engler et al., 2006) or CSF markers oftau and b amyloid (Clark et al., 2003) are much more likelyto discrimination pathologies in vivo. Thirdly, the sampleof typical AD cases in our series was relatively small andit is likely that alternative pathologies would be found ina larger sample of clinically diagnosed AD particularly ofolder onset. Our findings apply to younger patientspresenting to a specialist clinic.In conclusion, a clinical diagnosis of typical AD of

relatively younger onset appears to be almost alwaysconcurrent with AD pathology, but the converse is nottrue. AD pathology is frequently found in patients withatypical cortical syndromes, suggesting that diagnosis of ADneeds to be considered even in patients who present withfocal dementia without significant memory loss, especiallyin cases with PCA, CBS and PNFA. The development ofmore specific biomarkers is needed to improve in vivodiagnosis of the pathological substrate in such cases. A greatdegree of heterogeneity in clinical presentations of ADexists and memory can be spared even into advanced stagesof disease. Our findings have implications for under-standing the relationship between type of pathology andclinical dementia syndromes, as well as for early diagnosisand treatment.

AcknowledgementsThis work was supported by MRC programme grants tothe senior author. SA spent time in Cambridge courtesyof a Commonwealth Fellowship. The study would not havebeen possible without Angela O’Sullivan, Kate Dawson andCharlene Connor who supported the patients and familiesin life and co-ordinated brain donation.

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