Lancet Neurology 2012 Feb;11(2):170-8.
Available from: http://www.thelancet.com/journals/laneur/issue/current
Posterior Cortical Atrophy
Sebastian J Crutch PhD1, Manja Lehmann PhD1,2, Jonathan M Schott MD1, Gil D Rabinovici
MD2, Martin N Rossor FRCP1 & Nick C Fox FRCP1
1
Dementia Research Centre, Institute of Neurology, University College London, London
WC1N 3BG, UK
2
Memory and Aging Center, University of California San Francisco, San Francisco, CA 94117,
USA
Address for correspondence:
Dr Sebastian Crutch
Dementia Research Centre
Box 16
National Hospital for Neurology and Neurosurgery
Queen Square
London
WC1N 3BG
UK
Tel: +44 (0)20 3448 3113
Fax: +44 (0)20 7676 2066
Email: s.crutch@drc.ion.ucl.ac.uk
Word count: 3954
Number of references: 79
Abstract
Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterized by a
progressive decline in visuospatial, visuoperceptual, literacy and praxic skills. The progressive
neurodegeneration affecting parietal, occipital and occipito-temporal cortices which underlies
PCA is attributable to Alzheimer’s disease (AD) in the majority of patients. However,
alternative underlying aetiologies including Dementia with Lewy Bodies (DLB), corticobasal
degeneration (CBD) and prion disease have also been identified, and not all PCA patients
have atrophy on clinical imaging. This heterogeneity has led to diagnostic and terminological
inconsistencies, caused difficulty comparing studies from different centres, and limited the
generalizability of clinical trials and investigations of factors driving phenotypic variability.
Significant challenges remain in identifying the factors associated with both the selective
vulnerability of posterior cortical regions and the young age of onset seen in PCA. Greater
awareness of the syndrome and agreement over the correspondence between syndromeand disease-level classifications are required in order to improve diagnostic accuracy,
research study design and clinical management.
Introduction
Posterior Cortical Atrophy (PCA) is a neurodegenerative condition characterised by a
progressive, often dramatic and relatively selective decline in visual processing skills and
other functions subserved by parietal, occipital and occipito-temporal regions. Age at onset is
typically between 50-65 years and the syndrome is associated with a variety of underlying
pathologies. PCA has been recognised for more than two decades, and yet the condition is
relatively neglected by researchers. Patients often experience a considerable delay in the
time to diagnosis owing to the young age at onset and unusual presenting symptoms. In
addition, the term PCA has been applied inconsistently, making it difficult to draw
comparisons across studies. Whilst there is an increasing move to define neurodegenerative
diseases by their underlying pathology, such progress in relation to PCA is limited currently by
a lack of specificity in the available diagnostic criteria, and a lack of clarity regarding the
relationships between PCA and related syndromic classifications such as aphasic, amnestic
and dysexecutive AD phenotypes and corticobasal syndrome (CBS).
This review outlines the clinical, psychological, imaging, epidemiological, genetic and
pathological features of PCA. We argue that within pathological subgroups, characterising
atypical phenotypes such as PCA will enable the identification of biological factors which
promote or protect against pathological changes in specific brain networks. Problems with
and possible solutions to current diagnostic and terminological conundrums are considered,
with particular reference to implications for future clinical and research trial design involving
individuals with PCA. We also aim to increase awareness and improve identification of early
and unusual symptoms of PCA, and to provide guidance on the provision of support, care and
education for patients, carers and healthcare professionals.
History and Definitions
The term PCA was first introduced to describe patients with predominant deficits in higherorder visual processing, a subset of whom also presented with marked atrophy in parietooccipital areas 1. The syndrome outlined was consistent with other early reports of patients
with similar clinical characteristics
2-9
. In the absence of histopathological data, Benson et al
felt that the clinical presentation was sufficiently distinct from that of Alzheimer’s or Pick’s
disease as ‘to warrant classing them separately until definitive pathologic information
becomes available’. Subsequent histopathological studies identified AD as the most common
underlying pathology, leading to the synonymous use of the terms PCA, ‘biparietal AD’, and
‘visual variant of AD’ in some studies
10-14
. The term ‘progressive posterior cortical dysfunction’
has also been used to describe the clinical symptoms in these patients in the absence of clear
posterior atrophy
. However, PCA is also associated with non-AD pathologies (see
15
‘Pathology’), which has led to suggestions for PCA to be considered a distinct nosological
entity with its own diagnostic criteria 16, 17.
Epidemiology
The prevalence and incidence of PCA are currently unknown, and dependent upon the
adoption of consistent diagnostic criteria. Furthermore, any figure is likely to be an
underestimate because of poor general awareness of the syndrome’s existence. However,
Snowden et al. found that that 5% of 523 patients with AD presenting to a single specialist
cognitive disorders centre had a visual presentation (also labelled posterior cortical atrophy)
18
. Age at onset tends to be much earlier in PCA than in typical amnestic AD, with most
studies reporting PCA symptom onset in patients’ mid 50s and early 60s
studies have reported a wider age spread (45-74 years
20
17, 19
although some
, 40-86 years ). In terms of gender
21
distribution, some studies have reported no difference in the prevalence based on gender 15, 17,
19
, whereas others have reported an over-representation among women 18, 20-24.
Neuropsychological features
The most frequently cited neuropsychological deficits in PCA are visuospatial and
visuoperceptual impairments, alexia and features of Balint’s syndrome (simultanagnosia,
oculomotor apraxia, optic ataxia, environmental agnosia) and Gerstmann’s syndrome
(acalculia, agraphia, finger agnosia, left/right disorientation)
15, 17, 19-21, 25-31
. Working memory
deficits and limb apraxia have also been emphasised . Longitudinal studies have shown that
20
anterograde memory, executive functions and linguistic skills, which are sometimes strikingly
preserved in the earlier stages of the disease, gradually deteriorate in some patients as they
progress to a more global dementia state 10, 19, 23.
Although higher order visual problems such as object and space perception problems are
more commonly reported, many such difficulties are at least partially underpinned by deficits
in more basic visual processing (e.g. form, motion, colour, point localisation). In a detailed
comparison of basic and higher order perception, all PCA patients demonstrated impairment
in at least one basic visual process, emphasising the vulnerability of fundamental aspects of
vision associated with occipital cortical dysfunction
32
. This study also revealed specific
correlations of basic visual processing with higher-order visuospatial and visuoperceptual
skills, but not with non-visual parietal functions (such as calculation and spelling), suggesting
the specific involvement of visual networks in PCA.
In combination, the basic and higher order visual deficits in PCA have predictable
consequences on performance on general neuropsychological tests, e.g. performance IQ is
often up to 30-40 points lower than verbal IQ scores. Performance on cognitive tasks with any
significant visual component (e.g. visual memory recall, Trail Making, Stroop test) are
vulnerable to impairment and misinterpretation, and thus accurate assessment requires the
selection of tasks which minimise visual demands (e.g. auditory-verbal memory tasks, naming
from verbal description).
Many patients with PCA also experience unusual symptoms or ‘positive perceptual
phenomena’ including abnormally prolonged colour after-images
; the perception of movement of static stimuli
34, 35
reversal of vision
35
35
; reverse size phenomena
33
; and in one case even 180˚ upside-down
(see Figure 1). Reading skills may be limited by numerous processes,
including visual disorientation (e.g. getting lost on the page), reverse size phenomena (i.e.
accurately perceiving small but not large print), and visual crowding (impaired identification of
the constituent individual letters of a word owing to excessive integration of visual features
from surrounding letters
40
36-38
The condition may also lead to primary peripheral dyslexias
39,
. Anecdotally, individuals with PCA frequently report heightened sensitivity to glare from
shiny surfaces, and experience a range of localised sensation and pain phenomena and
disturbances of balance and bodily orientation which may potentially be linked to deranged
visuo-vestibular interactions.
Questions remain over whether PCA should be considered a unitary clinico-anatomical
syndrome or rather a collection of related but distinct syndromic subtypes. Extrapolating from
basic neuroscientific evidence of distinct cortical streams which process different types of
visual information
41, 42
, it has been suggested that separate parietal (dorsal), occipitotemporal
(ventral) and primary visual (striate cortex; caudal) forms of PCA exist
12, 13
. However, these
claims are based on findings from single case reports. Subsequent neuropsychological case
series studies have failed to find evidence to support a pure ventral stream syndrome
19
, and
have revealed considerable overlap in the neuropsychological profiles and patterns of cortical
thinning in patients with behaviourally-defined predominant dorsal or ventral stream
impairments
32
. Rather, these findings suggest that phenotypic differences may be more
appropriately considered to represent points on a continuum of variation within PCA.
Clinical features
The clinical presentation of PCA is influenced by several factors, including the time taken
before an individual presents to medical services or is referred to a cognitive specialist; the
individual’s specific pattern of deficits; in some cases the underlying pathology; and each
patient’s psychological response to their symptoms. The relative rarity of PCA, the sometimes
unusual nature of its symptoms, and the relatively young age at onset leads to misdiagnosis
of many patients as depressed, anxious or even malingering in the early stages of the
disease. Early anxiety is at least anecdotally a common feature, perhaps reflecting that
patients with PCA typically have relatively intact insight into there being a problem, even if its
nature is unclear. Even to experienced cognitive neurologists, the initial history may be more
suggestive of anxiety, until examination reveals impairment referable to parietal and/or
occipital lobe function. Patients are frequently first referred to opticians and ophthalmologists
believing that an ocular abnormality is responsible for their visual symptoms, sometimes even
leading to unnecessary medical procedures such as cataract surgery.
The symptoms reported by a patient with PCA are likely to reflect broadly their individual
pattern of neuropsychological impairment. Visual symptoms are perhaps more likely than
other posterior deficits to be volunteered, with individuals describing difficulties reading lines
of text, judging distances (often leading to repeated minor car accidents or problems parking),
identifying static objects within the visual field, or problems with stairs and escalators. Visual
symptoms such as light sensitivity or visual distortions may be mistaken for migraine. Careful
history taking may reveal some of the more unusual visual phenomena described above,
including the presence of prolonged after-images or visual crowding. Individuals may
volunteer problems using common objects reflecting dyspraxia, or progressive difficulty with
calculations or spelling. The presence of other neurological symptoms, including visual
hallucinations (reported in up to 25% of PCA patients)
19, 21, 43
, and rapid eye movement sleep
behaviour disorder may be suggestive of underlying dementia with Lewy bodies (DLB). Very
occasionally, there may be a history consistent with occipital lobe seizures.
Careful bedside testing can elicit signs of disproportionate parietal/occipital dysfunction,
including but not limited to visual disorientation, difficulties resolving degraded stimuli,
ideational and/or ideomotor dyspraxia, dyscalculia, and problems with spelling. The physical
examination in most cases of PCA is unremarkable, although in the presence of severe
cortical visual problems interpretation of visual acuity and visual fields may be difficult, with
hemianopia often misdiagnosed owing to the presence of higher-order visual attentional
problems. Finger myoclonus is also not uncommon: Snowden et al. reported similar
frequencies of extrapyramidal signs (41%), myoclonus (24%) and grasp reflex (26%) in PCA
compared with those found in typical AD
. Nonetheless, the presence of features of clear
18
symmetrical motor parkinsonism (suggestive of Lewy body pathology), or prominent
asymmetric myoclonus and dystonia (suggestive of corticobasal degeneration) may give
important clues to the underlying aetiology, although there are currently relatively sparse
pathological data on which these clinical observations can be confirmed.
Neuroimaging
Increasingly sophisticated image analysis tools have been used to localize and quantify
(typically group) differences in patterns of atrophy in patients with PCA compared either with
controls or with patients with typical AD. Cross-sectional voxel-based morphometry (VBM)
has revealed widespread grey matter differences between PCA patients and healthy controls,
with the most significant reductions found in regions of the occipital and parietal lobes,
followed by regions in the temporal lobe
24, 30
. Direct comparison between PCA and typical AD
using both VBM and cortical thickness measures have demonstrated greater right parietal
and less left medial temporal and hippocampal atrophy in PCA. It should be noted that a
number of studies report asymmetric atrophy patterns in PCA (R>L), but these differences
may reflect selection biases in the diagnosis and recruitment of patients with prominent visual
dysfunction. Limited diffusion tensor imaging (DTI) data also suggest PCA reduces the
integrity of white matter tracts in posterior brain regions
44-46
. However, considerable regional
overlap in atrophy has also been reported, with regions including the posterior cingulate gyri,
precuneus, and inferior parietal lobe being affected in both PCA and typical AD
. Such
23
findings suggest that PCA, when underpinned by AD, exists on a spectrum of variation with
other AD phenotypes
23, 32
. Fluid registration of longitudinally-acquired structural MR images
illustrates the evolution of PCA (see Figure 2), with group studies indicating that, by five years
symptom duration, atrophy is widespread throughout the cortex including medial temporal
lobe structures 31.
Data from functional imaging studies using single photon emission computed tomography
(SPECT) and fluorodeoxyglucose positron emission tomography (FDG-PET) are largely
consistent with structural changes in parieto-occipital areas (see Box 1, Figure B)
20, 47-50, 51
. In
addition to posterior regions, FDG-PET has revealed specific areas of hypometabolism in the
frontal eye fields bilaterally which may occur secondary to loss of input from occipitoparietal
regions and underpin ocular apraxia in PCA
. A limited number of studies have also
20, 52
assessed patterns of amyloid deposition using Pittsburgh compound B (PIB)-PET in PCA.
Single case studies and small series have reported increased Aβ accumulation predominantly
in the occipital and parietal lobes relative to individuals with typical AD
53-56
. However, two
studies that compared PIB uptake in larger groups of PCA patients to typical AD reported that
there was no significant difference in amyloid deposition between PCA and typical AD, with
both groups showing diffuse PIB uptake throughout frontal, temporoparietal and occipital
cortex (see Box 1) 22, 57.
Genetics
To date there have been no reports of a PCA phenotype associated with autosomal dominant
familial AD, but a recent case series described the PCA syndrome in familial prion disease
associated with 5-octapeptide insertion into the prion protein (5-OPRI) 58 . Available PCA case
series suggest that there is no significant difference in the number of patients with a positive
family history of dementia in PCA compared with typical AD
17, 21
. Some studies have found
significant differences in apolipoprotein E (ApoE) genotypes in patients with PCA versus
amnestic AD
14, 18, 59
. Other studies, however, have reported no difference in ApoE between
PCA and typical AD
17, 21-23, 60
(see also
61-63
for estimates in typical AD, and
64
for healthy
controls; see Table 1 for a summary ApoE ε4 prevalence data in PCA, AD and controls).
Discrepancies between these studies may reflect differences in factors such as inclusion
criteria used to define PCA and typical AD, and age at onset. In particular the lack of
pathological confirmation is a major limitation in these studies; questions remain as to
whether ApoE ε4 drives the degenerative pattern in patients with AD (i.e. to or away from
medial temporal structures); whether the lower frequency of ApoE ε4 in PCA seen in some
studies is due to patients with non-AD pathology; or whether different (as yet unrecognised)
genetic factors underlie PCA compared to ‘typical’ late onset AD. Studies using larger sample
sizes, consistent definitions of PCA, and post-mortem confirmation of diagnosis will be
required to obtain more conclusive results; it will be of considerable interest to assess the
frequencies of other genetic risk factors for sporadic AD determined in genome wide
association studies.
Pathology
Pathological studies have all shown that AD is the most common underlying cause of PCA
15, 21, 65-67
13,
. However, a small number of cases are attributable to other aetiologies such as
corticobasal degeneration (CBD) 15, 68, 69, Dementia with Lewy Bodies (DLB) 15, 70, prion disease
(including CJD and familial fatal insomnia)
, and subcortical gliosis 71. In the largest series
15, 71
to date, Renner et al. reported pathological data of 21 PCA patients of whom 13 (62%) had
AD, 2 had AD-Lewy Body variant pathology (10%), 1 had AD with coexisting Parkinson’s
disease (5%), 1 had DLB with coexisting subcortical gliosis (5%), 2 had CBD (10%), and 2
had prion disease (10%, CJD and FFI)
. Tang-Wai et al. reported 7/9 (78%) PCA patients
15
had AD pathology, whereas the remaining 2 (22%) had CBD 21.
Although the patterns of the distribution of pathology has been shown to be different in PCA
compared with typical AD, the exact pattern of the pathological changes is inconsistent and
based on very small numbers of cases. Some studies have demonstrated differences in both
plaques and neurofibrillary tangles between PCA and typical AD
found no differences in plaque distribution
10, 12, 72
, whereas others have
. For example, Levine et al. reported the
15, 21
pathological findings of 1 PCA patient who showed greatest density of senile plaques and
neurofibrillary tangles in occipitoparietal regions, and lowest density in frontal lobe regions
10
.
Hof et al. reported similar findings with plaques and tangles found predominantly in primary
visual and visual association areas around the occipito-parieto-temporal junction, whereas
frontal regions such as the prefrontal cortex showed very low densities of pathological
changes
72, 73
. In contrast, Tang-Wai et al. compared pathological changes in 9 PCA patients
with 30 typical AD patients. The PCA group showed significantly higher density of
neurofibrillary tangles in visual and visual association cortices and fewer tangles and senile
plaques in the hippocampus and subiculum. However, density of senile plaques in other
cortical areas was comparable in both groups 21. Reasons for the discrepant findings in these
autopsy studies may include differences in inclusion criteria and demographic characteristics
(such as age and disease severity) as well as differences in the methods used to quantify the
pathological changes (such as different staining techniques, and discrimination between
diffuse and neuritic plaques).
Studies assessing CSF biomarkers (Aβ1-42, T-tau and P-tau181) have reported similar findings
in PCA compared with AD
27, 56, 60, 74
, supporting previous reports that PCA is typically
associated with underlying AD pathology.
Diagnostic and research criteria
Two sets of diagnostic criteria for PCA have been proposed
17, 21
. Proposed core features for a
diagnosis of PCA include: (i) insidious onset and gradual progression; (ii) presentation of
visual deficits in the absence of ocular disease; (iii) relatively preserved episodic memory,
verbal fluency and personal insight; (iv) presence of symptoms including visual agnosia,
simultanagnosia, optic ataxia, ocular apraxia, dyspraxia and environmental disorientation; and
(v) absence of stroke or tumour. Supportive features include alexia, ideomotor apraxia,
agraphia, acalculia, onset before the age of 65 years and neuroimaging evidence of posterior
cortical atrophy or hypoperfusion.
Whilst these criteria have proved useful in a number of clinical and research contexts, they
are based on clinical experience at single centres and have not been validated more widely.
In the absence of objective evidence linking clinical phenotype to underlying pathology, there
continues to be inconsistency, with the term PCA being used as a descriptive, syndromic term
and as a diagnostic label. Such inconsistencies present a number of problems in the
evaluation of differential diagnoses and particularly in the design and interpretation of
research studies and clinical trials. First, whilst a syndromic classification may be adequate
for some types of research study (e.g. brain-behaviour, behavioural intervention), other
investigations require direct consideration of the likely underlying pathology (e.g. clinical trials
of disease-specific medicinal products). Second, there is currently no evidence base on which
to adjudicate whether pharmacological treatments for AD are effective in individuals with PCA
attributable to probable AD, or whether individuals with PCA should be included/excluded
from conventional AD clinical trials (e.g. because of the potential unsuitability of study
outcome measures [e.g. visual memory tasks] selected for patients with more typical
amnestic or global clinical presentations). Third, current criteria provide no guidance as to the
degree of specificity required for a diagnosis of PCA. For example, in the relatively large
series reported by Renner et al (2004), 9/27 patients presented with the PCA syndrome as a
relatively isolated disorder, whereas in 18/27 it was the prominent feature of a more
generalised dementia15. A number of studies have suggested PCA, where attributable to
probable AD, lies on a phenotypic continuum with other typical and atypical AD phenotypes
(e.g. amnestic AD, global cognitive impairment, logopenic/phonological aphasia) 18, 23, 32 , but
the boundaries between such phenotypes are defined imprecisely. Fourth, the ‘presentation of
visual complaints’ is a core feature of existing criteria but some patients with
neurodegenerative conditions present with predominant impairment of other posterior cortical
functions such as calculation, spelling and praxis
6, 18, 27, 48, 75
; such individuals could be
considered to fall within the PCA spectrum. Fifth, the value of biomarkers may differ in PCA
compared to typical AD or DLB (e.g. relative absence of hippocampal atrophy). This is
particularly important given the increasing incorporation of such biomarkers in diseasespecific diagnostic criteria 76, 77 .
Future resolution of these issues and development of clinical and research criteria for the
definition of PCA are likely to require consensus opinion from multiple specialist centres
supported by objective evidence of the relationship between clinical presentation,
neuroimaging and CSF biomarkers, and histopathological data. Establishing the relative
likelihood of different pathologies in large, multi-centre datasets would improve the
discrimination of potential disease subtypes necessary for trials involving disease-modifying
compounds. One possible approach would be to apply a range of criteria to a multi-centre
dataset to determine sets of inclusion/exclusion criteria which identify specific disease
subgroups (e.g. PCA-AD). Consensus criteria might also investigate frameworks for
operationalising criteria in terms of a quantifiable set of diagnostic markers, for the purpose of
determining entry into research studies and to improve comparability of data between
institutions.
Management
Although there are no published reports that assess the effectiveness of acetyl cholinesterase
inhibitors (e.g. donepezil, rivastigmine and galantamine) in PCA, these are frequently, and
(given that AD is statistically the most likely underlying pathology) in our view appropriately,
administered. Clinical experience and limited single case reports suggest some clinical benefit
78
, most likely in patients with underlying AD or DLB pathology. It may also be appropriate to
consider
anti-depressant
medication
in
patients
with
persistent
low
mood,
and
levodopa/carbidopa trials in patients with parkinsonism.
Due to poor awareness of the syndrome’s existence, patients with PCA often receive limited
or inappropriate care and advice, catering to problems which are less significant to the
individual (e.g. memory problems) whilst critical perceptual difficulties (e.g. many activities in
day centres and nursing homes are visually mediated) are often not considered. The relative
preservation of skills such as memory, language and insight in PCA, especially in the mild to
moderate stages of the disease, enable patients to take advantage of peer support meetings
and group, couple and individual psychological therapies where the need exists. Support
group meetings are particularly useful for reducing social isolation, sharing of the experience
of what is often a particularly long and difficult route to diagnosis, and for exchanging practical
tips and coping strategies and advice. Patients with PCA often benefit from resources
designed primarily for the blind and partially sighted, such as mobile phones with simplified
displays, voice recognition software, talking books and watches, culinary aids, and lamps to
increase ambient light levels in the home. Referral to an occupational therapist or sensory
team may be appropriate to help maximise function. It may also be necessary for an
individual to be referred to an ophthalmologist in order to register as partially sighted under
statutory invalidity schemes, which may provide access to financial and social benefits and
services. Driving a car is clearly not appropriate for many patients with PCA, and particularly
those with prominent visual disturbance. Physical therapy can also be helpful for patients with
parkinsonism and gait disturbance. Little empirical evidence exists examining the impact of
management
strategies
in
PCA,
but
a
rehabilitation
programme
which
included
psychoeducation, compensatory strategies, and cognitive exercises was tested in a single
individual with PCA 79, resulting in small improvements in visuoperceptual functioning.
Conclusions
Posterior cortical atrophy is a debilitating and under-recognised focal degenerative syndrome
which is associated with a range of different disease pathologies. The core features of the
syndrome are sufficiently homogeneous to justify considering PCA an independent nosology,
with AD as the most common underlying cause. However a lack of consistency in the
classification of PCA is likely to continue unless diagnostic criteria and terminology are
standardized. The proposed criteria in this review attempt to take both the clinical and
histopathological features of PCA into account, and to introduce quantifiable behavioural
inclusion criteria for research studies involving PCA. Better understanding and awareness of
the syndrome among the medical and lay communities is necessary to improve diagnosis,
treatment and support services provided to individuals with PCA and their families. Dissecting
out the distinctive patterns of structural, functional, cognitive and genetic changes in PCA may
lead to new insights into the pathogenesis and clinical features of typical AD, and to more
general mechanisms of visual network function and degeneration. Dedicated trials are
needed to assess the
effectiveness of pharmacological and non-pharmacological
interventions in PCA, and to identify factors driving phenotypic variability in this small but
significant population of patients typically with early onset dementia.
Acknowledgments
This work was undertaken at UCLH/UCL who received a proportion of funding from the
Department of Health’s NIHR Biomedical Research Centres funding scheme. The Dementia
Research Centre is an Alzheimer’s Research UK Co-ordinating Centre and has also received
equipment funded by the Alzheimer’s Research UK. SC is supported by an Alzheimer’s
Research UK Senior Research Fellowship and Equipment Grant; ML is supported by the
Alzheimer’s Society; JMS is a UK HEFCE Clinical Senior Lecturer and receives grant support
from Alzheimer’s Research UK; GDR receives research support from the NIH [NIA K23AG031861 (PI)], the Alzheimer’s Association, and the John Douglas French Alzheimer’s
Foundation; NCF is supported by an MRC (UK) Senior Clinical Fellowship, and MNR and
NCF hold National Institute for Health Research (NIHR) Senior Investigator awards.
Contributors
All authors contributed to the writing and reviewing of this paper.
Conflicts of interest
NCF has served on the scientific advisory boards of Alzheimer's Research Forum,
Alzheimer's Society and Alzheimer's Research Trust. He holds a patent for QA Box that might
accrue revenue. In the past 5 years, his research group has received payment for
consultancy or for conducting studies from Abbott Laboratories, Elan Pharmaceuticals, Eisai,
Eli Lilly, GE Healthcare, IXICO, Lundbeck, Pfizer Inc, Sanofi-Aventis, and Wyeth
Pharmaceuticals.
JMS
has
received
payment
for
conducting
studies
from AVID
Radiopharmaceuticals. SJC, ML, GDR and MNR have no conflicts of interest.
Search strategy and selection criteria
References for this Review were identified through searches of PubMed with the search
terms "Posterior Cortical Atrophy", "biparietal Alzheimer’s disease", "visual dementia", and
"Balint’s syndrome dementia" for articles published between 1970 and November 2011.
Articles were also identified through searches of the authors' own files. Only papers published
in English were reviewed, with the exception of historical manuscripts (pre-1988). The final
reference list was generated on the basis of originality and relevance to the broad scope of
this Review.
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Table 1. Overview of prevalence of ApoE ε4 in PCA, AD and controls. Shown are data from 7 studies that have reported ApoE ε4 frequency in PCA, and compared these
with typical (or sporadic) AD and controls.
PCA
Study
Total N Age at onset
Mendez et al. 2002
15
Tang-Wai et al. 2004
AD
Controls
N with
ApoE
ε4-frequency ε4-positive N
Age at onset N with
§
ApoE
ε4-frequency ε4-positiveN
ε4-frequencyε4positive
58.2(5.1)
8
25%
50%
176 ‡
-
176
40%
-
-
-
40
60.5 (8.9)
27
26%
48%
5107 †
-
5107
37%
59%
6262 † 14%
26%
Schott et al. 2006 *
10
56.1 (4.1)
10
10%
20%
29
65.6 (6.9)
29
52%
86%
-
-
-
Snowden et al. 2007 *
24
58.0 (4.0)
-
-
30%
321
58.0 (4.0)
-
-
82%
14%
27%
Migliaccio et al., 2009
14
-
11
-
55%
16
-
9
-
56%
44
-
23%
Baumann et al. 2010
9
56.7 (7.6)
9
-
39%
11
58.3 (5.1)
11
-
50%
14
-
14%
Rosenbloom et al. 2011
12
57.5 (7.4)
9
33%
44%
14
58.8 (9.6)
11
59%
73%
-
-
-
§
reported significant difference in ApoE ε4 between PCA and AD
†
Farrer et al. 1997
‡
Saunders et al. 1993
¶
Pendleton et al. 2002
§
for whole PCA and AD groups, age at onset for subsample of patients with ApoE unknown, except Schott et al. and Baumann et al.
¥
amnestic AD; proportion ε4-positive in memory/semantic AD group = 80%
*
¥
767
¶
-
Figure 1. Examples of visual dysfunction in PCA. (A) Impaired global perception of fragmented images which are comprised of multiple constituent parts, such as
numbers on an electronic information board, is a common early complaint © Yew Wah Kok | Dreamstime.com. (B) Unusual visual symptoms include the reverse size
effect, in which a reduced effective field of vision renders large stimuli more difficult to identify than small stimuli. Patients commonly report significantly greater difficulty
reading newspaper headlines than the small print © Janaka Dharmasena | Dreamstime.com. (C-D) Eyetracking studies contrasting scene perception in healthy
individuals (C) and patients with PCA (D) suggest poor top-down guidance and control of oculomotor function. Circles represent fixation locations and circle size
represents fixation duration. PCA patients fixate prominent features initially (e.g. dome on pier), but subsequently fixate relatively uninformative aspects of the scene
(e.g. sea/sky) and miss important contextual details (e.g. beachfront/near end of pier; Shakespeare and Crutch, unpublished).
A
B
C
D
Figure 2. Registered serial MR images showing axial views of an individual with PCA at four time points (ages 59–63 years old). Repeat scans were fluid-registered to
the baseline image and colour-coded voxel-compression maps were produced. The scale shows the percentage volume change per voxel (–20 to 20%) with green and
blue representing contraction and yellow and red representing expansion.
Box 1: Case study
Images are in neurologic orientation. L – left; R – right.
Case history: 62 year-old right-handed woman with four years of progressive
visuospatial dysfunction. Her first symptom was difficulty seeing when driving at night.
In the following years she frequently “dented” her car when parking, tended to “bump”
into doors on her right side and had trouble locating items even when they were
directly in front of her. She reported problems reading, trouble distinguishing between
currency bills and difficulty deciding whether to push or pull a door in order to open it.
When she watched television, images appeared to “move slowly.” She was referred to
the cognitive neurology clinic by an ophthalmologist who had ruled-out primary ocular
disease. On neurologic evaluation she was fully oriented and was an excellent
historian. On visual fields testing she was inconsistent counting fingers in the right
hemifield. Pupillary responses and extraocular movements were normal, though she
was slow initiating saccades and had difficulty reaching for items under visual
guidance. Her physical neurologic examination was otherwise normal. On cognitive
testing MMSE was 26/30, and she showed severe impairment when copying
intersecting pentagons and the Benson figure (Figure A). She was able to name
colours correctly but showed moderate difficulty matching faces. She had severe
difficulty reading, which was improved by spelling words out loud, and had mild deficits
in confrontation naming (improved with cues) and category fluency. Verbal memory,
phonemic fluency and attention were intact. She could not complete many tasks due
to visual dysfunction. Brain MRI showed marked atrophy in bilateral parietal, posterior
temporal and lateral occipital cortex (Fig B, top row), and FDG-PET (Fig B, middle
row) showed hypometabolism in the same regions, left worse than right. Frontal
cortex, medial temporal cortex and hippocampus were spared. PIB-PET showed
diffuse cortical uptake throughout posterior and anterior cortical regions alike (Figure
B, bottom row), consistent with underlying amyloid-beta plaques.