Posterior cortical atrophy misdiagnosed as typical Alzheimer's disease: Clinical and neuropsychological evolution over eight years. A case report

A 64-year-old man (GK) was referred to our memory clinic because of progressive memory and concentration problems. His symptoms had started 3 years earlier with gradually increasing visual problems for which no ophthalmologic explanations could be found. Neuropsychological assessment with detailed examination of the visuoperception revealed striking impairments in the higher-order visual functions, leading to a probable diagnosis of posterior cortical atrophy (PCA). The results of magnetic resonance imaging and cerebrospinal fluid examination supported the diagnosis. PCA is considered the posterior variant of Alzheimer's disease that typically presents with problems in visuoperception or, less frequent, apraxia. Despite its clear clinical features, the diagnosis of PCA is often delayed because of the focus on ophthalmologic examination. In this case report, the diagnosis of PCA in a 64-year-old man was not considered until further neuropsychological decay was evident. We argue that screening of higher-order visual functions can significantly contribute to an early diagnosis and treatment of PCA.

A 58-year-old right handed woman, with 12 years of formal education, had a five-year history of slowly progressive blurred vision and apraxia. Five years before the examination she gradually became blurred vision and had difficulties identifying static objects within the visual field. Then she went to an ophthalmologist and received cataract surgery. However, the symptoms were not improved after surgery. Two years later, she had difficulty doing household chores and was unable to dress herself. She developed an anxiety disorder in the absence of prominent language or memory deficits. Five years after onset, she showed global cognitive decline and abilities of daily life decline. On neurological examination she was alert. Neuropsychological testing revealed a mini-mental state examination (MMSE) score of 20/30 with anomia, agraphia, alexia and partial impairment on time orientation. Biochemical investigations for disorders involving thyroid function, vitamin B 12 , and folate were unremarkable. A brain MRI showed diffuse cortical atrophy and hippocampus atrophy. An 18 F-FDG PET scan showed bilateral hypometabolism at the frontal lobes, tempoparietooccipital adjunction, posterior cingulate cortices and precuneus, insular lobes, caudate nuclei and right thalamus. An 11 C-PIB PET scan showed bilateral amyloid deposits at bilateral frontal lobes and occipital lobes, left temporal lobe and insular, basal ganglia, bilateral cingulate cortices and precuneus. No PSEN1, PSEN2 or APP mutations were identified. This early-onset patient had an unusual cognitive complaint, including visual agnosia and apraxia. The clinical features, structural and functional imaging findings of this case were compatible with the diagnosis of Posterior Cortical Atrophy (PCA). PCA is a neurodegenerative condition characterized by a progressive, often dramatic and relatively selective decline in visual processing skills and other functions subserved by parietal, occipital and occipito-temporal regions, relatively intact memory and language in the early stages, and atrophy of posterior brain regions. Often considered as an atypical or variant form of Alzheimer’s disease (AD), PCA typically presents in the mid-50s or early 60s with a variety of unusual symptoms, such as difficulty in interpreting, locating, or reaching for objects under visual guidance or difficulty in navigating. Understanding numbers and reading and writing or spelling may also be affected and, as the disease progresses, patients often develop a more diffuse pattern of cognitive dysfunction, ultimately leading to dementia. The vast majority (>80%) of PCA patients are found to have AD pathology as the cause of dementia at autopsy. Both PCA and AD patients show a similar pattern of high cortical binding on amyloid positron emission tomography (PET) imaging, and analogous changes in cerebrospinal fluid (CSF) level of Aβ42, total tau, and phosphorylated tau. PCA and AD show overlapping atrophy and hypometabolism/hypoperfusion in temporoparietal regions, suggesting a common anatomic focus of neurodegeneration. Structural neuroimaging with either MRI or CT initially shows greater atrophy of visual processing areas in parietotemporo-occipital cortex and relative sparing of critical memory regions in the medial temporal lobe. Over time, the neuroimaging profile of PCA may also merge with that of typical AD. This patient has five-year history of blurred vision and apraxia. At the time of examination, she has been in the stage of global cognitive declining. Diffuse cortical atrophy and hippocampus atrophy in MRI is very difficult to distinguish from typical AD. Hypometabolism and amyloid deposits from PET scan also showed overlapping with typical AD. doi: 10.3969/j.issn.1672-6731.2014.07.018

Background: Predominant and progressive complex visual disorders are often due to posterior cortical atrophy (PCA), a rare early-onset dementing syndrome presenting with visual complaints. In clinicopathological studies, PCA is most commonly considered a form of Alzheimer’s disease (AD); no prior study has evaluated clinical differences between PCA and AD. Methods: This study identified 15 patients who presented with progressive complex visual disorders and predominant occipitoparietal hypoperfusion on SPECT. These patients were retrospectively compared on clinical variables with 30 patients with clinically probable AD matched for gender, age and duration of illness. Results: The PCA patients presented with alexia, elements of Balint’s syndrome, apperceptive visual agnosia, dressing apraxia and environmental disorientation along with elements of Gerstmann’s syndrome. Compared to the AD patients, the 15 PCA patients (mean age of onset 58 years, range 51–64) had significantly better verbal fluency, less memory difficulty, more depression and greater insight into their illness but similar familial and apolipoprotein E risk factors. In the PCA patients, MRI often showed occipitoparietal atrophy without detectable mesiotemporal atrophy. Conclusions: PCA is a distinct clinical syndrome and not just AD with prominent visual deficits. Compared to AD controls, PCA patients have better language and memory but more insight and depression and more posterior atrophy on MRI. These results indicate clinical criteria for the diagnosis of PCA and recommend specific interventions such as visual aids and antidepressant medications. Similar risk factors and course suggest that PCA is most commonly an early-onset posteriorly shifted AD variant.

Non-amnestic (or atypical) presentations of neurodegenerative dementias are underrecognized and underdiagnosed, including posterior cortical atrophy (PCA) syndrome, which is characterized by prominent visuospatial and visuoperceptual dysfunction at presentation. It is most commonly due to Alzheimer's disease pathology, while Lewy body disease, corticobasal degeneration, and prion disease are neuropathological entities that are less frequently associated with PCA. The diagnosis of PCA is often delayed, to the detriment of the patient, and awareness and understanding of PCA will improve detection, prognostication, and treatment. The natural history of PCA appears to be distinct from typical Alzheimer's disease and significant heterogeneity exists within the PCA syndrome, with the underlying causes of this heterogeneity beginning to be explored. Functional and molecular imaging can assist in better understanding PCA, particularly assessment of network disruptions that contribute to clinical phenotypes. Cerebrospinal fluid biomarkers are useful to detect underlying pathology, but measures of retinal thickness are less promising. There are currently no adequate treatment options for PCA. Continued efforts to characterize PCA are needed, and greater awareness and understanding of atypical presentations of neurodegenerative dementias could serve to elucidate pathobiological mechanisms of underlying disease.

Background Posterior cortical atrophy (PCA) is a kind of progressive neurodegenerative disease with cortical visual impairment as the first symptom. Because of rare clinical incidence, early onset age, special clinical symptoms and unobvious MRI abnormality, the definitive diagnosis of PCA is difficult. This study used 18 F-fluoro-2-deoxy-D-glucose ( 18 F-FDG) PET and 11 C-Pittsburgh compound B ( 11 C-PIB) PET for PCA patients with unobvious MRI abnormality, so as to discuss the value of PET in the early diagnosis of PCA. Methods Five patients diagnosed as PCA in our hospital between April 2012 and March 2015 were enrolled in this study. Cognitive function was measured by Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL) and Clock Drawing Test (CDT). Brain MRI, 18 F-FDG PET and 11 C-PIB PET were performed to analyze glucose metabolism and perfusion of posterior cortex. Results Neuropsychological tests revealed that the ability of writing, calculating, visuospatial and executive function of all these patients were impaired. Color vision tests showed abnormal results. MRI showed that the posterior atrophy (PA) scores were 0-2 (average 1) on the left side and 0-1 (average 0.80) on the right side. The medial temporal atrophy (MTA) scores were 1-3 (average 1.80) on the left side and 1-4 (average 2) on the right side. The ventricular enlargement (VE) scores were 1-2 (average 1.80) on the left side and 1-2 (average 1.60) on the right side. 18 F-FDG PET showed glucose metabolism decreased obviously on bilateral temporo-parieto-occipital cortex, precuneus and cingulate gyrus, and slightly on frontal lobes and subcortical structure. 11 C-PIB PET showed radioactive 11 C-PIB deposition on bilateral frontal, temporal, parietal and occipital cortex, and the outline of cerebellar cortex was clear. Conclusions For PCA patients whose parietal and occipital cortical atrophy is not obvious on MRI, 18 F-FDG PET combined with 11 C-PIB PET plays an important role in early diagnosis. DOI: 10.3969/j.issn.1672-6731.2015.08.005

Posterior cortical atrophy (PCA) is a clinicoradiologic neurodegenerative syndrome characterized by predominant impairment of higher visual functions. Neuroimaging and neuropathological studies show that PCA is probably an atypical presentation of Alzheimer’s disease. However, in China PCA has rarely been studied and remains largely unknown. Our study therefore aimed to analyze the clinical manifestations and patterns of cerebral atrophy, amyloid beta deposition and regional glucose metabolism in Chinese PCA patients, comparing them directly with those of typical Alzheimer’s disease (TAD). Seven PCA patients, 6 TAD patients and 5 controls underwent neuropsychological assessment, MRI scan, 11C-PIB PET scan and 18F-FDG PET scan. Cerebral atrophy including ventricular enlargement, posterior atrophy and medial temporal lobe atrophy were evaluated with MRI. The uptake of 11C-PIB was quantified at the voxel level using the standardized uptake value ratio. Comparisons of regional cerebral glucose metabolism were calculated with statistical parametric mapping. PCA patients showed significant impairment on visuospatial function in neuropsychological assessment. And PCA patients showed more severe posterior atrophy and less severe left medial temporal lobe atrophy compared with TAD patients. The data from 11C-PIB PET scanning showed that amyloid beta deposition in PCA was comparable to TAD. Moreover, in PCA the results from 18F-FDG PET scanning revealed significant hypometabolism in the temporoparietooccipital region and identified specific hypometabolism in the right occipital lobe, compared with TAD. Our study thus provides a preliminary view of PCA in Chinese patients. A further study with a larger number of subjects would be recommended to confirm these findings.

Association between precuneus volume and autobiographical memory impairment in posterior cortical atrophy: Beyond the visual syndrome.

INTRODUCTIONDelay in diagnosis of posterior cortical atrophy (PCA) syndrome is common, and the lack of familiarity with assessment tools for identifying visual cortical dysfunction is a contributing factor. We propose recommendations for the approach to the evaluation of PCA clinical features during the office visit, the neuropsychological evaluation, and the research setting. A recommended screening battery for eye clinics is also proposed.METHODSRecommendations were developed using results from a web‐based survey of members of Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Atypical Alzheimer's Disease Professional Interest Area (PIA), literature review, and consensus by the PCA assessment working party of the Atypical Alzheimer's Disease PIA.RESULTSSurvey results revealed robust agreement for assessment tool preferences for PCA features, and many respondents indicated that they reserve assessment tools for use only when PCA is suspected. For some PCA features, curated tools were preferred over validated battery tools, particularly for the office visit. Consensus recommendations superseded survey preferences for two core cognitive features within the 2017 PCA diagnostic criteria.DISCUSSIONThese consensus recommendations provide an evaluation framework for PCA clinical features and can facilitate timely and accurate recognition and diagnosis of PCA. Broader use of these tools should be sought, and development and validation of novel PCA clinical outcome assessments are needed to improve our understanding of atypical AD and other dementias and support the inclusion of those with PCA in treatment trials.

Posterior cortical atrophy is a clinico-radiological syndrome characterized by progressive decline in visual processing and atrophy of posterior brain regions. With the majority of cases attributable to Alzheimer's disease and recent evidence for genetic risk factors specifically related to posterior cortical atrophy, the syndrome can provide important insights into selective vulnerability and phenotypic diversity. The present study describes the first major longitudinal investigation of posterior cortical atrophy disease progression. Three hundred and sixty-one individuals (117 posterior cortical atrophy, 106 typical Alzheimer's disease, 138 controls) fulfilling consensus criteria for posterior cortical atrophy-pure and typical Alzheimer's disease were recruited from three centres in the UK, Spain and USA. Participants underwent up to six annual assessments involving MRI scans and neuropsychological testing. We constructed longitudinal trajectories of regional brain volumes within posterior cortical atrophy and typical Alzheimer's disease using differential equation models. We compared and contrasted the order in which regional brain volumes become abnormal within posterior cortical atrophy and typical Alzheimer's disease using event-based models. We also examined trajectories of cognitive decline and the order in which different cognitive tests show abnormality using the same models. Temporally aligned trajectories for eight regions of interest revealed distinct (P < 0.002) patterns of progression in posterior cortical atrophy and typical Alzheimer's disease. Patients with posterior cortical atrophy showed early occipital and parietal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion leading to tissue loss of comparable extent later. Hippocampal, entorhinal and frontal regions underwent a lower rate of change and never approached the extent of posterior cortical involvement. Patients with typical Alzheimer's disease showed early hippocampal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion. Cognitive models showed tests sensitive to visuospatial dysfunction declined earlier in posterior cortical atrophy than typical Alzheimer's disease whilst tests sensitive to working memory impairment declined earlier in typical Alzheimer's disease than posterior cortical atrophy. These findings indicate that posterior cortical atrophy and typical Alzheimer's disease have distinct sites of onset and different profiles of spatial and temporal progression. The ordering of disease events both motivates investigation of biological factors underpinning phenotypic heterogeneity, and informs the selection of measures for clinical trials in posterior cortical atrophy.

Previous studies suggest that posterior cortical atrophy may be a useful marker for early onset Alzheimer's disease (AD). Dementia with Lewy bodies (DLB) is associated with less temporal lobe atrophy than AD, though posterior cortical atrophy may be greater. Therefore, we assessed whether visual rating scales for assessing posterior atrophy (PA), medial temporal lobe atrophy (MTA), and ventricular enlargement (VEn) aid in the discrimination between AD, DLB, and normal aging. T1-weighted MRI scans acquired at 3 Tesla were visually rated for PA (range 0-3), MTA (range 0-4), and VEn (range 0-3) in older subjects with AD (n = 36), DLB (n = 35), and healthy controls (n = 35). The diagnostic utility of MTA, PA, and VEn visual ratings in distinguishing AD and DLB from controls as well as AD from DLB was investigated. Significantly higher MTA ratings were associated with AD and DLB compared to controls (p < 0.001). MTA ratings were greater in AD relative to DLB (U = 384.5, p = 0.004). For PA ratings, scores did not differ between groups (p = 0.20). VEn ratings were significantly higher in AD and DLB compared to controls (p = 0.003), but similar between AD and DLB (U = 384.5, p = 0.4). Unlike findings reported in younger subjects, visual ratings for PA are not a reliable marker at older ages for distinguishing AD from controls, or for distinguishing DLB from AD. However, visual ratings of MTA and VEn may be useful markers in distinguishing both AD and DLB from older subjects without dementia.

Cortical thickness and voxel-based morphometry in posterior cortical atrophy and typical Alzheimer's disease.

While the clinical presentation of posterior cortical atrophy is clearly distinct from typical Alzheimer's disease, neuropathological studies have suggested that most patients with posterior cortical atrophy have Alzheimer's disease with an atypical visual presentation. We analysed in vivo pathophysiological markers of Alzheimer's disease such as cerebrospinal fluid biomarkers and positron emission tomography imaging with ¹¹C-labelled Pittsburgh compound-B in posterior cortical atrophy to determine whether biochemical profile and fibrillar amyloid-β burden topography are associated with the clinical presentation. Nine patients with posterior cortical atrophy and nine with typical Alzheimer's disease individually matched for age, duration and severity of the disease and 10 cognitively normal age-matched controls were included. ¹¹C-labelled Pittsburgh compound-B images were analysed both using volumes of interest and on a voxel-wise basis using statistical parametric mapping, taking into account the individual regional cortical atrophy. Cerebrospinal fluid biomarkers did not differ between posterior cortical atrophy and patients with Alzheimer's disease. Compared with normal controls, both posterior cortical atrophy and Alzheimer's disease groups showed increased ¹¹C-labelled Pittsburgh compound-B uptake. No significant difference was found in regional or global ¹¹C-labelled Pittsburgh compound-B binding between posterior cortical atrophy and Alzheimer's disease groups with both volumes of interest and voxel-wise basis using statistical parametric mapping methods. Our findings demonstrate that cerebrospinal fluid biomarkers and positron emission tomography imaging with ¹¹C-labelled Pittsburgh compound-B may be useful in identifying an atypical visual form of Alzheimer's disease. The similar topography of fibrillar amyloid-β deposition between typical Alzheimer's disease and posterior cortical atrophy groups suggests that, although amyloid-β accumulation plays a critical role in the pathogenesis of Alzheimer's disease, other factors such as neurofibrillary tangles may contribute to the different clinical features observed in posterior cortical atrophy.

The clinico-neuroradiological syndrome posterior cortical atrophy is the cardinal 'visual dementia' and most common atypical Alzheimer's disease phenotype, offering insights into mechanisms underlying clinical heterogeneity, pathological propagation and basic visual phenomena (e.g. visual crowding). Given the extensive attention paid to patients' (higher order) perceptual function, it is surprising that there have been no systematic analyses of basic oculomotor function in this population. Here 20 patients with posterior cortical atrophy, 17 patients with typical Alzheimer's disease and 22 healthy controls completed tests of fixation, saccade (including fixation/target gap and overlap conditions) and smooth pursuit eye movements using an infrared pupil-tracking system. Participants underwent detailed neuropsychological and neurological examinations, with a proportion also undertaking brain imaging and analysis of molecular pathology. In contrast to informal clinical evaluations of oculomotor dysfunction frequency (previous studies: 38%, current clinical examination: 33%), detailed eyetracking investigations revealed eye movement abnormalities in 80% of patients with posterior cortical atrophy (compared to 17% typical Alzheimer's disease, 5% controls). The greatest differences between posterior cortical atrophy and typical Alzheimer's disease were seen in saccadic performance. Patients with posterior cortical atrophy made significantly shorter saccades especially for distant targets. They also exhibited a significant exacerbation of the normal gap/overlap effect, consistent with 'sticky fixation'. Time to reach saccadic targets was significantly associated with parietal and occipital cortical thickness measures. On fixation stability tasks, patients with typical Alzheimer's disease showed more square wave jerks whose frequency was associated with lower cerebellar grey matter volume, while patients with posterior cortical atrophy showed large saccadic intrusions whose frequency correlated significantly with generalized reductions in cortical thickness. Patients with both posterior cortical atrophy and typical Alzheimer's disease showed lower gain in smooth pursuit compared to controls. The current study establishes that eye movement abnormalities are near-ubiquitous in posterior cortical atrophy, and highlights multiple aspects of saccadic performance which distinguish posterior cortical atrophy from typical Alzheimer's disease. We suggest the posterior cortical atrophy oculomotor profile (e.g. exacerbation of the saccadic gap/overlap effect, preserved saccadic velocity) reflects weak input from degraded occipito-parietal spatial representations of stimulus location into a superior collicular spatial map for eye movement regulation. This may indicate greater impairment of identification of oculomotor targets rather than generation of oculomotor movements. The results highlight the critical role of spatial attention and object identification but also precise stimulus localization in explaining the complex real world perception deficits observed in posterior cortical atrophy and many other patients with dementia-related visual impairment.

Posterior cortical atrophy is a dementia syndrome with symptoms of cortical visual dysfunction, associated with amyloid plaques and neurofibrillary tangles predominantly affecting visual association cortex. Most patients diagnosed with posterior cortical atrophy will finally develop a typical Alzheimer's disease. However, there are a variety of neuropathological processes, which could lead towards a clinical presentation of posterior cortical atrophy. Mutations in the presenilin 1 gene, affecting the function of γ-secretase, are the most common genetic cause of familial, early-onset Alzheimer's disease. Here we present a patient with a clinical diagnosis of posterior cortical atrophy who harbors a novel Presenilin 1 mutation (I211M). In silico analysis predicts that the mutation could influence the interaction between presenilin 1 and presenilin1 enhancer-2 protein, a protein partner within the γ-secretase complex. These findings along with published literature support the inclusion of posterior cortical atrophy on the Alzheimer's disease spectrum.

Atrophy, metabolism and cognition in the posterior cortical atrophy spectrum based on Alzheimer's disease cerebrospinal fluid biomarkers.