Evaluating pathogenic dementia variants in posterior cortical atrophy.
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ABSTRACT:
SUBMITTER: Carrasquillo MM
PROVIDER: S-EPMC4688220 | biostudies-literature | 2016 Jan
REPOSITORIES: biostudies-literature
Publications
Evaluating pathogenic dementia variants in posterior cortical atrophy.
Carrasquillo Minerva M MM Barber Imelda I Lincoln Sarah J SJ Murray Melissa E ME Camsari Gamze Balci GB Khan Qurat Ul Ain QUA Nguyen Thuy T Ma Li L Bisceglio Gina D GD Crook Julia E JE Younkin Steven G SG Dickson Dennis W DW Boeve Bradley F BF Graff-Radford Neill R NR Morgan Kevin K Ertekin-Taner Nilüfer N
Neurobiology of aging 20151008
Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia ...[more]
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Project description:ObjectiveTo determine whether atrophy relates to phenotypical variants of posterior cortical atrophy (PCA) recently proposed in clinical criteria (i.e., dorsal, ventral, dominant-parietal, and caudal) we assessed associations between latent atrophy factors and cognition.MethodsWe employed a data-driven Bayesian modeling framework based on latent Dirichlet allocation to identify latent atrophy factors in a multicenter cohort of 119 individuals with PCA (age 64 ± 7 years, 38% male, Mini-Mental State Examination 21 ± 5, 71% β-amyloid positive, 29% β-amyloid status unknown). The model uses standardized gray matter density images as input (adjusted for age, sex, intracranial volume, MRI scanner field strength, and whole-brain gray matter volume) and provides voxelwise probabilistic maps for a predetermined number of atrophy factors, allowing every individual to express each factor to a degree without a priori classification. Individual factor expressions were correlated to 4 PCA-specific cognitive domains (object perception, space perception, nonvisual/parietal functions, and primary visual processing) using general linear models.ResultsThe model revealed 4 distinct yet partially overlapping atrophy factors: right-dorsal, right-ventral, left-ventral, and limbic. We found that object perception and primary visual processing were associated with atrophy that predominantly reflects the right-ventral factor. Furthermore, space perception was associated with atrophy that predominantly represents the right-dorsal and right-ventral factors. However, individual participant profiles revealed that the large majority expressed multiple atrophy factors and had mixed clinical profiles with impairments across multiple domains, rather than displaying a discrete clinical-radiologic phenotype.ConclusionOur results indicate that specific brain behavior networks are vulnerable in PCA, but most individuals display a constellation of affected brain regions and symptoms, indicating that classification into 4 mutually exclusive variants is unlikely to be clinically useful.
| S-EPMC7713727 | biostudies-literature
Project description:There is general agreement that perisylvian language cortex plays a major role in lexical and semantic processing; but the contribution of additional, more widespread, brain areas in the processing of different semantic word categories remains controversial. We investigated word processing in two groups of patients whose neurodegenerative diseases preferentially affect specific parts of the brain, to determine whether their performance would vary as a function of semantic categories proposed to recruit those brain regions. Cohorts with (i) Semantic Dementia (SD), who have anterior temporal-lobe atrophy, and (ii) Posterior Cortical Atrophy (PCA), who have predominantly parieto-occipital atrophy, performed a lexical decision test on words from five different lexico-semantic categories: colour (e.g., yellow), form (oval), number (seven), spatial prepositions (under) and function words (also). Sets of pseudo-word foils matched the target words in length and bi-/tri-gram frequency. Word-frequency was matched between the two visual word categories (colour and form) and across the three other categories (number, prepositions, and function words). Age-matched healthy individuals served as controls. Although broad word processing deficits were apparent in both patient groups, the deficit was strongest for colour words in SD and for spatial prepositions in PCA. The patterns of performance on the lexical decision task demonstrate (a) general lexicosemantic processing deficits in both groups, though more prominent in SD than in PCA, and (b) differential involvement of anterior-temporal and posterior-parietal cortex in the processing of specific semantic categories of words.
| S-EPMC5542041 | biostudies-other
Project description:ObjectiveTo investigate association of genetic risk factors for late-onset Alzheimer disease (LOAD) with risk of posterior cortical atrophy (PCA), a syndrome of visual impairment with predominant Alzheimer disease (AD) pathology in posterior cortical regions, and with risk of "posterior AD" neuropathology.MethodsWe assessed 81 participants with PCA diagnosed clinically and 54 with neuropathologic diagnosis of posterior AD vs 2,523 controls for association with 11 significant single nucleotide polymorphisms (SNPs) from published LOAD risk genome-wide association studies.ResultsThere was highly significant association with APOE ε4 and increased risk of PCA (p = 0.0003, odds ratio [OR] = 3.17) and posterior AD (p = 1.11 × 10(-17), OR = 6.43). No other locus was significant after corrections for multiple testing, although rs11136000 near CLU (p = 0.019, OR = 0.60) and rs744373 near BIN1 (p = 0.025, OR = 1. 63) associated nominally significantly with posterior AD, and rs3851179 at the PICALM locus had significant association with PCA (p = 0.0003, OR = 2.84). ABCA7 locus SNP rs3764650, which was also tested under the recessive model because of Hardy-Weinberg disequilibrium, also had nominally significant association with PCA risk. The direction of association at APOE, CLU, and BIN1 loci was the same for participants with PCA and posterior AD. The effects for all SNPs, except rs3851179, were consistent with those for LOAD risk.ConclusionsWe identified a significant effect for APOE and nominate CLU, BIN1, and ABCA7 as additional risk loci for PCA and posterior AD. Our findings suggest that at least some of the genetic risk factors for LOAD are shared with these atypical conditions and provide effect-size estimates for their future genetic studies.
| S-EPMC4001196 | biostudies-literature
Project description:Flortaucipir (tau) positron emission tomography (PET) binding distinguishes individuals with clinically well-established posterior cortical atrophy (PCA) due to Alzheimer disease (AD) from cognitively normal (CN) controls. However, it is not known whether tau-PET binding patterns differentiate individuals with PCA from those with amnestic AD, particularly early in the symptomatic stages of disease.Flortaucipir and florbetapir (?-amyloid) PET imaging were performed in individuals with early-stage PCA (N=5), amnestic AD dementia (N=22), and CN controls (N=47). Average tau and ?-amyloid deposition were quantified using standard uptake value ratios and compared at a voxelwise level, controlling for age.PCA patients [median age-at-onset, 59 (51 to 61) years] were younger at symptom onset than similarly staged individuals with amnestic AD [75 (60 to 85) years] or CN controls [73 (61 to 90) years; P=0.002]. Flortaucipir uptake was higher in individuals with early-stage symptomatic PCA versus those with early-stage amnestic AD or CN controls, and greatest in posterior regions. Regional elevations in florbetapir were observed in areas of greatest tau deposition in PCA patients.Flortaucipir uptake distinguished individuals with PCA and amnestic AD dementia early in the symptomatic course. The posterior brain regions appear to be uniquely vulnerable to tau deposition in PCA, aligning with clinical deficits that define this disease subtype.
| S-EPMC5443698 | biostudies-literature
Project description:BackgroundPosterior cortical atrophy (PCA) and semantic dementia (SD) are focal syndromes involving different cerebral regions. This study aimed to demonstrate the existence of abnormal functional connectivity (FC) with an affected network in PCA and SD.MethodsA total of 10 patients with PCA, 12 patients with SD, and 11 controls were recruited to undergo a detailed clinical history interview and physical examination, neuropsychological assessments, and PET/MRI scan. Seed-based FC analyses were conducted to construct FC in language network, visual network, and salience network. The two-sample t-test was performed to reveal distinct FC patterns in PCA and SD, and we further related the FC difference to cognition. Meanwhile, the uptake value of fluorodeoxyglucose in regions with FC alteration was also extracted for comparison.ResultsWe found a global cognitive impairment in patients with PCA and SD. The results of FC analyses showed that patients with PCA present decreased FC in left precentral gyrus to left V1 and increased FC in right inferior frontal gyrus to right V1 in the visual network, right medial frontal gyrus and left fusiform to left anterior temporal lobe and post-superior temporal gyrus in the language network, and left superior temporal gyrus to left anterior insula in the salience network, which were related to cognitive function. Patients with SD had decreased FC from right superior frontal gyrus, right middle frontal gyrus and right superior frontal gyrus to left anterior temporal lobe, or post-superior temporal gyrus in the language network, as well as left superior frontal gyrus to right anterior insula in the salience network, positively relating to cognitive function, but increased FC in the right superior temporal gyrus to left anterior temporal lobe in the language network, and right insula and left anterior cingulum to right anterior insula in the salience network, negatively relating to cognitive function. Most of the regions with FC change in patients with PCA and SD had abnormal metabolism simultaneously.ConclusionAbnormal connectivity spread over the cortex involving language and salience networks was common in patients with PCA and SD, whereas FC change involving the visual network was unique to patients with PCA. The FC changes were matched for cognitive deficits.
| S-EPMC9099291 | biostudies-literature
Project description:This study investigated the functional brain connectome architecture in patients with Posterior Cortical Atrophy (PCA). Eighteen PCA patients and 29 age- and sex- matched healthy controls were consecutively recruited in a specialized referral center. Participants underwent neurologic examination, cerebrospinal fluid (CSF) examination for Alzheimer's disease (AD) biomarkers, cognitive assessment, and brain MRI. For a smaller subset of participants, FDG-PET examination was available. We assessed topological brain network properties and regional functional connectivity as well as intra- and inter-hemispheric connectivity, using graph analysis and connectomics. Supplementary analyses were performed to explore the association between the CSF AD profile and the connectome status, and taking into account hypometabolic, atrophic, and spared regions (nodes). PCA patients showed diffuse functional connectome alterations at both global and regional level, as well as a connectivity breakdown between the posterior brain nodes. They had a widespread loss of both intra- and inter-hemispheric connections, exceeding the structural damage, and including the frontal connections. In PCA, connectome alterations were identified in all the brain nodes irrespectively of their structural and metabolic classification and were associated with a connectivity breakdown between damaged and spared areas. Taken together, these findings suggest the potentially high sensitivity of graph-analysis and connectomic in capturing the progression and maybe early signs of neurodegeneration in PCA patients.
| S-EPMC6931188 | biostudies-literature
Project description:ObjectiveWe report (1) the quantitative investigation of text reading in posterior cortical atrophy (PCA), and (2) the effects of 2 novel software-based reading aids that result in dramatic improvements in the reading ability of patients with PCA.MethodsReading performance, eye movements, and fixations were assessed in patients with PCA and typical Alzheimer disease and in healthy controls (experiment 1). Two reading aids (single- and double-word) were evaluated based on the notion that reducing the spatial and oculomotor demands of text reading might support reading in PCA (experiment 2).ResultsMean reading accuracy in patients with PCA was significantly worse (57%) compared with both patients with typical Alzheimer disease (98%) and healthy controls (99%); spatial aspects of passages were the primary determinants of text reading ability in PCA. Both aids led to considerable gains in reading accuracy (PCA mean reading accuracy: single-word reading aid = 96%; individual patient improvement range: 6%-270%) and self-rated measures of reading. Data suggest a greater efficiency of fixations and eye movements under the single-word reading aid in patients with PCA.ConclusionsThese findings demonstrate how neurologic characterization of a neurodegenerative syndrome (PCA) and detailed cognitive analysis of an important everyday skill (reading) can combine to yield aids capable of supporting important everyday functional abilities.Classification of evidenceThis study provides Class III evidence that for patients with PCA, 2 software-based reading aids (single-word and double-word) improve reading accuracy.
| S-EPMC4520813 | biostudies-literature
Project description:BackgroundPosterior cortical atrophy (PCA) is typically considered to be a visual syndrome, primarily characterised by progressive impairment of visuoperceptual and visuospatial skills. However, patients commonly describe early difficulties with word retrieval. This paper details the first systematic analysis of linguistic function in PCA. Characterising and quantifying the aphasia associated with PCA is important for clarifying diagnostic and selection criteria for clinical and research studies.Methods15 patients with PCA, seven patients with logopenic/phonological aphasia (LPA) and 18 age matched healthy participants completed a detailed battery of linguistic tests evaluating auditory input processing, repetition and working memory, lexical and grammatical comprehension, single word retrieval and fluency, and spontaneous speech.ResultsRelative to healthy controls, PCA patients exhibited language impairments across all of the domains examined, but with anomia, reduced phonemic fluency and slowed speech rate the most prominent deficits. PCA performance most closely resembled that of LPA patients on tests of auditory input processing, repetition and digit span, but was relatively stronger on tasks of comprehension and spontaneous speech.ConclusionsThe study demonstrates that in addition to the well reported degradation of vision, literacy and numeracy, PCA is characterised by progressive oral language dysfunction with prominent word retrieval difficulties. Overlap in the linguistic profiles of PCA and LPA, which are both most commonly caused by Alzheimer's disease, further emphasises the notion of a phenotypic continuum between typical and atypical manifestations of the disease. Clarifying the boundaries between Alzheimer's disease phenotypes has important implications for diagnosis, clinical trial recruitment and investigations into biological factors driving phenotypic heterogeneity in Alzheimer's disease. Rehabilitation strategies to ameliorate the phonological deficit in PCA are required.
| S-EPMC4667396 | biostudies-literature
Project description:ObjectivesTo investigate the global cortical and regional quantitative features of cortical neural architecture in the brains of patients with posterior cortical atrophy (PCA) and typical Alzheimer's disease (tAD) compared with elderly healthy controls (HC).MethodsA novel diffusion MRI method, that has been shown to correlate with minicolumnar organization changes in the cerebral cortex, was used as a surrogate of neuropathological changes in dementia. A cohort of 15 PCA patients, 23 tAD and 22 healthy elderly controls (HC) were enrolled to investigate the changes in cortical diffusivity among groups. For each subject, 3 T MRI T1-weighted images and diffusion tensor imaging (DTI) scans were analysed to extract novel cortical DTI derived measures (AngleR, PerpPD and ParlPD). Receiver operating characteristics (ROC) curve analysis and the area under the curve (AUC) were used to assess the group discrimination capability of the method.ResultsThe results showed that the global cortical DTI derived measures were able to detect differences, in both PCA and tAD patients compared to healthy controls. The AngleR was the best measure to discriminate HC from tAD (AUC?=?0.922), while PerpPD was the best measure to discriminate HC from PCA (AUC?=?0.961). Finally, the best global measure to differentiate the two patient groups was ParlPD (AUC?=?0.771). The comparison between PCA and tAD patients revealed a different pattern of damage within the AD spectrum and the regional comparisons identified significant differences in key regions including parietal and temporal lobe cortical areas. The best AUCs were shown by PerpPD right lingual cortex (AUC?=?0.856), PerpPD right superior parietal cortex (AUC?=?0.842) and ParlPD right lateral occipital cortex (AUC?=?0.826).ConclusionsDiagnostic group differences were found, suggesting that the new cortical DTI analysis method may be useful to investigate cortical changes in dementia, providing better characterization of neurodegeneration, and potentially aiding differential diagnosis and prognostic accuracy.
| S-EPMC7815619 | biostudies-literature
Project description:We present longitudinal clinical, cognitive, and neuroimaging data from a 63-year-old woman who enrolled in research as a normal control and evolved posterior cortical atrophy (PCA) over 5 year follow-up. At baseline she reported only subtle difficulty driving and performed normally on cognitive tests, but already demonstrated atrophy in left visual association cortex. With follow-up she developed insidiously progressive visuospatial and visuoperceptual deficits, correlating with progressive atrophy in bilateral visual areas. Amyloid PET was positive. This case tracks the evolution of PCA from the prodromal stage, and illustrates challenges to early diagnosis as well as the utility of imaging biomarkers.
| S-EPMC4318700 | biostudies-literature