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Results of MRI and SPECT examination of a control subject. Magnetic Resonance Imaging and Single Photon Emission Computed Tomography demonstrating the normal scans of a control, age-matched patient with no signs of any neurodegenerative disorder. doi:10.1371/journal.pone.0061074.g003
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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 neu...
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... atrophy was less pronounced in the frontal and temporal lobes, and the hippocampal structures of the temporal lobes were mostly preserved. Single Photon Emission Computed Tomography (SPECT) demonstrated severe hypoperfusion within the parietal, occipital and temporal lobes bilaterally ( Figure 2; compare with Figure 3 showing MRI/SPECT brain images from a control subject). Visual evoked potentials test showed reduced amplitude of P100 with prolonged latency (138 ms) on the left and normal amplitude with prolonged latency on the right (123 ms). ...
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Citations
... Non-AD pathologies underlying PCA include Lewy body disease (LBD), frontotemporal lobar degeneration (FTLD) with tau or TDP-43 inclusions and (rarely) prion disease. The PCA syndrome is nearly always sporadic, though in rare cases the syndrome has been reported in patients carrying known pathogenic mutations associated with autosomal dominant AD (PSEN1/PSEN2) or FTLD (GRN, MAPT) [3,[13][14][15][16][17]. In PCA-AD, a greater degree of AD pathology (neurofibrillary tangles) has been documented in occipital and cortical regions compared to people who have more typical, memory-led AD [4,[18][19][20][21]. ...
Purpose of review
The study aims to provide a summary of recent developments for diagnosing and managing posterior cortical atrophy (PCA). We present current efforts to improve PCA characterisation and recommendations regarding use of clinical, neuropsychological and biomarker methods in PCA diagnosis and management and highlight current knowledge gaps.
Recent findings
Recent multi-centre consensus recommendations provide PCA criteria with implications for different management strategies (e.g. targeting clinical features and/or disease). Studies emphasise the preponderance of primary or co-existing Alzheimer’s disease (AD) pathology underpinning PCA. Evidence of approaches to manage PCA symptoms is largely derived from small studies.
Summary
PCA diagnosis is frequently delayed, and people are likely to receive misdiagnoses of ocular or psychological conditions. Current treatment of PCA is symptomatic — pharmacological and non-pharmacological — and the use of most treatment options is based on small studies or expert opinion. Recommendations for non-pharmacological approaches include interdisciplinary management tailored to the PCA clinical profile — visual-spatial — rather than memory-led, predominantly young onset — and psychosocial implications. Whilst emerging disease-modifying treatments have not been tested in PCA, an accurate and timely diagnosis of PCA and determining underlying pathology is of increasing importance in the advent of disease-modifying therapies for AD and other albeit rare causes of PCA.
... A total of 144 subjects (127 AD vs. 17 FTD/non-AD) diagnosed with PCA, from 40 studies, were included in this review (Beaufils et al. 2013;Caroppo et al. 2015;Chan et al. 2015;Coppi et al. 2014;Cretin et al. 2015;de Souza et al. 2018;Duker et al. 2012;Fitzpatrick et al. 2019;Giunta et al. 2021;Jellinger et al. 2011;Kawakatsu et al. 2017;Koch et al. 2004;Lorusso et al. 2020;Mares et al. 2015;Meyer and Hudock 2018;Migliaccio et al. 2016;Mitchell et al. 2017;Nedelska et al. 2019;Ossenkoppele et al. 2015;Pavisic et al. 2019;Pelak et al. 2011;Pellegrini et al. 2017;Peng et al. 2016;Reñé et al. 2012;Renner et al. 2004;Rocher et al. 2020;Rosini et al. 2017;Rossi et al. 2014;Salvadori et al. 2018;Shea and Chu 2014;Singh et al. 2015;Sitek et al. 2013;Spagnolo et al. 2011;Sugimoto et al. 2012;Tenovuo et al. 2008;Wagner et al. 2018;Whitwell et al. 2017;Zangrandi et al. 2020). ...
Posterior cortical atrophy (PCA) is a neurodegenerative disorder characterized by an early prominent deficit of visual functions associated with signs and symptoms that are the expression of dysfunction of posterior brain regions. Although PCA is commonly associated with Alzheimer’s disease (AD), in recent years new pathological substrates have emerged. Among them, frontotemporal lobar degeneration (FTLD) is the most commonly reported but, to date, little is known about the clinical features of PCA due to FTLD. We conducted a systematic search in the main biomedical database MEDLINE. We searched for all clinical PCA reports that assessed the pathological basis of such syndrome with at least one of the following: (1) neuropathological examination, (2) cerebrospinal fluid biomarkers, (3) amyloid-PET imaging and (4) genetic testing. Of 369 potentially eligible studies, 40 fulfilled the inclusion criteria with an overall number of 144 patients (127 PCA-AD vs. 17 PCA-FTD/non-AD). We found that hallucinations/illusions were present in none of the probable PCA-FTD/non-AD subjects while were reported in 15 out of 97 PCA-AD individuals. Optic ataxia and Parkinsonism showed a significantly greater prevalence in probable PCA FTD/non-AD than in PCA-AD whereas myoclonus and disorientation in time and space were significantly more frequent in PCA-AD than in probable PCA FTD/non-AD. We also found a predominance of a left-side pattern of atrophy/hypometabolism in the probable PCA FTD/non-AD. Clinical features such as optic ataxia, Parkinsonism, myoclonus, hallucinations and disorientation in time and space suggest the underlying pathological basis of PCA and help in leading the diagnostic protocol consequently.
... Conversely, atypical presentations of autosomal dominant AD can occur, so that patients with mutations that cause AD receive clinical diagnoses other than AD; for example, PSEN1 mutations have been identified in patients who have been diagnosed with FTD, prion disease and dementia-motor syndromes 23,64,65 . Interestingly, the posterior cortical atrophy variant of AD, which involves progressive impairment of higher visual processing, has a young age of onset but is almost invariably a sporadic condition [66][67][68] and has only rarely been reported as possible autosomal dominant AD (a novel PSEN1 variant) 69 . ...
Techniques for clinical genetic testing in dementia disorders have advanced rapidly but remain to be more widely implemented in practice. A positive genetic test offers a precise molecular diagnosis, can help members of an affected family to determine personal risk, provides a basis for reproductive choices and can offer options for clinical trials. The likelihood of identifying a specific genetic cause of dementia depends on the clinical condition, the age at onset and family history. Attempts to match phenotypes to single genes are mostly inadvisable owing to clinical overlap between the dementias, genetic heterogeneity, pleiotropy and concurrent mutations. Currently, the appropriate genetic test in most cases of dementia is a next-generation sequencing gene panel, though some conditions necessitate specific types of test such as repeat expansion testing. Whole-exome and whole-genome sequencing are becoming financially feasible but raise or exacerbate complex issues such as variants of uncertain significance, secondary findings and the potential for re-analysis in light of new information. However, the capacity for data analysis and counselling is already restricting the provision of genetic testing. Patients and their relatives need to be given reliable information to enable them to make informed choices about tests, treatments and data sharing; the ability of patients with dementia to make decisions must be considered when providing this information.
... While PCA is rarely related to an autosomal dominant-inherited condition [11], it is important nonetheless to take a comprehensive family history, as complex genetic factors may play a role in PCA. For example, mutations in PSEN1 [78] and the HTT gene [79] have been described in suspected cases of PCA, along with a report of familial prion disease associated with a 5-octapeptide insertion in the prion protein (5-OPRI) [80]. Mutations in two of the three most common known genetic causes of frontotemporal lobar degeneration -microtubule associated protein tau (MAPT) [81] and progranulin (GRN) [12] -have been identified recently in PCA patients, although both reported cases lacked neuropathologic confirmation. ...
Posterior cortical atrophy (PCA) is a progressive neurocognitive syndrome, most commonly associated with the loss of complex visuospatial functions. Diagnosis is challenging, and international consensus classification and nomenclature for PCA subtypes have only recently been reached. Presently, no established treatments exist. Efforts to develop treatments are hampered by the lack of standardized methods to monitor illness progression. Although measures developed from work with Alzheimer's disease and other dementias provide a foundation for diagnosing and monitoring progression, PCA presents unique challenges for clinicians counseling patients and families on clinical status and prognosis, and experts designing clinical trials of interventions. Here, we review issues facing PCA clinical research and care, summarize our approach to diagnosis and monitoring of disease progression, and outline ideas for developing tools for these purposes.
... ZNRF3, which was identified as one of the loci in the Consortium for Refractive Error and Myopia (CREAM) study, was also identified in the present study as a hypermethylated gene 28 . Mutations were previously observed in PSEN1 in a patient with posterior cortical atrophy and myopia 29 and we identified methylation on this gene in the present study. The differential expression of SOCS1 has been observed in corneal cells of myopic patients 30 and SOCS1 deficient mice develop severe eye diseases 31 . ...
Myopia, commonly referred to as nearsightedness, is one of the most common causes of visual disability throughout the world. It affects more people worldwide than any other chronic visual impairment condition. Although the prevalence varies among various ethnic groups, the incidence of myopia is increasing in all populations across globe. Thus, it is considered a pressing public health problem. Both genetics and environment play a role in development of myopia. To elucidate the epigenetic mechanism(s) underlying the pathophysiology of high-myopia, we conducted methylation profiling in 18 cases and 18 matched controls (aged 4–12 years), using Illumina MethylationEPIC BeadChips array. The degree of myopia was variable among subjects, ranging from −6 to −15D. We identified 1541 hypermethylated CpGs, representing 1745 genes (2.0-fold or higher) (false discovery rate (FDR) p ≤ 0.05), multiple CpGs were p < 5 × 10−8 with a receiver operating characteristic area under the curve (ROC-AUC) ≥ 0.75 in high-myopia subjects compared to controls. Among these, 48 CpGs had excellent correlation (AUC ≥ 0.90). Herein, we present the first genome-wide DNA methylation analysis in a unique high-myopia cohort, showing extensive and discrete methylation changes relative to controls. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination.
... Familiäre Fälle, die auf eine PSEN1-Mutation zurückgehen, weisen in einem geringen Anteil auch atypische klinische Symptome wie sprachliche Auffälligkeiten, Defizite im Bereich der Exekutivfunktionen oder -wie auch vereinzelt PSEN2-Fälle -Verhaltensauffälligkeiten auf [523][524][525][526][527]. In einer Übersichtsarbeit über 85 PSEN1-Fälle lag der Anteil atypischer klinischer Präsentationen bei 14 % [523]. Für die posteriore kortikale Atrophie gibt es Einzelfallberichte, die auf Mutationen in Alzheimer-assoziierten Genen wie PSEN1 und PSEN2 oder zur LOAD-assoziierten Mutation wie u. a. TREM2 zurückgehen, aber auch Mutationen in FTLD-assoziierten Genen wie MAPT und GRN [528][529][530][531][532][533][534]. Zusammenfassend lässt sich feststellen, dass es keine sicheren und klaren Häufigkeitsangaben von atypischen Syndromen innerhalb der bekannten autosomaldominant vererbten Formen der Alzheimer-Krankheit gibt. ...
... To date, 230 mutations in PSEN1, 39 in PSEN2, and 67 in APP have been registered in the AD/FTD mutation database ([2), including several identified by our team [3][4][5][6]. ...
Epigenetic mechanisms play an important role in the development and progression of various neurodegenerative diseases. Abnormal methylation of numerous genes responsible for regulation of transcription, DNA replication, and apoptosis has been linked to Alzheimer's disease (AD) pathology. We have recently performed whole transcriptome profiling of familial early-onset Alzheimer's disease (fEOAD) patients-derived fibroblasts. On this basis, we demonstrated a strong dysregulation of cell cycle checkpoints and DNA damage response (DDR) in both fibroblasts and reprogrammed neurons. Here we show that aging-correlated hypermethylation of KLF14 and TRIM59 genes associates with abnormalities in DNA repair and cell cycle control in fEOAD. Based on the resulting transcriptome networks we found that hypermethylation of KLF14 might be associated with epigenetic regulation of chromatin organization and mRNA processing followed by hypermethylation of TRIM59 likely associated with the G2/M 3 cell cycle phase and p53 role in DNA repair with BRCA1 protein as the key player. We propose that hypermethylation of KLF14 could constitute a superior epigenetic mechanism for TRIM59 hypermethylation. The methylation status of both genes affects genome stability and might contribute to proapoptotic signaling in AD. Since this study combines data obtained from various tissues from AD patients, it reinforces the view that genetic methylation status in the blood may be a valuable predictor of molecular processes occurring in affected tissues. Further research is necessary to define detailed role of TRIM59 and KLF4 in neurodegeneration of neurons. Keywords cell cycle checkpoints, DNA damage response (DDR), whole transcriptome profiling, DNA methylation, early-onset Alzheimer's disease Graphical abstract 4
... Il a également été rapporté que certains cas sont attribuables à d'autres altérations neuropathologiques, telles que la dégénérescence cortico-basale (DCB) [4,5,11], la démence à corps de Lewy (DCL) [4,5], ainsi que les maladies à prion (y compris la maladie de Creutzfeldt-Jakob et l'insomnie fatale familiale) [4,12]. Très rarement, une mutation génétique, progranuline ou préséniline, a été identifiée [13,14]. ...
In this review of the literature on posterior cortical atrophy (PCA), the history of the disease is first told through the studies of Frank Benson and Oliver Sacks. Then, we detail the possible underlying pathologies, Alzheimer's disease being the most common cause. Clinical, cognitive, and biological features are described, with a specific focus on the neuroimaging. We also describe the emotional aspects of PCA. These aspects are often overlooked, but deserve a particular attention due to their impact on the quality of life and prognostic implications for the patients. A multilevel care strategy for PCA patients is suggested.
... Genomic DNA was extracted from peripheral blood leukocytes using salting-out method. Genomic DNA was sequenced for exons 3-13 of PSEN1, exons 1-12 of PSEN2, and exons 16 and 17 of APP, as we described previously [9,10]. ...
The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-β. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-β pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.
... In rare instances mutations in presenilin-1 (PSEN1) (Sitek, Narozanska, Peplonska, Filipek, & Barczak et al., 2013) and presenilin-2 (PSEN2 Tremolizzo, Susani, Mapelli, Isella, & Bertola et al., 2015); also a cause of autosomal dominant forms of early-onset AD (Lanoiselee, Nicolas, Wallon, Rovelet-Lecrux, & Lacour et al., 2017)); granulin (GRN (Caroppo, Belin, Grabli, Maillet, & De Septenville et al., 2015); associated with typical AD and frontotemporal lobar degeneration (Galimberti & Scarpini, 2012;Perry, Lehmann, Yokoyama, Karydas, & Lee et al., 2013)); microtubule associated protein tau (MAPT (Wojtas, Heggeli, Finch, Baker, & Dejesus-Hernandez et al., 2012); associated with frontotemporal dementia (Che, Zhao, Huang, Li, & Ren et al., 2017;Zhang, Xing, Tan, Tan, & Yu, 2016) and identified as a risk factor for progressive supranuclear palsy (Hoglinger, Melhem, Dickson, Sleiman, & Wang et al., 2011)); prion protein (PRNP (Guerreiro, Bras, Wojtas, Rademakers, & Hardy et al., 2014); also present in Creutzfeldt-Jakob Disease, kuru, fatal familial insomnia, and Gerstmann-Sträussler syndrome among others (Solomon, Schepker, & Harris, 2010)) and triggering receptor expressed on myeloid cells 2 (TREM2 ; known to cause autosomal recessive forms of dementia (Guerreiro, Lohmann, Brás, Gibbs, & Rohrer et al., 2013;Paloneva, Manninen, Christman, Hovanes, & Mandelin et al., 2002)), have been detected in subjects with PCA. One study of a family with an early and long-standing prion dementia manifesting with PCA was found to be associated with this syndrome and to have a 5-octapeptide insertion into the prion protein gene (Depaz et al., 2012). ...
Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by initial predominant visuoperceptual deficits followed by a progressive decline in other cognitive functions. This syndrome has not been as thoroughly described as other dementias, particularly from a neuropsychological evolution perspective with only a few studies describing the evolution of its cognitive progression. In this investigation we review the literature on this rare condition and we perform a 7-year neuropsychological and neuroradiological follow-up of a 64-year-old man with PCA. The subject's deficits initially appeared in his visuoperceptual skills with later affectation appearing in language and other cognitive functions, this being coherent with the patient's parieto-temporal atrophy evolution.
