Primary Progressive Aphasia has a Unique Signature Distinct from Dementia of the Alzheimer’s Type and Behavioral Variant Frontotemporal Dementia Regardless of Pathology

Gefen, Tamar; Mao, Qinwen; Kohler, Missia; Moeller, Stacey; Kawles, Allegra; Coventry, Christina; Spencer, Callen; Lilek, Jaclyn; Ajroud, Kaouther; Feldman, Alexander; Flanagan, Margaret E.; Rogalskı, Emily; Weıntraub, Sandra; Rademaker, Alfred; Geula, Changiz; Mesulam, Marsel; Bigio, Eileen H.

doi:10.1093/jnen/nlaa080

Cited by 5 publications

(7 citation statements)

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“…This is classified as part of the studies conducted in A431E carriers as the results were reported per participant. Of the studies conducted on brain tissue, four were performed in PSEN variant carriers ( Maarouf et al, 2008 ; Roher et al, 2013 ; Beck et al, 2016 ; Gefen et al, 2020 ) and two in EOAD cases ( Albrecht et al, 2009 ; Ringman et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

“…We found A431E in studies mixed with other genetic variants; in Table 4 , we classified the articles analyzing PSEN variants. Eight studies focused on PSEN1 variants ( Rogaeva et al, 2001 ; Ringman et al, 2004 , 2005 , 2007a ; Joshi et al, 2012 ; Beck et al, 2016 ; Soosman et al, 2016 ; Gefen et al, 2020 ) and, in three more, variants in PSEN1 and PSEN2 are analyzed ( Leverenz et al, 2006 ; Maarouf et al, 2008 ; Roher et al, 2013 ).…”

Section: Resultsmentioning

confidence: 99%

“…Two articles study brain tissue of carriers of PSEN1 variants, and one presents a significant upregulation of six genes related to mitochondrial unfolded protein response ( Beck et al, 2016 ) with primarily differences between primary progressive aphasia (PPA), AD, and a behavioral variant of frontotemporal dementia ( Gefen et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…Although the sample size of these studies was small and the minority were carriers of A431E, it is important to highlight that the neuropathological findings in postmortem studies allow in the first instance the differentiation between EOAD due to A431E variant or others in PSEN1 , and variants in PSEN2 or APP , SAD, and dementias caused by other conditions such as PPA and bvFTD ( Gefen et al, 2020 ), and may ultimately be of help for the differential diagnosis ( Braak and Braak, 1991 ; McKhann et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

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PSEN1 c.1292C<A Variant and Early-Onset Alzheimer’s Disease: A Scoping Review

Orozco-Barajas

Oropeza-Ruvalcaba²,

Canales-Aguirre

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive loss of cognitive function, with β-amyloid plaques and neurofibrillary tangles being its major pathological findings. Although the disease mainly affects the elderly, c. 5–10% of the cases are due to PSEN1, PSEN2, and APP mutations, principally associated with an early onset of the disease. The A413E (rs63750083) PSEN1 variant, identified in 2001, is associated with early-onset Alzheimer’s disease (EOAD). Although there is scant knowledge about the disease’s clinical manifestations and particular features, significant clinical heterogeneity was reported, with a high incidence of spastic paraparesis (SP), language impairments, and psychiatric and motor manifestations. This scoping review aims to synthesize findings related to the A431E variant of PSEN1. In the search, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the guidelines proposed by Arksey and O’Malley. We searched and identified 247 studies including the A431E variant of PSEN1 from 2001 to 2021 in five databases and one search engine. After the removal of duplicates, and apply inclusion criteria, 42 studies were finally included. We considered a narrative synthesis with a qualitative approach for the analysis of the data. Given the study sample conformation, we divided the results into those carried out only with participants carrying A431E (seven studies), subjects with PSEN variants (11 studies), and variants associated with EOAD in PSEN1, PSEN2, and APP (24 studies). The resulting synthesis indicates most studies involve Mexican and Mexican-American participants in preclinical stages. The articles analyzed included carrier characteristics in categories such as genetics, clinical, imaging techniques, neuropsychology, neuropathology, and biomarkers. Some studies also considered family members’ beliefs and caregivers’ experiences. Heterogeneity in both the studies found and carrier samples of EOAD-related gene variants does not allow for the generalization of the findings. Future research should focus on reporting data on the progression of carrier characteristics through time and reporting results independently or comparing them across variants.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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PSEN1 c.1292C<A Variant and Early-Onset Alzheimer’s Disease: A Scoping Review

Orozco-Barajas

Oropeza-Ruvalcaba²,

Canales-Aguirre

et al. 2022

Front. Aging Neurosci.

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“…17 Both PPA and bvFTD can show underlying FTLD-TDP. [19][20][21][22] The one common denominator for all neuropathologies associated with PPA and bvFTD is their predilection for the language dominant hemisphere (PPA), or frontal-network anatomical loci (bvFTD)selectively vulnerable regions to pathology for unknown reasons. FTLD-TDP cases had a global Clinical Dementia Rating range of 0.5 to 1 at initial visit.…”

Section: Participant Characteristics and Demographic Informationmentioning

confidence: 99%

Distinct Patterns of Hippocampal Pathology in Alzheimer's Disease with Transactive Response DNA‐binding Protein 43

Minogue,

Kawles,

Zouridakis

et al. 2023

Annals of Neurology

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ObjectiveAge‐related dementia syndromes are often not related to a single pathophysiologic process, leading to multiple neuropathologies found at autopsy. An amnestic dementia syndrome can be associated with Alzheimer's disease (AD) with comorbid TDP‐43 pathology (AD/TDP). Here, we investigated neuronal integrity and pathologic burden of TDP‐43 and tau along the well‐charted trisynaptic hippocampal circuit [dentate gyrus (DG), CA3, and CA1] in participants with amnestic dementia due to AD/TDP, amnestic dementia due to AD alone, or non‐amnestic dementia due to TDP‐43 proteinopathy associated with frontotemporal lobar degeneration (FTLD‐TDP).MethodsForty‐eight extensively characterized cases (14 AD, 16 AD/TDP, 18 FTLD‐TDP) were analyzed using digital HALO software (Indica Labs) to quantify pathologic burden and neuronal loss.ResultsIn AD/TDP and FTLD‐TDP, TDP‐43 immunoreactivity was greatest in the DG. Tau immunoreactivity was significantly greater in DG and CA3 in AD/TDP compared to pure AD. All clinical groups showed the highest amounts of neurons in DG, followed by CA3, then CA1. The AD and AD/TDP groups showed lower neuronal counts compared to the FTLD‐TDP group across all hippocampal subregions consistent with the salience of the amnestic phenotype.InterpretationWe conclude that AD/TDP can be distinguished from AD and FTLD‐TDP based on differential regional distributions of hippocampal tau and TDP‐43. Findings suggest that tau aggregation in AD/TDP may be enhanced by TDP‐43.This article is protected by copyright. All rights reserved.

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