Apolipoprotein E4 in the temporal variant of frontotemporal dementia.
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ABSTRACT:
SUBMITTER: Rosso SM
PROVIDER: S-EPMC1737932 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundRight temporal frontotemporal dementia (FTD) is an anatomic variant of FTD associated with relatively distinct behavioral and cognitive symptoms. We aimed to determine whether right temporal FTD is a homogeneous clinical, imaging, and pathologic/genetic entity.MethodsIn this case-control study, 101 subjects with FTD were identified. Atlas-based parcellation generated temporal, frontal, and parietal grey matter volumes which were used to identify subjects with a right temporal dominant atrophy pattern. Clinical, neuropsychological, genetic, and neuropathologic features were reviewed. The subjects with right temporal FTD were grouped by initial clinical diagnosis and voxel-based morphometry was used to assess grey matter loss in the different groups, compared to controls, and each other.ResultsWe identified 20 subjects with right temporal FTD. Twelve had been initially diagnosed with behavioral variant FTD (bvFTD), and the other 8 with semantic dementia (SMD). Personality change and inappropriate behaviors were more frequent in the bvFTD group, while prosopagnosia, word-finding difficulties, comprehension problems, and topographagnosia were more frequent in the SMD group. The bvFTD group showed greater loss in frontal lobes than the SMD group. The SMD group showed greater fusiform loss than the bvFTD group. All 8 bvFTD subjects with pathologic/genetic diagnosis showed abnormalities in tau protein (7 with tau mutations), while all three SMD subjects with pathology showed abnormalities in TDP-43 (p = 0.006).ConclusionsWe have identified 2 subtypes of right temporal variant frontotemporal dementia (FTD) allowing further differentiation of FTD subjects with underlying tau pathology from those with TDP-43 pathology.
| S-EPMC2779005 | biostudies-literature
Project description:Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disorder associated with atrophy of the frontal and temporal lobes. Most patients with focal temporal lobe atrophy present with either the semantic dementia subtype of FTD or the behavioral variant subtype. For patients with temporal variant FTD, the most common cause found on post-mortem examination has been a TDP-43 (transactive response DNA-binding protein 43 kDa) proteinopathy, but tauopathies have also been described, including Pick's disease and mutations in the microtubule-associated protein tau (MAPT) gene. We report the clinical and imaging features of 2 patients with temporal variant FTD associated with a rare frontotemporal lobar degeneration pathology known as globular glial tauopathy. The pathologic diagnosis of globular glial tauopathy should be considered in patients with temporal variant FTD, particularly those who have atypical semantic dementia or an atypical parkinsonian syndrome in association with the right temporal variant.
| S-EPMC4478068 | biostudies-literature
Project description:The temporal variant of frontotemporal dementia (tv-FTD) is a progressive neurodegenerative disease with a complex clinical picture mainly characterized by behavioral and language disorders. In this work, we describe clinical, genetic, neuroanatomical and neuropathological (only in one case) features of two patients with tv-FTD carrying C9orf72 repeat expansion. The first patient (AB) presented with a 1-year disease duration showing focal right anterior temporal lobe (ATL) atrophy on magnetic resonance imaging (MRI). The second patient (BC) came to medical attention 13 years after disease onset and showed a prominent bilateral ATL involvement. Both patients showed naming deficits, impairment in identifying known faces and proper names, and personality changes with new onset behavioral rigidity, and progressing language difficulties to single-word and sentence comprehension difficulties. They were classified as tv-FTD. Clinical, cognitive and MRI follow-up were performed. As cognitive impairment progressed, MRI atrophy worsened in ATL and frontotemporal areas in both patients. Both cases had clear family histories of neurological and/or psychiatric disease. Genetic testing revealed a C9orf72 hexanucleotide repeat expansion in both cases. BC passed away after 15 years of disease and autopsy showed the expected TDP-type B pathology. These genetic cases of tv-FTD highlight the susceptibility of ATL to C9orf72-related pathology and emphasize the importance of genetical testing in FTD-spectrum disorders, regardless of the clinical phenotype.
| S-EPMC7467111 | biostudies-literature
Project description:BackgroundRight temporal variant frontotemporal dementia (rtvFTD) has been generally considered as a right sided variant of semantic variant primary progressive aphasia (svPPA), which is a genetically sporadic disorder. Recently, we have shown that rtvFTD has a unique clinical syndrome compared to svPPA and behavioral variant frontotemporal dementia.ObjectiveWe challenge the assumption that rtvFTD is a sporadic, non-familial variant of FTD by identifying potential autosomal dominant inheritance and related genes in rtvFTD.MethodsWe collected all subjects with a diagnosis of FTD or primary progressive aphasia who had undergone genetic screening (n = 284) and subsequently who had a genetic variant (n = 48) with a diagnosis of rtvFTD (n = 6) in 2 specialized memory clinics.ResultsGenetic variants in FTD related genes were found in 33% of genetically screened rtvFTD cases; including MAPT (n = 4), GRN (n = 1), and TARDBP (n = 1) genes, whereas only one svPPA case had a genetic variant in our combined cohorts. Additionally, 4 out of 6 rtvFTD subjects had a strong family history for dementia.ConclusionOur results demonstrate that rtvFTD, unlike svPPA, is not a pure sporadic, but a heterogeneous potential genetic variant of FTD, and screening for genetic causes for FTD should be performed in patients with rtvFTD.
| S-EPMC7990443 | biostudies-literature
Project description:Although the right temporal variant frontotemporal dementia (rtvFTD) is characterised by distinct clinical and radiological features, its underlying histopathology remains elusive. Being considered a right-sided variant of semantic variant primary progressive aphasia (svPPA), TDP-43 type C pathology has been linked to the syndrome, but this has not been studied in detail in large cohorts. In this case report and systematic review, we report the autopsy results of five subjects diagnosed with rtvFTD from our cohort and 44 single rtvFTD subjects from the literature. Macroscopic pathological evaluation of the combined results revealed that rtvFTD demonstrated either a frontotemporal or temporal evolution, even if the degeneration started in the right temporal lobe initially. FTLD-TDP type C was the most common underlying pathology in rtvFTD, however, in 64% of rtvFTD, other underlying pathologies than FTLD-TDP type C were present, such as Tau-MAPT and FTLD-TDP type A and B. Additionally, accompanying motor neuron or corticospinal tract degeneration was observed in 28% of rtvFTD patients. Our results show that in contrast to the general assumption, rtvFTD might not be a pure FTLD-TDP type C disorder, unlike its left temporal counterpart svPPA. Large sample size pathological studies are warranted to understand the diverse pathologies of the right and left temporal variants of frontotemporal dementia.
| S-EPMC8330072 | biostudies-literature
Project description:Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.
| S-EPMC5841140 | biostudies-literature
Project description:"Reserve" refers to the individual clinical differences in response to a neuropathological burden. We explored the behavioral reserve (BR) and associated neural substrates in 40 participants with behavioral variant frontotemporal dementia (bvFTD) who were assessed with the frontal behavioral inventory (FBI) and magnetic resonance imaging. Because neuroimaging abnormality showed a high negative correlation with the FBI negative (but not positive) symptom scores, we developed a linear model only to calculate the nBR (BR for negative symptoms) marker using neuroimaging abnormalities and the FBI score. Participants were divided into high nBR and low nBR groups based on the nBR marker. The FBI negative symptom score was lower in the high nBR group than in the low nBR group having the same neuroimaging abnormalities. However, the high nBR group noted a steeper decline in cortical atrophy and showed less atrophy in the left frontotemporal cortices than the low nBR group. In addition, the fractional anisotropy (FA) values were greater in the high nBR than in the low nBR group, except in the sensory-motor and occipital areas. We identified an nBR-related functional network composed of bilateral frontotemporal areas and the left occipital pole. We propose the concept of BR in bvFTD, and these findings can help predict the disease progression.
| S-EPMC9252599 | biostudies-literature
Project description:Many neuropsychiatric disorders are marked by abnormal behaviour and decision-making, but prevailing diagnostic criteria for such behaviours are typically qualitative and often ambiguous. Behavioural variant frontotemporal dementia and semantic variant primary progressive aphasia (also called semantic dementia) are two clinical variants of frontotemporal dementia with overlapping but distinct anatomical substrates known to cause profound changes in decision-making. We investigated whether abnormal decision-making in these syndromes could be more precisely characterized in terms of dissociable abnormalities in patients' subjective evaluations of valence (positive versus negative outcome) and of time (present versus future outcome). We presented 28 patients with behavioural variant frontotemporal dementia, 14 patients with semantic variant primary progressive aphasia, 25 patients with Alzheimer's disease (as disease controls), and 61 healthy older control subjects with experimental tasks assaying loss aversion and delay discounting. In general linear models controlling for age, gender, education and Mini-Mental State Examination score, patients with behavioural variant frontotemporal dementia were less averse to losses than control subjects (P < 0.001), while patients with semantic variant primary progressive aphasia discounted delayed rewards more steeply than controls (P = 0.019). There was no relationship between loss aversion and delay discounting across the sample, nor in any of the subgroups. These findings suggest that abnormal behaviours in neurodegenerative disease may result from the disruption of either of two dissociable neural processes for evaluating the outcomes of action. More broadly, these findings suggest a role for computational methods to supplement traditional qualitative characterizations in the differential diagnosis of neuropsychiatric disorders.
| S-EPMC4861653 | biostudies-literature
Project description:Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are the two common forms of dementia. FTD syndromes are characterized by lobar atrophy (frontotemporal lobar degeneration or FTLD) and the presence of either cellular TDP43 (FTLD-TDP), tau (FTLD-tau), or FUS aggregates, while extracellular ?-amyloid plaques and hyperphosphorylated tau tangles develop in AD. Oxidative stress can induce these pathological modifications in disease models, and is thought to play a role in these syndromes. Apolipoprotein D (apoD) is a glial-expressed lipocalin known to protect against oxidative stress, with increased levels in AD, supporting a protective role. The expression of apoD has not been studied in FTLD. This study assesses apoD expression in FTLD-TDP and FTLD-tau in comparison to AD and controls. It also analyzes the effect of apoD on TARDBP (TDP43 gene) and ?-amyloid precursor protein (APP). The expression of apoD was analyzed by Western blotting in FTLD-TDP, FTLD-tau, AD, and control post-mortem brain tissue. An apoD-overexpressing cell model was used to study the impact of increased apoD on APP and TARDBP expression. We confirm that apoD expression was increased in AD but surprisingly it was not affected in either of the two main pathological forms of FTLD. Under oxidative stress conditions, apoD had no effect on TDP43 expression but it did decrease APP expression. This suggests that apoD does not act as a neuroprotective factor in FTLD in the same way as in AD. This could contribute to the more rapid degeneration observed in FTLD.
| S-EPMC6344390 | biostudies-literature
Project description:Frontotemporal dementia (FTD) is a common cause of early onset dementia with behavioral variant FTD (bvFTD) being the most common form. bvFTD is characterized clinically by behavioral and personality changes, eating abnormalities, and pathologically, by systemic lipid dysregulation that impacts on survival. As lipoprotein metabolism is at the core of lipid dysregulation, here, we analyzed the composition, both proteins and lipids, of the two major lipoprotein classes in blood - high density lipoproteins (HDLs) and low density lipoproteins (LDLs). Fasted plasmas from bvFTD and Alzheimer's disease (AD) patients and controls were fractionated using fast protein liquid chromatography (FPLC) and samples analyzed by lipid assays, ELISA and western blotting. We found that apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II) levels in HDLs were decreased in bvFTD compared to controls, whereas apolipoprotein B (apoB) levels in LDLs were unaltered. We also found that cholesterol and triglyceride levels in FPLC fractions were altered in bvFTD compared to controls. The apoB:apoA-I ratio and the standard lipid ratios were significantly increased in bvFTD compared to AD and controls. Furthermore, we found that plasma apolipoprotein C-I and paraoxonase 1 levels were significantly altered in bvFTD and AD, respectively, compared controls. This study represents the first apolipoprotein analysis of bvFTD, and our results suggest altered HDL function and elevated cardiovascular disease risk in bvFTD.
| S-EPMC6246632 | biostudies-other