Frontotemporal Dementia Research Articles (Page 1)

The Importance of Offering Genetic Counseling and Testing to All Persons Diagnosed With Frontotemporal Degeneration Spectrum Disorders.

On the potential roles of TDP-43 in the formation of membraneless organelles and their transformation into toxic aggregates.

Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia, and related tauopathies have gained prominence in the development of therapies for these conditions. Glial responses are key features of AD and frontotemporal dementia, and are associated with neuroinflammation. Numerous transgenic mouse models that recapitulate critical AD-like pathology and cognitive impairment have been developed to examine pathogenic mechanisms and evaluate therapeutic approaches targeting tau and glial reactivity. Glial reactivity and neuroinflammation coincide with tau hyperphosphorylation, which induces behavioral impairment; however, the specific correlation between glial cell activation and abnormal behavior remains unknown. In this study, we investigated changes in glial cell gene expressions related to abnormal behaviors in rTg4510 mice, which phenocopy the tau pathology, neuroinflammation, and neurodegeneration observed in human tauopathies. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nest-building behavior compared with control mice. Paired association learning was also impaired in 4-month-old rTg4510 mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a longer time in the open arms of the plus-maze test than control mice. Using a magnetic-activated cell-sorting technique, we analyzed glial cell gene expressions related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Regression analysis of glial gene expressions and behavioral tests revealed that various glial reactivities were associated with behavioral abnormalities. Our findings suggest specific genetic characteristics of glial cells that may lead to abnormal behavior in rTg4510 mice.

The socioeconomic burden of early onset dementia (EOD) defined as disease onset before the age of 65 years, is substantial due to its widespread disabling effects in relatively young individuals. While dementia is widely recognised as a major contributor to mortality among the elderly, only a limited number of studies have assessed survival and factors associated with prognosis specifically in EOD. A population-based cohort study, encompassing all incident EOD cases from two defined regions in Finland. The survival and all-cause mortality rates in EOD and its subtypes were evaluated from January 2010 to December 2021. All visits at the dementia outpatient clinics were reviewed and manually re-assessed (n=12 490), resulting in 794 validated EOD cases of Alzheimer's disease (AD), frontotemporal dementia (FTD), alpha-synucleinopathy (α-SYNU) and other EOD spectra. Region-, age- and sex-matched control groups without neurodegenerative diseases were created from nonselective general population data registers (1:10 case to control ratio, 7930 controls in total). The median survival for EOD was 8.7 years, with the shortest survival in the FTD (6.9 years) and α-SYNU groups (7.0 years), followed by the AD group (9.9 years). Compared with controls, mortality was significantly higher in the total EOD group (HR=6.56, 95% CI=5.56-7.74, p<0.001). Among the dementia subtypes, FTD spectrum patients had the highest all-cause mortality risk compared with controls (HR=13.75, 95% CI=10.25-18.43, p<0.001). Male sex, older age, several comorbidities and lower level of education were associated with increased mortality, but these were not EOD-specific. EOD diagnosis significantly deteriorates patients' survival, with significant variation between different diagnostic groups and in relation to patients' demographic factors.

Introduction: Dementia is increasingly common in older adults, yet limited data exists on its baseline prevalence among those hospitalized with acute coronary syndrome (ACS). This study aims to address that gap by examining the prevalence and subtypes of dementia in older (≥65 years) adults. Methods: These baseline results are part of a retrospective longitudinal cohort study of Kaiser Permanente Northern California members over age 65 years with ACS hospitalization or stable CAD diagnosis from January 2010 to December 2020. Descriptive statistics were used for baseline demographics and clinical variables including prior comorbidities. The prevalence of dementia at baseline, as well as the distribution of type of baseline dementia, was compared in the ACS hospitalization and non-ACS hospitalization groups using Chi-Square test. Results: A total of 189136 patients were included with a mean age 75.2 years. Patients hospitalized for ACS were more likely to be female sex (42.6% versus 41.7%, p=0.022), older (76.7 years versus 74.9 years, p&lt;0.001), and present with higher rates of comorbidities based on the Charlson Comorbidity Index (3.1 versus 2.5, p&lt;0.001) compared to patients without an ACS hospitalization. The overall baseline prevalence of dementia was 5.1%. Patients hospitalized with ACS had a significantly higher baseline prevalence of dementia (5.87% versus 4.97%, p&lt;0.0001). Among patients with dementia, the most common subtype was Alzheimer’s disease (AD, 85.4%), followed by vascular dementia (6.4%), Lewy body/Parkinson’s dementia (LB/P, 4.0%), unspecified types (3.8%), and frontotemporal dementia (0.5%), The distribution of dementia subtypes differed significantly with modestly lower rates of LB/P and Vascular dementia in the ACS hospitalization group (p=0.0215, Table 1). Conclusions: In this large, integrated healthcare cohort, dementia was present in over 1 in 20 older adults in the full cohort, with a significantly higher prevalence among those hospitalized with ACS. AD was the predominant subtype, but small differences in subtype distribution were observed between ACS and non-ACS groups. These findings underscore the importance of recognizing baseline cognitive impairment in the acute cardiovascular care of older adults and may inform future strategies for risk stratification and individualized decision-making.

Background: Atrial fibrillation (AF) has been linked to dementia in prior observational studies. Whether this reflects a causal relationship remains to be a topic for debate, as both are strongly associated with age and various comorbid conditions. Prior mendelian randomization (MR) studies have been performed to establish causality by using genetic variants as instruments for AF. We conducted a meta-analysis of MR studies to assess the association between genetically predicted AF and dementia, including Alzheimer’s disease (AD) and other subtypes, which has never been attempted before. Methods: We systematically identified published two-sample MR analyses of AF (using different genome-wide association study instruments, e.g. AFGen consortium meta-analysis, FinnGen) in relation to dementia outcomes. All outcome summary statistics were drawn from large-scale consortia (e.g. International Genomics of Alzheimer's Project (IGAP) for AD) and cohorts of predominantly European ancestry. We extracted odds ratios (ORs) for each dementia subtype and combined estimates using random-effects meta-analysis. Heterogeneity was evaluated with the I 2 statistics. P&lt;0.05 was considered statistically significant. Results: This meta-analysis (5 studies) pooled data from approximately 211,000 AF cases and over 2.6 million controls across large-scale GWAS consortia (AFGen, FinnGen, UK Biobank, IGAP, PGC-ALZ, and others), predominantly in individuals of European ancestry (Table 2). Genetically predicted AF showed a significant positive association with vascular dementia (pooled OR 1.21; 95%CI 1.07–1.37; heterogeneity I 2 44.2%). In contrast, there was no significant association between AF and AD (pooled OR 1.00, 95%CI 0.98–1.02; P=0.47). Similarly, no causal effect was observed on Lewy body dementia (LBD) or frontotemporal dementia (FTD) (Figure 1). All MR estimates were directionally consistent across studies and there was no evidence of pleiotropy in sensitivity analyses as well. Conclusion: In our meta-analysis of MR studies, a genetic predisposition to AF was associated with higher odds of vascular dementia, however no clear causal link was evident for combined dementia, AD, other dementia subtypes. These findings suggest AF itself may contribute to vascular dementia. Further research is warranted to understand pathophysiology of AF leading to vascular dementia and to inform preventive strategies aimed at reducing cognitive morbidity and improving long-term outcomes in AF patients.

Background: Dementia and coronary artery disease (CAD) frequently coexist in older adults, complicating acute coronary syndrome (ACS) management. The prevalence of dementia among patients undergoing revascularization versus medical management and the distribution of dementia subtypes in this context remain poorly described. Methods: In this longitudinal cohort study of adults ≥65 years with ACS hospitalization within an integrated health system from 2010–2020, patients were classified by initial management: percutaneous coronary intervention (PCI), coronary artery bypass artery grafting (CABG), or ACS without revascularization (Norevasc). Baseline dementia and dementia type was identified by ICD-10 codes prior to hospitalization. Descriptive statistics were used to delineate baseline demographics and clinical variables including prior comorbidities. The prevalence of dementia at baseline, as well as the distribution of type of baseline dementia, was compared in the Revascularization vs. Not groups using Chi-Square test. Results: 26,749 patients were included in this analysis (9,009 PCI or CABG and 17,740 No Revascularization). Patients referred for PCI/CABG were younger (74.9 vs. 77.7; p &lt; 0.001), less likely to be women (34.1% vs. 46.9% p &lt; 0.001) and had fewer comorbidities via Elixhauser Comorbidity Index (4.6 vs. 5.5; p &lt; 0.001). The overall baseline prevalence of dementia was 5.9% with a differential as follows: PCI, 2.0%; CABG, 0.62%; and Norevasc, 7.9% (p &lt; 0.001, Table 1). Among those with baseline dementia, the most common subtype was Alzheimer’s disease (85.7%), followed by vascular dementia (5.7%), Lewy body/Parkinson’s dementia (3.7%), unspecified types (3.6%), and frontotemporal dementia (1.0%). The distribution of dementia subtypes did not differ significantly between patients referred for revascularization vs. not (p = 0.51; Table 2). Conclusion: In this large, real-world cohort, baseline dementia was most prevalent among ACS patients managed without revascularization and least common among those undergoing CABG. Alzheimer’s disease was the predominant subtype regardless of management strategy. These findings highlight the importance of routine cognitive assessment in older adults hospitalized with ACS and support further research into tailored care for this higher complexity population.

TDP-43 is a ubiquitously expressed RNA-binding protein that aggregates in the brains of patients suffering from neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease. Aggregated TDP-43 in these diseases is hyperphosphorylated in its C-terminal intrinsically disordered region, while physiological TDP-43 is normally unphosphorylated. Whether TDP-43 phosphorylation is a pathological driver, or rather a protective antagonist of TDP-43 aggregation and consequently neurodegeneration, is still debated and a matter of ongoing research. Here, we review current knowledge about TDP-43 phosphorylation in disease and the kinases and phosphatases that regulate this post-translational modification. We discuss how TDP-43 phosphorylation is thought to shape TDP-43's phase separation, aggregation and toxicity in neurodegenerative diseases. We highlight recent research that provides evidence that hyperphosphorylation antagonizes TDP-43 phase separation and aggregation, and speculate about a potential role of condensates in TDP-43 phosphorylation.

Frontotemporal dementia as a consequence of GRN mutations: From disease cause to models to therapies.

A meta-analysis of genetic variant pathogenicity and sex differences in UBQLN2-linked amyotrophic lateral sclerosis and frontotemporal dementia.

Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks.

ABSTRACTProgranulin (GRN) mutations, most of which cause progranulin haploinsufficiency, are a major genetic cause of frontotemporal dementia (FTD). Restoring progranulin to people with GRN mutations is a promising therapeutic strategy and understanding progranulin's mechanism of action may enable the design of optimal progranulin‐based therapies. Progranulin is constitutively secreted and interacts with several receptors, but is also taken up and trafficked to lysosomes where it is necessary for maintaining normal lysosomal function. Progranulin promotes neuronal growth and survival, but it is not clear if these actions are mediated by extracellular signaling or by regulation of lysosomal function. In previous work we showed that progranulin acts in neuronal lysosomes to promote neuronal survival. In this study we investigated the mechanism by which progranulin promotes neuronal growth using lentiviral vectors expressing either progranulin (PGRN) or a non‐secreted, lysosome‐targeted progranulin (L‐PGRN) in rat primary hippocampal neurons and astrocytes. Using lentiviral vectors driven by non‐selective (PGK), neuron‐selective (hSyn), or astrocyte‐selective (GFAP) promoters, we found that delivering L‐PGRN to astrocytes, but not neurons, promoted dendritic outgrowth in primary hippocampal cultures. L‐PGRN–transduced astrocytes grown on transwell inserts also promoted the growth of co‐cultured neurons. RNA sequencing of astrocytes indicated that L‐PGRN downregulated transcriptomic pathways associated with cellular reactivity. Analysis of astrocyte conditioned medium showed that transduction with L‐PGRN reduced the secretion of PAI‐1, a protease inhibitor that inhibits neuronal outgrowth in hippocampal cultures. Collectively, these data indicate that delivering progranulin to astrocytic lysosomes may inhibit the secretion of factors that restrain neuronal outgrowth. Consistent with this hypothesis, depleting astrocytes from hippocampal cultures increased dendritic outgrowth and occluded the pro‐growth effects of L‐PGRN. These data show that under these culture conditions, progranulin secretion is not required to promote dendritic outgrowth. Instead, progranulin increased dendritic outgrowth by a non‐cell autonomous mechanism involving actions in astrocytic lysosomes. These data add to a growing body of evidence that progranulin may act on astrocytes to promote neuronal health.

Attention-augmented stockwell transform and convolutional neural network framework for electroencephalogram-based multi-class classification of Frontotemporal Dementia

The phenocopy syndrome of behavioural variant frontotemporal dementia (phFTD) refers to patients exhibiting clinical features of the behavioural variant of frontotemporal dementia (bvFTD), but lacking objective functional decline and neuroimaging abnormalities consistent with bvFTD. Although symptoms do not progress into dementia, they are disruptive and cause long-term family dysfunction. This case study aims to explore the social, biographical and demographic features of 8 patients with phFTD and their partners. The feasibility and subjective experience of a support group were explored. Eight phFTD patients and their partners completed self-report questionnaires assessing quality of life, family functioning, and coping styles. Most phFTD patients had some psychological vulnerability or reported a positive family history for psychiatric disorders. All couples showed challenges within family functioning and low quality of life (QOL) in both patients and their spouses. PhFTD patients predominantly utilized passive coping strategies whereas their partners tended to employ more active coping strategies. Our explorative study supports the hypothesis of a multifactorial biopsychosocial vulnerability in phFTD patients. In contrast to bvFTD patients, phFTD patients selfreport low quality of life. The discrepancy in coping styles between patients and their partners possibly contributes to the heavy impact on expressed burden.

Age-related hearing loss affects one-third of the population over 65 years. However, the diverse pathologies underlying these heterogeneous phenotypes complicate genetic studies. Here we show that by applying computational phenotyping approaches based on audiometrically measured hearing loss, we can overcome challenges associated with accurate phenotyping for older adults with hearing loss. Using this phenotyping strategy, we uncover differences in the associations observed between genetic variants and sensory and metabolic hearing loss. Sex-stratified analyses of these sexually dimorphic hearing loss phenotypes reveal a locus of relevance to sensory hearing loss in males, but not females. Enrichment analyses implicate genes involved in frontotemporal dementia in metabolic hearing loss, while genes relating to sensory processing of sound by hair cells are implicated in sensory hearing loss. Our study enhances our understanding of these two hearing loss phenotypes, representing the first step in the development of more precise treatments for these pathologically distinct hearing loss phenotypes.

Motor neuron hyperexcitability is a broadly observed yet poorly understood feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Nuclear depletion and cytoplasmic aggregation of the RNA splicing protein TAR DNA-binding protein 43 (TDP-43) are observed in most ALS and FTD patients. Here we show that TDP-43 dysfunction causes mis-splicing of KCNQ2, which encodes a voltage-gated potassium channel (Kv7.2) that regulates neuronal excitability. Using iPSC-derived neurons and postmortem ALS/FTD brain and spinal cord tissue we find widespread, disease-specific and TDP-43-specific skipping of an exon encoding the KCNQ2 pore domain. The mis-spliced mRNA escapes degradation and is translated into a nonfunctional protein with severely reduced ion conductance that aggregates in the endoplasmic reticulum and causes intrinsic hyperexcitability in ALS neuronal models. This event, which correlates with higher phosphorylated TDP-43 levels and earlier age of disease onset in patients, can be rescued by splice-modulating antisense oligonucleotides that dampen hyperexcitability in induced pluripotent stem cell cortical neurons and spinal motor neurons with TDP-43 depletion. Our work reveals that nuclear TDP-43 maintains the fidelity of KCNQ2 expression and function and provides a mechanistic link between established excitability disruption in ALS/FTD patients and TDP-43 dysfunction.

Inherited biallelic mutations in the CLN7 gene result in the variant late infantile onset neuronal ceroid lipofuscinosis, a subtype of Batten disease (BD), a severe and fatal childhood neurodegenerative disease. Intriguingly, CLN7 genetic variants have also been associated with retinopathies, amyotrophic lateral sclerosis, and frontotemporal dementia. CLN7 encodes a transmembrane protein localizing to endolysosomal membranes with outward-facing chloride channel activity. Loss of CLN7 function results in cortical neurons accumulating swollen lipofuscin-containing lysosomes, leading to neuroinflammation and neurodegeneration. The molecular mechanisms underlying CLN7 BD neuropathology are not completely understood. We have generated iPSC lines from two CLN7 BD patients and age-matched unaffected controls to interrogate intracellular molecular phenotypes in iPSC-derived neural progenitor cells (iNPC). Taking a multi-omics approach we have identified disease-modified activities in endolysosomal transport in iNPCBD that lead to lysosomal dysfunction and decreased mitophagy, resulting in the accumulation of metabolically defective mitochondria. We further observe a breakdown in nuclear functions that centre on RNA processing and nuclear export, linking to CLN7 protein interactions at the stress granule. We have identified dual and distinct functions for CLN7, promoting cell survival during the cellular stress response. CLN7 loss of function in BD results in neuronal apoptosis.

Identifying modifiable factors influencing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) risk is important for prevention. Blood biomarkers, particularly cholesterol, have been associated with neurodegenerative risk, but findings in ALS are inconsistent, and data on FTD are limited. We conducted a population-based cohort study using UK primary care records from QResearch linked with Hospital Episode Statistics. Adults with biomarker data recorded between 1998 and 2023 were included. We examined associations of low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), total cholesterol, triglycerides, creatinine, creatine kinase, and HbA1c with ALS and FTD risk. Cox proportional hazards models were used to estimate associations. Two-sample Mendelian randomization (MR) was applied to explore genetically predicted associations of selected biomarkers. There were up to 2,695 ALS and 781 FTD diagnoses, with a median follow-up duration of 9.4 and 10.5 years, respectively. Higher LDL-C (hazard ratio [HR]per 1-SD = 1.07, 95% confidence interval [CI] = 1.02-1.11) and total cholesterol levels (HRper 1-SD = 1.06, 95% CI = 1.02-1.10) were linearly associated with higher ALS risk. Age-stratified analysis showed a stronger association for total cholesterol in those ≥ 60 years (HRper 1-SD = 1.08, 95% CI = 1.04-1.13, Pinteraction = 0.003). Higher creatinine was inversely associated with FTD risk (HRper 1-SD = 0.90, 95% CI = 0.83-0.97), supported by MR (odds ratio [OR] inverse variance weighted (IVW), per 1-SD = 0.73, 95% CI = 0.56-0.96). HbA1c showed a U-shaped association with FTD (Pnon-linearity = 0.006). LDL and total cholesterol may provide insights into early disease changes or the etiology of ALS, whereas creatinine and HbA1c may be relevant for FTD. Research in monogenic ALS and FTD is needed to determine whether these biomarkers inform targeted prevention or intervention strategies. ANN NEUROL 2025.

The eyes and the central nervous system (CNS) develop from the same embryonic tissue which explains why retinal changes have been observed in various neurological and neurodegenerative diseases. These changes can be visualized in vivo on acellular and subcellular level using optical coherence tomography (OCT). This article summarizes which retinal changes occur and how these could be used as potential biomarkers of neurodegenerative diseases. The article gives an overview of the literature on the relationship between neurodegeneration, OCT-based retinal characteristics and cognitive functions. A literature search was carried out in PubMed until February 2025. The search terms "neurodegeneration", "dementia", "mild cognitive impairment", "mild neurocognitive disorder", "OCT", "OCT angiography (OCT-A)", "retinal biomarkers", "retinal layer", "RNFLT", and "GCL" were used. Relevant publications were reviewed, analyzed and summarized. In OCT‑A Alzheimer's disease, frontotemporal dementia, vascular dementia, amyotrophic lateral sclerosis, multiple sclerosis (MS) and Parkinson's disease demonstrate an association with areduced retinal nerve fiber layer (RNFL) and the ganglion cell layer (GCL) thickness as well as an enlarged foveal avascular zone. So far retinal changes could not be specifically assigned to aparticular form of neurodegenerative disease,; however, they could be meaningful in neuropsychological/radiological examinations and for longitudinal monitoring, as already recommended for MS. Further longitudinal studies are needed to identify and validate retinal biomarkers (patterns).

BackgroundWhile cortical atrophy has been widely studied in dementia, emerging evidence highlights the role of subcortical degeneration, particularly in deep gray matter structures such as the thalamus, claustrum, and basal nuclei, in both Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, disease-specific subcortical patterns remain undercharacterized.ObjectiveTo quantify deep gray matter atrophy across the AD continuum (mild cognitive impairment and AD) and three FTD subtypes (bvFTD, svFTD, PNFA), and to assess longitudinal atrophy, cognitive associations, and diagnostic classification.MethodsWe applied a novel segmentation pipeline (sTHOMAS) to T1-weighted MRI data from 380 participants in the ADNI cohort and 274 participants in the FTLDNI cohort, with longitudinal follow-up available for 237 participants. Group differences were assessed using ANCOVA (adjusted for age and sex), followed by post hoc comparisons and effect size estimation (Cohen's d). Neuropsychological associations were examined using partial correlations. A hierarchical Random Forest model was trained to classify diagnostic groups.ResultsPronounced atrophy was observed in the mediodorsal, anteroventral, pulvinar thalamic nuclei, and nucleus accumbens, and claustrum in both AD and FTD, but was significantly greater in bvFTD. Longitudinal analysis revealed the fastest progression in bvFTD. Classification achieved 96.8% accuracy (AUC = 0.99) for AD versus FTD and 77.7% accuracy (AUC = 0.83) for PNFA versus svFTD. Subcortical atrophy correlated to executive, language, and semantic deficits.ConclusionsAtrophy in the mediodorsal, pulvinar, anteroventral thalamic nuclei, nucleus accumbens, and claustrum distinguishes AD from FTD and differentiates FTD subtypes. These subcortical structures represent promising biomarkers for diagnosis and monitoring of neurodegeneration.