Socioemotional Dysfunction From Temporal Lobe Involvement in Frontotemporal Dementia: A Preliminary Report.

OBJECTIVE: Socioemotional changes, rather than cognitive impairments, are the feature that defines behavioral variant frontotemporal dementia (bvFTD). Investigators have attributed the socioemotional changes in bvFTD and other dementias to frontal lobe dysfunction; however, recent work implies a further contribution from right anterior temporal disease. The authors evaluated relationships between regional brain atrophy and socioemotional changes in both bvFTD and early-onset Alzheimer's disease (EOAD). METHODS: This study explored the neuroanatomical correlations of performance on the Socioemotional Dysfunction Scale (SDS), an instrument previously shown to document socioemotional changes in bvFTD, among 13 patients with bvFTD not preselected for anterior temporal involvement and 16 age-matched patients with early-onset Alzheimer's disease (EOAD). SDS scores were correlated with volumes of regions of interest assessed with tensor-based morphometric analysis of MRI images. RESULTS: As expected, the bvFTD group had significantly higher SDS scores overall and smaller frontal regions compared with the EOAD group, which in turn had smaller volumes in temporoparietal regions. SDS scores significantly correlated with lateral anterior temporal lobe (ATL) atrophy, and a regression analysis that controlled for diagnosis indicated that SDS scores predicted lateral ATL volume. Within the bvFTD group, higher SDS scores were associated with smaller lateral and right ATL regions, as well as a smaller orbitofrontal cortex. Within the EOAD group, higher SDS scores were associated with a smaller right parietal cortex. CONCLUSIONS: This study confirms that, in addition to orbitofrontal disease, there is a prominent right and lateral ATL origin of socioemotional changes in bvFTD and further suggests that right parietal involvement contributes to socioemotional changes in EOAD.

Genetic evidence for causal association between migraine and dementia: a mendelian randomization study.

BACKGROUND: There is an association between migraine and dementia, however, their causal relationship remains unclear. This study employed bidirectional two-sample Mendelian randomization (MR) to investigate the potential causal relationship between migraine and dementia and its subtypes: Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). METHODS: Summary-level statistics data were obtained from publicly available genome-wide association studies (GWAS) for both migraine and five types of dementia. Single nucleotide polymorphisms (SNPs) associated with migraine and each dementia subtype were selected. MR analysis was conducted using inverse variance weighting (IVW) and weighted median (WM) methods. Sensitivity analyses included Cochran's Q test, MR pleiotropy residual sum and outlier (MR-PRESSO) analysis, the intercept of MR-Egger, and leave-one-out analysis. RESULTS: Migraine showed a significant causal relationship with AD and VaD, whereas no causal relationship was observed with all-cause dementia, FTD, or DLB. Migraine may be a potential risk factor for AD (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 0.02-0.14; P = 0.007), while VaD may be a potential risk factor for migraine (OR: 1.04; 95% CI: 0.02-0.06; P = 7.760E-5). Sensitivity analyses demonstrated the robustness of our findings. CONCLUSION: Our study suggest that migraine may have potential causal relationships with AD and VaD. Migraine may be a risk factor for AD, and VaD may be a risk factor for migraine. Our study contributes to unraveling the comprehensive genetic associations between migraine and various types of dementia, and our findings will enhance the academic understanding of the comorbidity between migraine and dementia.

Clinical recognition of frontotemporal dementia with right anterior temporal predominance: A multicenter retrospective cohort study.

INTRODUCTION: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. HIGHLIGHTS: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.

'A lightbulb moment': carers' experiences of behavioural symptoms in motor neurone disease before and after MiNDToolkit.

BACKGROUND: To explore carers' experiences of behavioural symptoms in Motor Neurone Disease (MND), before and after using the MiNDToolkit, a novel internet-based psychoeducational intervention to support management of behavioural symptoms (BehSymp) in MND. The study also investigated carers' views and acceptability of MiNDToolkit. METHODS: A qualitative process evaluation of carers engagement with, and acceptability of, the MiNDToolkit conducted using semi-structured interviews with carers (n = 11). All interviews were audio-recorded, professionally transcribed verbatim and analysed thematically. RESULTS: Five themes were identified: (1) In the dark: carers' experiences and reactions to BehSymp; (2) Others can see: the role of HCPs in identifying symptoms - and perceived opportunities for carers to receive support; (3) Shedding light: carers implementation and perceived impact of the MiNDToolkit content; (4) Acceptability and carers' engagement with MiNDToolkit; (5) Future implementation. Carers' experience of BehSymp was particularly distressing when symptoms were apparently out of context. MiNDToolkit appeared to support learning that BehSymp were part of MND. Content resonated with carers, who reported learning about the full picture of MND, which led to acceptance and use of newly learned strategies. Engagement with the platform was good, with varied input from HCPs. Greater and nuanced involvement from HCPs seem important to support management of BehSymp. Recommendations for a full-scale trial emerged, including adding a paper booklet to accompany the intervention and creation of new modules on emotional lability, changes in relationships, and transitioning to a care home. CONCLUSIONS: MiNDToolkit was acceptable to carers overall. Recommended improvements should be actioned in a full-scale trial.

Allostatic interoceptive overload across psychiatric and neurological conditions.

Emerging theories emphasize the crucial role of allostasis (anticipatory and adaptive regulation of the body's biological processes) and interoception (integration, anticipation, and regulation of internal bodily states) in adjusting physiological responses to environmental and bodily demands. This review explores the disruptions in integrated allostatic interoceptive mechanisms in psychiatric and neurological disorders, including anxiety, depression, Alzheimer's disease, and frontotemporal dementia. We assess the biological mechanisms associated with allostatic interoception, including whole-body cascades, brain structure and function of the allostatic interoceptive network, heart-brain interactions, respiratory-brain interactions, the gut-brain-microbiota axis, peripheral biological processes (inflammatory, immune), and epigenetic pathways. These processes span psychiatric and neurological conditions and call for developing dimensional and trans-nosological frameworks. We synthesize new pathways to understand how allostatic interoceptive processes modulate interactions between environmental demands and biological functions in brain disorders. We discuss current limitations of the framework and future transdisciplinary developments. This review opens a new research agenda for understanding how allostatic interoception involves brain predictive coding in psychiatry and neurology, allowing for better clinical application and the development of new therapeutic interventions.

Identification of a pathogenic mutation in ARPP21 in patients with amyotrophic lateral sclerosis.

BACKGROUND AND OBJECTIVE: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing. METHODS: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region. RESULTS: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes. CONCLUSIONS: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.

Reversal of cognitive deficits in FUSR521G amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction.

Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUSR521G or SOD1G93A to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUSR521G mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1G93A mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.

Changes of brain functional network in Alzheimer's disease and frontotemporal dementia: a graph-theoretic analysis.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias, presenting with similar clinical features that challenge accurate diagnosis. Despite extensive research, the underlying pathophysiological mechanisms remain unclear, and effective treatments are limited. This study aims to investigate the alterations in brain network connectivity associated with AD and FTD to enhance our understanding of their pathophysiology and establish a scientific foundation for their diagnosis and treatment. METHODS: We analyzed preprocessed electroencephalogram (EEG) data from the OpenNeuro public dataset, comprising 36 patients with AD, 23 patients with FTD, and 29 healthy controls (HC). Participants were in a resting state with eyes closed. We estimated the average functional connectivity using the Phase Lag Index (PLI) for lower frequencies (delta and theta) and the Amplitude Envelope Correlation with leakage correction (AEC-c) for higher frequencies (alpha, beta, and gamma). Graph theory was applied to calculate topological parameters, including mean node degree, clustering coefficient, characteristic path length, global and local efficiency. A permutation test was then utilized to assess changes in brain network connectivity in AD and FTD based on these parameters. RESULTS: Both AD and FTD patients showed increased mean PLI values in the theta frequency band, along with increases in average node degree, clustering coefficient, global efficiency, and local efficiency. Conversely, mean AEC-c values in the alpha frequency band were notably diminished, which was accompanied by decreases average node degree, clustering coefficient, global efficiency, and local efficiency. Furthermore, AD patients in the occipital region showed an increase in theta band node degree and decreased alpha band clustering coefficient and local efficiency, a pattern not observed in FTD. CONCLUSIONS: Our findings reveal distinct abnormalities in the functional network topology and connectivity in AD and FTD, which may contribute to a better understanding of the pathophysiological mechanisms of these diseases. Specifically, patients with AD demonstrated a more widespread change in functional connectivity, while those with FTD retained connectivity in the occipital lobe. These observations could provide valuable insights for developing electrophysiological markers to differentiate between the two diseases.

The relative brain signal variability increases in the behavioral variant of frontotemporal dementia and Alzheimer's disease but not in schizophrenia.

Overlapping symptoms between Alzheimer's disease (AD), behavioral variant of frontotemporal dementia (bvFTD), and schizophrenia (SZ) can lead to misdiagnosis and delays in appropriate treatment, especially in cases of early-onset dementia. To determine the potential of brain signal variability as a diagnostic tool, we assessed the coefficient of variation of the BOLD signal (CVBOLD) in 234 participants spanning bvFTD (n = 53), AD (n = 17), SZ (n = 23), and controls (n = 141). All underwent functional and structural MRI scans. Data unveiled a notable increase in CVBOLD in bvFTD patients across both datasets (local and international, p < 0.05), revealing an association with clinical scores (CDR and MMSE, r = 0.46 and r = -0.48, p < 0.0001). While SZ and control group demonstrated no significant differences, a comparative analysis between AD and bvFTD patients spotlighted elevated CVBOLD in the frontopolar cortices for the latter (p < 0.05). Furthermore, CVBOLD not only presented excellent diagnostic accuracy for bvFTD (AUC 0.78-0.95) but also showcased longitudinal repeatability. During a one-year follow-up, the CVBOLD levels increased by an average of 35% in the bvFTD group, compared to a 2% increase in the control group (p < 0.05). Our findings suggest that CVBOLD holds promise as a biomarker for bvFTD, offering potential for monitoring disease progression and differentiating bvFTD from AD and SZ.

Brain perfusion SPECT in dementia: what radiologists should know.

The findings of brain perfusion single-photon emission computed tomography (SPECT), which detects abnormalities often before changes manifest in morphological imaging, mainly reflect neurodegeneration and contribute to dementia evaluation. A major shift is about to occur in dementia practice to the approach of diagnosing based on biomarkers and treating with disease-modifying drugs. Accordingly, brain perfusion SPECT will be required to serve as a biomarker of neurodegeneration. Hypoperfusion in Alzheimer's disease (AD) is typically seen in the posterior cingulate cortex and precuneus early in the disease, followed by the temporoparietal cortices. On the other hand, atypical presentations of AD such as the posterior variant, logopenic variant, frontal variant, and corticobasal syndrome exhibit hypoperfusion in areas related to symptoms. Additionally, hypoperfusion especially in the precuneus and parietal association cortex can serve as a predictor of progression from mild cognitive impairment to AD. In dementia with Lewy bodies (DLB), the differentiating feature is the presence of hypoperfusion in the occipital lobes in addition to that observed in AD. Hypoperfusion of the occipital lobe is not a remarkable finding, as it is assumed to reflect functional loss due to impairment of the cholinergic and dopaminergic systems rather than degeneration per se. Moreover, the cingulate island sign reflects the degree of AD pathology comorbid in DLB. Frontotemporal dementia is characterized by regional hypoperfusion according to the three clinical types, and the background pathology is diverse. Idiopathic normal pressure hydrocephalus shows apparent hypoperfusion around the Sylvian fissure and corpus callosum and apparent hyperperfusion in high-convexity areas. The cortex or striatum with diffusion restriction on magnetic resonance imaging in prion diseases reflects spongiform degeneration and brain perfusion SPECT reveals hypoperfusion in the same areas. Brain perfusion SPECT findings in dementia should be carefully interpreted considering background pathology.

Clinical and genetic characteristics of 1672 cases of amyotrophic lateral sclerosis in China: a single-center retrospective study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, continuous discoveries of new ALS-causing genes have enhanced the understanding of the genotype-phenotype relationship in ALS, aiding in disease progression prediction and providing a more comprehensive basis for genetic diagnosis. METHODS: A total of 1672 ALS patients who visited the Neurology Department of Peking Union Medical College Hospital between January 2014 and December 2022 and met the revised El Escorial diagnostic criteria were included. Clinical data were collected, whole exome sequencing and dynamic mutation screening of the C9ORF72 gene were performed, and the clinical phenotypes and genotypes of the patients were analyzed. RESULTS: The average age of onset for the 1672 ALS patients was 52.6 ± 11.2 years (range 17-85 years), with a median disease duration of 14 months at the time of visit (interquartile range 9-24 months, range 2-204 months). The male to female ratio was 833:839. The patients included 297 (17.8%) with bulbar onset, 198 (11.8%) with flail arm/leg syndrome, 89 (5.3%) with familial ALS, and 52 (3.1%) with concomitant frontotemporal dementia (FTD). Pathogenic variants associated with ALS were detected in 175 patients (10.5% of the cohort), with the most common mutations being SOD1, FUS, and ANXA11. Among patients with familial ALS, 56.2% (50/89) had genetic mutations, compared to 7.9% (125/1583) in sporadic ALS cases. From the perspective of phenotype-genotype correlation, (1) In ALS-FTD patients, the most common genetic mutations were ANXA11 and C9ORF72 repeat expansions. Patients with flail arm/leg syndrome more frequently carried mutations in SOD1, ANXA11, and hnRNPA1; (2) Despite genetic heterogeneity, it was observed that mutations in FUS and NEK1 were more common in males, and patients with FUS mutations had a younger age of onset; mutations in SOD1 and SQSTM1 were more likely to present with lower limb onset. CONCLUSION: This study provides comprehensive data on the genetic characteristics of ALS patients in China through large-scale clinical data and genetic analysis of 1672 cases. Differences in age of onset, onset site, and clinical phenotype among ALS patients with different genotypes can help clinicians better predict disease progression and provide a basis for precise diagnosis and individualized treatment.

Exploring the Regulatory Landscape of Dementia: Insights from Non-Coding RNAs.

Dementia, a multifaceted neurological syndrome characterized by cognitive decline, poses significant challenges to daily functioning. The main causes of dementia, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), and vascular dementia (VD), have different symptoms and etiologies. Genetic regulators, specifically non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are known to play important roles in dementia pathogenesis. MiRNAs, small non-coding RNAs, regulate gene expression by binding to the 3' untranslated regions of target messenger RNAs (mRNAs), while lncRNAs and circRNAs act as molecular sponges for miRNAs, thereby regulating gene expression. The emerging concept of competing endogenous RNA (ceRNA) interactions, involving lncRNAs and circRNAs as competitors for miRNA binding, has gained attention as potential biomarkers and therapeutic targets in dementia-related disorders. This review explores the regulatory roles of ncRNAs, particularly miRNAs, and the intricate dynamics of ceRNA interactions, providing insights into dementia pathogenesis and potential therapeutic avenues.

New Value of Acorus tatarinowii/gramineus Leaves as a Dietary Source for Dementia Prevention.

The rhizomes of Acorus tatarinowii Schott and Acorus gramineus Solander are widely used for treating amnesia in traditional Chinese medicine. In contrast, their leaves are usually discarded without their medicinal properties being known. Here, we found that the hot water extract of leaves improved cognition and tau pathology in model mice of frontotemporal dementia, similar to or even better than that of rhizomes. To explore the optimal method of processing, we made three preparations from dried leaves: hot water extract, extraction residue, and non-extracted simple crush powder. Among them, the simple crush powder had the strongest effect on tauopathy in mice. The crush powder also ameliorated Aß and α-synuclein pathologies and restored cognition in mouse models of Alzheimer's disease and dementia with Lewy bodies. These findings suggest the potential of Acorus tatarinowii/gramineus leaves as a dietary source for dementia prevention and reveal that simple crushing is a better way to maximize their efficacy.

Frequency of C9orf72, GRN, and MAPT pathogenic variants in patients recruited at the Belgrade Memory Center.

Most of the heritability in frontotemporal dementia (FTD) is accounted for by autosomal dominant hexanucleotide expansion in the chromosome 9 open reading frame 72 (C9orf72), pathogenic/likely pathogenic variants in progranulin (GRN), and microtubule-associated protein tau (MAPT) genes. Until now, there has been no systematic analysis of these genes in the Serbian population. Herein, we assessed the frequency of the C9orf72 expansion, pathogenic/likely pathogenic variants in GRN and MAPT in a well-characterized group of 472 subjects (FTD, Alzheimer's disease - AD, mild cognitive impairment - MCI, and unspecified dementia - UnD), recruited in the Memory Center, Neurology Clinic, University Clinical Center of Serbia. The C9orf72 repeat expansion was detected in 6.98% of FTD cases (13.46% familial; 2.6% sporadic). In the UnD subgroup, C9orf72 repeat expansions were detected in 4.08% (8% familial) individuals. Pathogenic variants in the GRN were found in 2.85% of familial FTD cases. Interestingly, no MAPT pathogenic/likely pathogenic variants were detected, suggesting possible geographical specificity. Our findings highlight the importance of wider implementation of genetic testing in neurological and psychiatric practice managing patients with cognitive-behavioral and motor symptoms.

Long-term, home-based transcranial direct current stimulation coupled with computerized cognitive training in frontotemporal dementia: A case report.

We present the case of a 62-year-old woman with probable behavioral variant of frontotemporal dementia (bvFTD) with cognitive/language deficits who demonstrated improved performance on cognitive/language testing and in functional tasks following long-term, home-based transcranial direct current stimulation (tDCS) coupled with computerized cognitive training (CCT). The patient underwent home-based tDCS (anode on the left prefrontal cortex and cathode on the right homologue) for 46 sessions over 10 weeks along with CCT. On post-treatment testing, the patient improved by 3 points on the Mini-Mental State Exam (MMSE) (23 to 26). She also showed improvement on several cognitive/language tasks, such as immediate recall of single words and word pairs, total accurate words in sentence repetition, delayed recall, semantic processing, and sentence level comprehension. There was no decline in several other cognitive and language tasks. Family members reported subjective improvements in expressiveness, communication, and interaction with others as well as increased attention to grooming and style which contrasted with her pre-treatment condition. This report suggests that home-based tDCS combined with CCT for an extended period may slow decline, and improve cognitive/language performance and everyday function in FTD.

Long-term, Home-based Transcranial Direct Current Stimulation Coupled with Computerized Cognitive Training in Frontotemporal Dementia: A Case Report: A 62-year-old woman with probable behavioral variant of frontotemporal dementia (bvFTD) improved on cognitive/language testing and in functional tasks following long-term, home-based transcranial direct current stimulation (tDCS) coupled with computerized cognitive training (CCT). The patient underwent home-based tDCS for 46 sessions over 10 weeks along with CCT. On post-treatment testing, the patient improved by three points on the Mini-Mental State Exam (MMSE) (23 to 26). She also improved immediate recall of single words and word pairs, total accurate words in sentence repetition, delayed recall, semantic processing, and sentence level comprehension. There was no decline in several other cognitive and language tasks. Family members described improvements in expressiveness, communication, and interaction with others and increased attention to grooming and style which was different from her pre-treatment condition. This case report suggests that home-based tDCS combined with CCT for an extended period may slow decline and improve cognitive/language performance and everyday function in FTD.

Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations.

BACKGROUND: Our study aims to evaluate the genetic and phenotypic spectrum of Frontotemporal dementia (FTD) gene variant carriers in Chinese populations, investigate mutation frequencies, and assess the functional properties of TBK1 and OPTN variants. METHODS: Clinically diagnosed FTD patients underwent genetic analysis through exome sequencing, repeat-primed polymerase chain reaction, and Sanger sequencing. TBK1 and OPTN variants were biologically characterized in vitro using immunofluorescence, immunoprecipitation, and immunoblotting analysis. The frequencies of genes implicated in FTD in China were analyzed through a literature review and meta-analysis. RESULTS: Of the 261 Chinese FTD patients, 61 (23.4%) carried potential causative variants in FTD-related genes, including MAPT (n = 17), TBK1 (n = 7), OPTN (n = 6), GRN (n = 6), ANXA11 (n = 4), CHMP2B (n = 3), C9orf72 GGGGCC repeats (n = 2), CYLD (n = 2), PRNP (n = 2), SQSTM1 (n = 2), TARDBP (n = 2), VCP (n = 1), CCNF (n = 1), CHCHD10 (n = 1), SIGMAR1 (n = 1), CHCHD2 (n = 1), FUS (n = 1), TMEM106B (n = 1), and UBQLN2 (n = 1). 29 variants can be considered novel, including the MAPT p.D54N, p.E342K, p.R221P, p.T263I, TBK1 p.E696G, p.I37T, p.E232Q, p.S398F, p.T78A, p.Q150P, p.W259fs, OPTN p.R144G, p.F475V, GRN p.V473fs, p.C307fs, p.R101fs, CHMP2B p.K6N, p.R186Q, ANXA11 p.Q155*, CYLD p.T157I, SQSTM1 p.S403A, UBQLN2 p.P509H, CCNF p.S160N, CHCHD10 p.A8T, SIGMAR1 p.S117L, CHCHD2 p.P53fs, FUS p.S235G & p.S236G, and TMEM106B p.L144V variants. Patients with TBK1 and OPTN variants presented with heterogeneous clinical phenotypes. Functional analysis demonstrated that TBK1 I37T and E232Q mutants showed decreased autophosphorylation, and the OPTN phosphorylation was reduced by the TBK1 I37T mutant. The OPTN-TBK1 complex formation was enhanced by the TBK1 E696G mutant, while OPTN R144G and F475V mutants exhibited reduced recruitment to autophagosomes compared to the wild-type. The overall frequency of TBK1 and OPTN in Chinese FTD patients was 2.0% and 0.3%, respectively. CONCLUSIONS: Our study demonstrates the extensive genetic and phenotypic heterogeneity of Chinese FTD patients. TBK1 mutations are the second most frequent cause of clinical FTD after MAPT in the Chinese.

Can neurodevelopmental disorders influence the course of neurodegenerative diseases? A scoping review.

This scoping review aims at giving an overview of the possible influence of neurodevelopmental disorders (NDDs) on cognitive-behavioral neurodegenerative diseases (CBNDs). Based on the PRISMA-ScR checklist, it details the methods of NDDs screening, the identified NDDs-CBNDs associations, as well as the criteria and types of association. The last literature search was performed in June 2023. In the final study, 32 articles were included. Analysis first showed that NDDs were mainly detected through medical records screening. Second, the association of specific learning disorders and major or mild neurocognitive disorder due to Alzheimer's disease was the most investigated. Third, associations were mostly based on prevalence comparisons. Finally, 66 % of studies reported a positive association between NDDs and CBNDs. Notably, up to 67 % of positive associations were observed with atypical forms of certain CBNDs. Authors' interpretations suggest that NDDs could constitute a risk factor for CBNDs. However, the influence of NDDs on CBNDs still lacks evidence and biological support, possibly due to the heterogeneity of methods and criteria employed. Developing validated assessment tools for all NDDs and conducting cohort studies could be beneficial for research, and clinical practice. Indeed, this review also underlines the importance of adopting a life-span approach regarding CBNDs.

Neurofilaments and progranulin are related to atrophy in frontotemporal lobar degeneration - A transdiagnostic study cross-validating atrophy and fluid biomarkers.

INTRODUCTION: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging. METHODS: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry. RESULTS: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects. DISCUSSION: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy. HIGHLIGHTS: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.

Flight to insight: maximizing the potential of Drosophila models of C9orf72-FTD.

Advancements in understanding the pathogenesis of C9orf72-associated frontotemporal dementia (C9orf72-FTD) have highlighted the role of repeat-associated non-ATG (RAN) translation and dipeptide repeat proteins (DPRs), with Drosophila melanogaster models providing valuable insights. While studies have primarily focused on RAN translation and DPR toxicity, emerging areas of investigation in fly models have expanded to neuronal dysfunction, autophagy impairment, and synaptic dysfunction, providing potential directions for new therapeutic targets and mechanisms of neurodegeneration. Despite this progress, there are still significant gaps in Drosophila models of C9orf72-FTD, namely in the areas of metabolism and circadian rhythm. Metabolic dysregulation, particularly lipid metabolism, autophagy, and insulin signaling, has been implicated in disease progression with findings from animal models and human patients with C9orf72 repeat expansions. Moreover, circadian disruptions have been observed in C9of72-FTD, with alterations in rest-activity patterns and cellular circadian machinery, suggesting a potential role in disease pathophysiology. Drosophila models offer unique opportunities to explore these aspects of C9orf72-FTD and identify novel therapeutic targets aimed at mitigating neurodegeneration.

Alterations to metabolic hormones in amyotrophic lateral sclerosis and frontotemporal dementia postmortem human tissue.

Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in the CNS is predominantly carried out within the hypothalamus, extra-hypothalamic CNS areas contain metabolic hormone receptors, including those for leptin (LEPR), insulin (INSR), and neuropeptide Y (NPY), indicating that they may play a role in biological processes underlying pathogenic disease processes. The status of these hormones within regions vulnerable in ALS/FTD is not well described. This study sought to determine whether the expression of these hormones and their receptors is altered in pathology-rich regions in cases of human FTD (superior frontal gyrus and insular cortex) and ALS (primary motor cortex and lumbar spinal cord) with TDP-43 pathology compared to matched healthy controls. LEPR mRNA was increased within the superior frontal gyrus of FTD cases and within primary motor cortex and lumbar spinal cord of ALS cases; INSR mRNA was increased in superior frontal gyrus and insular cortex of FTD cases. NPY protein was decreased in primary motor cortex and lumbar spinal cord of ALS cases. Our results demonstrate that metabolic hormones undergo complex alterations in ALS and FTD and suggest that these hormones could play critical roles in the pathogenesis of these diseases.