Frontotemporal Dementia Caused by CHMP2B Mutations

CHMP2B mutations are a rare cause of autosomal dominant frontotemporal dementia (FTD). The best studied example is frontotemporal dementia linked to chromosome 3 (FTD-3) which occurs in a large Danish family, with a further CHMP2B mutation identified in an unrelated Belgian familial FTD patient. These mutations lead to C-terminal truncations of the CHMP2B protein and we will review recent advances in our understanding of the molecular effects of these mutant truncated proteins on vesicular fusion events within the endosome-lysosome and autophagy degradation pathways. We will also review the clinical features of FTD caused by CHMP2B truncation mutations as well as new brain imaging and neuropathological findings. Finally, we collate the current data on CHMP2B missense mutations, which have been reported in FTD and motor neuron disease

Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation

Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD

The clinical spectrum of sporadic and familial forms of frontotemporal dementia

The term frontotemporal dementia (FTD) describes a clinically, genetically and pathologically diverse group of neurodegenerative disorders. Symptoms of FTD can present in individuals in their twenties through to their nineties, but the mean age at onset is in the sixth decade. The most common presentation is with a change in personality and impaired social conduct (behavioural variant FTD). Less frequently patients present with language problems (primary progressive aphasia). Both of these groups of patients can develop motor features consistent with either motor neuron disease (usually the amyotrophic lateral sclerosis variant) or parkinsonism (most commonly a progressive supranuclear palsy or corticobasal syndrome). In about a third of cases FTD is familial, with mutations in the progranulin, microtubule-associated protein tau and chromosome 9 open reading frame 72 genes being the major causes. Mutations in a number of other genes including TANK-binding kinase 1 are rare causes of familial FTD. This review aims to clarify the often confusing terminology of FTD, and outline the various clinical features and diagnostic criteria of sporadic and familial FTD syndromes. It will also discuss the current major challenges in FTD research and clinical practice, and potential areas for future research. This article is protected by copyright. All rights reserved

CSF neurofilament light concentration is increased in presymptomatic CHMP2B mutation carriers

OBJECTIVE: A rare cause of familial frontotemporal dementia (FTD) is a mutation in the CHMP2B gene on chromosome 3 (FTD-3), described in a Danish family. Here we examine whether CSF biomarkers change in the preclinical phase of the disease. METHODS: In this cross-sectional explorative study, we analyzed CSF samples from 16 mutation carriers and 14 noncarriers from the Danish FTD-3 family. CSF biomarkers included total tau (t-tau) and neurofilament light chain (NfL) as a marker for neurodegeneration, phosphorylated tau (p-tau) as a marker for tau pathology, β-amyloid (Aβ) 38, 40, and 42 (Aβ₃₈, Aβ₄₀, and Aβ₄₂). to monitor Aβ metabolism, and YKL-40 as a marker of neuroinflammation. Aβ isoform concentrations were measured using a multiplexed immunoassay; t-tau, p-tau, NfL, and YKL-40 concentrations were measured using sandwich ELISAs. RESULTS: CSF NfL concentration was significantly increased in mutation carriers vs noncarriers. Further, CSF NfL concentration was significantly higher in symptomatic mutation carriers compared to presymptomatic carriers, and also significantly higher in presymptomatic carriers compared to noncarriers. No differences in t-tau and p-tau and YKL-40 concentrations between controls and mutation carriers were observed. CSF concentrations of the Aβ peptides Aβ₃₈ and Aβ₄₀ but not Aβ₄₂ were significantly lower in mutation carriers compared to noncarriers. CONCLUSIONS: Increased NfL levels in presymptomatic individuals and in symptomatic patients with FTD-3 indicate a continuous process of neurodegeneration from the presymptomatic to symptomatic state. Although not specific for FTD-3 pathology, our data suggest that CSF NfL could serve as a valuable biomarker to detect onset of neurodegeneration in FTD-3 mutation carriers

Positron emission tomography in vivo characterisation of the pathology of frontotemporal dementia

Frontotemporal dementia (FTD) is clinically and pathologically diverse, encompassing the behavioural variant FTD; non-fluent variant primary progressive aphasia; and semantic variant primary progressive aphasia. These are usually associated with either tau or TDP-43 pathology, with highly variable clinicopathological correlations. Neuroinflammation also contributes to the pathogenesis of FTD, but its relevance to the disease spectrum is incompletely understood. There is a critical need for better understanding of how drivers of pathophysiology, such as neuroinflammation and protein aggregation, relate to the heterogeneity of clinical disease in vivo. This knowledge gap currently forms a significant barrier to the development of effective treatments in FTD. I review the clinical, pathological and genetic features of FTD and the role of PET for measuring in vivo components of pathophysiology in this setting. I then describe a series of case studies and group analysis of FTD syndromes, using positron emission tomography (PET) radioligands to visualise and quantify different aspects of pathophysiology in vivo. [18F]AV-1451tau was introduced primarily to study tau pathology in Alzheimer’s disease using, which differs from FTD tauopathy in several respects. I examined the sensitivity and specificity of [18F]AV-1451 in FTD, in vivo, through (i) [18F]AV-1451 imaging of the FTLD-tau pathology in a case of FTD due to a MAPT 10+16 mutation in the microtubule associated protein tau, and a second pre-symptomatic case with the same mutation; (ii) [18F]AV-1451 imaging of a cohort of seven cases with Semantic Dementia and one case of FTD from a C9orf72 expansion, both strongly associated with TDP-43 pathology without tau; and (iii) the increase in [18F]AV-1451 binding, and changes in the distribution of binding, in thirty one patients spanning the three major FTD syndromes in comparison to matched controls. The literature on the role of neuroinflammation in FTD is more limited. I used the PET ligand [11C]PK-11195, as an established marker of activated microglia. I report the elevation in [11C]PK-11195 binding, and the change in its distribution, in a case of a pre-symptomatic MAPT 10+16 mutation carrier; and in twenty nine patients spanning the three major FTD syndromes in comparison to matched controls. In addition to reporting the correlations between PET ligand binding and disease severity, I describe the relationship across regions and across syndromes between [18F]AV-1451 and [11C]PK-11195 binding. In view of the marked variations in affinity of [18F]AV-1451 for different tau isoforms and TDP43-pathology, my analyses focus on multivariate distributions rather than absolute binding potential. The results show high correlations between [18F]AV-1451 and [11C]PK-11195 binding in each FTD syndrome. However, in the healthy MAPT 10+16 carrier, the distribution of elevated [11C]PK-11195 binding is much more extensive that the elevation of [18F]AV-1451, suggesting that inflammation might precede the aggregation of tau. I discuss the limitations of the PET ligands, and summarise the insights into FTD pathogenesis arising from my series of observational studies. The role of new PET ligands, and the integration of PET in future clinical trials are discussed

Neuroinflammation in frontotemporal dementia

Frontotemporal dementia (FTD) is a clinically and pathologically diverse disease with few reliable biomarkers and no effective treatments. Increasing evidence suggests that chronic neuroinflammation and microglial dysfunction contribute to disease, particularly in genetic FTD due to progranulin (GRN) mutations. This thesis examines the clinical, histological and fluid biomarker evidence of immune dysregulation and neuroinflammation in FTD, with a focus on microglia. Assessment of systemic autoimmune diseases in individuals with genetic FTD demonstrates that non-thyroid autoimmune diseases are more prevalent in GRN mutation carriers than controls. Exploration of the histopathological correlates of MRI white matter hyperintensities (WMH) in a patient with FTD due to a GRN mutation links severe WMH in the frontal lobes to extensive white matter demyelination and microglial dystrophy. Immunohistochemical assessment of microglia in frontal and temporal post-mortem brain tissue from individuals with different sporadic and genetic subtypes of frontotemporal lobar degeneration (FTLD), Alzheimer’s disease (AD) and controls demonstrates regional differences in microglial burden, activation and dystrophy, which vary by microglial phenotype, pathological subtype and disease mechanism. Measurement of levels of glia-derived biomarkers (sTREM2, YKL-40 and chitotriosidase) in cerebrospinal fluid (CSF) of individuals with sporadic and genetic FTD and controls shows that levels are elevated in certain subgroups, particularly in those with GRN mutations, or likely underlying AD rather than FTLD. Investigation of these biomarkers in CSF of presymptomatic mutation carriers (PMC) and symptomatic individuals with genetic FTD reveals raised chitotriosidase levels in GRN and MAPT mutation carriers with FTD, with elevation several years before expected onset in GRN PMC. In conclusion, this thesis provides multimodal evidence of dysregulated neuroinflammation in FTD and highlights the role of microglial dysfunction and senescence in the pathogenesis of FTLD, particularly in GRN mutation carriers. Further investigation of these processes may guide therapeutic and biomarker approaches for use in future clinical trials

Increased Cortical Thickness and Caudate Volume Precede Atrophy in PSEN1 Mutation Carriers

Neuroimaging studies of familial Alzheimer's disease allow investigation of the disease process before clinical onset. We performed semi-automated MRI analysis to evaluate cortical thickness (CTh), grey matter (GM) volumes, and GM diffusivity indexes in PSEN1 mutation carriers (MC). We recruited 11 MC from 4 families with PSEN1 mutations (L286P, M139T, K239N) and 6 familial and 12 non-familial healthy controls. MC were classified as either asymptomatic (n=6) or symptomatic (n=5). Subjects underwent structural and diffusion-weighted 3-Tesla MRI scanning. CTh and GM volumes of subcortical structures and diffusivity indexes were calculated and group comparisons were performed. Structural images were reanalyzed with voxel-based morphometry methodology. Cerebrospinal fluid amyloid-β1-42 levels (Aβ) were measured. We found that symptomatic MC presented widespread cortical thinning, especially in precuneus and parietotemporal areas (p<0.01) and increased mean diffusivity (MD) in these areas compared to controls. Unexpectedly, asymptomatic MC, 9.9 years prior to the predicted age of disease onset, presented increased CTh in the precuneus and parietotemporal areas (p<0.01), increased caudate volumes (p<0.01), and decreased MD (p<0.05) in these areas compared to HC. In MC, CTh correlated with adjusted age. Aβ values were within normal limits in AMC. In conclusion, at early preclinical stages, CTh in the precuneus and parietotemporal regions and caudate volume increase in PSEN1 MC and decrease thereafter with disease progression. The different trends in MD in asymptomatic and symptomatic MC suggest that different microstructural changes underlie the contrasting morphometric findings. Reactive neuronal hypertrophy or/and inflammation may account for increased CTh and decreased MD in asymptomatic MC