The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these ...diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression.
Frontotemporal dementia (FTD) is a common form of dementia with heterogeneous clinical presentations and distinct clinical syndromes. This article will review currently available therapies for FTD, ...its related disorders and their clinical evidence. It will also discuss recent advancements in FTD pathophysiology, treatment development, biomarker advancement and their relation to recently completed or currently ongoing clinical trials as well as future implications.
Frontotemporal dementia (FTD) is a type of dementia with distinct clinical syndromes. Current treatments involve off‐label use of medications for symptomatic management and cannot modify disease course. Advancements in FTD pathophysiology, genetics, and biomarkers have led to development of small molecules targeting the underlying pathology in hopes of achieving a disease‐modifying effect. This article will review current therapies for FTD, discuss advancements in FTD pathophysiology, therapy development, biomarker advancement, their relation to recent clinical trials and future implications.
This article is part of the Frontotemporal Dementia special issue.
Frontotemporal dementia (FTD) is a type of dementia with distinct clinical syndromes. Current treatments involve off‐label use of medications for symptomatic management and cannot modify disease course. Advancements in FTD pathophysiology, genetics, and biomarkers have led to development of small molecules targeting the underlying pathology in hopes of achieving a disease‐modifying effect. This article will review current therapies for FTD, discuss advancements in FTD pathophysiology, therapy development, biomarker advancement, their relation to recent clinical trials and future implications.
This article is part of the Frontotemporal Dementia special issue.
In this multicentre study in clinical settings, we assessed the accuracy of optimized procedures for FDG-PET brain metabolism and CSF classifications in predicting or excluding the conversion to ...Alzheimer's disease (AD) dementia and non-AD dementias.
We included 80 MCI subjects with neurological and neuropsychological assessments, FDG-PET scan and CSF measures at entry, all with clinical follow-up. FDG-PET data were analysed with a validated voxel-based SPM method. Resulting single-subject SPM maps were classified by five imaging experts according to the disease-specific patterns, as “typical-AD”, “atypical-AD” (i.e. posterior cortical atrophy, asymmetric logopenic AD variant, frontal-AD variant), “non-AD” (i.e. behavioural variant FTD, corticobasal degeneration, semantic variant FTD; dementia with Lewy bodies) or “negative” patterns. To perform the statistical analyses, the individual patterns were grouped either as “AD dementia vs. non-AD dementia (all diseases)” or as “FTD vs. non-FTD (all diseases)”. Aβ42, total and phosphorylated Tau CSF-levels were classified dichotomously, and using the Erlangen Score algorithm. Multivariate logistic models tested the prognostic accuracy of FDG-PET-SPM and CSF dichotomous classifications. Accuracy of Erlangen score and Erlangen Score aided by FDG-PET SPM classification was evaluated.
The multivariate logistic model identified FDG-PET “AD” SPM classification (Expβ = 19.35, 95% C.I. 4.8–77.8, p < 0.001) and CSF Aβ42 (Expβ = 6.5, 95% C.I. 1.64–25.43, p < 0.05) as the best predictors of conversion from MCI to AD dementia. The “FTD” SPM pattern significantly predicted conversion to FTD dementias at follow-up (Expβ = 14, 95% C.I. 3.1–63, p < 0.001). Overall, FDG-PET-SPM classification was the most accurate biomarker, able to correctly differentiate either the MCI subjects who converted to AD or FTD dementias, and those who remained stable or reverted to normal cognition (Expβ = 17.9, 95% C.I. 4.55–70.46, p < 0.001).
Our results support the relevant role of FDG-PET-SPM classification in predicting progression to different dementia conditions in prodromal MCI phase, and in the exclusion of progression, outperforming CSF biomarkers.
•Appropriate biomarkers measures improve early dementia diagnosis in MCI.•FDG-PET-SPM maps and CSF Aβ42 are the best predictors of AD dementia conversion.•FDG-PET-SPM maps accurately predict conversion to different dementia conditions.•A negative FDG-PET-SPM pattern characterizes stable or reverter MCI cases.
Frontotemporal Dementia Olney, Nicholas T; Spina, Salvatore; Miller, Bruce L
Neurologic clinics,
05/2017, Letnik:
35, Številka:
2
Journal Article
Recenzirano
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Frontotemporal dementia (FTD) is a heterogeneous disorder with distinct clinical phenotypes associated with multiple neuropathologic entities. Presently, the term FTD encompasses clinical disorders ...that include changes in behavior, language, executive control, and often motor symptoms. The core FTD spectrum disorders include behavioral variant FTD, nonfluent/agrammatic variant primary progressive aphasia, and semantic variant PPA. Related FTD disorders include frontotemporal dementia with motor neuron disease, progressive supranuclear palsy syndrome, and corticobasal syndrome. In this article, the authors discuss the clinical presentation, diagnostic criteria, neuropathology, genetics, and treatments of these disorders.
Frontotemporal dementia (FTD), the second most common type of presenile dementia, is a heterogeneous neurodegenerative disease characterized by progressive behavioural and/or language problems, and ...includes a range of clinical, genetic and pathological subtypes. The diagnostic process is hampered by this heterogeneity, and correct diagnosis is becoming increasingly important to enable future clinical trials of disease-modifying treatments. Reliable biomarkers will enable us to better discriminate between FTD and other forms of dementia and to predict disease progression in the clinical setting. Given that different underlying pathologies probably require specific pharmacological interventions, robust biomarkers are essential for the selection of patients with specific FTD subtypes. This Review emphasizes the increasing availability and potential applications of structural and functional imaging biomarkers, and cerebrospinal fluid and blood fluid biomarkers in sporadic and genetic FTD. The relevance of new MRI modalities - such as voxel-based morphometry, diffusion tensor imaging and arterial spin labelling - in the early stages of FTD is discussed, together with the ability of these modalities to classify FTD subtypes. We highlight promising new fluid biomarkers for staging and monitoring of FTD, and underline the importance of large, multicentre studies of individuals with presymptomatic FTD. Harmonization in the collection and analysis of data across different centres is crucial for the implementation of new biomarkers in clinical practice, and will become a great challenge in the next few years.
Neurodegenerative diseases are a common cause of morbidity and cognitive impairment in older adults. Most clinicians who care for the elderly are not trained to diagnose these conditions, perhaps ...other than typical Alzheimer's disease (AD). Each of these disorders has varied epidemiology, clinical symptomatology, laboratory and neuroimaging features, neuropathology, and management. Thus, it is important that clinicians be able to differentiate and diagnose these conditions accurately. This review summarizes and highlights clinical aspects of several of the most commonly encountered neurodegenerative diseases, including AD, frontotemporal dementia (FTD) and its variants, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and Huntington's disease (HD). For each condition, we provide a brief overview of the epidemiology, defining clinical symptoms and diagnostic criteria, relevant imaging and laboratory features, genetics, pathology, treatments, and differential diagnosis.
A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To ...investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy.
•Mouse model expressing ALS/FTD associated C9ORF72 hexanucleotide repeat expansion•Formation of sense and antisense C9ORF72 RNA transcript foci•Dipeptide repeat proteins produced by repeat-associated non-ATG translation•Formation of cytoplasmic inclusions containing dipeptide repeat proteins
Peters et al. report that transgenic mice expressing ALS/FTD-associated C9ORF72 hexanucleotide expansions develop histopathological features of c9ALS/FTD (RNA foci and aggregates of non-ATG translated dipeptides) but not motor neuron disease. These features are attenuated in vitro by anti-C9ORF72 microRNA.
Frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative disorders with different pathological signatures, genetic variability and complex disease mechanisms, for which no ...effective treatments exist. Despite advances in understanding the underlying pathology of FTD, sensitive and specific fluid biomarkers for this disease are lacking. As in other types of dementia, mounting evidence suggests that neuroinflammation is involved in the progression of FTD, including cortical inflammation, microglial activation, astrogliosis and differential expression of inflammation-related proteins in the periphery. Furthermore, an overlap between FTD and autoimmune disease has been identified. The most substantial evidence, however, comes from genetic studies, and several FTD-related genes are also implicated in neuroinflammation. This Review discusses specific evidence of neuroinflammatory mechanisms in FTD and describes how advances in our understanding of these mechanisms, in FTD as well as in other neurodegenerative diseases, might facilitate the development and implementation of diagnostic tools and disease-modifying treatments for FTD.
Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three ...clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30-50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2-21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for disease-specific therapeutic trials in the future.
Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A ...better understanding of NfL dynamics is essential for upcoming therapeutic trials. We aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia.
We recruited participants from 14 centres collaborating in the Genetic Frontotemporal Dementia Initiative (GENFI), which is a multicentre cohort study of families with genetic frontotemporal dementia done across Europe and Canada. Eligible participants (aged ≥18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more. Participants were excluded if they had neurological comorbidities that were likely to affect NfL, including cerebrovascular events. We measured NfL longitudinally in serum samples collected between June 8, 2012, and Dec 8, 2017, through follow-up visits annually or every 2 years, which also included MRI and neuropsychological assessments. Using mixed-effects models, we analysed NfL changes over time and correlated them with longitudinal imaging and clinical parameters, controlling for age, sex, and study site. The primary outcome was the course of NfL over time in the various stages of genetic frontotemporal dementia.
We included 59 symptomatic carriers and 149 presymptomatic carriers of a mutation in GRN, C9orf72, or MAPT, and 127 non-carriers. Nine presymptomatic carriers became symptomatic during follow-up (so-called converters). Baseline NfL was elevated in symptomatic carriers (median 52 pg/mL IQR 24–69) compared with presymptomatic carriers (9 pg/mL 6–13; p<0·0001) and non-carriers (8 pg/mL 6–11; p<0·0001), and was higher in converters than in non-converting carriers (19 pg/mL 17–28 vs 8 pg/mL 6–11; p=0·0007; adjusted for age). During follow-up, NfL increased in converters (b=0·097 SE 0·018; p<0·0001). In symptomatic mutation carriers overall, NfL did not change during follow-up (b=0·017 SE 0·010; p=0·101) and remained elevated. Rates of NfL change over time were associated with rate of decline in Mini Mental State Examination (b=–94·7 SE 33·9; p=0·003) and atrophy rate in several grey matter regions, but not with change in Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale score (b=–3·46 SE 46·3; p=0·941).
Our findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy. The characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker.
ZonMw and the Bluefield project.
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