The clinical spectrum of sporadic and familial forms of frontotemporal dementia

Woollacott, Ione O.C.; Rohrer, Jonathan D.

doi:10.1111/jnc.13654

Cited by 117 publications

(127 citation statements)

References 293 publications

(695 reference statements)

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“…In a model of Alzheimer’s disease using J20 transgenic mice that harbor a familial mutant of human amyloid precursor protein 105 , C1q deposition preceded synapse elimination and plaque formation, and mice deficient in complement signaling had fewer phagocytic microglia and reduced synaptic elimination 15 . Loss of C1q also protected mice from synaptic elimination and downstream behavioral phenotypes in a model of dementia caused by deficiency of progranulin, a pleotropic protein that has a major role in genetic causes of frontotemporal dementia 106 . Progranulin-deficient microglia show increased lysosomal activity and complement production, leading to preferential elimination of inhibitory neurons 107 .…”

Section: Inflammation-induced Cns Dysfunction In Parenchymal Infectionmentioning

confidence: 94%

Infectious immunity in the central nervous system and brain function

2017

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Inflammation is emerging as a critical mechanism underlying neurological disorders of various etiologies, yet its role in altering brain function as a consequence of neuroinfectious disease remains unclear. Although acute alterations in mental status due to inflammation are a hallmark of central nervous system (CNS) infections with neurotropic pathogens, post-infectious neurologic dysfunction has traditionally been attributed to irreversible damage caused by the pathogens themselves. More recently, studies indicate that pathogen eradication within the CNS may require immune responses that interfere with neural cell function and communication without affecting their survival. In this Review we explore inflammatory processes underlying neurological impairments caused by CNS infection and discuss their potential links to established mechanisms of psychiatric and neurodegenerative diseases.

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Section: Inflammation-induced Cns Dysfunction In Parenchymal Infectionmentioning

confidence: 94%

Infectious immunity in the central nervous system and brain function

2017

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“…Up to 15% of patients with FTD concomitantly develop motor neuron disease (MND), and 10–20% of patients with MND develop FTD,3 suggesting that the two disorders lie on a clinical continuum. Pathogenic G 4 C 2 repeat expansions in chromosome 9 open reading frame 72 ( C9orf72) are the most common genetic cause of autosomal‐dominant FTD and amyotrophic lateral sclerosis (ALS) 4, 5.…”

Section: Introductionmentioning

confidence: 99%

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Meeter

Gendron

Sias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72‐associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72‐associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

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“…For example, frontotemporal dementia (FTD) comprises a group of clinical syndromes unified by underlying frontotemporal lobar degeneration (FTLD) pathology, which leads to disorders of behavior, language and executive function (Woollacott and Rohrer, 2016). FTD is the second most common form of dementia after Alzheimer’s disease in those under 65 years of age, and is characterized by progressive degeneration of frontal and anterior temporal lobes.…”

Section: Introductionmentioning

confidence: 99%

Early Cognitive/Social Deficits and Late Motor Phenotype in Conditional Wild-Type TDP-43 Transgenic Mice

Alfieri

Silva

Igaz

2016

Front. Aging Neurosci.

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Frontotemporal Dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two neurodegenerative diseases associated to mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43). To investigate in depth the behavioral phenotype associated with this proteinopathy, we used as a model transgenic (Tg) mice conditionally overexpressing human wild-type TDP 43 protein (hTDP-43-WT) in forebrain neurons. We previously characterized these mice at the neuropathological level and found progressive neurodegeneration and other features that evoke human TDP-43 proteinopathies of the FTD/ALS spectrum. In the present study we analyzed the behavior of mice at multiple domains, including motor, social and cognitive performance. Our results indicate that young hTDP-43-WT Tg mice (1 month after post-weaning transgene induction) present a normal motor phenotype compared to control littermates, as assessed by accelerated rotarod performance, spontaneous locomotor activity in the open field test and a mild degree of spasticity shown by a clasping phenotype. Analysis of social and cognitive behavior showed a rapid installment of deficits in social interaction, working memory (Y-maze test) and recognition memory (novel object recognition test) in the absence of overt motor abnormalities. To investigate if the motor phenotype worsen with age, we analyzed the behavior of mice after long-term (up to 12 months) transgene induction. Our results reveal a decreased performance on the rotarod test and in the hanging wire test, indicating a motor phenotype that was absent in younger mice. In addition, long-term hTDP-43-WT expression led to hyperlocomotion in the open field test. In sum, these results demonstrate a time-dependent emergence of a motor phenotype in older hTDP-43-WT Tg mice, recapitulating aspects of clinical FTD presentations with motor involvement in human patients, and providing a complementary animal model for studying TDP-43 proteinopathies.

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The clinical spectrum of sporadic and familial forms of frontotemporal dementia

Cited by 117 publications

References 293 publications

Infectious immunity in the central nervous system and brain function

Infectious immunity in the central nervous system and brain function

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Early Cognitive/Social Deficits and Late Motor Phenotype in Conditional Wild-Type TDP-43 Transgenic Mice

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