New directions for frontotemporal dementia drug discovery

Trojanowski, John Q.; Duff, Karen; Fillit, Howard; Koroshetz, Walter J.; Kuret, Jeff; Murphy, Diane D.; Refolo, Lorenzo M.

doi:10.1016/j.jalz.2007.06.001

Cited by 29 publications

(17 citation statements)

References 20 publications

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“…The hallmark of FTD is tauopathies or ubiquitin immunoreactive inclusions by the presences of neuronal and glial inclusions [48, 49] in gray and white matter. WM pathologies in FTD have been reported with astrocytic gliosis and oligodendroglial apoptosis, which may ultimately result in axonal degeneration [50–53].…”

Section: Discussionmentioning

confidence: 99%

Joint Assessment of Structural, Perfusion, and Diffusion MRI in Alzheimer′s Disease and Frontotemporal Dementia

Zhang

Schuff

Ching

et al. 2011

International Journal of Alzheimer's Disease

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Most MRI studies of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have assessed structural, perfusion and diffusion abnormalities separately while ignoring the relationships across imaging modalities. This paper aimed to assess brain gray (GM) and white matter (WM) abnormalities jointly to elucidate differences in abnormal MRI patterns between the diseases. Twenty AD, 20 FTD patients, and 21 healthy control subjects were imaged using a 4 Tesla MRI. GM loss and GM hypoperfusion were measured using high-resolution T1 and arterial spin labeling MRI (ASL-MRI). WM degradation was measured with diffusion tensor imaging (DTI). Using a new analytical approach, the study found greater WM degenerations in FTD than AD at mild abnormality levels. Furthermore, the GM loss and WM degeneration exceeded the reduced perfusion in FTD whereas, in AD, structural and functional damages were similar. Joint assessments of multimodal MRI have potential value to provide new imaging markers for improved differential diagnoses between FTD and AD.

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Section: Discussionmentioning

confidence: 99%

Joint Assessment of Structural, Perfusion, and Diffusion MRI in Alzheimer′s Disease and Frontotemporal Dementia

Zhang

Schuff

Ching

et al. 2011

International Journal of Alzheimer's Disease

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“…1 H MRS is a noninvasive acquisition technique that is present on all modern clinical MR scanners and can implemented in multicenter projects. 38 These early findings suggest the possibility that 1 H MRS may be used as a noninvasive imaging marker for neuroprotective interventions, 39,40 before there is significant loss of neuronal integrity in MAPT mutation carriers as well as in other proteinopathies such as AD. Validating 1 H MRS abnormalities as biomarkers of taumediated pathology will require longitudinal follow-up.…”

Section: Discussionmentioning

confidence: 99%

MRS in presymptomatic MAPT mutation carriers

Kantarci¹,

Boeve²,

Wszołek³

et al. 2010

Neurology

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(1)H MRS metabolite abnormalities characterized by an elevated mI/Cr and decreased NAA/mI are present several years before the onset of symptoms in MAPT mutation carriers. The data suggest an ordered sequencing of the (1)H MRS and MRI biomarkers. MI/Cr, a possible index of glial proliferation, precedes the decrease in neuronal integrity marker NAA/Cr and hippocampal atrophy. (1)H MRS may be a useful inclusion biomarker for preventive trials in presymptomatic carriers of MAPT mutations and possibly other proteinopathies.

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“…ubiquitination), inhibition of tau expression, tau-independent microtubule stabilization and immunosuppression. [193,232] Lithium and valproic acid are GSK3β inhibitors that are approved for other indications and are being considered for FTLD clinical trials. Tau drug discovery is also a major focus of the pharmaceutical industry given the apparent role of tau in the pathogenesis of Alzheimer’s disease.…”

Section: Treatmentmentioning

confidence: 99%

Frontotemporal Lobar Degeneration

2010

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Frontotemporal lobar degeneration (FTLD) is a clinically and pathologically heterogeneous syndrome, characterized by progressive decline in behaviour or language associated with degeneration of the frontal and anterior temporal lobes. While the seminal cases were described at the turn of the 20th century, FTLD has only recently been appreciated as a leading cause of dementia, particularly in patients presenting before the age of 65 years. Three distinct clinical variants of FTLD have been described: (i) behavioural-variant frontotemporal dementia, characterized by changes in behaviour and personality in association with frontal-predominant cortical degeneration; (ii) semantic dementia, a syndrome of progressive loss of knowledge about words and objects associated with anterior temporal neuronal loss; and (iii) progressive nonfluent aphasia, characterized by effortful language output, loss of grammar and motor speech deficits in the setting of left perisylvian cortical atrophy.The majority of pathologies associated with FTLD clinical syndromes include either tau-positive (FTLD-TAU) or TAR DNA-binding protein 43 (TDP-43)-positive (FTLD-TDP) inclusion bodies. FTLD overlaps clinically and pathologically with the atypical parkinsonian disorders corticobasal degeneration and progressive supranuclear palsy, and with amyotrophic lateral sclerosis. The majority of familial FTLD cases are caused by mutations in the genes encoding microtubuleassociated protein tau (leading to FTLD-TAU) or progranulin (leading to FTLD-TDP). The clinical and pathologic heterogeneity of FTLD poses a significant diagnostic challenge, and in vivo prediction of underlying histopathology can be significantly improved by supplementing the clinical evaluation with genetic tests and emerging biological markers. Current pharmacotherapy for FTLD focuses on manipulating serotonergic or dopaminergic neurotransmitter systems to ameliorate behavioural or motor symptoms. However, recent advances in FTLD genetics and molecular pathology make the prospect of biologically driven, disease-specific therapies for FTLD seem closer than ever.Frontotemporal lobar degeneration (FTLD) is a clinically and pathologically heterogeneous syndrome, characterized by a progressive decline in behaviour or language associated with degeneration of the frontal and anterior temporal lobes. The original cases described by Arnold Pick and Alois Alzheimer (new references #1, #2) [84] demonstrated neuronal inclusions that were later shown to be tau-positive at histopathology. The link between tau and FTLD was further strengthened by the discovery that mutations in the microtubuleassociated protein tau (MAPT) gene cause familial FTLD. [126 -128] NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript DNA-binding protein 43 (TDP-43) was identified as the major ubiquitinated protein associated with tau-negative FTLD, [96] and mutations in the progranulin (PGRN) gene were shown to be responsible for the majority of familial tau-negative cases. [129 -131] The...

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New directions for frontotemporal dementia drug discovery

Cited by 29 publications

References 20 publications

Joint Assessment of Structural, Perfusion, and Diffusion MRI in Alzheimer′s Disease and Frontotemporal Dementia

Joint Assessment of Structural, Perfusion, and Diffusion MRI in Alzheimer′s Disease and Frontotemporal Dementia

MRS in presymptomatic MAPT mutation carriers

Frontotemporal Lobar Degeneration

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