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Therapeutic trial design for frontotemporal dementia and related disorders

Published on Apr 1, 2019in Journal of Neurology, Neurosurgery, and Psychiatry8.272
· DOI :10.1136/jnnp-2018-318603
Philippe Desmarais3
Estimated H-index: 3
,
Jonathan D. Rohrer50
Estimated H-index: 50
+ 13 AuthorsMario Masellis27
Estimated H-index: 27
Abstract
The frontotemporal dementia (FTD) spectrum is a heterogeneous group of neurodegenerative syndromes with overlapping clinical, molecular and pathological features, all of which challenge the design of clinical trials in these conditions. To date, no pharmacological interventions have been proven effective in significantly modifying the course of these disorders. This study critically reviews the construct and methodology of previously published randomised controlled trials (RCTs) in FTD spectrum disorders in order to identify limitations and potential reasons for negative results. Moreover, recommendations based on the identified gaps are elaborated in order to guide future clinical trial design. A systematic literature review was carried out and presented in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. A total of 23 RCTs in cohorts with diagnoses of behavioural and language variants of FTD, corticobasal syndrome and progressive supranuclear palsy syndrome were identified out of the 943 citations retrieved and were included in the qualitative review. Most studies identified were early-phase clinical trials that were small in size, short in duration and frequently underpowered. Diagnoses of populations enrolled in clinical trials were based on clinical presentation and rarely included precision-medicine tools, such as genetic and molecular testing. Uniformity and standardisation of research outcomes in the FTD spectrum are essential. Several elements should be carefully considered and planned in future clinical trials. We anticipate that precision-medicine approaches will be crucial to adequately address heterogeneity in the FTD spectrum research.
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References59
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#1Cyril Pottier (Mayo Clinic)H-Index: 14
#2Xiaolai Zhou (Mayo Clinic)H-Index: 8
Last. Rosa Rademakers (Mayo Clinic)H-Index: 77
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Summary Background Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods The study was done in three stages: a discovery stage, a rep...
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#2Gil D. Rabinovici (HWNI: Helen Wills Neuroscience Institute)H-Index: 50
Last. Maria Luisa Gorno-Tempini (UCSF: University of California, San Francisco)H-Index: 68
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Importance The ability to predict the pathology underlying different neurodegenerative syndromes is of critical importance owing to the advent of molecule-specific therapies. Objective To determine the rates of positron emission tomography (PET) amyloid positivity in the main clinical variants of primary progressive aphasia (PPA). Design, Setting, and Participants This prospective clinical-pathologic case series was conducted at a tertiary research clinic specialized in cognitive disorders. Pati...
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#1Adam L. Boxer (UCSF: University of California, San Francisco)H-Index: 49
#2Jin-Tai Yu (Qingdao University)H-Index: 48
Last. Günter U. Höglinger (TUM: Technische Universität München)H-Index: 40
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Summary Progressive supranuclear palsy (PSP), previously believed to be a common cause of atypical parkinsonism, is now recognised as a range of motor and behavioural syndromes that are associated with a characteristic 4-repeat tau neuropathology. New research criteria that recognise early presentations of PSP and operationalise diagnosis of the full spectrum of clinical phenotypes have been reported. The Movement Disorders Society PSP diagnostic criteria include syndromes with few or mild sympt...
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#2David J. IrwinH-Index: 33
Last. Murray GrossmanH-Index: 88
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Objective: To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA). Methods: We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups usi...
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#1Günter U. Höglinger (German Center for Neurodegenerative Diseases)H-Index: 40
#2Gesine Respondek (German Center for Neurodegenerative Diseases)H-Index: 12
Last. Irene LitvanH-Index: 79
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Background: PSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome. Objective: We aimed to provide an evidence- and consensus-based revision of the clinical diagnostic criteria for PSP. Methods: We searched the PubMed, Cochrane, Medlin...
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#1Jennifer S. Yokoyama (UCSF: University of California, San Francisco)H-Index: 20
#2Celeste M. Karch (UW: University of Washington)H-Index: 25
Last. Rahul S. Desikan (UCSF: University of California, San Francisco)H-Index: 33
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Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (tota...
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#1Raffaele FerrariH-Index: 15
#2Yunpeng Wang (Oslo University Hospital)H-Index: 25
Last. Rahul S. Desikan (UCSF: University of California, San Francisco)H-Index: 33
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Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer9s disease (AD) and Parkinson9s disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Cons...
39 CitationsSource
Objective: An investigator-initiated, multicenter, randomized, placebo-controlled, double-blind clinical trial to determine whether coenzyme Q10 (CoQ10) is safe, well tolerated, and effective in slowing functional decline in progressive supranuclear palsy (PSP). Methods: Sixty-one participants received CoQ10 (2,400 mg/d) or placebo for up to 12 months. Progressive Supranuclear Palsy Rating Scale (PSPRS), Unified Parkinson9s Disease Rating Scale, activities of daily living, Mini-Mental State Exam...
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#1Emily Rogalski (NU: Northwestern University)H-Index: 27
#2Jaiashre Sridhar (NU: Northwestern University)H-Index: 4
Last. Marek-Marsel MesulamH-Index: 133
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Objective: To identify features of primary progressive aphasia (PPA) associated with Alzheimer disease (AD) neuropathology. A related objective was to determine whether logopenic PPA is a clinical marker for AD. Methods: A total of 139 prospectively enrolled participants with a root diagnosis of PPA constituted the reference set. Those with autopsy or biomarker evidence of AD, and who had been evaluated at mild disease stages (Aphasia Quotient ≥85), were included (n = 19). All had quantitative l...
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#1Georg Nuebling (LMU: Ludwig Maximilian University of Munich)H-Index: 3
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Last. Stefan Lorenzl (LMU: Ludwig Maximilian University of Munich)H-Index: 21
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To date, pharmacological treatment options for progressive supranuclear palsy (PSP), a neurodegenerative tauopathy, are limited. The MAO-B inhibitor rasagiline has shown neuroprotective effects in preclinical models of neurodegeneration. To evaluate the safety, tolerability and therapeutic effect of rasagiline on symptom progression in PSP. In this 1-year randomized, double-blind, placebo-controlled trial, 44 patients fulfilling the NINDS-PSP criteria were randomized to 1 mg/d rasagiline or plac...
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Cited By2
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#1Adam L. Boxer (UCSF: University of California, San Francisco)H-Index: 49
#2Michael HornbergerH-Index: 121
Last. Nadine TattonH-Index: 1
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Abstract Introduction Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed. Methods In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD. Results Challenges exist for conducting clinical trials in FTLD. Two of the greates...
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#1Stefano Gazzina (University of Brescia)H-Index: 10
#2Mario Grassi (UNIPV: University of Pavia)H-Index: 30
Last. Barbara Borroni (University of Brescia)H-Index: 48
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Objective Cognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time. Methods Two-hundred twent...
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