Active clinical trials for "Frontotemporal Dementia"

The purpose of the study is to test whether low level electric stimulation, called transcranial Direct Current Stimulation (tDCS), on the part of the brain (i.e., pre-supplementary motor area) thought to aid in memory will improve speech and language difficulties in patients with primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS). The primary outcome measures are neuropsychological assessments of speech and language functions, and the secondary measures are neuropsychological assessments of other cognitive abilities and electroencephalography (EEG) measures.

Study J4B-MC-OKAA is a Phase 1/2, multi-center, open-label ascending dose, first-in-human study that will evaluate the safety and effect of intra-cisternal LY3884963 administration on progranulin protein (PGRN) levels in patients with frontotemporal dementia with progranulin mutations (FTD-GRN). Two escalating dose (low dose and medium dose) cohorts are planned, as well as one bridging cohort which will allocate patients to receive either low or medium dose. The duration of the study is 5 years. During the first year, patients will be evaluated for the effect of LY3884963 on safety, tolerability, immunogenicity, biomarkers, and efficacy. Patients will follow up for an additional 4 years to monitor safety and changes on selected biomarkers and clinical outcomes.

Within the spectrum of fronto-temporal lobar degeneration (FTLD) semantic dementia (SD) causes profound language dysfunction. SD damages semantic processing typically in the temporal poles (anterior temporal lobes, ATL). It is an early onset disease (often before 65 years of age) affecting about 4000 patients in France and for which no validated treatment is available. For several years a growing number of studies have explored the effects of transcranial stimulation (TCS) on aphasic patients following stroke. Several studies have targeted left-sided language areas and/or homotopical right-sided regions with excitatory or inhibitory TCS, respectively, according to the principle of inter-hemispheric inhibition. In addition, repetitive multi-day TCS has provided evidence for long-lasting language effects (>6 months) presumably linked to stimulation-induced neuroplasticity. Such investigations have provided promising results and have demonstrated that the stimulation site is a determining factor by showing that stimulation of cortical areas belonging to the language network usually results in more convincing effects than stimulating areas outside that network. Despite these findings the use of TCS in degenerative language diseases, such as primary progressive aphasias including SD, has only been explored in few small cohort studies and, surprisingly, they have not targeted language-related cortices. This project proposes the application of multi-day repetitive TCS with direct current (tDCS) in a large population of SD patients (N=60). It is built on a exploratory investigation of our team which has used three single tDCS sessions in a double-blind sham-controlled study. Excitatory and inhibitory tDCS to the left and right temporal pole, respectively, demonstrated highly significant transient effects (20 min) on semantic processing in 12 SD patients, providing 'proof of concept' and the rationale for this project. The aim here consists of using repetitive multi-day tDCS for a potential therapeutic outcome leading to long-lasting semantic improvement via neuroplasticity. The project is grounded on 2 hypotheses: i) tDCS to temporal poles (left-excitatory, right-inhibitory) reactivates semantic processing in SD, ii) repetitive tDCS during ten days could induce neuroplasticity and therapeutic language improvement.

Primary progressive aphasia (PPA) is a neurodegenerative disease that affects first and foremost language abilities. There are three different variants of PPA, each a relatively distinct speech and language profile. For individuals with non-fluent variant PPA (nfvPPA), a core symptom is apraxia of speech (AOS), which is defined as an oral motor speech disorder. Such a disorder inhibits one's ability to translate speech plans into motor plans and results in longer segmental durations and reduced rate of syllabic production. This research project investigates the behavioral and neuromodulatory effects of transcranial direct current stimulation (tDCS) during language therapy in participants with nfvPPA over time. Anodal tDCS targeting the left inferior frontal gyrus (IFG) administered in combination with language therapy is expected to be more beneficial when compared to language therapy alone (sham). The investigators believe tDCS during language therapy will 1) improve language performance or decrease rate of decline, 2) promote better-sustained effects at 2 weeks and 2 months post-treatment, and 3) produce generalization to untrained language items and some other cognitive functions. Resting-state fMRI, diffusion tensor imaging (DTI), and volumetric data are also collected to investigate changes in functional brain connectivity associated with tDCS in individuals with PPA. A better understanding of the therapeutic and neuromodulatory mechanisms of tDCS as an adjunct to language therapy in nfvPPA may have a significant impact on the development of effective therapies for PPA, and may offer insight into ways of impeding neurodegeneration that may improve patients' quality of life, as well as extend patients' ability to work and manage patients' affairs.

Frontotemporal dementia (FTD), the most common dementia in individuals younger than 60 years of age, has no disease-modifying treatment. Neuroimaging studies have revealed salience and default mode network dysfunction, frontotemporal atrophy and hypometabolism as pathophysiological hallmarks of behavioral variant FTD (bvFTD). A key brain structure affected by bvFTD is the subgenual cingulate (SGC), which serves as a hub for multi-axonal projections to and from the ventromedial prefrontal, dorsal anterior cingulate, orbitofrontal, and dorsolateral frontal cortices, and limbic structures. The disruption of these SGC projections in bvFTD result in the core clinical features of apathy, disinhibition, loss of empathy, compulsivity, hyperorality and loss of executive function. The central goal of this proposal is to use deep brain stimulation (DBS) for modulation of the SGC downstream projections to treat bvFTD. Investigators hypothesize that SGC DBS will drive activity in the dysfunctional networks, reverse hypometabolism, and potentially improve symptoms. To determine the physiologic effects and mechanisms of SGC DBS, investigators will assess cerebral metabolism by FDG-PET, connectivity by rsfMRI and MEG, atrophy by volumetric MRI, and neurodegenerative and neuroinflammatory biomarkers. The safety and preliminary efficacy data obtained in these patients will inform the possible future role of DBS in apathetic bvFTD.

Difficulties with speech and language are the first and most notable symptoms of primary progressive aphasia (PPA). While there is evidence that demonstrates positive effects of speech-language treatment for individuals with PPA who only speak one language (monolinguals), there is a significant need for investigating the effects of treatment that is optimized for bilingual speakers with PPA. This stage 2 efficacy clinical trial seeks to establish the effects of culturally and linguistically tailored speech-language interventions administered to bilingual individuals with PPA. The overall aim of the intervention component of this study is to establish the relationships between the bilingual experience (e.g., how often each language is used, how "strong" each language is) and treatment response of bilinguals with PPA. Specifically, the investigators will evaluate the benefits of tailored speech-language intervention administered in both languages to bilingual individuals with PPA (60 individuals will be recruited). The investigators will conduct an assessment before treatment, after treatment and at two follow-ups (6 and 12-months post-treatment) in both languages. When possible, a structural scan of the brain (magnetic resonance image) will be collected before treatment in order to identify if brain regions implicated in bilingualism are associated with response to treatment. In addition to the intervention described herein, 30 bilingual individuals with PPA will be recruited to complete behavioral cognitive-linguistic testing and will not receive intervention. Results will provide important knowledge about the neural mechanisms of language re-learning and will address how specific characteristics of bilingualism influence cognitive reserve and linguistic resilience in PPA.

PBFT02 is a gene therapy for frontotemporal dementia intended to deliver a functional copy of the GRN gene to the brain. This study will assess the safety, tolerability and efficacy of this treatment in patients with frontotemporal dementia and mutations in the progranulin gene (FTD-GRN).

Primary Progressive Aphasia (PPA) is a syndrome due to different neurodegenerative disorders selectively disrupting language functions. PPA specialist care is underdeveloped. There are very few specialists (neurologists, psychiatrists, neuropsychologists and speech therapists) and few hospitals- or community-based services dedicated to diagnosis and continuing care. Currently, healthcare systems struggle to provide adequate coverage of diagnostic services, and care is too often fragmented, uncoordinated, and unresponsive to the needs of people with PPA and their families. Recently attention has been gained by digital-health technologies, such immunoassay analyzer and high-field MRI, the most promising approaches to increase our understanding of neurodegeneration, and by new non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) that allow a personalized treatment approach. Our goal is to develop a new treatment approach in PPA in which the regional secondary care centers participating in this project should be the hub of a regional network. The MAINSTREAM (WP2- Efficacy of personalized training in the early stage of PPA) looks forward to introduce and evaluate therapeutic innovation such as tDCS coupled with language therapy in rehabilitation settings (WP2 Early Treatment). This objective will be pursued by conducting a randomized controlled pilot study in order to evaluate the efficacy of a combined treatment of Active (anodal) tDCS and individualized language training compared to Placebo tDCS combined with individualized language training in a subgroup of mild PPA defined using the Progressive Aphasia Severity Scale (PASS) (Sapolsky D, Domoto-Reilly K, Dickerson BCJA. Use of the Progressive Aphasia Severity Scale (PASS) in Monitoring Speech and Language Status in PPA. (2014) 28(8-9):993-1003).

This is a Phase 1/2, multicenter, randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of DNL593 in two parts followed by an optional open-label extension (OLE) period. Part A will evaluate the safety, tolerability, PK, and PD of single doses of DNL593 in healthy male and healthy female participants of nonchildbearing potential. Part B will evaluate the safety, tolerability, PK, and PD of multiple doses of DNL593 in participants with frontotemporal dementia (FTD) over 25 weeks. Part B will be followed by Part C, an optional 18-month OLE period available for all participants who complete Part B.

The purpose of the study is to test the safety and tolerability of twice daily Verdiperstat in patients with semantic variant primary progressive aphasia (svPPA) due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Three-fourths of the participants will receive Verdiperstat and one-fourth will receive Placebo during the 24-week treatment duration.