Frontotemporal dementia - Emerging treatments

Tau-directed therapies

Frontotemporal dementia (FTD) syndromes that have a predominantly tau pathology are attractive for testing tau-directed therapeutics.[206] These include: tau aggregation inhibitors (e.g., leuco-methylthioninium); blockers of tau modification (e.g., tau acetylation inhibitors); vaccines against tau aggregation; and microtubule stabilizers (e.g., paclitaxel; patients with FTD present microtubule destabilization as a result of a compromised tau binding to these structures).[207][208][209][210] Although tau-directed therapies are still in very early stages of investigation, the diversity of research in this area offers hope to this currently limited field. Some tau-directed therapeutic strategies undergoing phase 3 clinical trials include small molecules, therapeutic antibodies such as donanemab, lecanemab, remternetug, and gantenerumab, and agents that target synaptic compartments.[211]

Therapies for patients with FTD associated with identified mutations

The progranulin stimulator amiodarone has been investigated as a possible therapy for patients with FTD who have a mutation in the GRN gene.[212] The gene therapy AVB-101 to treat disease progression in patients with FTD with GRN gene mutations has been granted orphan drug designation and is being assessed for efficacy in clinical trials.[213] Newer treatments in development for GRN mutations include the use of adeno-associated viral vector therapies, recombinant progranulin protein replacement, antibody delivery of progranulin to the brain, and the use of monoclonal antibodies targeting sortilin, a protein involved in progranulin degradation, to investigate the effect of increased progranulin concentration on patients with GRN mutations.[162] Another suggested approach is the use of antisense oligonucleotides for patients with FTD with repeat expansions in the C9orf72 gene.[214] These possible treatments are still in very early stages of investigation.

Neflamapimod

There is preliminary evidence that neflamapimod, an investigational small molecule drug which targets the protein kinase p38 MAPK, may improve outcomes for patients with dementia with Lewy bodies.[215] It has been granted orphan drug designation in the US for the treatment of FTD, and investigations are ongoing.

Treatments for behavioral and psychologic symptoms of dementia

There is preliminary evidence that the voltage-gated calcium-channel blockers gabapentin and pregabalin may be effective for treating aggression in patients with dementia, but in the absence of randomized controlled trials no firm conclusions can be drawn.[216] Initial studies suggest apathy in FTD may respond to agomelatine.[217] One small phase 2 randomized controlled trial has shown some benefit in using intermittent intranasal oxytocin to reduce apathy in patients with FTD, and appears to be safe and well tolerated.[218] Another small study noted a trend towards reduced apathy in FTD when patients were treated with trazodone.[219] Dextroamphetamine showed limited improvement in apathy in behavioral variant FTD (bvFTD). Studies with quetiapine and melatonin did not show improvement.[189] There is limited evidence that apathy may respond to selective serotonin-reuptake inhibitors (SSRIs). Studies have shown variable clinical efficacy for treating disinhibition with SSRIs. In one meta-analysis, SSRIs were associated with improvements in disinhibition.[220] Overall, the quality of evidence remains weak for the use of SSRIs to treat disinhibition. Anecdotal evidence on the use of aripiprazole in disinhibition suggests modest improvement. Similarly, disinhibition has shown some response to lithium. One placebo-controlled study with trazodone improved eating abnormalities, irritability, agitation, and depressive symptoms. However, trazodone did not improve disinhibition.[219] There is limited evidence for the treatment of compulsive behaviors in bvFTD. SSRIs and tricyclic antidepressants show limited response.[135][150][189][221] SSRIs and tricyclic antidepressants may be useful in controlling pseudobulbar affect behaviors but the evidence for their use in patients with parkinsonian disorders is lacking.[199] One small study showed anodal transcranial direct current (tDCS) applied bilaterally over the frontotemporal cortex for 20 minutes may improve neuropsychiatric symptoms in FTD patients immediately after tDCS treatment.[222] These findings need replication.