Drug discovery for rare dementias

Written by Howard Fillit, MD Founding Executive Director and Chief Science Officer, Alzheimer’s Drug Discovery Foundation (NY, USA)

February 28 is Rare Disease Day. Dementia is not often thought of in the context of rare diseases because it’s most common cause, Alzheimer’s disease, affects nearly 50 million people worldwide. However, there are other, rarer causes of dementia. The Alzheimer’s Drug Discovery Foundation (ADDF; NY, USA), where I serve as Chief Science Officer, supports drug research for several of these.
Understanding non-Alzheimer’s dementias

Vascular cognitive impairment is the second most common form of dementia. It is actually a collection of several syndromes including subcortical leukoencephalopathy. This is a type of small vessel disease that damages white matter, leading to subcortical strokes as well as declines in executive function and processing speed. Small strokes can also be a cause of vascular dementia when they occur in specific regions of the brain responsible for aspects of cognition.

Lewy bodies are the characteristic pathological feature of Parkinson’s disease dementia and dementia with Lewy bodies (DLB). Lewy bodies are comprised predominantly of alpha-synuclein proteins. Parkinson’s disease mainly affects an area of the brain stem associated with motor functions, while DLB’s damage is more widespread, occurring throughout the cerebral cortex. Both can cause sleep disorders, changes in behavior and hallucinations.

Progressive supranuclear palsy (PSP) is a rare disease that can be misdiagnosed as Parkinson’s. Like Parkinson’s, it affects the brain stem and can cause motor problems and it is clinically characterized by a paralysis of upward gaze. However, PSP is marked by abnormal tau proteins, not Lewy bodies. The abnormal aggregation of tau into tangles is also found in Alzheimer’s and in chronic traumatic encephalopathy, primary age-related tauopathy and patients with specific forms of frontotemporal dementia (FTD).

“It’s critical to understand the underlying pathology in order to properly care for them…”

FTD encompasses several disorders, including FTD behavioral variant, corticobasal degeneration and primary progressive aphasia, with symptoms including behavioral and language changes, and executive dysfunction [1]. While some cases involve tau tangles, others present with aggregations of TDP-43. This protein is also a hallmark of amyotrophic lateral sclerosis.

Another rare cause of dementia is hippocampal sclerosis, a disease that is difficult to diagnose and often mistaken for Alzheimer’s. In many cases, it is accompanied by temporal lobe epilepsy. Though the causes of hippocampal sclerosis remain unknown, research points to the potential involvement of TDP-43 and vascular factors.

“Many small molecule drugs are in development for rare dementias.”

The importance of biomarkers

Accurate diagnostic biomarkers are the first step to treating rarer forms of dementia. Often, patients present with symptoms of more than one type of dementia. It’s critical to understand the underlying pathology in order to properly care for them. Biomarkers are also essential to the success of clinical trials as they can demonstrate target engagement and clinical effects.

MRIs are utilized to scan for white matter hyperintensities, white matter atrophy and subcortical strokes in vascular cognitive impairment. Updated diagnostic criteria for DLB were released in 2017, though no biomarkers currently exist to directly measure Lewy bodies [2]. There are also no clinical biomarkers to detect TDP-43 in brain, though initial research suggests plasma and cerebrospinal fluid levels of phosphorylated TDP-43 protein may be disease indicators in a subset of FTD patients [3].

A team supported by the ALS Association (DC, USA) is developing a PET neuroimaging tracer for TDP-43 aggregates [4].  Sam Gandy, Associate Director of the Mount Sinai Alzheimer’s Disease Research Centre (NY, USA) and Neil Vasdev, Director of the Azriele Center for Neuro-Radiochemistry (Ontario, Canada), are among those validating PET ligands to image tau in the brain [5]. Researchsuggests that cerebrospinal fluid total-tau and phosphorylated-tau levels may also be good biomarkers [6].

This editorial was originally published on our sister site, MedChemNet: read the full article, including the drug pipeline for rare dementias, on MedChemNet here