Although the exact mechanisms of repeat expansions are unclear, research suggests that all models involve the formation and aberrant repair of unusual slipped-DNA structures formed by the repeats.³ The levels of slipped-DNAs are higher in affected tissues that have longer repeat expansions, causing more severe mutations. Therefore, a compound with specificity for slipped-DNAs that can stop or reverse the slipped-DNA expansion process may be a potential therapeutic approach for HD.³

In a study published in the journal Nature Genetics, researchers from The Hospital for Sick Children, Toronto, Canada, together with investigators from Osaka University, Osaka, Japan, report a compound called naphthyridine-azaquinolone (NA), that specifically binds slipped-CAG DNA intermediates of expansion mutations. The newly discovered molecule was tested in vivo, in a murine model and in vitro, in cells extracted from HD patients. In vitro, NA was shown to reduce the number of repeat expansion mutation associated with HD.³

As the largest somatic CAG expansions and most neurodegeneration occur in the striatum, in both HD mice and patients with HD, NA was injected directly into the left striatum of HD mice. While in the right striatum, a control region, saline was used. Following treatment with NA, the study reported less CAG expansion in the left striatum compared with the right striatum. Without treatment, the CAG repeat length distributions between both halves of the brain were identical.³

Additionally, researchers assessed the aggregation of mutated huntingtin protein (mHTT) in the HD mice, which is also used as a biomarker for Huntington’s disease severity. The level of aggregates in NA-treated striatum was significantly lower compared to controls (P = 0.0002), and there was a decrease in the number of medium spiny neurons expressing mHTT aggregates (P < 0.0001).³

Furthermore, NA did not show off-target effects anywhere else in the DNA, suggesting that NA is specific for structures formed by expanded CAG/ CTG repeats and will not deleteriously affect other repeats.³

These findings suggest that NA could be a possible therapy for individuals who inherit HD. ‘Administration of such small molecules, once optimized for therapy, to human brains might effectively target the root cause of repeat expansion diseases and address downstream deleterious effects.’ the investigators wrote.³

Written by Marta Palhas

References:

1. Wyant K, Ridder A, Dayalu P. Huntington’s Disease—Update on Treatments. Curr Neurol Neurosci Rep. 2017Apr;17(4).
2. NIH. Genetics Home Reference. Huntington disease (2020). Available from: https://ghr.nlm.nih.gov/condition/huntington-disease# Last accessed 06/05/2020.
3. Nakamori M, Panigrahi G, Lanni S et al. A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo. Nat Genet. 2020 Feb;52(2):146-159.

A retrospective study recently published in Parkinsonism & Related Disorders investigated whether serum vitamin B12 levels at PD diagnosis was associated with risk of dementia. Clinical data collected as part of the Rochester Epidemiology Project was used to identify the individuals with clinically diagnosed PD between January 1, 1991, and December 31, 2010. Researchers identified 25 patients with clinically diagnosed PD who did not have dementia at the time of diagnosis and whose data included serum vitamin B12 levels within one year prior or 90 days after the diagnosis of PD. The median age at PD diagnosis was 74.0 years (55–88). Among the 25 patients included, 15 (60%) were later diagnosed with dementia at a median age of 79.4 years (71.6–92.3).³

In an interview with VJDementia, Rodolfo Savica, MD, PhD and Stuart McCarter, MD, from Mayo Clinic, Rochester, MN, discuss the rationale of this study, the key findings and the potential impact on clinical practice. This interview was recorded during an online conference call with The Video Journal of Dementia (VJDementia).

Results showed that levels of vitamin B12 at PD diagnosis in patients who did not develop dementia were higher than in those who developed dementia (648.5 ng/L vs 452 ng/L, p < 0.05). Additionally, the vitamin B12 cutoff value of <587 ng/L was 87% sensitive and 70% specific (AUC 0.79, 95% CI 0.60–0.98) at distinguishing patients with dementia. The researchers further observed that for every 100 ng/L increase in vitamin B12 level, there was a decrease in dementia risk (hazard ratio 0.31, 95% CI 0.44–0.95).³

In the interview, Dr McCarter highlights that ‘this is a small study that helps provide some of that prognostic information for patients. I think it gives us, as clinicians, something exciting to look into in the future as to how we may help build on this or if there is anything we can do to modulate this effect that may help patients even more’.

Overall, these findings suggest that higher serum vitamin B12 levels at PD diagnosis correlate with a lower future dementia risk. However, further evaluation of vitamin B12 status in PD is needed, and clinical trials investigating interventional B vitamin supplements should be considered. Dr Savica comments that ‘we need to look more carefully in a larger prospective study’.

Written by Marta Palhas

References:

1. Barker R, Williams-Gray C. Mild Cognitive Impairment and Parkinson’s Disease – Something to Remember. J Parkinsons Dis. 2015;4(4):651-656.
2. 4. Luthra N, Marcus A, Hills N, Christine C. Vitamin B12 measurements across neurodegenerative disorders. J Clin Mov Disord. 2020;7(1).
3. McCarter S, Stang C, Turcano P et al. Higher vitamin B12 level at Parkinson’s disease diagnosis is associated with lower risk of future dementia. Parkinsonism Relat Disord. 2020 Mar;73:19-22.

Currently, changes in amyloid-β (Aβ) and total and phosphorylated tau levels in the cerebrospinal fluid or measurements of brain Aβ deposition with Aβ positron emission tomography (Aβ-PET) are used to differentiate between AD and other neurodegenerative dementias, such as frontotemporal lobar degeneration (FTLD).^1,2 With the potential development of new disease-modifying therapies, simple and accessible screening tests are needed. A blood-based test would be a less invasive, and less costly screening tool for diagnostic purposes, to select patients for clinical trials, and evaluate responses to investigational therapies.¹

The study led by Adam Boxer, MD, PhD, at the University of California, San Francisco, CA, tested the diagnostic ability of plasma pTau181 measurements to differentiate between AD and FTLD. Blood samples from more than 400 participants were collected. The study demonstrated that pTau181 concentration in plasma could distinguish healthy participants from those with AD, as well as differentiate patients with clinically diagnosed AD from those with FTLD.¹

Additionally, plasma pTau181 concentrations were strongly associated with two approved biomarker tests for AD – Aβ-PET and pTau181 levels in the cerebrospinal fluid.¹

In the future, the development and use of further biomarkers, such as plasma pTau181, could help with diagnosing patients earlier as well as evaluating therapies more efficiently in clinical trials.

Written by Marta Palhas

Edited by Thomas Southgate

References:

1. Thijssen E, La Joie R, Wolf A et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med. 2020 Mar;26(3):387-397.
2. Barthélemy N, Bateman R, Hirtz C et al. Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer’s disease and PET amyloid-positive patient identification. Alzheimers Res Ther. 2020 Mar;12(1).