Cerebrospinal fluid β-glucocerebrosidase activity is reduced in parkinson's disease patients

Important work as far as PD biomarkers go. People have been saying for a long time that variation in the GBA gene will be important in our understanding of the mechanisms of PD... and in the process suggest therapeutic targets. Here we see that the protein product is decreased in carriers and non-carriers of GBA variants (to a similar extent) when compared with controls. The area under curve is not overwhelming and the sensitivity/specificity do not convince that this will help significantly in diagnosing PD, but the fact that a relationship with cognition was observed (and expected) is encouraging. It may mean that this is a way of identifying patients with PD that are more at risk of cognitive impairment....

Mov Disord. 2017 Aug 26. doi: 10.1002/mds.27136. [Epub ahead of print]
Parnetti L, Paciotti S, Eusebi P, Dardis A, Zampieri S, Chiasserini D, Tasegian A, Tambasco N, Bembi B, Calabresi P, Beccari T.

http://onlinelibrary.wiley.com/doi/10.1002/mds.27136/abstract;jsessionid=261ACF845D0BD94B22AB757B2AC7C0F6.f03t01

BACKGROUND:
Reduced β-glucocerebrosidase activity was observed in postmortem brains of both GBA1 mutation carrier and noncarrier Parkinson's disease patients, suggesting that lower β-glucocerebrosidase activity is a key feature in the pathogenesis of PD. The objectives of this study were to confirm whether there is reduced β-glucocerebrosidase activity in the CSF of GBA1 mutation carrier and noncarrier PD patients and verify if other lysosomal enzymes show altered activity in the CSF.

METHODS:
CSF β-glucocerebrosidase, cathepsin D, and β-hexosaminidase activities were measured in 79 PD and 61 healthy controls from the BioFIND cohort. The whole GBA1 gene was sequenced.

RESULTS:
Enzyme activities were normalized according to CSF protein content (specific activity). β-glucocerebrosidase specific activity was significantly decreased in PD versus controls (-28%, P < 0.001). GBA1 mutations were found in 10 of 79 PD patients (12.7%) and 3 of 61 controls (4.9%). GBA1 mutation carrier PD patients showed significantly lower β-glucocerebrosidase specific activity versus noncarriers. β-glucocerebrosidase specific activity was also decreased in noncarrier PD patients versus controls (-25%, P < 0.001). Cathepsin D specific activity was lower in PD versus controls (-21%, P < 0.001). β-Hexosaminidase showed a similar trend. β-Glucocerebrosidase specific activity fairly discriminated PD from controls (area under the curve, 0.72; sensitivity, 0.67; specificity, 0.77). A combination of β-glucocerebrosidase, cathepsin D, and β-hexosaminidase improved diagnostic accuracy (area under the curve, 0.77; sensitivity, 0.71; specificity, 0.85). Lower β-glucocerebrosidase and β-hexosaminidase specific activities were associated with worse cognitive performance.

CONCLUSIONS:
CSF β-glucocerebrosidase activity is reduced in PD patients independent of their GBA1 mutation carrier status. Cathepsin D and β-hexosaminidase were also decreased. The possible link between altered CSF lysosomal enzyme activities and cognitive decline deserves further investigation.

© 2017 International Parkinson and Movement Disorder Society.

The nasal and gut microbiome in Parkinson's disease and idiopathic rapid eye movement sleep behavior disorder

Really nice work showing similarities between the gut microbiome of patients with PD and idiopathic REM sleep behaviour disorder (RBD). This adds to the wealth of data that suggests significant overlap between these conditions... we know that 30-50% of patients with PD have confirmed RBD. We also know that PD is a common outcome in patients with iRBD (along with dementia with Lewy bodies and other synucleinopathies). However, the role of an altered gut microbiome is yet to be clarified... does it contribute to the development of these two related conditions (PD and RBD) or is it consequence of these conditions (reverse causality)?? It is clear that much more work needs to be done in this field, but the link between PD and the gut continues to strengthen...

Mov Disord. 2017 Aug 26. doi: 10.1002/mds.27105. [Epub ahead of print]
Heintz-Buschart A, Pandey U, Wicke T, Sixel-Döring F, Janzen A, Sittig-Wiegand E, Trenkwalder C, Oertel WH, Mollenhauer B, Wilmes P.

http://onlinelibrary.wiley.com/doi/10.1002/mds.27105/abstract;jsessionid=1F71A24EFF3A356871C32DAE7194B99C.f02t01

BACKGROUND: Increasing evidence connects the gut microbiota and the onset and/or phenotype of Parkinson's disease (PD). Differences in the abundances of specific bacterial taxa have been reported in PD patients. It is, however, unknown whether these differences can be observed in individuals at high risk, for example, with idiopathic rapid eye movement sleep behavior disorder, a prodromal condition of α-synuclein aggregation disorders including PD.

OBJECTIVES: To compare microbiota in carefully preserved nasal wash and stool samples of subjects with idiopathic rapid eye movement sleep behavior disorder, manifest PD, and healthy individuals.

METHODS: Microbiota of flash-frozen stool and nasal wash samples from 76 PD patients, 21 idiopathic rapid eye movement sleep behavior disorder patients, and 78 healthy controls were assessed by 16S and 18S ribosomal RNA amplicon sequencing. Seventy variables, related to demographics, clinical parameters including nonmotor symptoms, and sample processing, were analyzed in relation to microbiome variability and controlled differential analyses were performed.

RESULTS: Differentially abundant gut microbes, such as Akkermansia, were observed in PD, but no strong differences in nasal microbiota. Eighty percent of the differential gut microbes in PD versus healthy controls showed similar trends in idiopathic rapid eye movement sleep behavior disorder, for example, Anaerotruncus and several Bacteroides spp., and correlated with nonmotor symptoms. Metagenomic sequencing of select samples enabled the reconstruction of genomes of so far uncharacterized differentially abundant organisms.

CONCLUSION: Our study reveals differential abundances of gut microbial taxa in PD and its prodrome idiopathic rapid eye movement sleep behavior disorder in comparison to the healthy controls, and highlights the potential of metagenomics to identify and characterize microbial taxa, which are enriched or depleted in PD and/or idiopathic rapid eye movement sleep behavior disorder.

Dementia as a preventable disease

This month The Lancet published their Commission on dementia. The case for attention on dementia is unquestionable - nearly 50 million people have dementia worldwide today, this will increase nearly 3 fold in the next 35 years; it affects not only the individual but their families and caregivers too; the cost of dementia is colossal - the current global cost of care is estimated to be US$800 billion/year. 

Despite these huge numbers, I do believe we are in an era where the tide is turning. 

Firstly, there is a recognition of the problem as evidenced by the focus that it is receiving not just by academics, but by the leaders of the world in the G8 and WHO ministerial conference in 2013 and 2015 respectively. This year UCL was awarded the Dementia Research Institute - a £250m national award to become a national and international hub for dementia research; building on incredible work done by the Dementia Research Institute at UCL and others. 

Secondly, although the two big drug trials of Biogen's aducanumab and Merck's verubecestat failed to show efficacy, there is much to be gained from these studies. Furthermore, the feeling of academics, industry and policy makers at this year's World Neuroscience Innovation Forum at the Crick Institute in London, was that despite the overall failure of these two drugs in the people they were tried in, we are on the cusp of success. 

Thirdly, and what this report really stresses strongly, is that although we may get new and very exciting but expensive drugs to stop or prevent some forms of dementia. So much can be done, for very little cost, to prevent it in the first place. 

DOI: http://dx.doi.org/10.1016/S0140-6736(17)31363-6

Dementia prevention, intervention, and care

Published: July 20, 2017

Executive Summary

Dementia is the greatest global challenge for health and social care in the 21st century: around 50 million people worldwide have dementia and this number is predicted to triple by 2050. The LancetCommission on dementia aims to review the best available evidence and produce recommendations on how to best manage, or even prevent, the dementia epidemic.

Dementia is not an inevitable consequence of ageing and the Commission identifies nine potentially modifiable health and lifestyle factors from different phases of life that, if eliminated, might prevent dementia. Although therapies are currently not available to modify the underlying disease process, the Commission outlines pharmacological and social interventions that are able to help manage the manifestations of dementia.

Body weight is a robust predictor of clinical progression in Huntington disease

These are very interesting results from another neurodegenerative disease, Huntington's (or HD). Although the authors use an observational study design, which like most observational studies can be susceptible to bias due to reverse causation and confounding, the results are very interesting. There is now evidence to suggest that higher BMI (note this is different to say obesity) appears to reduce risk of Parkinson's and Alzheimer's, and be associated with slower progression of HD and ALS. For PD at least in our paper the association was causal. 

Ann Neurol. 2017 Aug 5. doi: 10.1002/ana.25007. [Epub ahead of print]
van der Burg JMM, Gardiner SL, Ludolph AC, Landwehrmeyer GB, Roos RAC, Aziz NA.

http://onlinelibrary.wiley.com/doi/10.1002/ana.25007/full

Unintended weight loss is a hallmark of Huntington disease (HD), but it is unknown to what extent weight loss impacts the rate of disease progression. Therefore, using longitudinal data from the Enroll-HD study, we assessed the association between baseline body mass index (BMI) and the rate of clinical progression in 5,821 HD mutation carriers. We found that high baseline BMI was associated with a significantly slower rate of functional, motor, and cognitive deterioration (all p < 0.001), independent of mutant HTT CAG repeat size. Our findings provide strong rationale for exploration of systemic metabolism as a therapeutic target in HD.