Monday, 19 December 2016

Subtle motor disturbances in PREDICT-PD participants

Absolutely delighted to see this one in print... this is the culmination of a huge amount of work... ~20,000 miles driven by me to see participants in the PREDICT-PD study and hundreds of hours spent watching videos by Andrew Lees and Anette Schrag. We give an unbiased  estimate of the prevalence of mild parkinsonian signs in higher risk PREDICT-PD participants and show that the basic risk algorithm predicts motor dysfunction. This paper somewhat rejects the notion of 'premotor' PD and suggests the motor dysfunction occurs in the pre-diagnostic phase and can be ascertained remotely via video...

J Neurol Neurosurg Psychiatry. 2016 Dec 16. pii: jnnp-2016-314524. doi: 10.1136/jnnp-2016-314524. [Epub ahead of print]

Noyce AJ, Schrag A, Masters JM, Bestwick JP, Giovannoni G, Lees AJ.

http://jnnp.bmj.com/content/early/2016/12/16/jnnp-2016-314524.long

OBJECTIVE: The PREDICT-PD study aims to identify increased risk of Parkinson''s disease (PD) using online assessments of previously identified risk and early features of PD and an evidence-based scoring algorithm. We sought to determine whether higher risk participants (defined as those above the 15th centile of risk estimates) were more likely to have mild parkinsonian signs compared with lower risk participants.

METHODS: Video recordings of neurological examinations, including the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III, of 208 individuals who had previously completed an online risk assessment were scored blindly and independently by two movement-disorders experts. Higher risk and lower risk subjects were compared for MDS-UPDRS part III score (and derivations of this) to identify subclinical parkinsonism, and association of risk estimates with MDS-UPDRS III scores assessed.

RESULTS: Higher risk subjects had significantly higher median UPDRS part III scores (3, IQR 1-5.5) than lower risk subjects (1, IQR 0-3.0; p<0.001), and there was a significantly greater proportion of individuals classified as having subclinical parkinsonism. 18% of the higher risk subjects and 6% of the lower risk subjects exceeded the most stringent published cut-off for subtle parkinsonism of three definitions examined (p=0.027). Linear regression analysis demonstrated a continuous relationship of log-transformed risk estimates with UPDRS part III scores (increase in MDS-UPDRS per doubling of odds 0.52, 95% CI 0.31 to 0.72; p<0.001), which remained after adjustment for multiple vascular risk factors and scores on the Montreal Cognitive Assessment (0.58, 95% CI 0.30 to 0.87; p<0.001).

CONCLUSIONS: The PREDICT-PD algorithm identifies a population with an increased rate of motor disturbances.

Sunday, 11 December 2016

Association of Restless Legs Syndrome with Incident Parkinson Disease

Restless legs syndrome has been reported as a risk factor for PD... as with many of the other so called risk factors it is difficult to established whether they truly increase risk of PD or whether the association arises as a result of confounding by prevalent disease... in other words reverse causality. This means that Parkinson's disease is present, but not yet diagnosed, and restless legs syndrome is a symptom of Parkinson's. RLS gets diagnosed, followed by Parkinson's some years later... Parkinson's likely starts many years before a diagnosis is made...

Sleep. 2016 Nov 28. pii: sp-00400-16. [Epub ahead of print]
Bro D, O'Hara R, Primeau M, Hanson-Kahn A, Hallmayer J, Bernstein JA.

STUDY OBJECTIVES: The association between restless legs syndrome (RLS) and Parkinson's Disease (PD) has been extensively studied with inconclusive results, therefore we prospectively examined the associations of the presence of RLS with development of incident PD.

METHODS: From a nationally representative prospective cohort of almost 3.5 million US veterans (age: 60±14 years, 93% male, median follow-up time of 7.8 years (IQR: 6.4-8.4 years)), we created a propensity-matched cohort of 100,882 PD-free patients and examined the association between prevalent RLS and incident PD. This association was also assessed in the entire cohort. Associations were examined using Cox models.

RESULTS: There were 68 incident PD events (0.13%, incidence rate 1.87 [1.48-2.37]/10,000 patient-years) in the RLS negative group, and 185 incident PD events (0.37%, incidence rate 4.72 [4.09-5.45]/10,000 patient-years) in the RLS positive group in the propensity-matched cohort. Prevalent RLS was associated with more than two-fold higher risk of incident PD (hazard ratio (HR): 2.57, 95% confidence interval (CI): 1.95-3.39) compared to RLS negative patients. Qualitatively similar results were found when we examined the entire 3.5-million cohort: prevalent RLS was associated with more than two-fold higher risk of incident PD (multivariable adjusted HR: 2.81, 95%CI: 2.41-3.27).

CONCLUSIONS: RLS and PD share common risk factors. In this large cohort of US veterans, we found that prevalent RLS is associated with higher risk of incident PD during 8 years of follow-up, suggesting that RLS could be an early clinical feature of incident PD. KEYWORDS:

Saturday, 10 December 2016

Cognitive impairment in Parkinson's disease: impact on quality of life of carers

We often forget about the caregivers of patients with Parkinson's. Here we see evidence that cognitive impairment in the patient may affect the quality of life of the caregiver... understandably the greater the degree of cognitive impairment, the worse the quality of life. However I was somewhat surprised to learn that attentional deficits played the biggest part in this...

Int J Geriatr Psychiatry. 2016 Dec 7. doi: 10.1002/gps.4623. [Epub ahead of print]
Lawson RA, Yarnall AJ, Johnston F, Duncan GW, Khoo TK, Collerton D, Taylor JP, Burn DJ; ICICLE-PD study group.

BACKGROUND: The quality of life (QoL) of informal caregivers of people with Parkinson's disease (PD) (PwP) can be affected by the caring role. Because of cognitive symptoms and diminished activities of daily living, in addition to the management of motor symptoms, carers of PwP and cognitive impairment may experience increased levels of burden and poorer QoL compared with carers of PwP without cognitive impairment. This study aimed to investigate the impact of cognitive impairment in PD upon QoL of carers.

METHODS: Approximately 36 months after diagnosis, 66 dyadic couples of PwP and carers completed assessments. PwP completed a schedule of neuropsychological assessments and QoL measures; carers of PwP completed demographic questionnaires and assessments of QoL. Factor scores of attention, memory/executive function and global cognition, as derived by principal component analysis, were used to evaluate cognitive domains.

RESULTS: Hierarchical regression analysis found lower Montreal Cognitive Assessment was a significant independent predictor of poorer carer QoL, in addition to number of hours spent caregiving, carer depression and PD motor severity. Attentional deficits accounted for the largest proportion of variance of carer QoL. Carers of PwP and dementia (n = 9) had significantly poorer QoL scores compared with PwP and mild cognitive impairment (n = 18) or normal cognition (n = 39) carers (p < 0.01).

CONCLUSIONS: Attentional deficits were the strongest predictor of carer QoL compared with other cognitive predictors. Carers for those with PD dementia reported the poorest QoL. Interventions such as respite or cognitive behavioural therapy to improve mood and self-efficacy in carers may improve carer QoL.

Monday, 5 December 2016

LRRK2 levels and phosphorylation in Parkinson's disease brain and cases with restricted Lewy bodies

Interesting paper about the expression of LRRK-2 in the human brain... this may have implications for PD both in the prediagnostic phase and after diagnosis, if suitable therapeutic agents can be utilised...

Mov Disord. 2016 Dec 2. doi: 10.1002/mds.26892. [Epub ahead of print]
Dzamko N, Gysbers AM, Bandopadhyay R, Bolliger MF, Uchino A, Zhao Y, Takao M, Wauters S, van de Berg WD, Takahashi-Fujigasaki J, Nichols RJ, Holton JL, Murayama S, Halliday GM.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26892/abstract;jsessionid=4696EFBB2995341E653D346E26D6CFCA.f04t03

BACKGROUND: Leucine rich repeat kinase 2 (LRRK2) is a promising target for the treatment of Parkinson's disease; however, little is known about the expression of LRRK2 in human brain and if/how LRRK2 protein levels are altered in Parkinson's disease.

OBJECTIVES: We measured the protein levels of LRRK2 as well as its phosphorylation on serines 910, 935, and 973 in the postmortem brain tissue of Parkinson's disease patients and aged controls with and without Lewy bodies.

METHODS: LRRK2 and its phosphorylation were measured by immunoblot in brain regions differentially affected in Parkinson's disease (n = 30) as well as subjects with Lewy bodies restricted to the periphery and lower brain stem (n = 25) and matched controls without pathology (n = 25).

RESULTS: LRRK2 levels were increased in cases with restricted Lewy bodies, with a 30% increase measured in the substantia nigra. In clinical Parkinson's disease, levels of LRRK2 negatively correlated to disease duration and were comparable with controls. LRRK2 phosphorylation, however, particularly at serine 935, was reduced with clinical Parkinson's disease with a 36% reduction measured in the substantia nigra.

CONCLUSIONS: Our data show that LRRK2 phosphorylation is reduced with clinical PD, whereas LRRK2 expression is increased in early potential prodromal stages. These results contribute to a better understanding of the role of LRRK2 in idiopathic Parkinson's disease and may aid efforts aimed at therapeutically targeting the LRRK2 protein.

Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease

The paper made all the headlines last week... the microbiome is really heating up as a subject of interest in PD and other disorders. Here is some of the most convincing evidence to date that the microbiome is important to PD pathogenesis. Some caution is advised... the mouse models of PD have yielded promising findings in the past, only for these not to be replicated in human disease. The two microbiome studies that have been published in PD gave divergent results... 

Cell. 2016 Dec 1;167(6):1469-1480.e12. doi: 10.1016/j.cell.2016.11.018.
Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK.

The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.