Here's the latest one from the PREDICT-PD team... this shows that intermediate markers (smell loss, subjective RBD and slowed finger tapping) persist in the higher risk group over three years of follow-up... but most interestingly higher baseline risk scores are associated with new diagnoses of PD at three years of follow-up. This is the strongest indicator yet that the PREDICT-PD algorithm is working...
Mov Disord. 2017 Jan 16. doi: 10.1002/mds.26898. [Epub ahead of print]
Noyce AJ, R'Bibo L, Peress L, Bestwick JP, Adams-Carr KL, Mencacci NE, Hawkes CH, Masters JM, Wood N, Hardy J, Giovannoni G, Lees AJ, Schrag A.
http://onlinelibrary.wiley.com/doi/10.1002/mds.26898/abstract
BACKGROUND:
A number of early features can precede the diagnosis of Parkinson's disease (PD).
OBJECTIVE:
To test an online, evidence-based algorithm to identify risk indicators of PD in the UK population.
METHODS:
Participants aged 60 to 80 years without PD completed an online survey and keyboard-tapping task annually over 3 years, and underwent smell tests and genotyping for glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) mutations. Risk scores were calculated based on the results of a systematic review of risk factors and early features of PD, and individuals were grouped into higher (above 15th centile), medium, and lower risk groups (below 85th centile). Previously defined indicators of increased risk of PD ("intermediate markers"), including smell loss, rapid eye movement-sleep behavior disorder, and finger-tapping speed, and incident PD were used as outcomes. The correlation of risk scores with intermediate markers and movement of individuals between risk groups was assessed each year and prospectively. Exploratory Cox regression analyses with incident PD as the dependent variable were performed.
RESULTS:
A total of 1323 participants were recruited at baseline and >79% completed assessments each year. Annual risk scores were correlated with intermediate markers of PD each year and baseline scores were correlated with intermediate markers during follow-up (all P values < 0.001). Incident PD diagnoses during follow-up were significantly associated with baseline risk score (hazard ratio = 4.39, P = .045). GBA variants or G2019S LRRK2 mutations were found in 47 participants, and the predictive power for incident PD was improved by the addition of genetic variants to risk scores.
CONCLUSIONS:
The online PREDICT-PD algorithm is a unique and simple method to identify indicators of PD risk.
Tuesday, 17 January 2017
Wednesday, 11 January 2017
The relevance of gender in Parkinson's disease: a review
The consistent and clear gender differences particularly in risk of being diagnosed with PD are intriguing... although I would not say one gets a clear flavour of gender-specific differences in the course of PD after diagnosis... of course when there are gender-specific differences for a disease, there is always focus on sex-hormones. At least in terms of the risk of being diagnosed with PD there is no clear evidence that HRT, contraceptive pills or surgical menopause can account for the observed gender difference...
J Neurol. 2017 Jan 4. doi: 10.1007/s00415-016-8384-9. [Epub ahead of print]
Picillo M, Nicoletti A, Fetoni V, Garavaglia B, Barone P, Pellecchia MT.
https://www.ncbi.nlm.nih.gov/pubmed/28054129
Since the official and systematic inclusion of sex and gender in biomedical research, gender differences have been acknowledged as important determinants of both the susceptibility to develop neurodegenerative diseases in general population and the clinical and therapeutic management of neurodegenerative patients. In this review, we gathered the available evidence on gender differences in Parkinson's disease (PD) regarding clinical phenotype (including motor and non-motor symptoms), biomarkers, genetics and therapeutic management (including pharmacological and surgical treatment). Finally, we will briefly discuss the role of estrogens in determining such differences. Several data demonstrate that PD in women starts with a more benign phenotype, likely due to the effect of estrogens. However, as the disease progresses, women are at higher risk of developing highly disabling treatment-related complications, such as motor and non-motor fluctuations as well as dyskinesia, compared with men. In addition, women have lower chances of receiving effective treatment for PD as deep brain stimulation. Taken together these findings challenge the definition of a more benign phenotype in women. Still, much work needs to be done to better understand the interaction between gender, genetics and environmental factors in determining the PD risk and clinical features. Improving our understanding in this field may result in implementation of strategies to identify prodromal PD and speed efforts to discern new directions for disease tailored treatment and management.
J Neurol. 2017 Jan 4. doi: 10.1007/s00415-016-8384-9. [Epub ahead of print]
Picillo M, Nicoletti A, Fetoni V, Garavaglia B, Barone P, Pellecchia MT.
https://www.ncbi.nlm.nih.gov/pubmed/28054129
Since the official and systematic inclusion of sex and gender in biomedical research, gender differences have been acknowledged as important determinants of both the susceptibility to develop neurodegenerative diseases in general population and the clinical and therapeutic management of neurodegenerative patients. In this review, we gathered the available evidence on gender differences in Parkinson's disease (PD) regarding clinical phenotype (including motor and non-motor symptoms), biomarkers, genetics and therapeutic management (including pharmacological and surgical treatment). Finally, we will briefly discuss the role of estrogens in determining such differences. Several data demonstrate that PD in women starts with a more benign phenotype, likely due to the effect of estrogens. However, as the disease progresses, women are at higher risk of developing highly disabling treatment-related complications, such as motor and non-motor fluctuations as well as dyskinesia, compared with men. In addition, women have lower chances of receiving effective treatment for PD as deep brain stimulation. Taken together these findings challenge the definition of a more benign phenotype in women. Still, much work needs to be done to better understand the interaction between gender, genetics and environmental factors in determining the PD risk and clinical features. Improving our understanding in this field may result in implementation of strategies to identify prodromal PD and speed efforts to discern new directions for disease tailored treatment and management.
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.
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:
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.
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.
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.
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.
Friday, 18 November 2016
MicroRNAs in Cerebrospinal Fluid as Potential Biomarkers for Parkinson's Disease and Multiple System Atrophy
Studying microRNA may be another avenue to identify and define biomarkers for diseases like Parkinson's.... the work below describes differences between PD and controls, and MSA and controls, which is very encouraging. However, what we really need are biomarkers that show clear differences in the early stages of PD and sensitivity to change, as well as biomarkers which differentiate PD from atypical parkinson's...
Mol Neurobiol. 2016 Nov 14. [Epub ahead of print]
Marques TM, Kuiperij HB, Bruinsma IB, van Rumund A, Aerts MB, Esselink RA, Bloem BR, Verbeek MM.
http://link.springer.com/article/10.1007%2Fs12035-016-0253-0
Parkinson's disease (PD) and multiple system atrophy (MSA) are both part of the spectrum of neurodegenerative movement disorders and α-synucleinopathies with overlap of symptoms especially at early stages of the disease but with distinct disease progression and responses to dopaminergic treatment. Therefore, having biomarkers that specifically classify patients, which could discriminate PD from MSA, would be very useful. MicroRNAs (miRNAs) regulate protein translation and are observed in biological fluids, including cerebrospinal fluid (CSF), and may therefore have potential as biomarkers of disease. The aim of our study was to determine if miRNAs in CSF could be used as biomarkers for either PD or MSA. Using quantitative PCR (qPCR), we evaluated expression levels of 10 miRNAs in CSF patient samples from PD (n = 28), MSA (n = 17), and non-neurological controls (n = 28). We identified two miRNAs (miR-24 and miR-205) that distinguished PD from controls and four miRNAs that differentiated MSA from controls (miR-19a, miR-19b, miR-24, and miR-34c). Combinations of miRNAs accurately discriminated either PD (area under the curve (AUC) = 0.96) or MSA (AUC = 0.86) from controls. In MSA, we also observed that miR-24 and miR-148b correlated with cerebellar ataxia symptoms, suggesting that these miRNAs are involved in cerebellar degeneration in MSA. Our findings support the potential of miRNA panels as biomarkers for movement disorders and may provide more insights into the pathological mechanisms related to these disorders.
Mol Neurobiol. 2016 Nov 14. [Epub ahead of print]
Marques TM, Kuiperij HB, Bruinsma IB, van Rumund A, Aerts MB, Esselink RA, Bloem BR, Verbeek MM.
http://link.springer.com/article/10.1007%2Fs12035-016-0253-0
Parkinson's disease (PD) and multiple system atrophy (MSA) are both part of the spectrum of neurodegenerative movement disorders and α-synucleinopathies with overlap of symptoms especially at early stages of the disease but with distinct disease progression and responses to dopaminergic treatment. Therefore, having biomarkers that specifically classify patients, which could discriminate PD from MSA, would be very useful. MicroRNAs (miRNAs) regulate protein translation and are observed in biological fluids, including cerebrospinal fluid (CSF), and may therefore have potential as biomarkers of disease. The aim of our study was to determine if miRNAs in CSF could be used as biomarkers for either PD or MSA. Using quantitative PCR (qPCR), we evaluated expression levels of 10 miRNAs in CSF patient samples from PD (n = 28), MSA (n = 17), and non-neurological controls (n = 28). We identified two miRNAs (miR-24 and miR-205) that distinguished PD from controls and four miRNAs that differentiated MSA from controls (miR-19a, miR-19b, miR-24, and miR-34c). Combinations of miRNAs accurately discriminated either PD (area under the curve (AUC) = 0.96) or MSA (AUC = 0.86) from controls. In MSA, we also observed that miR-24 and miR-148b correlated with cerebellar ataxia symptoms, suggesting that these miRNAs are involved in cerebellar degeneration in MSA. Our findings support the potential of miRNA panels as biomarkers for movement disorders and may provide more insights into the pathological mechanisms related to these disorders.
Wednesday, 16 November 2016
Parkinson's disease and risk of prostate cancer: A Danish population-based case-control study, 1995-2010
Previous studies have suggested an increased risk of PD in those with prostate cancer. Although the exposure and outcome are the other way round here, this study suggests a negative association between the two diseases...
Cancer Epidemiol. 2016 Nov 10;45:157-161. doi: 10.1016/j.canep.2016.11.002. [Epub ahead of print]
Jespersen CG, Nørgaard M, Borre M.
INTRODUCTION: Prostate cancer growth and progression may be linked to neurogenesis and to medical anti- Parkinson treatment, but results are inconclusive. Therefore, we examined the association between Parkinson's disease and risk of prostate cancer in a population based case-control study.
METHODS: We identified 45,429 patients diagnosed with incident prostate cancer during 1997-2010 from the National Cancer Registry. Five age-matched population controls (n=227,145) were selected for each case. Odds ratios (ORs) adjusted for age and comorbidity for prostate cancer associated with Parkinson's disease were computed using conditional logistic regression. Analyses were stratified by duration of Parkinson's disease and stage of prostate cancer (localized and advanced).
RESULTS: In total, 245 patients (0,5%) and 1656 controls (0,7%) had Parkinson's disease. Overall, patients with Parkinson's disease had a 27% lower risk of prostate cancer compared with patients without Parkinson's disease (adjusted OR (ORa) 0.73; 95% confidence interval (CI), 0.63-0.83). Risk of prostate cancer decreased with increasing duration of Parkinson's disease. The odds ratios were slightly lower for advanced prostate cancer (ORa, 0.68; 95% CI, 0.52-0.88) than for localized prostate cancer (ORa 0.76; 95% CI, 0.61-0.93).
CONCLUSION: Parkinson's disease was associated with a risk reduction overall (27%), which decreased with increasing duration of Parkinson's disease.
Cancer Epidemiol. 2016 Nov 10;45:157-161. doi: 10.1016/j.canep.2016.11.002. [Epub ahead of print]
Jespersen CG, Nørgaard M, Borre M.
INTRODUCTION: Prostate cancer growth and progression may be linked to neurogenesis and to medical anti- Parkinson treatment, but results are inconclusive. Therefore, we examined the association between Parkinson's disease and risk of prostate cancer in a population based case-control study.
METHODS: We identified 45,429 patients diagnosed with incident prostate cancer during 1997-2010 from the National Cancer Registry. Five age-matched population controls (n=227,145) were selected for each case. Odds ratios (ORs) adjusted for age and comorbidity for prostate cancer associated with Parkinson's disease were computed using conditional logistic regression. Analyses were stratified by duration of Parkinson's disease and stage of prostate cancer (localized and advanced).
RESULTS: In total, 245 patients (0,5%) and 1656 controls (0,7%) had Parkinson's disease. Overall, patients with Parkinson's disease had a 27% lower risk of prostate cancer compared with patients without Parkinson's disease (adjusted OR (ORa) 0.73; 95% confidence interval (CI), 0.63-0.83). Risk of prostate cancer decreased with increasing duration of Parkinson's disease. The odds ratios were slightly lower for advanced prostate cancer (ORa, 0.68; 95% CI, 0.52-0.88) than for localized prostate cancer (ORa 0.76; 95% CI, 0.61-0.93).
CONCLUSION: Parkinson's disease was associated with a risk reduction overall (27%), which decreased with increasing duration of Parkinson's disease.
Tuesday, 15 November 2016
Medulla oblongata damage and cardiac autonomic dysfunction in Parkinson disease
As time goes on there are more and more MRI correlates for PD in general and PD-specific features... some of these may well extend into the pre-diagnostic phase and we already suspect that autonomic dysfunction occurs prior to a diagnosis of PD in some, if not the majority of, patients...
Neurology. 2016 Nov 11. pii: 10.1212/WNL.0000000000003426. [Epub ahead of print] Pyatigorskaya N, Mongin M, Valabregue R, Yahia-Cherif L, Ewenczyk C, Poupon C, Debellemaniere E, Vidailhet M, Arnulf I, Lehéricy S.
http://www.neurology.org/content/early/2016/11/11/WNL.0000000000003426.long
OBJECTIVE: To characterize medulla oblongata damage using diffusion tensor imaging (DTI) in Parkinson disease (PD) and correlate it with dysfunction of the cardiac sympathetic/vagal balance.
METHODS: Fifty-two patients with PD and 24 healthy controls were included in the study. All participants underwent clinical examination and 3T MRI using 3D T1-weighted imaging and DTI. DTI metrics were calculated within manually drawn regions of interest. Heart rate variability was evaluated using spectral analysis of the R-R cardiac interval during REM and slow-wave sleep based on continuous overnight electrocardiographic monitoring. Respiratory frequency was measured in 30-second contiguous epochs of REM and slow-wave sleep. The relationships between imaging and cardiac variables were calculated using partial correlations followed by the multiple comparisons permutation approach.
RESULTS: The changes in heart rate and respiratory frequency variability from slow-wave sleep to REM sleep in healthy controls were no longer detectable in patients with PD. There were significant increases in the mean (p = 0.006), axial (p = 0.006), and radial diffusivities (p = 0.005) in the medulla oblongata of patients with PD. In PD, diffusion changes were specifically correlated with a lower heart rate and respiratory frequency variability during REM sleep.
CONCLUSIONS: This study provides evidence that medulla oblongata damage underlies cardiac sympathetic/vagal balance and respiratory dysfunction in patients with PD.
Neurology. 2016 Nov 11. pii: 10.1212/WNL.0000000000003426. [Epub ahead of print] Pyatigorskaya N, Mongin M, Valabregue R, Yahia-Cherif L, Ewenczyk C, Poupon C, Debellemaniere E, Vidailhet M, Arnulf I, Lehéricy S.
http://www.neurology.org/content/early/2016/11/11/WNL.0000000000003426.long
OBJECTIVE: To characterize medulla oblongata damage using diffusion tensor imaging (DTI) in Parkinson disease (PD) and correlate it with dysfunction of the cardiac sympathetic/vagal balance.
METHODS: Fifty-two patients with PD and 24 healthy controls were included in the study. All participants underwent clinical examination and 3T MRI using 3D T1-weighted imaging and DTI. DTI metrics were calculated within manually drawn regions of interest. Heart rate variability was evaluated using spectral analysis of the R-R cardiac interval during REM and slow-wave sleep based on continuous overnight electrocardiographic monitoring. Respiratory frequency was measured in 30-second contiguous epochs of REM and slow-wave sleep. The relationships between imaging and cardiac variables were calculated using partial correlations followed by the multiple comparisons permutation approach.
RESULTS: The changes in heart rate and respiratory frequency variability from slow-wave sleep to REM sleep in healthy controls were no longer detectable in patients with PD. There were significant increases in the mean (p = 0.006), axial (p = 0.006), and radial diffusivities (p = 0.005) in the medulla oblongata of patients with PD. In PD, diffusion changes were specifically correlated with a lower heart rate and respiratory frequency variability during REM sleep.
CONCLUSIONS: This study provides evidence that medulla oblongata damage underlies cardiac sympathetic/vagal balance and respiratory dysfunction in patients with PD.
Thursday, 10 November 2016
Calcium Channel Antagonists as Disease-Modifying Therapy for Parkinson's Disease: Therapeutic Rationale and Current Status
I saw James Surmeier (http://physio.northwestern.edu/research/research-areas/systems-neuroscience.html#surmeier) talking on this subject at the Parkinson's UK Research Conference in Leeds earlier this week... he was very inspiring. I was already aware of the epidemiological research on this topic, but not the animal studies that support it... exciting times for calcium channel blockers and PD...
CNS Drugs. 2016 Nov 8. [Epub ahead of print]
Swart T, Hurley MJ.
http://link.springer.com/article/10.1007%2Fs40263-016-0393-9
Parkinson's disease is a disabling hypokinetic neurological movement disorder in which the aetiology is unknown in the majority of cases. Current pharmacological treatments, though effective at restoring movement, are only symptomatic and do nothing to slow disease progression. Electrophysiological, epidemiological and neuropathological studies have implicated CaV1.3 subtype calcium channels in the pathogenesis of the disorder, and drugs with some selectivity for this ion channel (brain-penetrant dihydropyridine calcium channel blockers) are neuroprotective in animal models of the disease. Dihydropyridines have been safely used for decades to treat hypertension and other cardiovascular disorders. A phase II clinical trial found that isradipine was safely tolerated by patients with Parkinson's disease, and a phase III trial is currently underway to determine whether treatment with isradipine is neuroprotective and therefore able to slow the progression of Parkinson's disease. This manuscript reviews the current information about the use of dihydropyridines as therapy for Parkinson's disease and discusses the possible mechanism of action of these drugs, highlighting CaV1.3 calcium channels as a potential therapeutic target for neuroprotection in Parkinson's disease.
CNS Drugs. 2016 Nov 8. [Epub ahead of print]
Swart T, Hurley MJ.
http://link.springer.com/article/10.1007%2Fs40263-016-0393-9
Parkinson's disease is a disabling hypokinetic neurological movement disorder in which the aetiology is unknown in the majority of cases. Current pharmacological treatments, though effective at restoring movement, are only symptomatic and do nothing to slow disease progression. Electrophysiological, epidemiological and neuropathological studies have implicated CaV1.3 subtype calcium channels in the pathogenesis of the disorder, and drugs with some selectivity for this ion channel (brain-penetrant dihydropyridine calcium channel blockers) are neuroprotective in animal models of the disease. Dihydropyridines have been safely used for decades to treat hypertension and other cardiovascular disorders. A phase II clinical trial found that isradipine was safely tolerated by patients with Parkinson's disease, and a phase III trial is currently underway to determine whether treatment with isradipine is neuroprotective and therefore able to slow the progression of Parkinson's disease. This manuscript reviews the current information about the use of dihydropyridines as therapy for Parkinson's disease and discusses the possible mechanism of action of these drugs, highlighting CaV1.3 calcium channels as a potential therapeutic target for neuroprotection in Parkinson's disease.
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