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.

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.

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.

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.

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.

Tuesday, 8 November 2016

Usefulness of Cardiac MIBG Scintigraphy, Olfactory Testing and Substantia Nigra Hyperechogenicity as Additional Diagnostic Markers for Distinguishing between Parkinson's Disease and Atypical Parkinsonian Syndromes

Combining (relatively) cheap investigations to differentiate Parkinson's from atypical Parkinson's may prove fruitful... certainly in most centres it is difficult to differentiate these conditions using SPECT imaging... and many people are not confident with the MRI differences...

PLoS One. 2016 Nov 3;11(11):e0165869. doi: 10.1371/journal.pone.0165869. eCollection 2016. Fujita H1, Suzuki K1, Numao A1, Watanabe Y1, Uchiyama T1,2, Miyamoto T3, Miyamoto M4, Hirata K1.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165869

BACKGROUND: We aimed to evaluate the utility of the combined use of cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy, olfactory testing, and substantia nigra (SN) hyperechogenicity on transcranial sonography (TCS) in differentiating Parkinson's disease (PD) from atypical parkinsonian syndromes (APSs), such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP).

METHODS: Cardiac MIBG scintigraphy, card-type odor identification testing (Open Essence (OE), Wako, Japan), and TCS were performed with 101 patients with PD and 38 patients with APSs (MSA and PSP). Receiver operating characteristic (ROC) curve analysis was used to assess the sensitivity and specificity of these batteries for diagnosing PD from APSs. The diagnostic accuracy of the three tests was also assessed among patients at the early disease stage (drug-naïve patients with a disease duration of 3 years or less).

RESULTS: In differentiating PD from APSs, the area under the ROC curve was 0.74 (95% CI, 0.65-0.83), 0.8 (95% CI, 0.73-0.87), and 0.75 (95% CI, 0.67-0.82) for TCS, cardiac MIBG scintigraphy, and olfactory testing, respectively. The diagnostic sensitivity and specificity were 53.1% and 91.7%, respectively, for TCS, 70.3% and 86.8%, respectively, for cardiac MIBG scintigraphy, 58.4% and 76.3%, respectively, for OE. Among early-stage patients, sensitivity and specificity were 50.0% and 93.8%, respectively, for TCS, 57.1% and 87.5%, respectively, for cardiac MIBG scintigraphy, and 54.8% and 79.2%, respectively, for OE. At least one positive result from 3 tests improved sensitivity (86.1%) but decreased specificity (63.2%). In contrast, at least 2 positive results from 3 tests had good discrimination for both early-stage patients (50.0% sensitivity and 93.8% specificity) and patients overall (57.8% sensitivity and 95.8% specificity). Positive results for all 3 tests yielded 100% specificity but low sensitivity (25%).

CONCLUSIONS: At least 2 positive results from among TCS, cardiac MIBG scintigraphy, and olfactory testing can support clinical diagnosis in distinguishing PD from APSs.

Saturday, 5 November 2016

Genome-wide association study in essential tremor identifies three new loci

Understanding the genetics of essential tremor has been difficult, but this is now a reasonably large GWAS study conducted by investigators who will have accurately characterise the phenotype... GWAS (like anything) depends on accurate diagnosis of the cases and ideally confident exclusion of the disease in controls... interestingly some of the previously reported 'hits' for essential tremor are not replicated here...

Brain. 2016 Oct 20. pii: aww242. [Epub ahead of print]

Müller SH, Girard SL, Hopfner F, Merner ND, Bourassa CV, Lorenz D, Clark LN, Tittmann L, Soto-Ortolaza AI, Klebe S, Hallett M, Schneider SA, Hodgkinson CA, Lieb W, Wszolek ZK, Pendziwiat M, Lorenzo-Betancor O, Poewe W, Ortega-Cubero S, Seppi K, Rajput A, Hussl A, Rajput AH, Berg D, Dion PA, Wurster I, Shulman JM, Srulijes K, Haubenberger D, Pastor P, Vilariño-Güell C, Postuma RB, Bernard G, Ladwig KH, Dupré N, Jankovic J, Strauch K, Panisset M, Winkelmann J, Testa CM, Reischl E, Zeuner KE, Ross OA, Arzberger T, Chouinard S, Deuschl G, Louis ED, Kuhlenbäumer G, Rouleau GA.



We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.

Tuesday, 1 November 2016

Additional Rare Variant Analysis in Parkinson's Disease Cases with and Without Known Pathogenic Mutations: Evidence for Oligogenic Inheritance

Great to see this paper published... it provides evidence for another layer of complexity to the genetics of Parkinson's, but also provides further explanation for this complexity... as time passes we realise there is not just genetic and non-genetic Parkinson's, but instead that genetic variability underpins a great deal of the heterogeneity of all Parkinson's disease...

Hum Mol Genet. 2016 Oct 18. pii: ddw348. [Epub ahead of print]
Lubbe SJ, Escott-Price V, Gibbs JR, Nalls MA, Bras J, Price TR, Nicolas A, Jansen IE, Mok KY, Pittman AM, Tomkins JE, Lewis PA, Noyce AJ, Lesage S, Sharma M, Schiff ER, Levine AP, Brice A, Gasser T, Hardy J, Heutink P, Wood NW, Singleton AB, Williams NM, Morris HR; for International Parkinson’s Disease Genomics Consortium.


Abstract

Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognized primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of no known mutation PD cases harbor a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of PD patients and their families.

Saturday, 29 October 2016

Neuropsychiatric characteristics of GBA-associated Parkinson disease

These findings support earlier observations about GBA-related PD... there does seem to be a tendency for increased neuro-psychiatric features, cognitive impairment and perhaps a more severe motor phenotype...

J Neurol Sci. 2016 Nov 15;370:63-69. doi: 10.1016/j.jns.2016.08.059. Epub 2016 Aug 30.
Swan M, Doan N, Ortega RA, Barrett M, Nichols W, Ozelius L, Soto-Valencia J, Boschung S, Deik A, Sarva H, Cabassa J, Johannes B, Raymond D, Marder K, Giladi N, Miravite J, Severt W, Sachdev R, Shanker V, Bressman S, Saunders-Pullman R.



Mutations in GBA1 are a well-established risk factor for Parkinson disease (PD). GBA-associated PD (GBA-PD) may have a higher burden of nonmotor symptoms than idiopathic PD (IPD). We sought to characterize the relationship between GBA-PD and neuropsychiatric symptoms. Subjects were screened for common GBA1 mutations. GBA-PD (n=31) and non-carrier (IPD; n=55) scores were compared on the Unified Parkinson Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Beck Depression Inventory (BDI), and the State-Trait Anxiety Index (STAI). In univariate comparisons, GBA-PD had a greater prevalence of depression (33.3%) versus IPD (13.2%) (p<0.05). In regression models controlling for age, sex, disease duration, motor disability, and MoCA score, GBA-PD had an increased odds of depression (OR 3.66, 95% CI 1.13-11.8) (p=0.03). Post-hoc analysis stratified by sex showed that, among men, GBA-PD had a higher burden of trait anxiety and depression than IPD; this finding was sustained in multivariate models. Among women, GBA-PD did not confer greater psychiatric morbidity than IPD. These results suggest that GBA1 mutations confer greater risk of neuropsychiatric morbidity in PD, and that sex may affect this association.

Wednesday, 26 October 2016

Associations between plasma ceramides and cognitive and neuropsychiatric manifestations in Parkinson's disease dementia

Here we see differences in levels of ceramides not only in those PD patients with cognitive impairment, but also in those without cognitive impairment compared with controls... I think we are going to hear a lot more about ceramides in the future...

J Neurol Sci. 2016 Nov 15;370:82-87. doi: 10.1016/j.jns.2016.09.028. Epub 2016 Sep 19.
Xing Y, Tang Y, Zhao L, Wang Q, Qin W, Ji X, Zhang J, Jia J.


BACKGROUND:
The abnormal metabolism of ceramides may account for the pathogenesis of Parkinson's disease dementia (PDD). However, the effect of ceramides on cognitive domain impairments and neuropsychiatric symptoms of PDD remains unknown.

METHODS:
A total of 38 PDD, 40 PD with no cognitive impairment (PD-NC) and 40 normal controls were included. A series of cognitive tests and the Neuropsychiatric Inventory (NPI) were used to assess cognitive domains and neuropsychiatric symptoms. A non-fasting blood sample was obtained from each subject. Plasma ceramide levels were tested by HPLC-MS/MS analysis.

RESULTS:
C14:0 and C24:1 levels were significantly higher in PDD than in PD-NC and normal controls. Verbal memory was negatively correlated with C14:0 and C24:1. After controlling for confounding factors, C22:0, C20:0 and C18:0 were significantly associated with hallucinations, anxiety and sleep behavior disturbances, respectively.

CONCLUSION:

In PDD, the increase in ceramide levels was correlated with decreased memory function and associated with higher odds of multiple neuropsychiatric symptoms.

Tuesday, 25 October 2016

Brain MR Contribution to the Differential Diagnosis of Parkinsonian Syndromes: An Update

Up-to-date article about the use of MRI in parkinsonian syndromes... it is likely that MRI will play a leading role in the future identification of prodromal PD in my opinion...

Parkinsons Dis. 2016;2016:2983638. Epub 2016 Sep 28.
Rizzo G, Zanigni S, De Blasi R, Grasso D, Martino D, Savica R, Logroscino G.



Brain magnetic resonance (MR) represents a useful and feasible tool for the differential diagnosis of Parkinson's disease. Conventional MR may reveal secondary forms of parkinsonism and may show peculiar brain alterations of atypical parkinsonian syndromes. Furthermore, advanced MR techniques, such as morphometric-volumetric analyses, diffusion-weighted imaging, diffusion tensor imaging, tractography, proton MR spectroscopy, and iron-content sensitive imaging, have been used to obtain quantitative parameters useful to increase the diagnostic accuracy. Currently, many MR studies have provided both qualitative and quantitative findings, reflecting the underlying neuropathological pattern of the different degenerative parkinsonian syndromes. Although the variability in the methods and results across the studies limits the conclusion about which technique is the best, specific radiologic phenotypes may be identified. Qualitative/quantitative MR changes in the substantia nigra do not discriminate between different parkinsonisms. In the absence of extranigral abnormalities, the diagnosis of PD is more probable, whereas basal ganglia changes (mainly in the putamen) suggest the diagnosis of an atypical parkinsonian syndrome. In this context, changes in pons, middle cerebellar peduncles, and cerebellum suggest the diagnosis of MSA, in midbrain and superior cerebellar peduncles the diagnosis of PSP, and in whole cerebral hemispheres (mainly in frontoparietal cortex with asymmetric distribution) the diagnosis of Corticobasal Syndrome.

Sunday, 23 October 2016

Cognitive impairment in Parkinson's disease: Association between patient-reported and clinically measured outcomes

Interesting to see that these are the bits that patients notice when cognition starts to deteriorate... I always feel that patients have a bit of agnosia, at least for the motor features, and I wonder if its the same for cognition...

Parkinsonism Relat Disord. 2016 Sep 27. pii: S1353-8020(16)30383-2. doi: 10.1016/j.parkreldis.2016.09.025. [Epub ahead of print]
Mills KA, Mari Z, Pontone GM, Pantelyat A, Zhang A, Yoritomo N, Powers E, Brandt J, Dawson TM, Rosenthal LS.


BACKGROUND:
In Parkinson's disease, the association between objective and patient-reported measures of cognitive dysfunction is unknown and highly relevant to research and clinical care.

OBJECTIVE:
To determine which cognitive domain-specific Montreal Cognitive Assessment (MoCA) subscores are most strongly associated with patient-reported cognitive impairment on question 1 (Q1) of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

METHODS:
We analyzed data from 759 PD participants and 481 persons without PD with in a retrospective, cross sectional analysis using data from the NINDS Parkinson's Disease Biomarkers Program (PDBP), a longitudinal, multicenter biomarker study. The relationship between a patient-reported cognitive rating (MDS-UPDRS q1.1) and objective cognitive assessments (MoCA) was assessed using multinomial logistic regression modeling and the outcomes reported as conditional odds ratios (cOR's) representing the relative odds of a participant reporting cognitive impairment that is "slight" versus "normal" on MDS-UPDRSq1.1 for a one unit increase in a MoCA sub-score, adjusted for age and education.

RESULTS:
In PD participants, changes in visuospatial-executive performance and memory had the most significant impact on subjective cognitive impairment. A 1-point increase in visuospatial-executive function decreased the chance of reporting a MDS-UPDRS Q1 score of "slight" versus "normal" by a factor of 0.686 (p < 0.001) and each 1 point improvement in delayed recall decreased the odds of reporting "slight" cognitive impairment by a factor of 0.836 (p < 0.001).

CONCLUSIONS:

Conversion from a PD patient's report of "normal" to "slight" cognitive impairment may be associated with changes in visuospatial-executive dysfunction and memory more than other cognitive domains.

Saturday, 22 October 2016

Transcranial Sonography and DaTSCAN in Early Stage Parkinson's Disease and Essential Tremor

Both imaging modalities demonstrating reasonable diagnostic accuracy here. The problem with TCS is the subjectivity of the assessment and the fact that is (probably) a static risk marker rather than and diagnostic aid...

Eur Neurol. 2016 Oct 18;76(5-6):252-255. [Epub ahead of print]
Jesus-Ribeiro J, Freire A, Sargento-Freitas J, Sousa M, Silva F, Moreira F, Cunha MJ, Walter U, Januário C.


BACKGROUND:
The diagnosis of Parkinson's disease (PD) can sometimes be a challenge in the early stages of the disease. Both transcranial sonography (TCS) and DaTSCAN are recommended as auxiliary examinations for the differential diagnosis of PD; however, only few data exist regarding their diagnostic accuracy in the early stage of PD and essential tremor (ET).

METHODS:
We evaluated patients with clinically suspected diagnosis of PD at early stages (Hoehn and Yahr ≤2) or ET. All patients underwent DaTSCAN and TCS with a maximum interval of 6 months. Final diagnosis was established after 1-year follow-up.

RESULTS:
From the 63 patients recruited, 3 were excluded due to transcranial insonability and 2 for uncertain clinical diagnosis. The final clinical diagnosis was ET in 44.8% and PD in 55.2%. Compared to clinical diagnosis of PD, TCS had a sensitivity of 87.5% and specificity of 96.2%; DaTSCAN sensitivity was 84.4% and specificity was 96.2%. Both diagnostic tests demonstrated a substantial level of agreement (Cohen's kappa coefficient: 0.83, 95% CI 0.68-0.97, p < 0.001).

CONCLUSION:

TCS and DaTSCAN have similar diagnostic accuracy for the diagnosis of early stage PD versus ET.

Thursday, 20 October 2016

Digitized Spiral Drawing: A Possible Biomarker for Early Parkinson's Disease

This is useful... it is likely that subtle motor dysfunction emerges a long time before a clinical diagnosis can be made on classical clinical criteria... evidence is accumulating on this subject. We need to find good ways of measuring this motor dysfunction and monitoring it in the pre-diagnostic phase...

PLoS One. 2016 Oct 12;11(10):e0162799. doi: 10.1371/journal.pone.0162799. eCollection 2016.
San Luciano M, Wang C, Ortega RA, Yu Q, Boschung S, Soto-Valencia J, Bressman SB, Lipton RB, Pullman S, Saunders-Pullman R.


INTRODUCTION:
Pre-clinical markers of Parkinson's Disease (PD) are needed, and to be relevant in pre-clinical disease, they should be quantifiably abnormal in early disease as well. Handwriting is impaired early in PD and can be evaluated using computerized analysis of drawn spirals, capturing kinematic, dynamic, and spatial abnormalities and calculating indices that quantify motor performance and disability. Digitized spiral drawing correlates with motor scores and may be more sensitive in detecting early changes than subjective ratings. However, whether changes in spiral drawing are abnormal compared with controls and whether changes are detected in early PD are unknown.

METHODS:
138 PD subjects (50 with early PD) and 150 controls drew spirals on a digitizing tablet, generating x, y, z (pressure) data-coordinates and time. Derived indices corresponded to overall spiral execution (severity), shape and kinematic irregularity (second order smoothness, first order zero-crossing), tightness, mean speed and variability of spiral width. Linear mixed effect adjusted models comparing these indices and cross-validation were performed. Receiver operating characteristic analysis was applied to examine discriminative validity of combined indices.

RESULTS:
All indices were significantly different between PD cases and controls, except for zero-crossing. A model using all indices had high discriminative validity (sensitivity = 0.86, specificity = 0.81). Discriminative validity was maintained in patients with early PD.

CONCLUSION:

Spiral analysis accurately discriminates subjects with PD and early PD from controls supporting a role as a promising quantitative biomarker. Further assessment is needed to determine whether spiral changes are PD specific compared with other disorders and if present in pre-clinical PD.

Wednesday, 19 October 2016

Transcranial sonography in dopa-responsive dystonia

This is interesting... GCH-1 mutations which cause DRD are a risk factor for PD it seems. Hyperechogenicity of the nigra also appears to be a risk factor for PD and is present in up to 80-90% of patients. Here we see a significant proportion of DRD patients have hyperechogenicity (albeit small sample size)....

Eur J Neurol. 2016 Oct 12. doi: 10.1111/ene.13172. [Epub ahead of print]
Svetel M, Tomić A, Mijajlović M, Dobričić V, Novaković I, Pekmezović T, Brajković L, Kostić VS.


BACKGROUND AND PURPOSE:
Mutations in the GCH1 gene, encoding GTP cyclohydrolase 1, the enzyme critically important for dopamine production in nigrostriatal neurons, are the most common cause of dopa-responsive dystonia (DRD), characterized predominantly by limb dystonia, although parkinsonian features may also be present. It has been suggested that DRD is a neurochemical rather than neurodegenerative disorder.

METHODS:
Transcranial brain sonography, which might be a risk marker for nigral injury, was obtained from 141 subjects divided into four groups: (i) 11 patients with genetically confirmed DRD; (ii) 55 consecutive patients with Parkinson's disease (PD); (iii) 30 patients diagnosed as isolated adult-onset focal dystonia; and (iv) 45 healthy controls (HCs).

RESULTS:
Substantia nigra hyperechogenicity was present in 63.6% of patients with DRD, which was significantly different in comparison to patients with dystonia (20%) and HCs (6.7%), but not in comparison to the PD group (87.3%). Also, values of the maximal areas of substantia nigra hyperechogenicity in patients with DRD were higher in comparison to HCs, but significantly lower than among the PD group.

CONCLUSIONS:

We suggested that the observed transcranial brain sonography features in patients with DRD might primarily be risk markers for particular clinical features (parkinsonism, dystonia) occurring in the specific genetic context (i.e. GCH1 mutations), or might reflect compensated neurodegenerative processes triggered by the long-lasting dopamine deficiency due to the profound delay in levodopa treatment in our patients with DRD.

Monday, 10 October 2016

Study of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration

This paper confirms that LRRK2 mutations can be found in pathologically confirmed cases of PSP and CBD... however they are much more common in PD and LRRK2 remains the most common dominantly inherited form of PD...

Mov Disord. 2016 Oct 6. doi: 10.1002/mds.26815. [Epub ahead of print]
Sanchez-Contreras M, Heckman MG, Tacik P, Diehl N, Brown PH, Soto-Ortolaza AI, Christopher EA, Walton RL, Ross OA, Golbe LI, Graff-Radford N, Wszolek ZK, Dickson DW, Rademakers R.

BACKGROUND:
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic cause of Parkinson's disease (PD). Unexpectedly, tau pathology has been reported in a subset of LRRK2 mutation carriers.

METHODS:
To estimate the frequency of pathogenic LRRK2 mutations and to evaluate the association of common LRRK2 variants with risk of primary tauopathies, we studied 1039 progressive supranuclear palsy (PSP) and 145 corticobasal degeneration patients from the Mayo Clinic Florida brain bank and 1790 controls ascertained at Mayo Clinic. Sanger sequencing of LRRK2 exons 30, 31, 35, and 41 was performed in all patients, and genotyping of all 17 known exonic variants with minor allele frequency >0.5% was performed in patients and controls.

RESULTS:
LRRK2 mutational screening identified 2 known pathogenic mutations (p.G2019S and p.R1441C), each in 1 PSP patient, the novel p.A1413T mutation in a PSP patient and the rare p.R1707K mutation in a corticobasal degeneration patient. Both p.A1413T and p.R1707K mutations were predicted damaging by at least 2 of 3 prediction programs and affect evolutionary conserved sites of LRRK2. Association analysis using common LRRK2 variants only showed nominal association of the p.L153L variant with PSP.

CONCLUSIONS:

Our study confirms the presence of pathogenic and potentially pathogenic LRRK2 mutations in pathologically confirmed primary tauopathies, albeit with low frequency. In contrast to PD, common LRRK2 variants do not appear to play a major role in determining PSP and corticobasal degeneration risk.

Sunday, 9 October 2016

Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3

Second important synuclein paper of the weekend... its very encouraging to see evidence accumulating and drug targets being found... it fells like a good time to be involved in PD research...

Science. 2016 Sep 30;353(6307). pii: aah3374.
Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, Kang HC, Zhang J, Xu J, Chen R, Park H, Andrabi SA, Kang SU, Gonçalves RA, Liang Y, Zhang S, Qi C, Lam S, Keiler JA, Tyson J, Kim D, Panicker N, Yun SP, Workman CJ, Vignali DA, Dawson VL, Ko HS, Dawson TM.



Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-synuclein (α-syn). The mechanism by which α-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds α-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the α-syn monomer exhibited minimal binding. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed α-syn PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. The identification of LAG3 as a receptor that binds α-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies.

Saturday, 8 October 2016

A de novo compound targeting α-synuclein improves deficits in models of Parkinson's disease

This type of research is really important... it shows that a drug can reduce the formation and accumulation of alpha-synuclein (the key protein that underlies PD) and also reduce evidence of damage caused by it. The authors then show its activity in mouse models that have excessive alpha-synuclein... It is important to learn what other effects these compounds have before considering them to be potentially trialled as treatment, but very encouraging to know that things affect the burden of synuclein!!

Brain. 2016 Sep 27. pii: aww238. [Epub ahead of print]
Wrasidlo W, Tsigelny IF, Price DL, Dutta G, Rockenstein E, Schwarz TC, Ledolter K, Bonhaus D, Paulino A, Eleuteri S, Skjevik ÅA, Kouznetsova VL, Spencer B, Desplats P, Gonzalez-Ruelas T, Trejo-Morales M, Overk CR, Winter S, Zhu C, Chesselet MF, Meier D, Moessler H, Konrat R, Masliah E.


Abstract

Abnormal accumulation and propagation of the neuronal protein α-synuclein has been hypothesized to underlie the pathogenesis of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Here we report a de novo-developed compound (NPT100-18A) that reduces α-synuclein toxicity through a novel mechanism that involves displacing α-synuclein from the membrane. This compound interacts with a domain in the C-terminus of α-synuclein. The E83R mutation reduces the compound interaction with the 80-90 amino acid region of α-synuclein and prevents the effects of NPT100-18A. In vitro studies showed that NPT100-18A reduced the formation of wild-type α-synuclein oligomers in membranes, reduced the neuronal accumulation of α-synuclein, and decreased markers of cell toxicity. In vivo studies were conducted in three different α-synuclein transgenic rodent models. Treatment with NPT100-18A ameliorated motor deficits in mThy1 wild-type α-synuclein transgenic mice in a dose-dependent manner at two independent institutions. Neuropathological examination showed that NPT100-18A decreased the accumulation of proteinase K-resistant α-synuclein aggregates in the CNS and was accompanied by the normalization of neuronal and inflammatory markers. These results were confirmed in a mutant line of α-synuclein transgenic mice that is prone to generate oligomers. In vivo imaging studies of α-synuclein-GFP transgenic mice using two-photon microscopy showed that NPT100-18A reduced the cortical synaptic accumulation of α-synuclein within 1 h post-administration. Taken together, these studies support the notion that altering the interaction of α-synuclein with the membrane might be a feasible therapeutic approach for developing new disease-modifying treatments of Parkinson's disease and other synucleinopathies.

Friday, 7 October 2016

A new computer vision-based approach to aid the diagnosis of Parkinson's disease

I am interested in PD handwriting... but the analysis is not straightforward and there are many varied features... I don't agree with the last statement. I think the handwriting change may be relatively early. Many patients have showed me evolving change in handwriting prior to diagnosis... sometimes many years before...

Comput Methods Programs Biomed. 2016 Nov;136:79-88. doi: 10.1016/j.cmpb.2016.08.005. Epub 2016 Aug 26.
Pereira CR, Pereira DR, Silva FA, Masieiro JP, Weber SA, Hook C, Papa JP.


BACKGROUND AND OBJECTIVE:
Even today, pointing out an exam that can diagnose a patient with Parkinson's disease (PD) accurately enough is not an easy task. Although a number of techniques have been used in search for a more precise method, detecting such illness and measuring its level of severity early enough to postpone its side effects are not straightforward. In this work, after reviewing a considerable number of works, we conclude that only a few techniques address the problem of PD recognition by means of micrography using computer vision techniques. Therefore, we consider the problem of aiding automatic PD diagnosis by means of spirals and meanders filled out in forms, which are then compared with the template for feature extraction.

METHODS:
In our work, both the template and the drawings are identified and separated automatically using image processing techniques, thus needing no user intervention. Since we have no registered images, the idea is to obtain a suitable representation of both template and drawings using the very same approach for all images in a fast and accurate approach.

RESULTS:
The results have shown that we can obtain very reasonable recognition rates (around ≈67%), with the most accurate class being the one represented by the patients, which outnumbered the control individuals in the proposed dataset.

CONCLUSIONS:

The proposed approach seemed to be suitable for aiding in automatic PD diagnosis by means of computer vision and machine learning techniques. Also, meander images play an important role, leading to higher accuracies than spiral images. We also observed that the main problem in detecting PD is the patients in the early stages, who can draw near-perfect objects, which are very similar to the ones made by control patients.

Wednesday, 5 October 2016

Lower serum uric acid is associated with mild cognitive impairment in early Parkinson's disease: a 4-year follow-up study

Multiple studies suggest that elevated serum urate is protective against PD and reductions may lead to a more severe clinical picture... now that alteration of serum urate is a target in a phase 3 clinical trial we will see for sure how it affects PD...

J Neural Transm (Vienna). 2016 Sep 28. [Epub ahead of print]
Pellecchia MT, Savastano R, Moccia M, Picillo M, Siano P, Erro R, Vallelunga A, Amboni M, Vitale C, Santangelo G, Barone P.


Abstract

Cognitive deficits are common in Parkinson's disease (PD) and many patients eventually develop dementia; however, its occurrence is unpredictable. Serum uric acid (UA) has been proposed as a biomarker of PD, both in the preclinical and clinical phase of the disease. The aim of this pilot study was to evaluate relationships between baseline serum UA levels and occurrence of mild cognitive impairment (MCI) at 4-year follow-up in a cohort of early PD patients. Early PD patients, not presenting concomitant diseases, cognitive impairment or treatment possibly interfering with UA levels, underwent neuropsychological testing at baseline and 4-year follow-up. UA levels were determined in serum at baseline. MCI was found in 23 out of 42 PD patients completing 4-year follow-up. Patients presenting MCI had significantly higher age at onset and lower Frontal Assessment Battery scores at baseline as compared with patients cognitively intact. Logistic regression analysis showed that both serum UA levels (OR = 0.54, p = 0.044) and age (OR = 1.16, p = 0.009) contribute to the occurrence of MCI at 4-year follow-up. Our pilot study suggests that lower levels of serum UA in the early disease stages are associated to the later occurrence of MCI. These results need to be confirmed by further studies on larger samples.

Saturday, 24 September 2016

Increased suicide risk and clinical correlates of suicide among patients with Parkinson's disease

These authors report a doubling in the rate of suicide in PD patients compared to controls... this feels pretty high and I cannot think of many, if any, patients I know of that have committed suicide. My impression is that it is more common in the atypical parkinsonisms. The authors do acknowledge this and say that the previous literature is mixed... some studies suggest higher risk and some lower risk. There is likely to be wide variability region to region and social support network and professional support (specialist nurses, doctors and support groups) are likely to be strong determinants... the results of such studies may not be generalisable to all populations...

Parkinsonism Relat Disord. 2016 Sep 6. pii: S1353-8020(16)30331-5. doi: 10.1016/j.parkreldis.2016.09.006. [Epub ahead of print]
Lee T, Lee HB, Ahn MH, Kim J, Kim MS, Chung SJ, Hong JP.


INTRODUCTION:
Parkinson's disease (PD) is a debilitating, neurodegenerative condition frequently complicated by psychiatric symptoms. Patients with PD may be at higher risk for suicide than the general population, but previous estimates are limited and conflicting. The aim of this study is to estimate the suicide rate based on the clinical case registry and to identify risk factors for suicide among patients diagnosed with PD.

METHODS:
The target sample consisted of 4362 patients diagnosed with PD who were evaluated at a general hospital in Seoul, South Korea, from 1996 to 2012. The standardized mortality ratio for suicide among PD patients was estimated. In order to identify the clinical correlates of suicide, case-control study was conducted based on retrospective chart review. The 29 suicide cases (age: 62.3 ± 13.7 years; females: 34.5%) were matched with 116 non-suicide controls (age: 63.5 ± 9.2 years; females 56.9%) by the year of initial PD evaluation.

RESULTS:
The SMR for suicide in PD patients was 1.99 (95% CI 1.33-2.85). Mean duration from time of initial diagnosis to suicide among cases was 6.1 ± 3.5 years. Case-control analysis revealed that male, initial extremity of motor symptom onset, history of depressive disorder, delusion, any psychiatric disorder, and higher L-dopa dosage were significantly associated with suicide among PD patients. Other PD-related variables such as UPDRS motor score were not significantly associated with death by suicide.

CONCLUSION:

Suicide risk in PD patients is approximately 2 times higher than that in the general population. Psychiatric disorders, and also L-dopa medication need further attention with respect to suicide.

Unsupervised home monitoring of Parkinson's disease motor symptoms using body-worn accelerometers.

This is not so much the future, as the present... there are now lots of devices that are available for monitoring of PD symptoms. One of the biggest issues is that almost all have been insufficiently validated... there are lots of examples of pilot studies and very few with replication... PD lends itself better than most other diseases to home monitoring... and this area will only grow over the coming years...

Parkinsonism Relat Disord. 2016 Sep 9. pii: S1353-8020(16)30334-0. doi: 10.1016/j.parkreldis.2016.09.009. [Epub ahead of print]
Fisher JM, Hammerla NY, Ploetz T, Andras P, Rochester L, Walker RW.


INTRODUCTION:
Current PD assessment methods have inherent limitations. There is need for an objective method to assist clinical decisions and to facilitate evaluation of treatments. Accelerometers, and analysis using artificial neural networks (ANN), have shown potential as a method of motor symptom evaluation. This work describes the development of a novel PD disease state detection system informed by algorithms based on data collected in an unsupervised, home environment. We evaluated whether this approach can reproduce patient-completed symptom diaries and clinical assessment of disease state.

METHODS:
34 participants with PD wore bilateral wrist-worn accelerometers for 4 h in a research facility (phase 1) and for 7 days at home whilst completing symptom diaries (phase 2). An ANN to predict disease state was developed based on home-derived accelerometer data. Using a leave-one-out approach, ANN performance was evaluated against patient-completed symptom diaries and against clinician rating of disease state.

RESULTS:
In the clinical setting, specificity for dyskinesia detection was extremely high (0.99); high specificity was also demonstrated for home-derived data (0.93), but with low sensitivity (0.38). In both settings, sensitivity for on/off detection was sub-optimal. ANN-derived values of the proportions of time in each disease state showed strong, significant correlations with patient-completed symptom diaries.

CONCLUSION:

Accurate, real-time evaluation of symptoms in an unsupervised, home environment, with this sensor system, is not yet achievable. In terms of the amounts of time spent in each disease state, ANN-derived results were comparable to those of symptom diaries, suggesting this method may provide a valuable outcome measure for medication trials.

Bone mass and vitamin D levels in Parkinson's disease: is there any difference between genders?

This study further confirms observations we made in our meta-analysis of bone health in PD... as with individuals that don't have PD... women are at higher risk than men...

J Phys Ther Sci. 2016 Aug;28(8):2204-9. doi: 10.1589/jpts.28.2204. Epub 2016 Aug 31.
Ozturk EA, Gundogdu I, Tonuk B, Kocer BG, Tombak Y, Comoglu S, Cakci A.



[Purpose] The aim of this study was to determine the bone mineral density, vitamin D level, and frequencies of osteopenia and osteoporosis in patients with Parkinson's disease and to compare male and female patients with the controls separately. 

[Subjects and Methods] One hundred fifteen Parkinson's disease patients (47 males, 68 females; age range: 55-85 years) and 117 age- and gender-matched controls (47 males, 70 females) were enrolled in the study. Bone mineral density measured by dual-energy X-ray absorptiometry and serum D vitamin levels of each participant were recorded. 

[Results] The mean lumbar spine, femur neck, and total femur bone mineral density levels, T-scores, and vitamin D levels were found to be significantly lower in Parkinson's disease patients in both genders. Furthermore, osteoporosis rates were found be significantly higher only in female Parkinson's disease patients compared with female controls. 

[Conclusion] Data from the present study revealed that while osteoporosis was significantly higher only in female Parkinson's disease patients, all Parkinson's disease patients had lower bone mineral density scores and vitamin D levels compared with the controls regardless of gender, suggesting that clinicians should pay attention to the osteoporosis risk in Parkinson's disease and that adequate preventive measures should be taken in order to limit the future risk due to osteoporotic fractures.

Thursday, 22 September 2016

Survival and dementia in GBA-associated Parkinson Disease: The mutation matters

This is really interesting isn't? I know that patients with GBA related PD tend to have a more severe form of Parkinson's and that dementia is common. I had assumed that the dementia was an important reason for shorter survival. The only concern I have is whether it is appropriate to adjust for dementia in the analysis... the problem is that although dementia is associated with the exposure (GBA status) and the outcome (death), it may be on the causal pathway between GBA status and death (which means that it ought not to be considered a confounding factor). I would be interested to see survival presented on two levels (dementia and non-dementia) rather than adjusted analysis....

Ann Neurol. 2016 Sep 15. doi: 10.1002/ana.24777. [Epub ahead of print]
Cilia R, Tunesi S, Marotta G, Cereda E, Siri PsyD C, Tesei S, Zecchinelli A, Canesi M, Mariani CB, Meucci N, Sacilotto G, Zini M, Barichella M, Magnani C, Duga S, Asselta R, Soldà G, Seresini A, Seia M, Pezzoli G, Goldwurm S.


Abstract

Objective To investigate survival, dementia and genotype-phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the Glucocerebrosidase gene (GBA). Methods We included 2764 unrelated consecutive PD patients: 123 GBA-carriers (67 mild-p.N370S, 56 severe mainly p.L444P) and 2641 non-carriers. Brain perfusion and dopamine transporter imaging was analyzed, including Dementia with Lewy Bodies (DLB) as additional control group. Results Multivariable analysis adjusted by gender, age at onset and disease duration attributed to GBA-carriers a greater risk for dementia (HR=3.16, p<0.001) and death (HR=1.85, p=0.002) than non-carriers. When dementia was introduced in the model as time-dependent covariate, the mortality risk remained greater in carriers (HR=1.65, p=0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination GBA-carriers had worse motor symptoms, particularly non-dopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (p<0.001), but similar mortality risk. Consistent with clinical data, GBA-carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD non-carriers. Neuroimaging features of carriers of mild mutations overlapped with PD non-carriers, while carriers of severe mutations were closer to DLB. Interpretation Survival is reduced in GBA-carriers compared to non-carriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by the type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. 

Monday, 19 September 2016

Weight Change Is a Characteristic Non-Motor Symptom in Drug-Naïve Parkinson's Disease Patients with Non-Tremor Dominant Subtype: A Nation-Wide Observational Study

Weight loss has been reported in a variety of studies after a diagnosis of PD has been made... it is interesting to see that here it appears to associated with just the non-tremor dominant (presumably akinetic rigid) type of PD rather than the tremor dominant type... It may be another feature contributing to the real heterogeneity that we see in PD...

PLoS One. 2016 Sep 13;11(9):e0162254. doi: 10.1371/journal.pone.0162254. eCollection 2016.
Mun JK, Youn J, Cho JW, Oh ES, Kim JS, Park S, Jang W, Park JS, Koh SB, Lee JH, Park HK, Kim HJ, Jeon BS, Shin HW, Choi SA, Kim SJ, Choi SM, Park JY, Kim JY, Chung SJ, Lee CS, Ahn TB, Kim WC, Kim HS, Cheon SM, Kim JW, Kim HT, Lee JY, Kim JS, Kim EJ, Kim JM, Lee KS, Kim JS, Kim MJ, Baik JS, Park KJ, Kim HJ, Park MY, Kang JH, Song SK, Kim YD, Yun JY, Lee HW, Song IU, Sohn YH, Lee PH, Park JH, Oh HG, Park KW, Kwon DY.


Abstract

Despite the clinical impact of non-motor symptoms (NMS) in Parkinson's disease (PD), the characteristic NMS in relation to the motor subtypes of PD is not well elucidated. In this study, we enrolled drug-naïve PD patients and compared NMS between PD subtypes. We enrolled 136 drug-naïve, early PD patients and 50 normal controls. All the enrolled PD patients were divided into tremor dominant (TD) and non-tremor dominant (NTD) subtypes. The Non-Motor Symptom Scale and scales for each NMS were completed. We compared NMS and the relationship of NMS with quality of life between normal controls and PD patients, and between the PD subtypes. Comparing with normal controls, PD patients complained of more NMS, especially mood/cognitive symptoms, gastrointestinal symptoms, unexplained pain, weight change, and change in taste or smell. Between the PD subtypes, the NTD subtype showed higher total NMS scale score and sub-score about weight change. Weight change was the characteristic NMS related to NTD subtype even after controlled other variables with logistic regression analysis. Even from the early stage, PD patients suffer from various NMS regardless of dopaminergic medication. Among the various NMS, weight change is the characteristic NMS associated with NTD subtype in PD patients.

Sunday, 18 September 2016

The clinical spectrum and natural history of pure akinesia with gait freezing

PAGF is a syndrome that can be recognised in the clinic and is considered a variant of PSP that tends to progress slowly... however PD and other pathologies have also been recognised at post mortem. As the authors say, defining the phenotype is important because it is often slowly progressive, associated with falls and lacks levodopa response...

J Neurol. 2016 Sep 13. [Epub ahead of print]
Owens E, Josephs KA, Savica R, Hassan A, Klassen B, Bower J, Maraganore D, Matsumoto J, Ahlskog JE.



Gait freezing as a presenting and relatively restricted condition is uncommon but a distinctive disorder. This entity was initially defined as "pure akinesia with gait freezing", and later a neuropathological substrate of progressive supranuclear palsy has been recognized. Limited studies have reported the clinical evolution after presentation, which is important for patient counseling. The objective of this study was to assess the demographic and clinical features, treatment-response, neuroimaging, and evolution of pure akinesia with gait freezing. A retrospective review of patients with this phenotype as previously defined was performed. Patients included had no or minimal limb rigidity and/or bradykinesia and no resting tremor, and all underwent neuroimaging of the brain after onset. Inclusion criteria were met by 30 patients, who were followed up to 21 years after symptom onset. During their course, 28 patients had falls (93 %), 12 patients had dysarthria (40 %), and 13 had handwriting changes (43 %). All patients had progression of their gait disorder over time, but with a variable interval until falls occurred. None of the patients developed vertical gaze palsy or met diagnostic criteria for an alternative parkinsonian disorder. Pure akinesia with gait freezing is a distinctive disorder that can be recognized in the clinic. Despite the previously reported progressive supranuclear palsy-like neuropathology, the clinical course is much less aggressive and disabling than classic Richardson syndrome, although fall risk eventually develops in nearly all patients. Bradykinesia, tremor, and rigidity do not develop, distinguishing pure akinesia with gait freezing from Parkinson's disease and other parkinsonian disorders.

Caffeine consumption and the 4-year progression of de novo Parkinson's disease

This is really interesting and there has been plenty about the relationship between caffeine and PD in the past... here the authors suggest that coffee drinkers have slower progression of a range of PD symptoms... whether this represents an effect on the underlying disease or improved symptom control remains to be seen...

Parkinsonism Relat Disord. 2016 Aug 4. pii: S1353-8020(16)30289-9. doi: 10.1016/j.parkreldis.2016.08.005. [Epub ahead of print]
Moccia M, Erro R, Picillo M, Vitale C, Longo K, Amboni M, Pellecchia MT, Barone P.


INTRODUCTION:
Higher caffeine consumption has been associated with reduced risk of Parkinson's disease (PD), and with a more benign progression of motor and non-motor symptoms (NMS). The present observational cohort study investigated motor and non-motor correlates of caffeine consumption in de novo PD.

METHODS:
79 newly diagnosed, drug naïve PD patients have been included and followed up for 4 years. The total caffeine use was calculated with the Caffeine Consumption Questionnaire. Following study variables were recorded at baseline, and after 2 and 4 years: UPDRS part III, UPDRS part IV, l-dopa Equivalent Daily Dose (LEDD), NMS Questionnaire (NMSQuest), and the time occurring from PD diagnosis to the need for l-dopa treatment. Age, gender and disease duration were included as covariates in the statistical models.

RESULTS:
The average daily caffeine consumption was 296.1 ± 157.2 mg. At Cox regression models, higher caffeine consumption was associated with a lower rate of starting l-Dopa treatment (HR = 0.630; 95%CI = 0.382-0.996). At the mixed-effects linear regression models considering the whole study period, each additional espresso cup per day (50 mg of caffeine) was more likely associated with 5-point lower UPDRS part III total score (Coef = -0.01; 95%CI = -0.02 to 0.00), with 50% reduced LEDD (Coef = -0.01; 95%CI = -0.15 to 0.00; p = 0.021), and with 5-point lower NMSQuest total score (Coef = -0.01; 95%CI = -0.01 to 0.00), but not with UPDRS part IV total score (Coef = -0.00; 95%CI = -0.00 to 0.00).

CONCLUSION:

Caffeine consumption was associated with a reduced accrual of motor and non-motor disability during 4-year follow-up in de novo PD, highlighting the rationale for using adenosine A2A antagonists since the early phases of PD.

The BRAIN test: a keyboard-tapping test to assess disability and clinical features of multiple sclerosis

Okay. Not strictly Parkinson's research but the BRAIN tap test comes from the PREDICT-PD team. Here we show that the BRAIN test can be u...