Thursday, 30 April 2015

Impact of Parkinson's disease risk loci on age at onset

Interesting results... the idea of using single and composite genetic risk markers is building....

Mov Disord. 2015 Apr 25. doi: 10.1002/mds.26237. [Epub ahead of print]
Lill CM, Hansen J, Olsen JH, Binder H, Ritz B, Bertram L.

BACKGROUND:
The aim of this study was to assess whether recently identified Parkinson's disease (PD) risk genes also influence age at onset in PD.

METHODS:
We genotyped 23 single-nucleotide polymorphisms in 1,526 Danish PD patients and performed linear regression analyses with age at onset. The combined impact of PD risk loci on age at onset was assessed by linear regression analyses using a weighted genetic risk score.

RESULTS:
The strongest effects were observed with rs12726330 in GBA (beta = -3.63, P = 2.0 × 10-5 ) and rs34311866 in TMEM175/GAK (beta = -1.19, P = 4.0 × 10-3 ), corresponding to a 3.6-y and 1.2-y decrease of age at onset per risk allele, respectively. The weighted genetic risk score yielded significant association with reduced onset age (P = 3.98 × 10-3 ), although the variance explained was small (0.6%), and the effect was mostly driven by polymorphisms in GBA and TMEM175/GAK.

CONCLUSIONS:

Overall, our study indicates that GBA and TMEM175/GAK significantly alter age at onset in PD

Monday, 27 April 2015

Parkinson's disease

New seminar on PD in the Lancet...

Lancet. 2015 Apr 17. pii: S0140-6736(14)61393-3. doi: 10.1016/S0140-6736(14)61393-3. [Epub ahead of print]
Kalia LV, Lang AE.


Parkinson's disease is a neurological disorder with evolving layers of complexity. It has long been characterised by the classical motor features of parkinsonism associated with Lewy bodies and loss of dopaminergic neurons in the substantia nigra. However, the symptomatology of Parkinson's disease is now recognised as heterogeneous, with clinically significant non-motor features. Similarly, its pathology involves extensive regions of the nervous system, various neurotransmitters, and protein aggregates other than just Lewy bodies. The cause of Parkinson's disease remains unknown, but risk of developing Parkinson's disease is no longer viewed as primarily due to environmental factors. Instead, Parkinson's disease seems to result from a complicated interplay of genetic and environmental factors affecting numerous fundamental cellular processes. The complexity of Parkinson's disease is accompanied by clinical challenges, including an inability to make a definitive diagnosis at the earliest stages of the disease and difficulties in the management of symptoms at later stages. Furthermore, there are no treatments that slow the neurodegenerative process. In this Seminar, we review these complexities and challenges of Parkinson's disease.

Longitudinal assessment of probable rapid eye movement sleep behaviour disorder in Parkinson's disease

One needs to be a little bit cautious with this questionnaire, which suggests pRBD in up to 15% of healthy controls too...nonetheless the prevalence in this study of PD subjects does appear in line with what other studies have reported recently - cross sectional prevalence of about 30%...remember RBD can only really be diagnosed using polysomnography...

Eur J Neurol. 2015 Apr 22. doi: 10.1111/ene.12723. [Epub ahead of print]
Bjørnarå KA, Dietrichs E, Toft M.

BACKGROUND AND PURPOSE:
Rapid eye movement (REM) sleep behaviour disorder (RBD) is frequently present in patients with Parkinson's disease (PD) and may have prognostic implications. There are few longitudinal studies of RBD in patients with PD. Our aim was to investigate whether RBD was a persistent feature in a follow-up study of 107 patients with PD.

METHODS:
After a mean follow-up time of 3 years, 96 patients were available for reassessment. Probable RBD (pRBD) was diagnosed by the REM sleep behaviour disorder screening questionnaire.

RESULTS:
At follow-up, pRBD was found in 49% of the patients, versus 38% at baseline. The pRBD status remained unchanged in three-quarters of the patients, whilst 17% had new pRBD symptoms. Disease duration was longer in the pRBD group, 9.4 vs. 7.6 years (P = 0.02).

CONCLUSIONS:

Probable RBD is a persistent feature in PD and probably increases over time.

Sunday, 26 April 2015

Variants associated with Gaucher disease in multiple system atrophy

The mutation rates perhaps appear low amongst controls but there appears to be a consistent difference between them and cases... does this implicate GBA in another synuclein-related disease...?

Ann Clin Transl Neurol. 2015 Apr;2(4):417-26. doi: 10.1002/acn3.185. Epub 2015 Feb 28.
Mitsui J, Matsukawa T, Sasaki H, Yabe I, Matsushima M, Dürr A, Brice A, Takashima H, Kikuchi A, Aoki M, Ishiura H, Yasuda T, Date H, Ahsan B, Iwata A, Goto J, Ichikawa Y, Nakahara Y, Momose Y, Takahashi Y, Hara K, Kakita A, Yamada M, Takahashi H, Onodera O, Nishizawa M, Watanabe H, Ito M, Sobue G, Ishikawa K, Mizusawa H, Kanai K, Hattori T, Kuwabara S, Arai K, Koyano S, Kuroiwa Y, Hasegawa K, Yuasa T, Yasui K, Nakashima K, Ito H, Izumi Y, Kaji R, Kato T, Kusunoki S, Osaki Y, Horiuchi M, Kondo T, Murayama S, Hattori N, Yamamoto M, Murata M, Satake W, Toda T, Filla A, Klockgether T, Wüllner U, Nicholson G, Gilman S, Tanner CM, Kukull WA, Stern MB, Lee VM, Trojanowski JQ, Masliah E, Low PA, Sandroni P, Ozelius LJ, Foroud T, Tsuji S.

OBJECTIVE:
Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series.

METHODS:
We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants.

RESULTS:
In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)).

INTERPRETATION:

The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

Friday, 24 April 2015

The MC1R melanoma risk variant p.R160W is associated with Parkinson disease

This must have slipped under my radar earlier in the year but it shows a possible association for melanoma and PD via a common variant. After correcting for multiple comparisons the p-value falls just short of statistical significance... but there is some evidence for association. The epidemiological literature supports an association between melanoma and PD after diagnosis, but not melanoma occurring before PD diagnosis...

Ann Neurol. 2015 May;77(5):889-94. doi: 10.1002/ana.24373. Epub 2015 Mar 13.
Tell-Marti G, Puig-Butille JA, Potrony M, Badenas C, Milà M, Malvehy J, Martí MJ, Ezquerra M, Fernández-Santiago R, Puig S.


Epidemiological studies have reported the co-occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratio = 2.10, gender- and age-adjusted p = 0.009, Bonferroni-corrected p = 0.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population.

An example of melanoma
(image from wikipedia.com)

Wednesday, 22 April 2015

Promising cannabinoid-based therapies for Parkinson's disease: motor symptoms to neuroprotection

Mol Neurodegener. 2015 Apr 8;10(1):17. [Epub ahead of print]
More SV, Choi DK.


Parkinson's disease (PD) is a slow insidious neurological disorder characterized by a loss of dopaminergic neurons in the midbrain. Although several recent preclinical advances have proposed to treat PD, there is hardly any clinically proved new therapeutic for its cure. Increasing evidence suggests a prominent modulatory function of the cannabinoid signaling system in the basal ganglia. Hence, use of cannabinoids as a new therapeutic target has been recommended as a promising therapy for PD. The elements of the endocannabinoid system are highly expressed in the neural circuit of basal ganglia wherein they bidirectionally interact with dopaminergic, glutamatergic, and GABAergic signaling systems. As the cannabinoid signaling system undergoes a biphasic pattern of change during progression of PD, it explains the motor inhibition typically observed in patients with PD. Cannabinoid agonists such as WIN-55,212-2 have been demonstrated experimentally as neuroprotective agents in PD, with respect to their ability to suppress excitotoxicity, glial activation, and oxidative injury that causes degeneration of dopaminergic neurons. Additional benefits provided by cannabinoid related compounds including CE-178253, oleoylethanolamide, nabilone and HU-210 have been reported to possess efficacy against bradykinesia and levodopa-induced dyskinesia in PD. Despite promising preclinical studies for PD, use of cannabinoids has not been studied extensively at the clinical level. In this review, we reassess the existing evidence suggesting involvement of the endocannabinoid system in the cause, symptomatology, and treatment of PD. We will try to identify future threads of research that will help in the understanding of the potential therapeutic benefits of the cannabinoid system for treating PD.

Tuesday, 21 April 2015

A clip from my interview with Channel 5 news on Monday 20th helping to raise awareness about Parkinson's disease



Half of people with Parkinsons in the UK have experienced hostility from the public, a quarter have had their symptoms mistaken for being drunk. Dr Alastair Noyce from Parkinson's UK spoke to us earlier about the damage this can cause.
Posted by Channel 5 News on Monday, 20 April 2015

Sunday, 19 April 2015

Clinical associations between gout and multiple sclerosis, Parkinson's disease and motor neuron disease: record-linkage studies

Not convinced by these results which go against almost every other study looking at a relationship between urate and Parkinson's...multiple lines of evidence converge to suggest the elevated serum urate may be protective against PD and this is a focus for therapeutic intervention...

BMC Neurol. 2015 Feb 28;15(1):16.
Pakpoor J, Seminog OO, Ramagopalan SV, Goldacre MJ.

BACKGROUND:
Uric acid has antioxidant effects on neurons. Abnormally high levels of uric acid are, however, associated with gout. Previous studies have suggested that high levels of uric acid (and the presence of gout) may exert a protective effect against the risk of developing some neurological diseases. We aimed to investigate this hypothesis in a large database of hospital admissions in England.

METHODS:
We analysed a database of linked statistical records of hospital admissions and death registrations in England (1999-2012). A cohort of people with gout was constructed and followed for development of multiple sclerosis (MS), Parkinson's disease (PD) or motor neuron disease (MND). Then, conversely, cohorts of all people in the database with MS, PD or MND were constructed and followed for subsequent gout. Rate ratios (RRs) were determined, comparing these cohorts with people in a reference cohort.

RESULTS:
In the gout cohort, we observed a modest elevation of the overall risk of subsequent MS, PD and MND (respectively, RR = 1.27 (95% confidence interval 1.03-1.55), 1.11 (1.05-1.17) and 1.28 (1.11-1.48) which was largely attributable to an increased risk observed in the early years after hospitalisation for gout. The increased risk of neurological disease did not remain after 5 years. In the cohorts of people with MS or PD, there was a significantly reduced risk of subsequent gout admission (RR = 0.79 (0.69-0.89) and 0.83 (0.79-0.87), respectively). This inverse association was sustained over time. There was also a reduced risk of MND following gout which only emerged more than five years following initial gout admission (RR at 5+ years 0.35 (0.15-0.68)).

CONCLUSIONS:

This study investigated the epidemiological evidence for a protective role of high serum concentration of uric acid, for which we used gout as a proxy, in the aetiology of MS, PD or MND. Our observations do not support this hypothesis. However, when the order was reversed, and we retrospectively followed up patients with MS, PD and MND for a number of years, we found a statistically significant deficit of gout. This suggests that there is relationship between some aspects of these neurodegenerative diseases and metabolism of uric acid.

Saturday, 18 April 2015

Parkinson’s disease dementia: a neural networks perspective

Great review from colleagues at the Institute of Neurology. This is treated as a somewhat taboo subject, with patients and relatives often unaware of the possibility (perhaps even probability) of PD dementia with long-term disease. One issue is the lack of really good treatments for it, which perhaps means that people don't want to discuss it. This review discusses some of the reasons why treatment is currently sub-optimal but suggests positive routes forward including novel targets for deep brain stimulation... the trials are already underway!

James Gratwicke , Marjan Jahanshahi , Thomas Foltynie
Brain 2015 First published online: 17 April 2015
DOI: http://dx.doi.org/10.1093/brain/awv104 

In the long-term, with progression of the illness, Parkinson’s disease dementia affects up to 90% of patients with Parkinson’s disease. With increasing life expectancy in western countries, Parkinson’s disease dementia is set to become even more prevalent in the future. However, current treatments only give modest symptomatic benefit at best. New treatments are slow in development because unlike the pathological processes underlying the motor deficits of Parkinson’s disease, the neural mechanisms underlying the dementing process and its associated cognitive deficits are still poorly understood. Recent insights from neuroscience research have begun to unravel the heterogeneous involvement of several distinct neural networks underlying the cognitive deficits in Parkinson’s disease dementia, and their modulation by both dopaminergic and non-dopaminergic transmitter systems in the brain. In this review we collate emerging evidence regarding these distinct brain networks to give a novel perspective on the pathological mechanisms underlying Parkinson’s disease dementia, and discuss how this may offer new therapeutic opportunities.

Region of the Nucleus Basalis of Maynert - a target for DBS
(picture from wikipedia.com) 

Friday, 17 April 2015

Pain in multiple system atrophy and progressive supranuclear palsy compared to Parkinson's disease

Interesting results on a topic that is not well-researched or understood...not surprising to see correlations with mood disorders, as these can often heighten sensitivity to pain...

Brain Behav. 2015 Mar 25:e00320. [Epub ahead of print]
Kass-Iliyya L, Kobylecki C, McDonald KR, Gerhard A, Silverdale MA.

BACKGROUND:
Pain is a common nonmotor symptom in Parkinson's disease (PD). The pathophysiology of pain in PD is not well understood. Pain characteristics have rarely been studied in atypical parkinsonian disorders such as Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP).

AIM OF THE STUDY:
We aimed to evaluate pain intensity, location, and associated symptoms in atypical parkinsonian disorders compared to PD.

METHODS:
Twenty-one patients with MSA, 16 patients with PSP, and 65 patients with PD were screened for pain using question 1.9 of the MDS-UPDRS. Pain intensity was quantified using the short form McGill Pain Questionnaire (SFMPQ). Pain locations were documented. Motor disability was measured using UPDRS-III. Affective symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS).

RESULTS:
Pain was significantly more common and more severe in PD and MSA compared to PSP (< 0.01). Pain locations were similar with limb pain being the most common followed by neck and back pain. Pain intensity correlated with HADS scores but not motor severity.

CONCLUSIONS:

Pain is more common and more intense in PD and MSA than PSP. Differences in distribution of neurodegenerative pathologies may underlie these differential pain profiles.

Thursday, 16 April 2015

Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Disease

Timely synthesis of data associating REM sleep behaviour disorder with PD and related disorders...there seems little doubt that it is a precursor stage to neurodegenerative disease...but it's the variety of synuclein-based diseases it produces that is also interesting...do we confine these disorders to silos when in fact they ought to be viewed more expansively or is there a greater danger in lumping these disorders all together...?

JAMA Neurol. 2015 Apr 13. doi: 10.1001/jamaneurol.2014.4563. [Epub ahead of print]
Howell MJ, Schenck CH.

IMPORTANCE:
The dream enactment of rapid eye movement sleep behavior disorder (RBD) is often the first indication of an impending α-synuclein disorder, such as Parkinson disease, multiple-system atrophy, or dementia with Lewy bodies.

OBJECTIVE:
To provide an overview of RBD from the onset of dream enactment through the emergence of a parkinsonian disorder.

EVIDENCE REVIEW:
Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized trials, and basic science investigations, were identified in a PubMed search of articles on RBD from January 1, 1986, through July 31, 2014.

FINDINGS:
Under normal conditions, vivid dream mentation combined with skeletal muscle paralysis characterizes rapid eye movement sleep. In RBD, α-synuclein abnormalities in the brainstem disinhibit rapid eye movement sleep motor activity, leading to dream enactment. The behaviors of RBD are often theatrical, with complexity, aggression, and violence; fighting and fleeing actions can be injurious to patients as well as bed partners. Rapid eye movement sleep behavior disorder is distinguished from other parasomnias by clinical features and the demonstration of rapid eye movement sleep without atonia on polysomnography. Consistent with early neurodegeneration, patients with RBD demonstrate subtle motor, cognitive, and autonomic impairments. Approximately 50% of patients with spontaneous RBD will convert to a parkinsonian disorder within a decade. Ultimately, nearly all (81%-90%) patients with RBD develop a neurodegenerative disorder. Among patients with Parkinson disease, RBD predicts a non-tremor-predominant subtype, gait freezing, and an aggressive clinical course. The most commonly cited RBD treatments include low-dose clonazepam or high-dose melatonin taken orally at bedtime.

CONCLUSIONS AND RELEVANCE:

Treatment of RBD can prevent injury to patients and bed partners. Because RBD is a prodromal syndrome of Parkinson disease (or related disorder), it represents a unique opportunity for developing and testing disease-modifying therapies.

Wednesday, 15 April 2015

Neurofilament light chain level in cerebrospinal fluid can differentiate Parkinson's disease from atypical parkinsonism: Evidence from a meta-analysis

Neurofilament light chain (NFL) has been demonstrated to be a biomarker for a range of neurological conditions. As such it is quite sensitive but not specific to any particular one. Interesting to see the standardised mean differences here between NFL in CSF of PD and atypical Parkinson's... I suspect a combination of CSF markers might prove more useful...

CSF being collected after lumbar puncture
(Image from aid4disabled.com)


J Neurol Sci. 2015 Apr 7. pii: S0022-510X(15)00188-4. doi: 10.1016/j.jns.2015.03.041. [Epub ahead of print]
Sako W, Murakami N, Izumi Y, Kaji R.


A reliable test that facilitates the accurate diagnosis of Parkinson's and disorders will help with both, clinical management and therapeutic research. In this context, neurofilament light chain (NFL) is candidate for a biomarker in cerebrospinal fluid (CSF). A comprehensive literature search yielded 4 eligible studies. We expressed between-group difference of NFL concentration in CSF as the standardized mean difference. Four studies involved 166 Parkinson's disease (PD), 116 multiple system atrophy (MSA) and 73 progressive supranuclear palsy (PSP) patients. Patients with MSA showed higher concentration of NFL concentration in CSF than those with PD (standardized mean difference=1.60, P<0.0001). These studies were homogeneous (P=0.17). NFL in CSF in PSP was significantly elevated relative to PD with homogeneous studies (standardized mean difference=2.04, P<0.0001; P=0.99). The present meta-analysis suggested that NFL concentration in CSF in MSA and PSP was significantly increased relative to PD, and that this could help us to separate PD from atypical parkinsonian syndromes.

Tuesday, 14 April 2015

The association between the C282Y and H63D polymorphisms of HFE gene and the risk of Parkinson's disease: A meta-analysis

Iron is an important factor in a number of neurodegenerative diseases including the rare NBIA (neurodegeneration with brain iron accumulation) disorders. In recent years, a potential role for iron in Parkinson's has emerged and even prompted clinical trials of drugs that alter body iron levels. Here are data suggesting a certain gene variant, important in iron handling, appears to protect against Parkinson's...

Iron (source Wikipedia)


Neurosci Lett. 2015 Apr 8. pii: S0304-3940(15)00283-9. doi: 10.1016/j.neulet.2015.04.010. [Epub ahead of print]
Xia J, Xu H, Jiang H, Xie J.


Impaired brain iron homeostasis has been considered as an important mechanism in Parkinson's diseases (PD). There are indications that C282Y and H63D polymorphisms of HFE genes involved in iron metabolism might contribute to the pathogenesis of PD in some cases. However, the investigation of the relationship between PD and the two polymorphisms had produced contradictory results. We performed a meta-analysis to assess the C282Y and H63D polymorphisms of HFE in PD susceptibility. PubMed, EMBASE and Web of Science were systematically searched to identify relevant researches. The strict selection criteria and exclusion standard were applied. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A fixed-effect or random-effect model was selected, depending on the results of the heterogeneity test. Fifteen studies were included in the meta-analysis (eight studies with 1,631 cases and 4,548 controls for C282Y; seven studies with 1,192 cases and 4,065 controls for H63D). For the C282Y polymorphism, significant associations were observed in the Recessive model (YY vs CY+CC: OR=0.22, 95% CI=0.09-0.57, P=0.002). This indicated that the C282Y polymorphism in HFE might be a potential protective factor for PD. However, no significant associations were found for any genetic model for the H63D polymorphism, suggesting that the H63D polymorphism might not be associated with PD.

Monday, 13 April 2015

Quantification of Diabetes Comorbidity Risks across Life Using Nation-Wide Big Claims Data.

Big data...supports association between diabetes and PD, but also other comorbidities of interest: depression and schizophrenia...

PLoS Comput Biol. 2015 Apr 9;11(4):e1004125. doi: 10.1371/journal.pcbi.1004125. eCollection 2015.
Klimek P, Kautzky-Willer A, Chmiel A, Schiller-Frühwirth I, Thurner S.


Despite substantial progress in the study of diabetes, important questions remain about its comorbidities and clinical heterogeneity. To explore these issues, we develop a framework allowing for the first time to quantify nation-wide risks and their age- and sex-dependence for each diabetic comorbidity, and whether the association may be consequential or causal, in a sample of almost two million patients. This study is equivalent to nearly 40,000 single clinical measurements. We confirm the highly controversial relation of increased risk for Parkinson's disease in diabetics, using a 10 times larger cohort than previous studies on this relation. Detection of type 1 diabetes leads detection of depressions, whereas there is a strong comorbidity relation between type 2 diabetes and schizophrenia, suggesting similar pathogenic or medication-related mechanisms. We find significant sex differences in the progression of, for instance, sleep disorders and congestive heart failure in diabetic patients. Hypertension is a highly sex-sensitive comorbidity with females being at lower risk during fertile age, but at higher risk otherwise. These results may be useful to improve screening practices in the general population. Clinical management of diabetes must address age- and sex-dependence of multiple comorbid conditions.

Sunday, 12 April 2015

Minimal change multiple system atrophy: An aggressive variant?

Not PD, but great work nonetheless from my colleague Helen who has done so much towards unravelling clinico-pathological aspects of atypical Parkinson's disorders such as MSA, CBS and PSP. Understanding more about PD and atypical Parkinson's ultimately requires more patients to commit to brain donation...it is not a pleasant topic I know, but it does move understanding further forwards and the Queen Square Brain Bank has been instrumental in these advances...

Mov Disord. 2015 Apr 8. doi: 10.1002/mds.26220. [Epub ahead of print]
Ling H, Asi YT, Petrovic IN, Ahmed Z, Prashanth LK, Hazrati LN, Nishizawa M, Ozawa T, Lang A, Lees AJ, Revesz T, Holton JL.


Glial cytoplasmic inclusions containing α-synuclein are the pathological hallmark of multiple system atrophy (MSA). Minimal change (MC-MSA) is an unusual MSA subtype with neuronal loss largely restricted to the substantia nigra and locus coeruleus. Immunohistochemistry on selected brain regions and semiquantitative assessment were performed on six MC-MSA and eight MSA control cases. More neuronal cytoplasmic inclusions were seen in the caudate and substantia nigra in MC-MSA than in MSA controls (P = 0.002), without any statistical difference in glial cytoplasmic inclusion load in any region. Severe glial cytoplasmic inclusion load was found in the ventrolateral medulla (P = 1.0) and nucleus raphe obscurus (P = 0.4) in both groups. When compared with MSA controls, the three MC-MSA cases who had died of sudden unexpected death had an earlier age of onset (mean: 38 vs. 57.6 y, P = 0.02), a numerically shorter disease duration (mean: 5.3 vs. 8 y, P = 0.2) and a more rapid clinical progression with most of the clinical milestones reached within 3 y of presentation, suggesting an aggressive variant of MSA. Another three MC-MSA cases, who had died of unrelated concurrent diseases, had an age of onset (mean: 57.7 y) and temporal course similar to controls, had less severe neuronal loss and gliosis in the medial and dorsolateral substantia nigra subregions (P < 0.05) than in MSA controls, and could be considered as a unique group with interrupted pathological progression. Significant respiratory dysfunction and early orthostatic hypotension were observed in all MC-MSA cases. Our findings could suggest that α-synuclein-associated oligodendroglial pathology may lead to neuronal dysfunction sufficient to cause clinical symptoms before overt neuronal loss in MSA.


The 'hot cross bun' sign above left is a typical imaging feature in MSA
(Image from physio-pedia.com)

Comparison of the Pharmacokinetics of An Oral Extended-Release Capsule Formulation of Carbidopa-Levodopa (IPX066), with Immediate-Release Carbidopa-Levodopa (Sinemet®), Sustained-Release Carbidopa-Levodopa (Sinemet® CR), and Carbidopa-Levodopa-Entacapone (Stalevo®).

Data from healthy subjects on extended release carbidopa-levodopa (IPX066) - aims to provide better control of motor symptoms and less fluctuations

J Clin Pharmacol. 2015 Apr 8. doi: 10.1002/jcph.514. [Epub ahead of print]
Hsu A, Yao HM, Gupta S, Modi NB.

IPX066 (ER CD-LD) is an oral extended-release capsule formulation of carbidopa (CD) and levodopa (LD). The single-dose pharmacokinetics of ER CD-LD (as 2 capsules, total dose 97.5 mg-390 mg CD-LD) versus immediate-release (IR) CD-LD (25 mg-100 mg), sustained release (CR) CD-LD (25 mg-100 mg), and CD-LD-entacapone (25 mg-100 mg-200 mg) was evaluated in healthy subjects. Following IR dosing, LD reached peak concentrations (Cmax ) at 1 hour; LD concentrations then decreased rapidly and were less than 10% of peak by 5 hours. With CR CD-LD and CD-LD-entacapone, LD Cmax occurred at 1.5 hours and concentrations were less than 10% of peak by 6.3 and 7.5 hours, respectively. The initial increase in LD concentration was similar between ER CD-LD and IR CD-LD, and faster than for CR CD-LD and CD-LD-entacapone. LD concentrations from ER CD-LD were sustained for approximately 5 hours and did not decrease to 10% of peak until 10.1 hours. Dose-normalized LD Cmax values for ER CD-LD were significantly lower (P <0.05) than for the other CD-LD products. Bioavailability of LD from ER CD-LD was 83.5%, 78.3%, and 58.8% relative to IR CD-LD, CR CD-LD, and CD-LD-entacapone, respectively.

Friday, 10 April 2015

Onset of Mild Cognitive Impairment in Parkinson Disease

Small numbers but findings generally in keeping with other studies...


Alzheimer Dis Assoc Disord. 2015 Apr 3. [Epub ahead of print]
Johnson DK, Langford Z, Garnier-Villarreal M, Morris JC, Galvin JE.

OBJECTIVE:
Characterize the onset and timing of cognitive decline in Parkinson disease (PD) from the first recognizable stage of cognitively symptomatic PD-mild cognitive impairment (PD-MCI) to PD dementia (PDD). Thirty-nine participants progressed from PD to PDD and 25 remained cognitively normal.

METHODS:
Bayesian-estimated disease-state models described the onset of an individual's cognitive decline across 12 subtests with a change point.

RESULTS:
Subtests measuring working memory, visuospatial processing ability, and crystalized memory changed significantly 3 to 5 years before their first nonzero Clinical Dementia Rating and progressively worsened from PD to PD-MCI to PDD. Crystalized memory deficits were the hallmark feature of imminent conversion of cognitive status. Episodic memory tasks were not sensitive to onset of PD-MCI. For cognitively intact PD, all 12 subtests showed modest linear decline without evidence of a change point.

CONCLUSIONS:

Longitudinal disease-state models support a prodromal dementia stage (PD-MCI) marked by early declines in working memory and visuospatial processing beginning 5 years before clinical diagnosis of PDD. Cognitive declines in PD affect motor ability (bradykinesia), working memory, and processing speed (bradyphrenia) resulting in PD-MCI where visuospatial imagery and memory retrieval deficits manifest before eventual development of overt dementia. Tests of episodic memory may not be sufficient to detect and quantify cognitive decline in PD.



Clock drawing is used to identify a variety of visuospatial deficits

Thursday, 9 April 2015

The diagnostic accuracy of dopamine transporter SPECT imaging to detect nigrostriatal cell loss in patients with Parkinson's disease or clinically uncertain parkinsonism: a systematic review

DAT SPECT is often useful in the clinic but is not 'bullet proof' by any means... I couldn't access the full article here but the diagnostic accuracy depends on who you are comparing the patients to - if it is healthy unaffected people then accuracy will be high... unfortunately lots of the things that mimic PD also give abnormal DAT SPECT scans...Here the authors are comparing DAT SPECT with pathological findings...

An example of normal and abnormal DAT SPECT scan
Normal - 'inverted comma' appearance, Abnormal - 'full stop' appearance

EJNMMI Res. 2015 Mar 17;5:12. doi: 10.1186/s13550-015-0087-1. eCollection 2015.
Suwijn SR, van Boheemen CJ, de Haan RJ, Tissingh G, Booij J, de Bie RM.


In specialized movement disorder centers, Parkinson's disease (PD) is wrongly diagnosed in 6 to 25% of cases. To improve the accuracy of the clinical diagnosis, it is necessary to have a reliable and practical reference standard. Dopamine transporter single-photon emission computed tomography (DAT SPECT) imaging might have the potential (high diagnostic accuracy and practical to use) to act as reference standard in detecting nigrostriatal cell loss in patients with (early stage) parkinsonism. We performed a systematic review to evaluate if DAT SPECT imaging can be used as such. Relevant studies were searched in the MEDLINE and EMBASE databases. Studies were selected when they met the following criteria: (1) all patients were adults with a clinical diagnosis of PD or clinically uncertain parkinsonism and (2) the study reported original data. In addition, studies needed to fulfill one of the two following criteria: (1) patients underwent at least one DAT SPECT and had a neuropathological confirmed diagnosis and (2) patients underwent at least two DAT SPECT scans, performed at least 2 years apart. The search identified 1,649 articles. Eight studies fulfilled our selection criteria and were included in this review. There was only one study including patients with diagnostic uncertainty. Sensitivity and specificity of DAT SPECT imaging to detect nigrostriatal cell loss were 98%. The other studies included patients with a diagnosis of PD in whom there was no uncertainty. In these studies, sensitivity was 100%. Our systematic review indicates that DAT SPECT imaging seems to be accurate to detect nigrostriatal cell loss in patients with parkinsonism.

Olfactory function in Parkinson's Disease - effects of training

Hard to explain physiologically/pathologically in PD (does this mean that olfaction improves or there is compensation??)...but may have importance and relevance to those of us performing serial smell tests as part of PD risk stratification...incidentally others have talked about olfactory trainin in the past (http://www.fifthsense.org.uk/support/smell-training/ & 




Acta Neurol Scand. 2015 Apr 6. doi: 10.1111/ane.12406. [Epub ahead of print]
Knudsen K, Flensborg Damholdt M, Mouridsen K, Borghammer P.

BACKGROUND:
Up to 90% of patients with Parkinson's disease (PD) exhibit olfactory dysfunction, but little is known about the effects of olfactory training. The study aim was to investigate whether the ability to identify olfactory stimuli can be improved by means of a brief training session. Furthermore, the impact of hyposmia on quality of life in PD was investigated by means of a questionnaire.

METHODS:
Olfactory function was rated in 34 patients with PD and in 26 controls before and after a training session. An additional 20 patients with PD served as a control group and were tested twice without an intervening training session. Long-term effects were evaluated in a small subset of patients. Cognitive tests and DaT SPECT scans were performed.

RESULTS:
We demonstrated significant same-day and long-term training effects in trained PD patients compared with non-trained PD patients. A slightly significant correlation was seen between the training effect and DaT putamen values, but not with cognitive test scores. Furthermore, patients with PD reported that hyposmia significantly decreased their quality of life.

CONCLUSIONS:

Patients with PD improved the number of correctly identified odors in an olfactory test through a brief training session. Olfactory training may have potential in rehabilitation of patients with PD.

Wednesday, 8 April 2015

Calcium channel blocker use and risk of Parkinson's disease: a meta-analysis

Interesting results and negative associations even greater than those we found in our 'meta' a couple of years ago. It seems worthwhile to further explore whether these well characterised and (relatively) harmless drugs can offer neuroprotective benefits in PD...

Pharmacoepidemiol Drug Saf. 2015 Apr 2. doi: 10.1002/pds.3781. [Epub ahead of print]
Lang Y, Gong D, Fan Y.

PURPOSES:
Whether calcium channel blocker (CCB) use contributes to a low risk of developing a first time diagnosis of Parkinson's disease (PD) remains controversial. We conducted a meta-analysis to investigate the relationship between CCB use and PD risk.

METHODS:
Pubmed, EMBASE, China National Knowledge Infrastructure, and WanFang databases were searched for papers through May 2014. Studies investigating the association between CCB use and the risk of first time diagnosis of PD were included. Pooled adjusted risk ratio (RR) and 95% confidence interval (CI) were calculated using a fixed-effect model.

RESULTS:
Five studies involving 208 248 CCB users were identified. Overall, CCB use was associated with a reduction in PD risk (RR = 0.76, 95%CI = 0.68-0.84) compared with the controls. Subgroup analysis showed that dihydropyridine CCB use reduced by 27% PD risk (RR = 0.73, 95%CI = 0.64-0.83) and non-dihydropyridine CCB use reduced by 30% PD risk (RR = 0.70, 95%CI = 0.50-0.93).

CONCLUSIONS:

Overall, CCB use as a class is associated with a reduction in PD risk. Both of dihydropyridine and non-dihydropyridine CCB use appear to reduce the risk of developing a first time diagnosis of PD. More well-designed prospective studies are needed to investigate the difference of the subtype of CCB user on PD risk.

Post-mortem Assessment of the Short and Long-Term Effects of the Trophic Factor Neurturin in Patients with α-Synucleinopathies

Interesting new post-mortem data on patients treated with neurotrophic factors... of course it is so hard to obtain information on the effect of these agents other than traditional clinical methods during life...

Neurobiol Dis. 2015 Apr 1. pii: S0969-9961(15)00095-9. doi: 10.1016/j.nbd.2015.03.023. [Epub ahead of print]
Bartus RT, Kordower JH, Johnson EM Jr, Brown L, Kruegel BR, Chu Y, Baumann TL, Lang AE, Olanow CW, Herzog CD.


Abstract

Substantial interest persists for developing neurotrophic factors to treat neurodegenerative diseases. At the same time, significant progress has been made in implementing gene therapy as a means to provide long-term expression of bioactive neurotrophic factors to targeted sites in the brain. Nonetheless, to date, no double-blind clinical trial has achieved positive results on its primary endpoint despite robust benefits achieved in animal models. A major issue with advancing the field is the paucity of information regarding the expression and effects of neurotrophic factors in human neurodegenerative brain, relative to the well-characterized responses in animal models. To help fill this information void, we examined post-mortem brain tissue from four patients with nigrostriatal degeneration who had participated in clinical trials testing gene delivery of neurturin to the putamen of patients. Each had died of unrelated causes ranging from 1.5-to-3-months (2 Parkinson's disease patients), to 4+-years (1 Parkinson's disease and 1 multiple-system atrophy-parkinsonian type patient) following gene therapy. Quantitative and immunohistochemical evaluation of neurturin, alpha-synuclein, tyrosine hydroxylase (TH) and an oligodendroglia marker (Olig 2) were performed in each brain. Comparable volumes-of-expression of neurturin were seen in the putamen in all cases (~15-22%; mean=18.5%). TH-signal in the putamen was extremely sparse in the shorter-term cases. A 6-fold increase was seen in longer-term cases, but was far less than achieved in animal models of nigrostriatal degeneration with similar or even far less NRTN exposure. Less than 1% of substantia nigra (SN) neurons stained for neurturin in the shorter-term cases. A 15-fold increase was seen in the longer-term cases, but neurturin was still only detected in ~5% of nigral cells. These data provide unique insight into the functional status of advanced, chronic nigrostriatal degeneration in human brain and the response of these neurons to neurotrophic factor stimulation. They demonstrate mild but persistent expression of gene-mediated neurturin over 4-years, with an apparent, time-related amplification of its transport and biological effects, albeit quite weak, and provide unique information to help plan and design future trials.

Tuesday, 7 April 2015

Cognitive and behavioral symptoms in Parkinson's disease patients with the G2019S and R1441G mutations of the LRRK2 gene

Interesting results - in keeping with previous studies and what one expects from the clinic. These distinctions are important for understanding how LRRK2-related PD differs from iPD. Now it is important to marry such observations up with imaging and pathological data...

Parkinsonism Relat Disord. 2015 Mar 2. pii: S1353-8020(15)00074-7. doi: 10.1016/j.parkreldis.2015.02.019. [Epub ahead of print]


Somme JH, Molano Salazar A, Gonzalez A, Tijero B, Berganzo K, Lezcano E, Fernandez Martinez M, Zarranz JJ, Gómez-Esteban JC.

OBJECTIVE:
To compare the cognitive and psychiatric status of patients with Parkinson's disease related to the G2019S and the R1441G mutations of the LRRK2 gene (LRRK2-PD) and idiopathic Parkinson's disease (iPD) patients.

METHODS:
We examined cognition and psychiatric symptoms in 27 patients with LRRK2-PD (12 G2019S and 15 R1441G) and 27 iPD patients.

RESULTS:
The groups were similar in age, education, disease duration, levodopa equivalent daily dose, and Unified Parkinson's Disease Rating Scale (UPDRS) II-IV; however, the LRRK2-PD showed less impairment on UPDRS-I (2.0 ± 1.7 vs. 4.2 ± 2.8, p = 0.003). The LRRK2-PD presented less frequent subjective cognitive complaints (18.5% vs. 63.0%, p = 0.002), and mild cognitive impairment or dementia (25.9% vs. 59.2%, p = 0.027). They also showed less impairment on scales for general cognition (Mattis dementia rating scale 131.2 ± 10.9 vs. 119 ± 24.0, p = 0.022), episodic verbal memory (Rey's auditory verbal learning test, immediate recall 39.2 ± 9.5 vs. 27.6 ± 12.8 p < 0.001, delayed recall 7.2 ± 3.7 vs. 4.7 ± 4.0 p = 0.022), and the Neuropsychiatric Inventory (9.7 ± 9.2 vs. 20.5 ± 14.3, p = 0.004, significant differences for apathy and hallucinations). The LRRK2-PD subjects were less frequently treated with antipsychotic medication (0% vs. 25.9%, p = 0.010). There were no significant differences between G2019S and R1441G mutation carriers.

CONCLUSIONS:

Mutations of the LRRK2 gene might cause PD associated with less cognitive and neuropsychiatric impairment as compared to iPD.

Monday, 6 April 2015

Inhibitors of Leucine-Rich Repeat Kinase 2 (LRRK2): Progress and Promise for the Treatment of Parkinson's Disease

Curr Top Med Chem. 2015;15(10):927-38.
Gilligan PJ.


Mutations in the gene for leucine-rich repeat kinase 2 (LRRK2) have been linked to several familial and sporadic late-onset cases of Parkinson's disease. The cumulative data for the effects of mutant forms of this enzyme on neuronal degradation and the pathophysiology of Parkinson's disease create a compelling case for drug discovery based on inhibition of the mutant forms of LRRK2. This review focuses on structure-activity relationships for inhibitors of LRRK2 and the data supporting a potential role of these agents in treating Parkinson's disease.

Sunday, 5 April 2015

Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study

This is an important observation and featured in Prof G's blog earlier today (link here) below. The suggestion made is concerning given the widespread use of these drugs. But although this looks like a good study, in my opinion the jury is still out. 

Well-conducted RCTs are the only real way to demonstrate causation. The methods employed here reduced the likelihood of confounding and reverse causality, but my concern is that reverse causality (in particular) could still be an issue. We don't know how long the prodromes of dementia and Parkinson's are therefore it is tricky to know how many years to exclude from follow up but I would suggest that 1-2 years is too few. This is certainly something that requires further exploration using similar and alternative study designs....



JAMA Intern Med. 2015 Mar 1;175(3):401-7. doi: 10.1001/jamainternmed.2014.7663.
Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB.

IMPORTANCE:
Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a few studies suggest that anticholinergics may be associated with an increased risk for dementia.

OBJECTIVE:
To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia.

DESIGN, SETTING, AND PARTICIPANTS:
Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington. We included 3434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses.

EXPOSURES:
Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was updated as participants were followed up over time.

MAIN OUTCOMES AND MEASURES:
Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities.

RESULTS:
The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia (637 of these [79.9%] developed Alzheimer disease). A 10-year cumulative dose-response relationship was observed for dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1095. A similar pattern of results was noted for Alzheimer disease. Results were robust in secondary, sensitivity, and post hoc analyses.

CONCLUSIONS AND RELEVANCE:

Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.

Motion Sensors to Assess and Monitor Medical and Surgical Management of Parkinson's Disease

And another paper on wearable tech to inform decisions on suitability for DBS... I feel a systematic review on the way!

World Neurosurg. 2015 Mar 27. pii: S1878-8750(15)00291-0. doi: 10.1016/j.wneu.2015.03.024. [Epub ahead of print]
Lieber B, Taylor B, Appelboom G, McKhann G, Connolly ES Jr.

Abstract

Patients with Parkinson's Disease (PD) often suffer from a resting tremor, bradykinesia, rigidity, postural instability and gait difficulty. Determining a patient's candidacy for Deep-Brain Stimulation (DBS) surgery and tracking their clinical response postoperatively requires that the frequency, duration, and severity of these symptoms be characterized in detail. Conventional means of assessing these symptoms, however, rely heavily on patient self-reporting, which often fails to provide the necessary level of detail. Wearable accelerometers are a novel tool that can detect and objectively characterize these movement abnormalities both in the clinical setting as well as in the patient's home environment. In this article, we review the role of accelerometers in surgical candidate selection, recording and predicting falls, recording and predicting freezing of gait, evaluating surgical outcomes, and evaluating postoperative recovery and in altering DBS settings. While accelerometry has yet to make it into the mainstream clinic, there is great promise for this technology in monitoring Parkinson's patients.

Saturday, 4 April 2015

Do physical exercise and reading reduce the risk of Parkinson's disease? a cross-sectional study on factors associated with Parkinson's disease in elderly Chinese veterans.

Difficult to claim 'physical activity and reading' are protective in the context of a cross-sectional study... the absence/deficit of these things could just be representative of the disease...




Neuropsychiatr Dis Treat. 2015 Mar 16;11:695-700. doi: 10.2147/NDT.S79707. eCollection 2015.
Zou YM, Tan JP, Li N, Yang JS, Yu BC, Yu JM, Zhao YM, Wang LN.

BACKGROUND:
The purpose of this study was to investigate risk factors for and factors protecting against Parkinson's disease (PD) in elderly Chinese veterans.

METHODS:
Using a database containing detailed information on the health status of the nervous system in elderly Chinese veterans, univariate and multivariate analyses of factors that may be associated with PD were performed. Univariate analysis of qualitative data was done using the Pearson Chi-square and Fisher's exact tests, and the Mann-Whitney U nonparametric test was used for univariate analysis of quantitative data. Multivariate logistic regression analysis was used to identify independent risk factors for and factors protecting against PD in elderly Chinese veterans.

RESULTS:
A total of 9,676 elderly Chinese veterans were enrolled, including 228 cases with PD and 183 cases with Parkinson's syndrome, with 9,265 non-PD subjects serving as controls. Age (odds ratio [OR] 1.343, 95% confidence interval [CI] 1.028-1.755) and medical history of essential tremor (OR 1.228, 95% CI 1.081-1.396) were identified as independent risk factors for PD, with age being the most important risk factor. Physical exercise (OR 0.478, 95% CI 0.355-0.643) and reading (OR 0.513, 95% CI 0.357-0.735) were identified as independent factors protecting against PD, and physical exercise showed better protection against PD relative to reading. Smoking, alcohol use, anemia, cerebral trauma, education level, and electromagnetic field exposure showed no association with PD.

CONCLUSION:

Physical exercise and reading may be independent factors that protect against PD among elderly Chinese veterans, while advancing age and medical history of essential tremor may be independent risk factors for PD. This study was cross-sectional, so further research is needed to confirm its results.

A Mobile Cloud-Based Parkinson's Disease Assessment System for Home-Based Monitoring

Two smartphone-based monitoring apps in one week! We are going to be spoiled for choice...

JMIR Mhealth Uhealth. 2015 Mar 26;3(1):e29.
Pan D, Dhall R, Lieberman A, Petitti DB.

BACKGROUND:
Parkinson's disease (PD) is the most prevalent movement disorder of the central nervous system, and affects more than 6.3 million people in the world. The characteristic motor features include tremor, bradykinesia, rigidity, and impaired postural stability. Current therapy based on augmentation or replacement of dopamine is designed to improve patients' motor performance but often leads to levodopa-induced adverse effects, such as dyskinesia and motor fluctuation. Clinicians must regularly monitor patients in order to identify these effects and other declines in motor function as soon as possible. Current clinical assessment for Parkinson's is subjective and mostly conducted by brief observations made during patient visits. Changes in patients' motor function between visits are hard to track and clinicians are not able to make the most informed decisions about the course of therapy without frequent visits. Frequent clinic visits increase the physical and economic burden on patients and their families.

OBJECTIVE:
In this project, we sought to design, develop, and evaluate a prototype mobile cloud-based mHealth app, "PD Dr", which collects quantitative and objective information about PD and would enable home-based assessment and monitoring of major PD symptoms.

METHODS:
We designed and developed a mobile app on the Android platform to collect PD-related motion data using the smartphone 3D accelerometer and to send the data to a cloud service for storage, data processing, and PD symptoms severity estimation. To evaluate this system, data from the system were collected from 40 patients with PD and compared with experts' rating on standardized rating scales.

RESULTS:
The evaluation showed that PD Dr could effectively capture important motion features that differentiate PD severity and identify critical symptoms. For hand resting tremor detection, the sensitivity was .77 and accuracy was .82. For gait difficulty detection, the sensitivity was .89 and accuracy was .81. In PD severity estimation, the captured motion features also demonstrated strong correlation with PD severity stage, hand resting tremor severity, and gait difficulty. The system is simple to use, user friendly, and economically affordable.

CONCLUSIONS:

The key contribution of this study was building a mobile PD assessment and monitoring system to extend current PD assessment based in the clinic setting to the home-based environment. The results of this study proved feasibility and a promising future for utilizing mobile technology in PD management.

Friday, 3 April 2015

ABCG2 variant has opposing effects on onset ages of Parkinson's disease and gout

More on urate and PD... all consistent with effects observed thus far

Ann Clin Transl Neurol. 2015 Mar;2(3):302-306. Epub 2015 Jan 19.
Matsuo H, Tomiyama H, Satake W, Chiba T, Onoue H, Kawamura Y, Nakayama A, Shimizu S, Sakiyama M, Funayama M, Nishioka K, Shimizu T, Kaida K, Kamakura K, Toda T, Hattori N, Shinomiya N.

Abstract

Uric acid (urate) has been suggested to play a protective role in Parkinson's disease onset through its antioxidant activity. Dysfunction of ABCG2, a high-capacity urate exporter, is a major cause for early-onset gout based on hyperuricemia. In this study, the effects of a dysfunctional ABCG2 variant (Q141K, rs2231142) were analyzed on the ages at onset of gout patients (N = 507) and Parkinson's disease patients (N = 1015). The Q141K variant hastened the gout onset (= 0.0027), but significantly associated with later Parkinson's disease onset (= 0.025). Our findings will be helpful for development of more effective prevention of Parkinson's disease.

Thursday, 2 April 2015

Association of Parkinson's Disease and Its Subtypes with Agricultural Pesticide Exposures in Men: A Case-Control Study in France

This is a really difficult area to make progress in...like looking at dietary factors and disease. Understanding the association between pesticides and PD is really important...

Environ Health Perspect. 2015 Mar 27. [Epub ahead of print]
Moisan F, Spinosi J, Delabre L, Gourlet V, Mazurie JL, Bénatru I, Goldberg M, Weisskopf MG, Imbernon E, Tzourio C, Elbaz A.

BACKGROUND:
Pesticides have been associated with Parkinson's disease (PD), but there are few data on important exposure characteristics such as dose-effect relations. It is unknown whether associations depend on clinical PD subtypes.

OBJECTIVES:
We examined quantitative aspects of occupational pesticide exposure associated with PD and investigated whether associations were similar across PD subtypes.

METHODS:
As part of a French population-based case-control study including men enrolled in the health insurance plan for farmers and agricultural workers, cases with clinically confirmed PD were identified through antiparkinsonian drug claims. Two controls were matched to each case. Using a comprehensive occupational questionnaire, we computed indicators for different dimensions of exposure (duration, cumulative exposure, intensity). We used conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CI) among exposed male farmers (133 cases, 298 controls). We examined the relation between pesticides and PD subtypes (tremor dominant/non-tremor dominant) using polytomous logistic regression.

RESULTS:
There appeared to be a stronger association with intensity than duration of pesticide exposure based on separate models and a synergistic interaction between duration and intensity (p-interaction = 0.04). High intensity exposure to insecticides was positively associated with PD among those with low intensity exposure to fungicides and vice versa, suggesting independent effects. Pesticide exposure in farms specialized in vineyards was associated with PD (OR = 2.56; 95% CI: 1.31, 4.98). The association with intensity of pesticide use was stronger, although not significantly (p-heterogeneity = 0.60), for tremor dominant (p--trend < 0.01) than for non-tremor dominant PD (p--trend = 0.24).

CONCLUSIONS:

This study helps to better characterize different aspects of pesticide exposure associated with PD, and shows a significant association of pesticides with tremor dominant PD in men, the most typical PD presentation.

Frequency and profile of Parkinson's disease prodromi in patients with malignant melanoma

Nice idea and results are encouraging... hadn't thought of using melanoma as a high risk group and surprised to see significant results given small numbers. The association of PD with melanoma has been the subject of previous meta-analysis http://www.neurology.org/content/76/23/2002.abstract


J Neurol Neurosurg Psychiatry. 2015 Mar 27. pii: jnnp-2014-310239. doi: 10.1136/jnnp-2014-310239. [Epub ahead of print]
Walter U, Heilmann E, Voss J, Riedel K, Zhivov A, Schäd SG, Gross GE, Benecke R, Trcka J.


OBJECTIVE:
The results of register studies suggest an association between Parkinson's disease (PD) and melanoma. We studied the frequency and profile of early markers of PD in patients with malignant melanoma.

METHODS:
100 participants were enrolled in a prospective observational study, of whom 65 had a history of high-risk cutaneous (n=53) or uveal (n=12) melanoma (31 women; age, 61.2±14.9 years) and another 35 served as control participants (19 women; 54.6±20.5 years). Participants underwent assessments of motor function (Unified PD Rating Scale; keyboard tapping test), olfactory function, colour vision, depressive symptoms, the Non-Motor Symptoms Questionnaire, and transcranial brain sonography. Raters were blinded to the diagnosis and clinical data of study participants.

RESULTS:
Patients with melanoma showed increased frequency of substantia nigra hyperechogenicity and prodromal motor and non-motor features of PD, especially asymmetric motor slowing and apathy. Hyposmia and colour vision disturbance were, however, infrequent. Larger echogenicity of substantia nigra correlated with lower serum iron in patients with melanoma, similar to previously reported findings in PD, and independently from the earlier findings, with lighter skin pigmentation. Substantia nigra hyperechogenicity, combined with motor asymmetry or hyposmia, was present at baseline in all participants with mild or definite parkinsonism diagnosed after 1 year. Parkinsonism was specifically related to melanoma location at the sun-exposed skin of the head or neck.

CONCLUSIONS:

History of melanoma was associated with increased prevalence of prodromal markers of PD. Their predictive value needs to be established in long-term investigations. The similarity of serum iron characteristics found in patients with melanoma and PD deserves further research.

Wednesday, 1 April 2015

Parkinson disease and risk of acute myocardial infarction: A population-based, propensity score-matched, longitudinal follow-up study

Surprised by this result and unfortunately cannot access the full article... can only assume that the propensity matching process does something here and the control group has a low proportion of classical vascular risk factors like many PD subjects do... it is not what one would expect having done PD clinics for years... looking forward to the full article.

Am Heart J. 2015 Apr;169(4):508-14. doi: 10.1016/j.ahj.2014.11.018. Epub 2014 Dec 20.
Liang HW, Huang YP, Pan SL.


OBJECTIVES:
Previous studies on the risk of acute myocardial infarction (AMI) in patients with Parkinson disease (PD) have generated inconsistent results. The purpose of this population-based longitudinal follow-up study was to investigate whether incident PD is associated with an increased risk of AMI.

METHODS:
A total of 3,211 subjects with at least 2 ambulatory visits with the principal diagnosis of PD in 2001 were enrolled in the PD group. The non-PD group consisted of 3,211 propensity score-matched subjects without PD. The propensity scores were computed using a logistic regression model that included age, sex, preexisting comorbidities, and socioeconomic status. The 3-year AMI-free survival rates of the 2 groups were estimated using the Kaplan-Meier method. Stratified Cox proportional hazard regression with patients matched by propensity score was used to estimate the effect of PD on subsequent occurrence of AMI.

RESULTS:
During the 3-year follow-up period, 83 subjects in the PD group and 53 in the non-PD group developed AMI (either fatal or nonfatal) events. The hazard ratio of AMI for the PD group compared with the non-PD group was 1.67 (95% CI 1.15-2.41, P = .0067). The AMI-free survival rate of the PD group was significantly lower than that of the non-PD group (P = .0032). The hazard ratios associated with PD for the combined end point 1 (AMI or cardiovascular death) and combined end point 2 (AMI or all-cause death) were 1.46 (95% CI 1.14-1.88, P = .0029) and 1.42 (95% CI 1.24-1.64, P < .0001), respectively.

CONCLUSIONS:

This study shows that PD is related to an increased risk of AMI. Further studies are required to investigate the mechanism underlying this association.