Saturday, 28 February 2015

Heart rate variability and the risk of Parkinson's disease: The Atherosclerosis Risk in Communities (ARIC) Study

Ann Neurol. 2015 Feb 23. doi: 10.1002/ana.24393. [Epub ahead of print]
Alonso A, Huang X, Mosley TH, Heiss G, Chen H.

Objectives: Autonomic dysfunction frequently occurs in the context of Parkinson's disease (PD) and may precede onset of motor symptoms. Limited data exist on the prospective association of heart rate variability (HRV), a marker of autonomic function, with PD risk. Methods: We included 12,162 participants of the Atherosclerosis Risk in Communities (ARIC) study, a community-based cohort, without a diagnosis of PD at baseline (1987-89) and with available HRV data (mean age 54, 57% women). A 2-minute electrocardiogram was used to measure HRV. Incident PD was identified through 2008 from multiple sources, and adjudicated. Multivariable Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of PD by quartiles of HRV measurements. Results: During a mean follow-up of 18 years, we identified 78 incident PD cases. Lower values of the root mean square of successive differences in normal-to-normal R-R intervals (rMSSD) and standard deviation of normal-to-normal R-R intervals (SDNN), markers of parasympathetic activity and total variability respectively, were associated with higher PD risk during follow-up. In multivariable models, the HR (95%CI) of PD in the bottom quartiles of rMSSD and SDNN compared to the top quartiles were 2.1 (1.0-4.3) and 2.9 (1.4-6.1), respectively. Other measures of cardiac autonomic function, including mean RR interval and frequency-domain measurements, were not associated with PD risk. Interpretation: In this prospective cohort, decreased HRV was associated with an increased risk of PD. Assessment of cardiac autonomic function may help identify individuals at risk for PD.

Friday, 27 February 2015

Effects of aging and gender on striatal and extrastriatal [123I]FP-CIT binding in Parkinson's disease

Neurobiol Aging. 2015 Jan 22. pii: S0197-4580(15)00049-4. doi: 10.1016/j.neurobiolaging.2015.01.016. [Epub ahead of print]
Kaasinen V, Joutsa J, Noponen T, Johansson J, Seppänen M.

To investigate the effects of aging and gender on brain dopamine and serotonin transporter bindings, we analyzed [123I]FP-CIT single-photon emission computed tomography scans of 231 Parkinson's disease (PD) patients and 230 controls. An automated region-of-interest-based method (BRASS automated analysis software) was used for striatal regions and a voxel-based method (Statistical Parametric Mapping software, SPM8) for the entire brain. In controls, aging was associated with a decline of 3.6%-4.6% per decade in striatal binding. Multiple extrastriatal regions also showed age-related declines. In PD patients, age-related declines were only observed in the caudate nuclei, thalamus, olfactory, and cingulate cortices with a comparable rate of decline as that in controls. Female subjects had higher caudate nucleus binding compared with males with a similar near-significant difference in the right putamen. The results demonstrate that the aging effect is limited in PD, which is possibly because of disease-related excess variation, and the results do not support the theory of accelerated aging of the dopaminergic system in PD. Women have higher caudate nucleus dopamine transporter binding compared with men in both normal and degenerated dopamine systems.

Thursday, 26 February 2015

Occupational exposures and Parkinson's disease mortality in a prospective Dutch cohort

Occup Environ Med. 2015 Feb 23. pii: oemed-2014-102209. doi: 10.1136/oemed-2014-102209. [Epub ahead of print]
Brouwer M, Koeman T, van den Brandt PA, Kromhout H, Schouten LJ, Peters S, Huss A, Vermeulen R.

We investigated the association between six occupational exposures (ie, pesticides, solvents, metals, diesel motor emissions (DME), extremely low frequency magnetic fields (ELF-MF) and electric shocks) and Parkinson's disease (PD) mortality in a large population-based prospective cohort study.

The Netherlands Cohort Study on diet and cancer enrolled 58 279 men and 62 573 women aged 55-69 years in 1986. Participants were followed up for cause-specific mortality over 17.3 years, until December 2003, resulting in 402 male and 207 female PD deaths. Following a case-cohort design, a subcohort of 5 000 participants was randomly sampled from the complete cohort. Information on occupational history and potential confounders was collected at baseline. Job-exposure matrices were applied to assign occupational exposures. Associations with PD mortality were evaluated using Cox regression.

Among men, elevated HRs were observed for exposure to pesticides (eg, ever high exposed, HR 1.27, 95% CI 0.86 to 1.88) and ever high exposed to ELF-MF (HR 1.54, 95% CI 1.00 to 2.36). No association with exposure duration or trend in cumulative exposure was observed for any of the occupational exposures. Results among women were unstable due to small numbers of high-exposed women.


Associations with PD mortality were observed for occupational exposure to pesticides and ELF-MF. However, the weight given to these findings is limited by the absence of a monotonic trend with either duration or cumulative exposure. No associations were found between PD mortality and occupational exposure to solvents, metals, DME or electric shocks.

β-amyloid and α-synuclein cooperate to block SNARE-dependent vesicle fusion

Biochemistry. 2015 Feb 25. [Epub ahead of print]
Choi BK, Kim JY, Cha MY, Mook-Jung I, Shin YK, Lee NK.

Alzheimer's disease (AD) and Parkinson's disease (PD) are caused by β-amyloid (Aβ) and α-synuclein (αS), respectively. Ample evidence suggests that these two pathogenic proteins are closely linked and have a synergistic effect on eliciting neurodegenerative disorders. However, the pathophysiological consequences of Aβ and αS co-existence are still elusive. Here, we show that large-sized αS oligomers, which are normally difficult to form, are readily generated by Aβ42-seeding and that these oligomers efficiently hamper neuronal SNARE-mediated vesicle fusion. The direct binding of the Aβ-seeded αS oligomers to the N-terminal domain of synaptobrevin-2, a vesicular SNARE protein, is responsible for the inhibition of fusion. In contrast, large-sized Aβ42 oligomers (or aggregates) or the products of αS incubated without Aβ42 have no effect on vesicle fusion. These results are confirmed by examining PC12 cell exocytosis. Our results suggest that Aβ and αS cooperate to escalate the production of toxic oligomers, whose main toxicity is the inhibition of vesicle fusion and consequently prompts synaptic dysfunction.

Monday, 23 February 2015

Multiple system atrophy: the application of genetics in understanding etiology

Clin Auton Res. 2015 Feb 17. [Epub ahead of print]
Federoff M, Schottlaender LV, Houlden H, Singleton A.

Classically defined phenotypically by a triad of cerebellar ataxia, parkinsonism, and autonomic dysfunction in conjunction with pyramidal signs, multiple system atrophy (MSA) is a rare and progressive neurodegenerative disease affecting an estimated 3-4 per every 100,000 individuals among adults 50-99 years of age. With a pathological hallmark of alpha-synuclein-immunoreactive glial cytoplasmic inclusions (GCIs; Papp-Lantos inclusions), MSA patients exhibit marked neurodegenerative changes in the striatonigral and/or olivopontocerebellar structures of the brain. As a member of the alpha-synucleinopathy family, which is defined by its well-demarcated alpha-synuclein-immunoreactive inclusions and aggregation, MSA's clinical presentation exhibits several overlapping features with other members including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Given the extensive fund of knowledge regarding the genetic etiology of PD revealed within the past several years, a genetic investigation of MSA is warranted. While a current genome-wide association study is underway for MSA to further clarify the role of associated genetic loci and single-nucleotide polymorphisms, several cases have presented solid preliminary evidence of a genetic etiology. Naturally, genes and variants manifesting known associations with PD (and other phenotypically similar neurodegenerative disorders), including SNCA and MAPT, have been comprehensively investigated in MSA patient cohorts. More recently variants in COQ2 have been linked to MSA in the Japanese population although this finding awaits replication. Nonetheless, significant positive associations with subsequent independent replication studies have been scarce. With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research. We believe that the application of next generation genetic methods to MSA will provide valuable insight into the underlying causes of this disease, and will be central to the identification of etiologic-based therapies.

Sunday, 22 February 2015

Dietary Factors in the Etiology of Parkinson's Disease

Biomed Res Int. 2015;2015:672838. Epub 2015 Jan 20.
Agim ZS, Cannon JR.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The majority of cases do not arise from purely genetic factors, implicating an important role of environmental factors in disease pathogenesis. Well-established environmental toxins important in PD include pesticides, herbicides, and heavy metals. However, many toxicants linked to PD and used in animal models are rarely encountered. In this context, other factors such as dietary components may represent daily exposures and have gained attention as disease modifiers. Several in vitro, in vivo, and human epidemiological studies have found a variety of dietary factors that modify PD risk. Here, we critically review findings on association between dietary factors, including vitamins, flavonoids, calorie intake, caffeine, alcohol, and metals consumed via food and fatty acids and PD. We have also discussed key data on heterocyclic amines that are produced in high-temperature cooked meat, which is a new emerging field in the assessment of dietary factors in neurological diseases. While more research is clearly needed, significant evidence exists that specific dietary factors can modify PD risk.

Friday, 20 February 2015

Head injury and risk for Parkinson disease: Results from a Danish case-control study

Just as momentum was starting to build in this area, this study suggests otherwise...

Neurology. 2015 Feb 13. pii: 10.1212/WNL.0000000000001362. [Epub ahead of print]
Kenborg L, Rugbjerg K, Lee PC, Ravnskjær L, Christensen J, Ritz B, Lassen CF.

To examine the association between head injuries throughout life and the risk for Parkinson disease (PD) in an interview-based case-control study.

We identified 1,705 patients diagnosed with PD at 10 neurologic centers in Denmark in 1996-2009 and verified their diagnoses in medical records. Patients were matched to 1,785 controls randomly selected from the Danish Central Population Register on sex and year of birth. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression.

We observed no association between any head injury before first cardinal symptom and PD (OR 1.02; 95% CI 0.88, 1.19). Examination of number of head injuries (1: OR 1.02; 95% CI 0.87, 1.20; ≥2: OR 1.03; 95% CI 0.72, 1.47) or hospitalization for a head injury (OR 0.89; 95% CI 0.70, 1.12) did not show an association with PD. For 954 study subjects with at least one head injury, there was no evidence of an association between loss of consciousness (OR 0.89; 95% CI 0.67, 1.17), duration of loss of consciousness (≤1 minute: OR 0.93; 95% CI 0.58, 1.49; 1-5 minutes: OR 0.74; 95% CI 0.51, 1.08; ≥5 minutes: OR 0.81; 95% CI 0.53, 1.24), or amnesia (OR 1.31; 95% CI 0.88, 1.95) and risk for PD. Application of a lag time of 10 years between head injury and first cardinal symptom resulted in similar risk estimates.

The results do not support the hypothesis that head injury increases the risk for PD.

© 2015 American Academy of Neurology.

Thursday, 19 February 2015

Parkinson risk in idiopathic REM sleep behavior disorder: Preparing for neuroprotective trials

Amazing to see this published and the results are very interesting. I can't help feeling we will need more than RBD to make in-roads into neuroprotective trials in the pre-diagnostic phase. This is one of, if not the biggest cohort of RBD subjects and would only be enough for half a clinical trial based on these calculations. And that is assuming a drug with an effect size of 0.5. That said, I think this is a significant step in the right direction... 

Neurology. 2015 Feb 13. pii: 10.1212/WNL.0000000000001364. [Epub ahead of print]
Postuma RB, Gagnon JF, Bertrand JA, Génier Marchand D, Montplaisir JY.

To precisely delineate clinical risk factors for conversion from idiopathic REM sleep behavior disorder (RBD) to Parkinson disease, dementia with Lewy bodies, and multiple system atrophy, in order to enable practical planning and stratification of neuroprotective trials against neurodegenerative synucleinopathy.

In a 10-year prospective cohort, we tested prodromal Parkinson disease markers in 89 patients with idiopathic RBD. With Kaplan-Meier analysis, we calculated risk of neurodegenerative synucleinopathy, and using Cox proportional hazards, tested the ability of prodromal markers to identify patients at higher disease risk. By combining predictive markers, we then designed stratification strategies to optimally select patients for definitive neuroprotective trials.

The risk of defined neurodegenerative synucleinopathy was high: 30% developed disease at 3 years, rising to 66% at 7.5 years. Advanced age (hazard ratio [HR] = 1.07), olfactory loss (HR = 2.8), abnormal color vision (HR = 3.1), subtle motor dysfunction (HR = 3.9), and nonuse of antidepressants (HR = 3.5) identified higher risk of disease conversion. However, mild cognitive impairment (HR = 1.8), depression (HR = 0.63), Parkinson personality, treatment with clonazepam (HR = 1.3) or melatonin (HR = 0.55), autonomic markers, and sex (HR = 1.37) did not clearly predict clinical neurodegeneration. Stratification with prodromal markers increased risk of neurodegenerative disease conversion by 200%, and combining markers allowed sample size reduction in neuroprotective trials by >40%. With a moderately effective agent (HR = 0.5), trials with fewer than 80 subjects per group can demonstrate definitive reductions in neurodegenerative disease.


Using stratification with simply assessed markers, it is now not only possible, but practical to include patients with RBD in neuroprotective trials against Parkinson disease, multiple system atrophy, and dementia with Lewy bodies.

Wednesday, 18 February 2015

Movement disorders and other motor abnormalities in adults with 22q11.2 Deletion Syndrome

Interesting to see more about this in the literature...

Am J Med Genet A. 2015 Feb 13. doi: 10.1002/ajmg.a.36928. [Epub ahead of print]
Boot E, Butcher NJ, van Amelsvoort TA, Lang AE, Marras C, Pondal M, Andrade DM, Fung WL, Bassett AS.

Movement abnormalities are frequently reported in children with 22q11.2 deletion syndrome (22q11.2DS), but knowledge in this area is scarce in the increasing adult population. We report on five individuals illustrative of movement disorders and other motor abnormalities in adults with 22q11.2DS. In addition to an increased susceptibility to neuropsychiatric disorders, seizures, and early-onset Parkinson disease, the underlying brain dysfunction associated with 22q11.2DS may give rise to an increased vulnerability to multiple movement abnormalities, including those influenced by medications. Movement abnormalities may also be secondary to treatable endocrine diseases and congenital musculoskeletal abnormalities. We propose that movement abnormalities may be common in adults with 22q11.2DS and discuss the implications and challenges important to clinical practice.

Tuesday, 17 February 2015

Risk and adverse outcomes of fractures in patients with Parkinson's disease: two nationwide studies

Cohort study showing the risk of fracture in PD is 2x the background rate. Estimate in line with our meta-analysis on the subject last year...

Osteoporos Int. 2015 Feb 12. [Epub ahead of print]
Huang YF, Cherng YG, Hsu SP, Yeh CC, Chou YC, Wu CH, Chen TL, Liao CC.

The association between Parkinson's disease and fracture was not completely understood. This nationwide study investigated increased risk of fracture in patients with Parkinson's disease. In the nested cohort study, Parkinson's disease was associated with pneumonia, septicemia, stroke, urinary tract infection, and mortality after fracture admission.

Falls are a common complication in people with Parkinson's disease (PD). This study evaluated fracture risk and post-fracture outcomes in patients with PD.

We identified 1,423 adults aged 40 years and older newly diagnosed with PD using the Taiwan National Health Insurance Research Database from 2000 to 2003. Comparison cohort consisted of 5,692 adults without PD randomly selected from the same dataset, frequency matched in age and sex. Followed-up events of fracture from January 1, 2000, until December 31, 2008, were ascertained from medical claims. Adjusted hazard ratios (HR) and 95 % confidence interval (CI) of fracture associated with PD were evaluated. Another nested cohort study of 397,766 hospitalized fracture patients analyzed for adjusted odds ratios (ORs) and 95 % CIs of adverse events after fracture among patients with and without PD between 2004 and 2010.

The incidences of fracture for people with and without PD were 39.5 and 23.9 per 1,000 person-years, respectively (p < 0.0001). Compared with control, the adjusted HR of fracture was 2.25 (95 % CI 1.97-2.58) for PD patients. Previous PD was associated with risks of pneumonia (OR 1.44, 95 % CI 1.36-1.52), septicemia (OR 1.41, 95 % CI 1.33-1.49), stroke (OR 1.40, 95 % CI 1.32-1.50), urinary tract infection (OR 1.53, 95 % CI 1.46-1.61), and mortality (OR 1.25, 95 % CI 1.15-1.35) after fracture.


PD was associated with higher risk of fracture. Patients with PD had more complications and mortality after fracture. Fracture prevention and attention to post-fracture adverse events are needed for this susceptible population.

Monday, 16 February 2015

Meta-analyses on prevalence of selected Parkinson's nonmotor symptoms before and after diagnosis.

New meta on prevalence of PD non-motor symptoms pre and post diagnosis...

Transl Neurodegener. 2015 Jan 8;4(1):1. doi: 10.1186/2047-9158-4-1. eCollection 2015.
Chen H, Zhao EJ, Zhang W, Lu Y, Liu R, Huang X, Ciesielski-Jones AJ, Justice MA, Cousins DS, Peddada S.

Nonmotor symptoms are common among patients with Parkinson's disease (PD) and some may precede disease diagnosis.

We conducted a meta-analysis on the prevalence of selected nonmotor symptoms before and after PD diagnosis, using random-effect models. We searched PubMed (1965 through October/November 2012) for the following symptoms: hyposmia, constipation, rapid eye movement sleep behavior disorder, excessive daytime sleepiness, depression, and anxiety. Eligible studies were publications in English with original data on one or more of these symptoms.

The search generated 2,373 non-duplicated publications and 332 met the inclusion criteria, mostly (n = 320) on symptoms after PD diagnosis. For all symptoms, the prevalence was substantially higher in PD cases than in controls, each affecting over a third of the patients. Hyposmia was the most prevalent (75.5% in cases vs. 19.1% in controls), followed by constipation (50% vs. 17.7%), anxiety (39.9% vs. 19.1%), rapid eye movement sleep behavior disorder (37.0% vs. 7.0%), depression (36.6% vs. 14.9%), and excessive daytime sleepiness (33.9% vs. 10.5%). We observed substantial heterogeneities across studies and meta-regression analyses suggested that several factors might have contributed to this. However, the prevalence estimates were fairly robust in several sensitivity analyses. Only 20 studies had data on any symptoms prior to PD diagnosis, but still the analyses revealed higher prevalence in future PD cases than in controls.


These symptoms are common among PD patients both before and after diagnosis. Further studies are needed to understand the natural history of nonmotor symptoms in PD and their etiological and clinical implications.

Sunday, 15 February 2015

CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study

Exciting if this is a new dominant cause of PD... looking forward to replication and biological/functional role...

Lancet Neurol. 2015 Feb 3. pii: S1474-4422(14)70266-2. doi: 10.1016/S1474-4422(14)70266-2. [Epub ahead of print]
Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, Li Y, Ogaki K, Ando M, Yoshino H, Tomiyama H, Nishioka K, Hasegawa K, Saiki H, Satake W, Mogushi K, Sasaki R, Kokubo Y, Kuzuhara S, Toda T, Mizuno Y, Uchiyama Y, Ohno K, Hattori N.

Identification of causative genes in mendelian forms of Parkinson's disease is valuable for understanding the cause of the disease. We did genetic studies in a Japanese family with autosomal dominant Parkinson's disease to identify novel causative genes.

We did a genome-wide linkage analysis on eight affected and five unaffected individuals from a family with autosomal dominant Parkinson's disease (family A). Subsequently, we did exome sequencing on three patients and whole-genome sequencing on one patient in family A. Variants were validated by Sanger sequencing in samples from patients with autosomal dominant Parkinson's disease, patients with sporadic Parkinson's disease, and controls. Participants were identified from the DNA bank of the Comprehensive Genetic Study on Parkinson's Disease and Related Disorders (Juntendo University School of Medicine, Tokyo, Japan) and were classified according to clinical information obtained by neurologists. Splicing abnormalities of CHCHD2 mutants were analysed in SH-SY5Y cells. We used the Fisher's exact test to calculate the significance of allele frequencies between patients with sporadic Parkinson's disease and unaffected controls, and we calculated odds ratios and 95% CIs of minor alleles.

We identified a missense mutation (CHCHD2, 182C>T, Thr61Ile) in family A by next-generation sequencing. We obtained samples from a further 340 index patients with autosomal dominant Parkinson's disease, 517 patients with sporadic Parkinson's disease, and 559 controls. Three CHCHD2 mutations in four of 341 index cases from independent families with autosomal dominant Parkinson's disease were detected by CHCHD2 mutation screening: 182C>T (Thr61Ile), 434G>A (Arg145Gln), and 300+5G>A. Two single nucleotide variants (-9T>G and 5C>T) in CHCHD2 were confirmed to have different frequencies between sporadic Parkinson's disease and controls, with odds ratios of 2·51 (95% CI 1·48-4·24; p=0·0004) and 4·69 (1·59-13·83, p=0·0025), respectively. One single nucleotide polymorphism (rs816411) was found in CHCHD2 from a previously reported genome-wide association study; however, there was no significant difference in its frequency between patients with Parkinson's disease and controls in a previously reported genome-wide association study (odds ratio 1·17, 95% CI 0·96-1·19; p=0·22). In SH-SY5Y cells, the 300+5G>A mutation but not the other two mutations caused exon 2 skipping.

CHCHD2 mutations are associated with, and might be a cause of, autosomal dominant Parkinson's disease. Further genetic studies in other populations are needed to confirm the pathogenicity of CHCHD2 mutations in autosomal dominant Parkinson's disease and susceptibility for sporadic Parkinson's disease, and further functional studies are needed to understand how mutant CHCHD2 might play a part in the pathophysiology of Parkinson's disease.


Japan Society for the Promotion of Science; Japanese Ministry of Education, Culture, Sports, Science and Technology; Japanese Ministry of Health, Labour and Welfare; Takeda Scientific Foundation; Cell Science Research Foundation; and Nakajima Foundation.

Saturday, 14 February 2015

Parkinson disease with REM sleep behavior disorder: Features, α-synuclein, and inflammation

Another study suggesting the frequency of RBD (by questionnaire) is 30%. It does seem high and healthy controls also tend to score in the RBD range far more than one would expect...

Neurology. 2015 Feb 6. pii: 10.1212/WNL.0000000000001308. [Epub ahead of print]
Hu Y, Yu SY, Zuo LJ, Cao CJ, Wang F, Chen ZJ, Du Y, Lian TH, Wang YJ, Chan P, Chen SD, Wang XM, Zhang W.

To investigate clinical features and potential mechanisms involving α-synuclein oligomer and inflammation in patients with Parkinson disease (PD) and probable REM sleep behavior disorder (PRBD).

We used the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) to evaluate patients with PD and classified each as PRBD or not probable (NPRBD). Data collection included demographic information and evaluation of clinical symptoms using a series of rating scales. We tested for α-synuclein oligomer and inflammatory factors in CSF and serum. Data analyses included comparisons between PRBD and NPRBD groups and correlation analyses among RBDSQ score and levels of the above factors.

The frequency of PRBD in patients with PD was 30.67%. The PRBD group had longer disease duration, more advanced disease stage, more severe motor symptoms, and other more severe nonmotor symptoms, including depression, anxiety, and fatigue. Levels of α-synuclein oligomer in CSF and serum in the PRBD group were elevated compared with NPRBD and control groups. RBDSQ score was increased with the elevated α-synuclein oligomer level in CSF, interleukin 1β and nitric oxide levels in CSF, and prostaglandin E2 level in serum in the PD group. The level of α-synuclein oligomer in CSF was enhanced with the deterioration of motor symptoms, and the elevated levels of interleukin 1β, nitric oxide, and tumor necrosis factor α in CSF in the PRBD group.


PRBD is common in patients with PD, especially those with longer disease duration and more severe motor and nonmotor symptoms. Elevated α-synuclein levels in CSF and serum may be correlated with PRBD through inflammation in central and peripheral nervous systems.

Friday, 13 February 2015

Differential effects of severe vs mild GBA mutations on Parkinson disease

Neurology. 2015 Feb 4. pii: 10.1212/WNL.0000000000001315. [Epub ahead of print]
Gan-Or Z, Amshalom I, Kilarski LL, Bar-Shira A, Gana-Weisz M, Mirelman A, Marder K, Bressman S, Giladi N, Orr-Urtreger A.

To better define the genotype-phenotype correlations between the type of GBA (glucosidase, beta, acid) mutation, severe or mild, and the risk and age at onset (AAO), and potential mechanism of Parkinson disease (PD).

We analyzed 1,000 patients of Ashkenazi-Jewish descent with PD for 7 founder GBA mutations, and conducted a meta-analysis of risk and AAO according to GBA genotype (severe or mild mutation). The meta-analysis included 11,453 patients with PD and 14,565 controls from worldwide populations. The statistical analysis was done with and without continuity correction (constant or empirical), considering biases that could potentially affect the results.

Among Ashkenazi-Jewish patients with PD, the odds ratios for PD were 2.2 and 10.3 for mild and severe GBA mutation carriers, respectively. The observed frequency of severe GBA mutation carriers among patients with PD was more than 4-fold than expected (4.4% vs 0.9%, respectively, p < 0.0001, Fisher exact test). In the different models of the meta-analysis, the odds ratios for PD ranged between 2.84 and 4.94 for mild GBA mutation carriers and 9.92 and 21.29 for severe GBA mutation carriers (p < 1 × 10-6 for all analyses). Pooled analysis demonstrated AAO of 53.1 (±11.2) and 58.1 (±10.6) years for severe and mild GBA mutation carriers, respectively (p = 4.3 × 10-5).


These data demonstrate that mild and severe heterozygous GBA mutations differentially affect the risk and the AAO of PD. Our results have important implications for genetic counseling and clinical follow-up.

Thursday, 12 February 2015

Cognitive profile of LRRK2-related Parkinson's disease

Interesting to see this... may turn out to be somewhat reassuring for the increasing numbers of patients being found to have LRRK2 related PD...

Mov Disord. 2015 Feb 4. doi: 10.1002/mds.26161. [Epub ahead of print]
Srivatsal S, Cholerton B, Leverenz JB, Wszolek ZK, Uitti RJ, Dickson DW, Weintraub D, Trojanowski JQ, Van Deerlin VM, Quinn JF, Chung KA, Peterson AL, Factor SA, Wood-Siverio C, Goldman JG, Stebbins GT, Bernard B, Ritz B, Rausch R, Espay AJ, Revilla FJ, Devoto J, Rosenthal LS, Dawson TM, Albert MS, Mata IF, Hu SC, Montine KS, Johnson C, Montine TJ, Edwards KL, Zhang J, Zabetian CP.

Increasing evidence suggests that genetic factors play a role in the variability associated with cognitive performance in Parkinson's disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2-related PD is not well-characterized.

A cohort of 1,447 PD patients enrolled in the PD Cognitive Genetics Consortium was screened for LRRK2 mutations and completed detailed cognitive testing. Associations between mutation carrier status and cognitive test scores were assessed using linear regression models.

LRRK2 mutation carriers (n = 29) demonstrated better performance on the Mini Mental State Examination (P = 0.03) and the Letter-Number Sequencing Test (P = 0.005). A smaller proportion of LRRK2 carriers were demented (P = 0.03).


Our cross-sectional study demonstrates better performance on certain cognitive tests, as well as lower rates of dementia in LRRK2-related PD. Future longitudinal studies are needed to determine whether LRRK2 mutation carriers exhibit slower cognitive decline.

Wednesday, 11 February 2015

PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease

Evidence that reducing heterogeneity inherent in the diagnosis of PD could maximise our understanding of the biology... until we are better at identifying PD in life we are always constrained by this matter.  

Neurology. 2015 Feb 6. pii: 10.1212/WNL.0000000000001332. [Epub ahead of print]
Beecham GW, Dickson DW, Scott WK, Martin ER, Schellenberg G, Nuytemans K, Larson EB, Buxbaum JD, Trojanowski JQ, Van Deerlin VM, Hurtig HI, Mash DC, Beach TG, Troncoso JC, Pletnikova O, Frosch MP, Ghetti B, Foroud TM, Honig LS, Marder K, Vonsattel JP, Goldman SM, Vinters HV, Ross OA, Wszolek ZK, Wang L, Dykxhoorn DM, Pericak-Vance MA, Montine TJ, Leverenz JB, Dawson TM, Vance JM.

To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls.

Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis.

A small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.2 × 10-8). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1.


We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.

Effect of Creatine Monohydrate on Clinical Progression in Patients With Parkinson Disease: A Randomized Clinical Trial

Negative results from recently concluded creatine in PD study

JAMA. 2015 Feb 10;313(6):584-593. doi: 10.1001/jama.2015.120.
Writing Group for the NINDS Exploratory Trials in Parkinson Disease (NET-PD) Investigators, Kieburtz K, Tilley BC, Elm JJ, Babcock D, Hauser R, Ross GW, Augustine AH, Augustine EU, Aminoff MJ, Bodis-Wollner IG, Boyd J, Cambi F, Chou K, Christine CW, Cines M, Dahodwala N, Derwent L, Dewey RB Jr, Hawthorne K, Houghton DJ, Kamp C, Leehey M, Lew MF, Liang GS, Luo ST, Mari Z, Morgan JC, Parashos S, Pérez A, Petrovitch H, Rajan S, Reichwein S, Roth JT, Schneider JS, Shannon KM, Simon DK, Simuni T, Singer C, Sudarsky L, Tanner CM, Umeh CC, Williams K, Wills AM.

There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies.

To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease.

The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013.

Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years).

The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes.

The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system.

Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease.

TRIAL REGISTRATION: Identifier:NCT00449865.

Tuesday, 3 February 2015

Olfactory dysfunction predicts early transition to a Lewy body disease in idiopathic RBD

Neurology. 2015 Jan 21. pii: 10.1212/WNL.0000000000001265. [Epub ahead of print]
Mahlknecht P, Iranzo A, Högl B, Frauscher B, Müller C, Santamaría J, Tolosa E, Serradell M, Mitterling T, Gschliesser V, Goebel G, Brugger F, Scherfler C, Poewe W, Seppi K; For the SINBAR (Sleep Innsbruck Barcelona) Group; For the SINBAR Sleep Innsbruck Barcelona Group.

The aim of the present study was to determine the predictive value of olfactory dysfunction for the early development of a synuclein-mediated neurodegenerative disease in subjects with idiopathic REM sleep behavior disorder (iRBD) over an observational period of 5 years.

Thirty-four patients with polysomnography-confirmed iRBD underwent olfactory testing using the entire Sniffin' Sticks test assessing odor identification, odor discrimination, and olfactory threshold. Patients with iRBD were prospectively followed up over a period of 4.9 ± 0.3 years (mean ± SD). The diagnosis of neurodegenerative diseases was based on current clinical diagnostic criteria.

After 2.4 ± 1.7 years (mean ± SD), 9 patients (26.5%) with iRBD developed a Lewy body disease (6 Parkinson disease and 3 dementia with Lewy bodies). The entire Sniffin' Sticks test and the identification subtest had the same overall diagnostic accuracy of 82.4% (95% confidence interval: 66.1%-92.0%) in predicting conversion. The relative risk for a Lewy body disease in the lowest tertile of olfactory function was 7.3 (95% confidence interval: 1.8-29.6) compared with the top 2 tertiles.


Assessment of olfactory function, particularly odor identification, may help to predict the development of a Lewy body disease in patients with iRBD over a relatively short time period and thus to identify patients suitable for future disease modification trials.

Monday, 2 February 2015

The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson's Disease

Neuron. 2015 Jan 21;85(2):257-273. doi: 10.1016/j.neuron.2014.12.007.
Pickrell AM, Youle RJ.

Understanding the function of genes mutated in hereditary forms of Parkinson's disease yields insight into disease etiology and reveals new pathways in cell biology. Although mutations or variants in many genes increase the susceptibility to Parkinson's disease, only a handful of monogenic causes of parkinsonism have been identified. Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson's disease. PINK1 accumulates on the outer membrane of damaged mitochondria, activates Parkin's E3 ubiquitin ligase activity, and recruits Parkin to the dysfunctional mitochondrion. Then, Parkin ubiquitinates outer mitochondrial membrane proteins to trigger selective autophagy. This review covers the normal functions that PINK1 and Parkin play within cells, their molecular mechanisms of action, and the pathophysiological consequences of their loss.

Sunday, 1 February 2015

Apathy and olfactory dysfunction in early Parkinson's disease

J Mov Disord. 2015 Jan;8(1):21-5. doi: 10.14802/jmd.14029. Epub 2015 Jan 13.
Hong JY, Sunwoo MK, Ham JH, Lee JJ, Lee PH, Sohn YH.

Olfactory and emotional dysfunctions are very common in patients with Parkinson's disease (PD). Olfaction and emotions share common neuroanatomical substrates. Therefore, in this study, we evaluated the association between olfactory and emotional dysfunctions in patients with PD.

Parkinson's disease patients who had been assessed for their olfactory function and neuropsychiatric symptoms including emotional dysfunction were included. A logistic regression analysis was performed to evaluate the association between low olfaction and different neuropsychiatric symptoms.

The patients with low olfaction (cross cultural smell identification test score ≤ 6) showed a higher prevalence of apathy when compared with those with high olfaction, whereas the frequencies of other neuropsychiatric symptoms were comparable between the two groups. A multivariate logistic regression analysis revealed that the presence of apathy/indifference [odds ratio (OR) = 2.859, p = 0.007], age 70 years or more (OR = 2.281, p = 0.009), and the male gender (OR = 1.916, p = 0.030) were significantly associated with low olfaction.


Our results demonstrate that apathy/indifference is a unique emotional dysfunction associated with olfactory dysfunction in PD. The findings also suggest that PD patients with low olfaction have a high prevalence of apathy.