Thursday, 31 December 2015

Free-water imaging in Parkinson's disease and atypical parkinsonism

Interesting and potentially important results here... imaging markers for PD and differentiation from atypical Parkinson's is essential... replication required but very promising results...

Brain. 2015 Dec 24. pii: awv361. [Epub ahead of print]
Planetta PJ, Ofori E, Pasternak O, Burciu RG, Shukla P, DeSimone JC, Okun MS, McFarland NR, Vaillancourt DE.



Conventional single tensor diffusion analysis models have provided mixed findings in the substantia nigra of Parkinson's disease, but recent work using a bi-tensor analysis model has shown more promising results. Using a bi-tensor model, free-water values were found to be increased in the posterior substantia nigra of Parkinson's disease compared with controls at a single site and in a multi-site cohort. Further, free-water increased longitudinally over 1 year in the posterior substantia nigra of Parkinson's disease. Here, we test the hypothesis that other parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy have elevated free-water in the substantia nigra. Equally important, however, is whether the bi-tensor diffusion model is able to detect alterations in other brain regions beyond the substantia nigra in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional anisotropy maps were compared across 72 individuals in the basal ganglia, midbrain, thalamus, dentate nucleus, cerebellar peduncles, cerebellar vermis and lobules V and VI, and corpus callosum. Compared with controls, free-water was increased in the anterior and posterior substantia nigra of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Despite no other changes in Parkinson's disease, we observed elevated free-water in all regions except the dentate nucleus, subthalamic nucleus, and corpus callosum of multiple system atrophy, and in all regions examined for progressive supranuclear palsy. Compared with controls, free-water-corrected fractional anisotropy values were increased for multiple system atrophy in the putamen and caudate, and increased for progressive supranuclear palsy in the putamen, caudate, thalamus, and vermis, and decreased in the superior cerebellar peduncle and corpus callosum. For all disease group comparisons, the support vector machine 10-fold cross-validation area under the curve was between 0.93-1.00 and there was high sensitivity and specificity. The regions and diffusion measures selected by the model varied across comparisons and are consistent with pathological studies. In conclusion, the current study used a novel bi-tensor diffusion analysis model to indicate that all forms of parkinsonism had elevated free-water in the substantia nigra. Beyond the substantia nigra, both multiple system atrophy and progressive supranuclear palsy, but not Parkinson's disease, showed a broad network of elevated free-water and altered free-water corrected fractional anisotropy that included the basal ganglia, thalamus, and cerebellum. These findings may be helpful in the differential diagnosis of parkinsonian disorders, and thereby facilitate the development and assessment of targeted therapies.

Wednesday, 30 December 2015

Parkinson disease male-to-female ratios increase with age: French nationwide study and meta-analysis.

This is an interesting result... and will be important not only for aetiological research into PD but also predictive modelling approaches...

J Neurol Neurosurg Psychiatry. 2015 Dec 23. pii: jnnp-2015-312283. doi: 10.1136/jnnp-2015-312283. [Epub ahead of print]

Moisan F, Kab S, Mohamed F, Canonico M, Le Guern M, Quintin C, Carcaillon L, Nicolau J, Duport N, Singh-Manoux A, Boussac-Zarebska M, Elbaz A.


BACKGROUND:
Parkinson's disease (PD) is 1.5 times more frequent in men than women. Whether age modifies this ratio is unclear. We examined whether male-to-female (M-F) ratios change with age through a French nationwide prevalence/incidence study (2010) and a meta-analysis of incidence studies.

METHODS:
We used French national drug claims databases to identify PD cases using a validated algorithm. We computed M-F prevalence/incidence ratios overall and by age using Poisson regression. Ratios were regressed on age to estimate their annual change. We identified all PD incidence studies with age/sex-specific data, and performed a meta-analysis of M-F ratios.

RESULTS:
On the basis of 149 672 prevalent (50% women) and 25 438 incident (49% women) cases, age-standardised rates were higher in men (prevalence=2.865/1000; incidence=0.490/1000 person-years) than women (prevalence=1.934/1000; incidence=0.328/1000 person-years). The overall M-F ratio was 1.48 for prevalence and 1.49 for incidence. Prevalence and incidence M-F ratios increased by 0.05 and 0.14, respectively, per 10 years of age. Incidence was similar in men and women under 50 years (M-F ratio <1.2, p>0.20), and over 1.6 (p<0.001) times higher in men than women above 80 years (p trend <0.001). A meta-analysis of 22 incidence studies (14 126 cases, 46% women) confirmed that M-F ratios increased with age (0.26 per 10 years, p trend=0.005).

CONCLUSIONS:

Age-increasing M-F ratios suggest that PD aetiology changes with age. Sex-related risk/protective factors may play a different role across the continuum of age at onset. This finding may inform aetiological PD research.

Tuesday, 29 December 2015

Hepatitis C virus infection as a risk factor for Parkinson disease: A nationwide cohort study

Interesting observation... I don't remember seeing this before...

Neurology. 2015 Dec 23. pii: 10.1212/WNL.0000000000002307. [Epub ahead of print]
Tsai HH, Liou HH, Muo CH, Lee CZ, Yen RF, Kao CH.

OBJECTIVE:
To determine whether hepatitis C virus (HCV) infection is a risk factor for developing Parkinson disease (PD).

METHODS:
This nationwide population-based cohort study was based on data obtained from a dataset of the Taiwan National Health Insurance Research Database for the period 2000 to 2010. A total of 49,967 patients with viral hepatitis were included for analysis. Furthermore, 199,868 people without viral hepatitis were included for comparisons. Patients with viral hepatitis were further grouped into 3 cohorts: hepatitis B virus (HBV) infection, HCV infection, and HBV-HCV coinfection. In each cohort, we calculated the incidence of developing PD. A Cox proportional hazards model was applied to estimate the risk of developing PD in terms of hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS:
The crude HRs for developing PD was 0.66 (95% CI = 0.55-0.80) for HBV infection, 2.50 (95% CI = 2.07-3.02) for HCV infection, and 1.28 (95% CI = 0.88-1.85) for HBV-HCV coinfection. The association between HCV and PD remained statistically significant after adjustments for age, sex, and comorbidities (adjusted HR = 1.29, 95% CI = 1.06-1.56).

CONCLUSIONS:

We conducted a large nationwide population-based study and found that patients with HCV exhibit a significantly increased risk of developing PD.

Thursday, 24 December 2015

Mendelian Randomization - the Key to Understanding Aspects of Parkinson's Disease Causation?

Nice early christmas present to have this published today... I anticipate this approach will take us forward in understanding the causal nature of Parkinson's... particularly when it comes to the associations with some of the stranger environmental exposures for PD...

Mov Disord. 2015 Dec 23. doi: 10.1002/mds.26492. [Epub ahead of print]
Noyce AJ, Nalls MA.


Parkinson's disease has multiple determinants and is associated with a wide range of exposures that appear to modify risk in traditional observational studies, including numerous lifestyle and environmental factors. Across other fields of medicine, Mendelian randomization has emerged as a powerful method to examine whether associations between exposures and disease outcomes are causal. Here we discuss the concept of Mendelian randomization, its potential relevance to Parkinson's disease, and suggest avenues through which the method could be employed to further understanding of the causal basis of Parkinson's disease.

Alpha-synuclein in gastric and colonic mucosa in Parkinson's disease: Limited role as a biomarker

Amazing how things change... 3-4 years ago there were a run of papers showing clear and definite differences in biopsies from GI tracts of patients in terms of staining for alpha-synuclein. Now there has been a run of studies showing no difference... I suspect the key lies in the final sentence of this abstract... the differences may be strain dependent... we should not give up on the gut...

Mov Disord. 2015 Dec 21. doi: 10.1002/mds.26473. [Epub ahead of print]
Chung SJ, Kim J, Lee HJ, Ryu HS, Kim K, Lee JH, Jung KW, Kim MJ, Kim MJ, Kim YJ, Yun SC, Lee JY, Hong SM, Myung SJ.

BACKGROUND:
Gastric and colonic alpha-synuclein immunoreactivity has been reported in patients with Parkinson's disease (PD). However, enteric alpha-synuclein also has been reported in healthy individuals.

OBJECTIVES:
We aimed to investigate the utility of alpha-synuclein immunoreactivity from gastric and colonic mucosal tissues obtained by routine endoscopy to detect PD, and to correlate the pathological burden of alpha-synuclein with motor and nonmotor features of PD.

METHODS:
We recruited 104 study subjects, consisting of 38 patients with PD, 13 patients with probable multiple system atrophy (MSA), and 53 healthy controls. Gastric and colonic mucosal tissues obtained by endoscopic gastroduodenoscopy and colonoscopy were assessed using alpha-synuclein immunohistochemistry. Detailed motor and nonmotor features of PD were correlated with enteric alpha-synuclein immunoreactivity.

RESULTS:
No difference was seen in the enteric α-SYN immunoreactivity among patients with PD (31.6% for stomach and 10.4% for colon), patients with MSA (40.0% for stomach and 8.0% for colon), and healthy controls (33.3% for stomach and 18.5% for colon). The frequency of positive alpha-synuclein immunoreactivity was higher in gastric biopsy tissues than in colonic biopsy tissues in all of the study groups (P < 0.05). No significant correlation was found between the presence of alpha-synuclein immunoreactivity and the motor and nonmotor features of PD.

CONCLUSIONS:

The presence of alpha-synuclein immunoreactivity in gastric and colonic mucosa was detected in a similar manner in patients with PD, patients with MSA, and controls, thus suggesting a limited role of enteric mucosal alpha-synuclein as a diagnostic biomarker for PD. Future studies are warranted to detect pathological alpha-synuclein strains.

Wednesday, 23 December 2015

A scan without evidence is not evidence of absence: Scans without evidence of dopaminergic deficit in a symptomatic leucine-rich repeat kinase 2 mutation carrier.

Further evidence that radio-tracer imaging can be normal despite the presence of clear motor signs perhaps due to early compensatory mechanisms...

Mov Disord. 2015 Dec 21. doi: 10.1002/mds.26450. [Epub ahead of print]
Wile DJ, Dinelle K, Vafai N, McKenzie J, Tsui JK, Schaffer P, Ding YS, Farrer M, Sossi V, Stoessl AJ.

INTRODUCTION:
The basis for SWEDD is unclear, with most cases representing PD mimics but some later developing PD with a dopaminergic deficit.

METHODS:
We studied a patient initially diagnosed with SWEDD (based on 18 F-dopa PET) who developed unequivocal PD associated with a leucine-rich repeat kinase 2 p.G2019S mutation. Repeat multitracer PET was performed at 17 years' disease duration, including (+)[11C]dihydrotetrabenazine, [11C](N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine (which binds the serotonin transporter), and 18 F-dopa.

RESULTS:
The patient showed bilateral striatal dopaminergic denervation (right putamen 28% of age-matched normal, left putamen 33%). 18 F-dopa uptake was decreased, particularly on the left (mean 31% of normal vs. 45% on the more affected right side). Serotonin transporter binding was relatively preserved in the putamen (right mean 90% of normal, left 81%) and several cortical regions.

CONCLUSIONS:

SWEDD can occur in genetically determined PD and may, in some cases, be the result of compensatory nondopaminergic mechanisms operating in early disease.

Tuesday, 22 December 2015

Sporadic Parkinson's disease: development and distribution of α-synuclein pathology

An update on the neuropathology of sporadic PD...

Neuropathol Appl Neurobiol. 2015 Dec 13. doi: 10.1111/nan.12298. [Epub ahead of print]
Del Tredici K, Braak H.



The development of α-synuclein-immunoreactive aggregates in selectively vulnerable neuronal types of the human central, peripheral, and enteric nervous systems is crucial for the pathogenesis of sporadic Parkinson's disease. The presence of these lesions persists into the end-phase of the disease, a process that is not subject to remission. The initial induction of α-synuclein misfolding and subsequent aggregation probably occurs in the olfactory bulb and/or the enteric nervous system. Each of these sites is exposed to potentially hostile environmental factors. Once formed, the aggregates appear to be capable of propagating transsynaptically from nerve cell to nerve cell in a virtually self-promoting pathological process. A regional distribution pattern of aggregated α-synuclein emerges that entails the involvement of only a few types of susceptible and axonally interconnected projection neurons within the human nervous system. One major route of disease progression may originate in the enteric nervous system and retrogradely reach the dorsal motor nucleus of the vagal nerve in the lower brainstem. From there, the disease process proceeds chiefly in a caudo-rostral direction through visceromotor and somatomotor brainstem centers to the midbrain, forebrain, and cerebral cortex. Spinal cord centers may become involved by means of descending projections from involved lower brainstem nuclei as well as by sympathetic projections connecting the enteric nervous system with postganglionic peripheral ganglia and preganglionic nuclei of the spinal cord. The development of experimental cellular and animal models is helping to explain the mechanisms of how abnormal α-synuclein can undergo aggregation and how transmission along axonal connectivities can occur, thereby encouraging the initiation of potential disease-modifying therapeutic strategies for sporadic Parkinson's disease.

Monday, 21 December 2015

Midlife milk consumption and substantia nigra neuron density at death

Clinico-pathological correlations between midlife milk consumption and observations made in the brains of subjects coming to post-mortem that did not have PD in life...

Neurology. 2015 Dec 9. pii: 10.1212/WNL.0000000000002254. [Epub ahead of print]
Abbott RD, Ross GW, Petrovitch H, Masaki KH, Launer LJ, Nelson JS, White LR, Tanner CM.

OBJECTIVE:
To examine the relationship between midlife milk intake and Parkinson disease (PD) incidence through associations with substantia nigra (SN) neuron density and organochlorine pesticide exposure in decedent brains from the Honolulu-Asia Aging Study.

METHODS:
Milk intake data were collected from 1965 to 1968 in 449 men aged 45-68 years with postmortem examinations from 1992 to 2004. Neuron density (count/mm2) was measured in quadrants from a transverse section of the SN. Additional measures included brain residues of heptachlor epoxide, an organochlorine pesticide found at excessively high levels in the milk supply in Hawaii in the early 1980s.

RESULTS:
Neuron density was lowest in nonsmoking decedents who consumed high amounts of milk (>16 oz/d). After removing cases of PD and dementia with Lewy bodies, adjusted neuron density in all but the dorsomedial quadrant was 41.5% lower for milk intake >16 oz/d vs intake that was less (95% confidence interval 22.7%-55.7%, p < 0.001). Among those who drank the most milk, residues of heptachlor epoxide were found in 9 of 10 brains as compared to 63.4% (26/41) for those who consumed no milk (p = 0.017). For those who were ever smokers, an association between milk intake and neuron density was absent.

CONCLUSIONS:

Milk intake is associated with SN neuron loss in decedent brains unaffected by PD. Whether contamination of milk with organochlorine pesticides has a role in SN neurodegeneration warrants further study.

Sunday, 20 December 2015

"Gunslinger's gait": a new cause of unilaterally reduced arm swing.

This made me laugh earlier in the week... great article about the walking pattern of high-ranking Russian officials!




BMJ. 2015 Dec 14;351:h6141. doi: 10.1136/bmj.h6141.
Araújo R, Ferreira JJ, Antonini A, Bloem BR.

OBJECTIVE:
 To postulate a new possible cause of a unilaterally reduced arm swing in addition to the known medical conditions such as shoulder pathology, Erb's palsy, stroke, and Parkinson's disease.

METHODS:
 Analysis of YouTube videos depicting the gait of highly ranked Russian officials.

RESULTS:
 We found a similar walking pattern in President Vladimir Putin, Prime Minister Dmitry Medvedev and three other highly ranked Russian officials, all presenting with a consistently reduced right arm swing in the absence of other overt neurological abnormalities.

CONCLUSIONS:

 We propose that this new gait pattern, which we term "gunslinger's gait," may result from a behavioural adaptation, possibly triggered by KGB or other forms of weapons training where trainees are taught to keep their right hand close to the chest while walking, allowing them to quickly draw a gun when faced with a foe. This should be included in the differential diagnosis of a unilaterally reduced arm swing.

Tuesday, 8 December 2015

Whole-Exome Sequencing in Familial Parkinson Disease.

Here we see whole exome sequencing used to potentially uncover more of the missing heritability of PD...these now need to be confirmed in other data sets...

JAMA Neurol. 2015 Nov 23:1-8. doi: 10.1001/jamaneurol.2015.3266. [Epub ahead of print]
Farlow JL, Robak LA, Hetrick K, Bowling K, Boerwinkle E, Coban-Akdemir ZH, Gambin T, Gibbs RA, Gu S, Jain P, Jankovic J, Jhangiani S, Kaw K, Lai D, Lin H, Ling H, Liu Y, Lupski JR, Muzny D, Porter P, Pugh E, White J, Doheny K, Myers RM, Shulman JM, Foroud T.


IMPORTANCE:
Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.

OBJECTIVE:
To identify genetic variants contributing to disease risk in familial PD.

DESIGN, SETTING, AND PARTICIPANTS:
A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.

MAIN OUTCOMES AND MEASURES:
Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.

RESULTS:
The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.

CONCLUSIONS AND RELEVANCE:

TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

Monday, 7 December 2015

Familial Aggregation and Co-Aggregation of Essential Tremor and Parkinson's Disease.

Certainly we see this in the clinic sometimes...

Neuroepidemiology. 2015 Nov 26;46(1):31-36. [Epub ahead of print]
Louis ED, Clark L, Ottman R.


BACKGROUND:
Current data suggest that the 2 common tremor disorders, essential tremor (ET) and Parkinson's disease (PD), may be associated with one another. Familial aggregation studies allow one to further explore their relatedness.

METHODS:
Probands with ET (n = 110), PD (n = 130) or both ET and PD (n = 27) and control probands (n = 177) reported whether they had relatives with these diseases or with non-specific tremor.

RESULTS:
A greater proportion of ET probands than control probands reported relatives with ET (30.0 vs. 2.8%, p < 0.001), non-specific tremor (38.2 vs. 13.6%, p < 0.001) and both ET and PD in different relatives (6.4 vs. 0.6%, p = 0.004). A greater proportion of PD probands than control probands reported relatives with PD (20.0 vs. 8.5%, p = 0.003), ET (11.5 vs. 2.8%, p = 0.002) and both ET and PD in different relatives (6.9 vs. 0.6%, p = 0.002).

CONCLUSIONS:

This study provides evidence for the aggregation of ET in ET families and PD in PD families, and the familial co-aggregation of ET and PD.

Sunday, 6 December 2015

Oculo-Visual Dysfunction in Parkinson's Disease.

Oculo-visual disturbance is frequently reported in PD. Further characterisation and recognition of when it begins are important, but difficult to study formally. Efforts close to home are underway...!

J Parkinsons Dis. 2015 Nov 24. [Epub ahead of print]
Armstrong RA



This review describes the oculo-visual problems likely to be encountered in Parkinson's disease (PD) with special reference to three questions: (1) are there visual symptoms characteristic of the prodromal phase of PD, (2) is PD dementia associated with specific visual changes, and (3) can visual symptoms help in the differential diagnosis of the parkinsonian syndromes, viz. PD, progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD)? Oculo-visual dysfunction in PD can involve visual acuity, dynamic contrast sensitivity, colour discrimination, pupil reactivity, eye movement, motion perception, and visual processing speeds. In addition, disturbance of visuo-spatial orientation, facial recognition problems, and chronic visual hallucinations may be present. Prodromal features of PD may include autonomic system dysfunction potentially affecting pupil reactivity, abnormal colour vision, abnormal stereopsis associated with postural instability, defects in smooth pursuit eye movements, and deficits in visuo-motor adaptation, especially when accompanied by idiopathic rapid eye movement (REM) sleep behaviour disorder. PD dementia is associated with the exacerbation of many oculo-visual problems but those involving eye movements, visuo-spatial function, and visual hallucinations are most characteristic. Useful diagnostic features in differentiating the parkinsonian symptoms are the presence of visual hallucinations, visuo-spatial problems, and variation in saccadic eye movement dysfunction.

Saturday, 5 December 2015

Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression

We are starting to learn much more about the genetic architecture of PD and how genes determine not only ones absolute risk of acquiring PD, but also account for a substantial proportion of the heterogeneity of PD.

Neurobiol Aging. 2015 Sep 30. pii: S0197-4580(15)00471-6. doi: 10.1016/j.neurobiolaging.2015.09.014. [Epub ahead of print]

Davis AA, Andruska KM, Benitez BA, Racette BA, Perlmutter JS, Cruchaga C.



Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression.

Friday, 4 December 2015

Skin nerve misfolded α-synuclein in pure autonomic failure and Parkinson disease.

Very interesting to see the continuation of the work of this group following the first report in 2014...especially given the strong results presented. Phosphorylated alpha-syn in biopsies from all subjects with a syncucleinopathy (PD and PAF) and the importance of the site of sampling reiterated.

Ann Neurol. 2015 Nov 25. doi: 10.1002/ana.24567. [Epub ahead of print]
Donadio V, Incensi A, Piccinini C, Cortelli P, Giannoccaro MP, Baruzzi A, Liguori R.


OBJECTIVE:
To characterize the expression in skin nerves of native (n-syn) and misfolded phosphorylated (p-syn) α-synucleins in pure autonomic failure (PAF) and idiopathic Parkinson disease (IPD). The specific aims were to: 1) define the importance of n-syn and p-syn as disease biomarkers; 2) ascertain differences in abnormal synuclein skin nerve deposits.

MATERIALS AND METHODS:
We studied 30 patients including 16 well-characterized IPD and 14 patients fulfilling PAF diagnostic criteria and 15 age-matched controls. Subjects underwent skin biopsy from proximal (i.e. cervical) and distal (i.e. thigh and leg) sites to study small nerve fiber and intraneural n-syn and p-syn.

RESULTS:
PAF and IPD showed a length-dependent somatic and autonomic small fiber loss, more severely expressed in patients with higher p-syn load. N-syn was similarly expressed in both groups of patients and controls. By contrast, p-syn was not evident in any skin sample of controls but was found in all PAF and IPD patients whilst with different skin innervation. In addition, abnormal α-syn deposits were found in all analyzed skin samples in PAF but in only 49% of samples with a higher positivity rate in the proximal site in IPD.

INTERPRETATION:

1) Intraneural p-syn was a reliable in vivo marker of PAF and IPD; 2) neuritic p-syn inclusions differed in PAF and IPD suggesting a different underlying pathogenesis; 3) searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF but it is critical in IPD.


Evaluation of 99mTc-TRODAT-1 SPECT in the diagnosis of Parkinson's disease versus other progressive movement disorders

Consistent with previous studies, there is little to differentiate Parkinson's disease from parkinsonian syndromes here, but as expected essential tremor and vascular PD subjects have better uptake...

Ann Nucl Med. 2015 Nov 26. [Epub ahead of print]
Fallahi B, Esmaeili A, Beiki D, Oveisgharan S, Noorollahi-Moghaddam H, Erfani M, Tafakhori A, Rohani M, Fard-Esfahani A, Emami-Ardekani A, Geramifar P, Eftekhari M.


OBJECTIVE:
Parkinson disease (PD), parkinsonian syndromes (PS) and essential tremor (ET) are different types of movement disorders which share some symptoms resulting in a difficulty of certain diagnosis. This study was conducted to determine the value of 99mTc-TRODAT-1 scan to differentiate PD from ET and other PS cases.

METHODS:
Totally, 75 patients were studied including 29 PD, 6 possible PD, 22 ET and 18 PS cases. A dual-head SPECT-CT was used to perform basal ganglia (BG) imaging following administration of 99mTc-TRODAT-1. The BG uptake values were normalized to whole brain and occipital activity. All patients were followed for 2-22 months to reach a certain diagnosis.

RESULTS:
Patients with ET and drug-induced parkinsonism show significantly higher normalized BG uptake as compared to the other subgroups; however, no significant difference was noted between PD and PS patients. The sensitivity and specificity of the findings for the differentiation between patients with the disease associated versus not associated with BG dysfunction were 80 and 83.3 %, respectively. A predictive positive value of 82.6 % was obtained using an additive scaling index defined as asymmetry and unevenness of uptake in putamen and/or caudate contralateral to the dominant side of current symptoms.

CONCLUSIONS:

99mTc-TRODAT-1 scan is an appropriate method to differentiate PD or PS versus ET. A combination of scan pattern including asymmetry of BG uptake and unevenness of activity in caudate and putamen along with the side of dominant symptoms may be valuable for the differentiation of Parkinson's disease from the other parkinsonian syndromes.

Thursday, 26 November 2015

Systematic review and meta-analysis of salivary protein concentration in Parkinson's disease

Our new meta published as a letter in Movement Disorders, therefore no abstract. Of the published studies thus far, it appears that total protein concentration is increased in the saliva of patients with PD. We have to use a method called Standardized Mean Difference (see figure below) because of differences in the way protein concentration was measured. The next question is... what are these proteins?

Mov Disord. 2015 Nov 19. doi: 10.1002/mds.26462. [Epub ahead of print]
Masters JM, Bestwick J, Warner TT, Giovannoni G, Proctor GB, Noyce AJ.



MDS research criteria for prodromal Parkinson's disease

Hmmm Bayesian methods using likelihood ratios to update age related odds of PD... where have I heard that approach before?? Nonetheless very important to formalise this approach and I think these criteria will be used widely...

Mov Disord. 2015 Oct;30(12):1600-11. doi: 10.1002/mds.26431.

Berg D, Postuma RB, Adler CH, Bloem BR, Chan P, Dubois B, Gasser T, Goetz CG, Halliday G, Joseph L, Lang AE, Liepelt-Scarfone I, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G.



This article describes research criteria and probability methodology for the diagnosis of prodromal PD. Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible. Given the lack of clear neuroprotective/disease-modifying therapy for prodromal PD, these criteria were developed for research purposes only. The criteria are based upon the likelihood of prodromal disease being present with probable prodromal PD defined as ≥80% certainty. Certainty estimates rely upon calculation of an individual's risk of having prodromal PD, using a Bayesian naïve classifier. In this methodology, a previous probability of prodromal disease is delineated based upon age. Then, the probability of prodromal PD is calculated by adding diagnostic information, expressed as likelihood ratios. This diagnostic information combines estimates of background risk (from environmental risk factors and genetic findings) and results of diagnostic marker testing. In order to be included, diagnostic markers had to have prospective evidence documenting ability to predict clinical PD. They include motor and nonmotor clinical symptoms, clinical signs, and ancillary diagnostic tests. These criteria represent a first step in the formal delineation of early stages of PD and will require constant updating as more information becomes available. © 2015 International Parkinson and Movement Disorder Society.

Wednesday, 25 November 2015

REM sleep behavior disorder, as assessed by questionnaire, in G2019S LRRK2 mutation PD and carriers.

Not sure I arrive at the same conclusions here... which should be suffixed with 'in LRRK2 mutation carriers'. There are differences between LRRK2 patients and patients with iPD and these differences likely extend into the pre-diagnostic phase too. That said, I think the RBDSQ is prone to significant inaccuracy... at least that is our experience.

Mov Disord. 2015 Sep 14. doi: 10.1002/mds.26413. [Epub ahead of print]

Saunders-Pullman R, Alcalay RN, Mirelman A, Wang C, Luciano MS, Ortega RA, Glickman A, Raymond D, Mejia-Santana H, Doan N, Johannes B, Yasinovsky K, Ozelius L, Clark L, Orr-Utreger A, Marder K, Giladi N, Bressman SB; AJ LRRK2 Consortium.


BACKGROUND:
Rapid eye movement sleep behavior disorder occurs with idiopathic Parkinson's disease (PD) and often precedes PD. Its frequency in LRRK2-PD and utility as a preclinical marker has not been established.

METHODS:
One hundred forty-four idiopathic PD, 142 LRRK2 G2019S mutation PD, 117 non-manifesting carriers, 93 related noncarriers, and 40 healthy controls completed the Rapid eye movement sleep Behavior Disorder Screening Questionnaire.

RESULTS:
Cut scores were met by 30.6% idiopathic PD, 19.7% LRRK2-PD, 6% nonmanifesting carriers, 20.4% related noncarriers, and 15% controls. The likelihood of abnormal scores was decreased in LRRK2-PD versus idiopathic PD (odds ratio = 0.55, P = 0.03), nonmanifesting carriers versus related noncarriers (OR = 0.25, P < 0.01), and PD of less than 3 years' duration, 1 of 19 LRRK2-PD versus 14 of 41 idiopathic PD (P < 0.05).

CONCLUSIONS:
A lower frequency of abnormal questionnaire scores is seen in LRRK2-PD, especially in early LRRK2-PD, and in nonmanifesting carriers. Therefore, the Rapid eye movement sleep Behavior Disorder Questionnaire is unlikely to serve as a preclinical marker for phenoconversion to PD. © 2015 International Parkinson and Movement Disorder Society.

Saturday, 14 November 2015

Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinson’s Disease Patients

Once potential biomarkers of a disease are discovered, it is important that they are 'validated' in a group of patients and controls different from the group in which the biomarker was initially discovered.

In this study, the researchers test for the presence of 10 candidate biomarkers (discovered in previous work) in the blood of patients very recently diagnosed with PD and controls.

A particular strength of this study is that the newly diagnosed patients had not yet been prescribed any treatments for Parkinson's. This removes the possibility that PD medications might be having an effect on the biomarker levels and suggests that the biomarkers are reflective of the underlying diseas process.

The researchers makes use of samples from the Parkinson's Progression Markers Initiative (PPMI) demonstrating, how large collaborative projects can help accelerate biomarker discovery.


ResearchBlogging.org Santiago JA, & Potashkin JA (2015). Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinson's Disease Patients. PloS one, 10 (11) PMID: 26566043




Abstract


Early diagnosis of Parkinson’s disease (PD) continues to be a major challenge in the field. The lack of a robust biomarker to detect early stage PD patients has considerably slowed the progress toward the development of potential therapeutic agents. We have previously evaluated several RNA biomarkers in whole blood from participants enrolled in two independent clinical studies. In these studies, PD patients were medicated, thus, expression of these biomarkers in de novo patients remains unknown. To this end, we tested ten RNA biomarkers in blood samples from 99 untreated PD patients and 101 HC nested in the cross-sectional Parkinson’s Progression Markers Initiative by quantitative real-time PCR. One biomarker out of ten, COPZ1 trended toward significance (nominal p = 0.009) when adjusting for age, sex, and educational level. Further, COPZ1, EFTUD2 and PTBP1 mRNAs correlated with clinical features in PD patients including the Hoehn and Yahr scale, Movement Disorder Society revision of Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA) score. Levels of EFTUD2 and PTBP1 were significantly higher in cognitively normal PD patients (PD-CN) compared to cognitively impaired PD patients (PD-MCI). Interestingly, blood glucose levels were significantly higher in PD and PD-MCI patients (≥ 100 mg/dL, pre-diabetes) compared to HC. Collectively, we report the association of three RNA biomarkers, COPZ1, EFTUD2 and PTBP1 with clinical features including cognitive decline in early drug-naïve PD patients. Further, our results show that drug-naïve PD and PD-MCI patients have glucose levels characteristic of pre-diabetes patients, suggesting that impaired glucose metabolism is an early event in PD. Evaluation of these potential biomarkers in a larger longitudinal study is warranted.

Risk factors for hip fracture in very old people: a population-based study

Once again PD shown to be a major risk factor for hip fracture in older persons...

Osteoporos Int. 2015 Nov 4. [Epub ahead of print]
Wiklund R, Toots A, Conradsson M, Olofsson B, Holmberg H, Rosendahl E, Gustafson Y, Littbrand H.


Abstract
Knowledge of risk factors for hip fracture among very old people is limited. Walking indoors with help from ≤1 person, Parkinson's disease, currently smoking, delirium in the previous month, underweight, and age were associated with increased risk of hip fracture and could be important for preventive strategy development.
INTRODUCTION:
The purpose of this study is to investigate risk factors for hip fracture among a representative sample of very old people.
METHODS:
In total, 953 participants from the Umeå 85+/Gerontological Regional Database population-based cohort study were interviewed and assessed during home visits. Associations of baseline characteristics with hip fracture during the maximum 5-year follow-up period were analyzed using Cox proportional hazards regression.
RESULTS:
Participants had a mean age of 89.3 ± 4.7 years; 65.8 % were women, 36.8 % lived in residential care facilities, 33.6 % had dementia, and 20.4 % had histories of hip fracture. During a mean follow-up period of 2.7 years, 96 (10.1 %) individuals sustained hip fracture. Walking indoors with help from no more than one person (hazard ratio [HR] = 8.57; 95 % confidence interval [CI], 1.90-38.71), Parkinson's disease (HR = 5.12; 95 % CI, 1.82-14.44), currently smoking (HR = 4.38; 95 % CI 2.06-9.33), delirium in the previous month (HR = 2.01; 95 % CI, 1.15-3.49), underweight (body mass index <22; HR = 1.74, 95 % CI, 1.09-2.77), and age (HR = 1.09; 95 % CI, 1.04-1.14) were associated independently with an increased risk of hip fracture. Hip prosthesis at baseline decreased the risk of hip fracture (HR = 0.37; 95 % CI, 0.15-0.91), but only for those with bilateral hip prostheses.
CONCLUSIONS:

Seven factors were associated independently with incident hip fracture during follow-up in this sample of very old people. These factors could have important clinical implications in identifying persons at high risk of hip fracture, as well as in the development of effective preventive strategies.

Friday, 13 November 2015

Coenzyme Q10 for Patients with Parkinson's disease: A Systematic Review and Meta-analysis

No effect in meta-analysis... but this could mean that it is ineffective or that rating scales don't reflect underlying disease.... 

CNS Neurol Disord Drug Targets. 2015 Nov 10. [Epub ahead of print]
Negida A, Menshawy A, El Ashal G, Elfouly Y, Hani Y, Hegazy Y, El Ghonimy S, Fouda S, Rashad Y.

Abstract

Introduction Coenzyme Q10 (CoQ10) is an antioxidant that enhances the activity of complex I and II in the Electron Transport Chain. Many preclinical and clinical studies evaluated CoQ10 for neuroprotection against Parkinson's disease (PD). The aim of this study is to synthesize evidence from published randomized controlled trials (RCTs) about the benefit of CoQ10 supplementation for patients with Parkinson's disease. Methods We followed the PRISMA statement guidelines during the preparation of this systematic review and meta-analysis. A computer literature search for (PubMed, EBSCO, Web of science and Ovid Midline) was carried out. We included RCTs comparing CoQ10 with placebo in terms of motor functions and quality of life. Outcomes of total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS I, UPDRS II, UPDRS III and Schwab and England scores were pooled as standardized mean difference (SMD) between two groups from baseline to the endpoint. Results Five RCTs (981 patients) were included in this study. The overall effect did not favor either of the two groups in terms of: total UPDRS score (SMD -0.05, 95%CI [-0.10, 0.15]), UPDRS I (SMD -0.03, 95% CI [-0.23, 0.17]), UPDRS II (SMD -0.10, 95%CI [-0.35, 0.15]), UPDRS III (SMD -0.05, 95%CI [-0.07, 0.17]) or Schwab and England score (SMD 0.08, 95%CI [-0.13, 0.29]). Conclusion CoQ10 supplementation does not slow functional decline nor provide any symptomatic benefit for patients with Parkinson's disease.

Saturday, 7 November 2015

A Validated Smartphone-Based Assessment of Gait and Gait Variability in Parkinson's Disease.

More smart phone tech for PD monitoring...

PLoS One. 2015 Oct 30;10(10):e0141694. doi: 10.1371/journal.pone.0141694. eCollection 2015.
Ellis RJ, Ng YS, Zhu S, Tan DM, Anderson B, Schlaug G, Wang Y.


BACKGROUND:
A well-established connection exists between increased gait variability and greater fall likelihood in Parkinson's disease (PD); however, a portable, validated means of quantifying gait variability (and testing the efficacy of any intervention) remains lacking. Furthermore, although rhythmic auditory cueing continues to receive attention as a promising gait therapy for PD, its widespread delivery remains bottlenecked. The present paper describes a smartphone-based mobile application ("SmartMOVE") to address both needs.

METHODS:
The accuracy of smartphone-based gait analysis (utilizing the smartphone's built-in tri-axial accelerometer and gyroscope to calculate successive step times and step lengths) was validated against two heel contact-based measurement devices: heel-mounted footswitch sensors (to capture step times) and an instrumented pressure sensor mat (to capture step lengths). 12 PD patients and 12 age-matched healthy controls walked along a 26-m path during self-paced and metronome-cued conditions, with all three devices recording simultaneously.

RESULTS:
Four outcome measures of gait and gait variability were calculated. Mixed-factorial analysis of variance revealed several instances in which between-group differences (e.g., increased gait variability in PD patients relative to healthy controls) yielded medium-to-large effect sizes (eta-squared values), and cueing-mediated changes (e.g., decreased gait variability when PD patients walked with auditory cues) yielded small-to-medium effect sizes-while at the same time, device-related measurement error yielded small-to-negligible effect sizes.

CONCLUSION:

These findings highlight specific opportunities for smartphone-based gait analysis to serve as an alternative to conventional gait analysis methods (e.g., footswitch systems or sensor-embedded walkways), particularly when those methods are cost-prohibitive, cumbersome, or inconvenient.

Friday, 6 November 2015

Increased CSF biomarkers of angiogenesis in Parkinson disease

The authors of this study have found increased biomarkers of angiogenesis (proteins related to new blood vessel formation) in the CSF of patients with PD and PD with dementia (PDD).

The authors also detected increased CSF/plasma albumin ratio in the patients with PD, which suggests a loss of integrity in the blood-brain barrier in patients with PD. Interestingly, the biomarkers of angiogenesis were correlated with CSF/plasma albumin ratio, leading the authors to suggest that angiogenic factors might contribute to cerebral microbleeds and reduced blood brain barrier function, which could in be involved in the pathogenesis of PD.

This idea that angiogenesis and reduced blood-brain barrier function might contribute to the disease process in PD is not entirely new. A few studies of animal models of PD and post-mortem studies of PD patients' brains have also found increased levels of VEGF (one of the markers of angiogenesis identified by this paper) and signs of vascular proliferation. However, it is a relatively unexplored area.

The study methodology seems robust. The the validation of the associations in a separate validation cohort, is particularly good practice; this helps ensure the initial findings are not due to chance.

I think the paper is a nice example of how biomarker research, though normally aimed at helping improve diagnosis of the condition, can lead to insights into how the disease process actually works and potentially even reveal new targets for disease modifying treatment.

Abstract

Objective: To study biomarkers of angiogenesis in Parkinson disease (PD), and how these are associated with clinical characteristics, blood–brain barrier (BBB) permeability, and cerebrovascular disease.

Methods: In this cross-sectional analysis, 38 elderly controls and 100 patients with PD (82 without dementia and 18 with dementia) were included from the prospective Swedish BioFinder study. CSF samples were analyzed for the angiogenesis biomarkers vascular endothelial growth factor (VEGF); its receptors, VEGFR-1 and VEGFR-2; placental growth factor (PlGF); angiopoietin 2 (Ang2); and interleukin-8. BBB permeability, white matter lesions (WMLs), and cerebral microbleeds (CMB) were assessed. CSF angiogenesis biomarkers were also measured in 2 validation cohorts: (1) 64 controls and 87 patients with PD with dementia; and (2) 35 controls and 93 patients with neuropathologically confirmed diagnosis of PD with and without dementia.

Results: Patients with PD without dementia displayed higher CSF levels of VEGF, PlGF, and sVEGFR-2, and lower levels of Ang2, compared to controls. Similar alterations in VEGF, PlGF, and Ang2 levels were observed in patients with PD with dementia. Angiogenesis markers were associated with gait difficulties and orthostatic hypotension as well as with more pronounced BBB permeability, WMLs, and CMB. Moreover, higher levels of VEGF and PlGF levels were associated with increased CSF levels of neurofilament light (a marker of neurodegeneration) and monocyte chemotactic protein–1 (a marker of glial activation). The main results were validated in the 2 additional cohorts.

Conclusions: CSF biomarkers of angiogenesis are increased in PD, and they are associated with gait difficulties, BBB dysfunction, WMLs, and CMB. Abnormal angiogenesis may be important in PD pathogenesis and contribute to dopa-resistant symptoms.

ResearchBlogging.org Janelidze S, Lindqvist D, Francardo V, Hall S, Zetterberg H, Blennow K, Adler CH, Beach TG, Serrano GE, van Westen D, Londos E, Cenci MA, & Hansson O (2015). Increased CSF biomarkers of angiogenesis in Parkinson disease. Neurology PMID: 26511451

Analysis of the genetic variability in Parkinson's disease from Southern Spain

Interesting to see the contribution of known PD genes (and some novel mutations) in this diverse region...

Neurobiol Aging. 2015 Oct 8. pii: S0197-4580(15)00477-7. doi: 10.1016/j.neurobiolaging.2015.09.020. [Epub ahead of print]
Bandrés-Ciga S, Mencacci NE, Durán R, Barrero FJ, Escamilla-Sevilla F, Morgan S, Hehir J, Vives F, Hardy J, Pittman AM.



To date, a large spectrum of genetic variants has been related to familial and sporadic Parkinson's disease (PD) in diverse populations worldwide. However, very little is known about the genetic landscape of PD in Southern Spain, despite its particular genetic landscape coming from multiple historical migrations. We included 134 PD patients in this study, of which 97 individuals were diagnosed with late-onset sporadic PD (LOPD), 28 with early-onset sporadic PD (EOPD), and 9 with familial PD (FPD). Genetic analysis was performed through a next-generation sequencing panel to screen 8 PD-related genes (LRRK2, SNCA, PARKIN, PINK1, DJ-1, VPS35, GBA, and GCH1) in EOPD and FPD groups and direct Sanger sequencing of GBA exons 8-11 and LRRK2 exons 31 and 41 in the LOPD group. In the EOPD and FPD groups, we identified 11 known pathogenic mutations among 15 patients (40.5 %). GBA (E326K, N370S, D409H, L444P) mutations were identified in 7 patients (18.9 %); LRRK2 (p.R1441G and p.G2019S) in 3 patients (8.1 %); biallelic PARK2 mutations (p.N52fs, p.V56E, p.C212Y) in 4 cases (10.8%) and PINK1 homozygous p.G309D in 1 patient (2.7 %). An EOPD patient carried a single PARK2 heterozygous mutation (p.R402C), and another had a novel heterozygous mutation in VPS35 (p.R32S), both of unknown significance. Moreover, pathogenic mutations in GBA (E326K, T369M, N370S, D409H, L444P) and LRRK2 (p.R1441G and p.G2019S) were identified in 13 patients (13.4 %) and 4 patients (4.1 %), respectively, in the LOPD group. A large number of known pathogenic mutations related to PD have been identified. In particular, GBA and LRRK2 mutations appear to be considerably frequent in our population, suggesting a strong Jewish influence. Further research is needed to study the contribution of the novel found mutation p.R32S in VPS35 to the pathogenesis of PD.

Thursday, 5 November 2015

The relationship between essential tremor and Parkinson's disease

We see this occasionally in the clinic... and there are lots of lines of evidence to suggest an association...

Parkinsonism Relat Disord. 2015 Oct 9. pii: S1353-8020(15)00421-6. doi: 10.1016/j.parkreldis.2015.09.032. [Epub ahead of print]
Thenganatt MA, Jankovic J.


Abstract

Essential tremor (ET) and Parkinson's disease (PD) are the two most common tremor disorders encountered in a movement disorders clinic. Although distinct clinical-pathological entities, both disorders may share overlapping features in addition to rest and postural tremor, such as bradykinesia, rigidity, gait and balance impairment and some non-motor signs. A subset of patients may have a combination of long-standing ET with subsequent PD (ET-PD). There are several lines of evidence from clinical, epidemiologic, imaging, genetic and pathologic studies supporting a link between ET and PD, greater than by chance alone. In this review we will discuss the latest data supporting a relationship between ET and PD and the implications for possible pathogenic link and treatment.

Wednesday, 4 November 2015

Methods in Neuroepidemiology Characterization of European Longitudinal Cohort Studies in Parkinson's Disease - Report of the JPND Working Group BioLoC-PD

Neuroepidemiology. 2015 Nov 3;45(4):282-297. [Epub ahead of print]
Lerche S, Liepelt-Scarfone I, Alves G, Barone P, Behnke S, Ben-Shlomo Y, Berendse H, Burn D, Dodel R, Grosset D, Heinzel S, Hu M, Kasten M, Krüger R, Maetzler W, Moccia M, Mollenhauer B, Oertel W, Roeben B, Sünkel U, Walter U, Wirdefeldt K, Berg D.


BACKGROUND:
Enormous effort is being put into the identification and characterization of symptoms that may be used as predictive and progression markers in Parkinson's disease (PD). An impressive number of PD patients and individuals at risk for or in the prodromal stage of PD are currently followed in longitudinal studies; however, there does not exist an overview on the kind of markers evaluated and the assessments used.

METHODS:
Information on the design, sample size, evaluated markers and assessments of 21 studies of the Joint Programme - Neurodegenerative Disease Research BioLoC-PD working group were collected by questionnaire. The studies were classified into at risk/prodromal or clinical PD cohorts. The assessments were grouped into quantitative assessments, investigator-rated assessments, investigator interviews, patient-rated questionnaires and caregiver-rated questionnaires.

RESULTS:
Compilation of these data revealed an interesting consensus on evaluated markers, but there was an enormous variability of assessments. Furthermore, there is a remarkable similarity in the markers assessed and evaluation methods applied in the risk/prodromal and clinical PD cohorts.

CONCLUSIONS:

The inventory of the longitudinal cohorts that are part of the BioLoC-PD consortium reveals that there is a growing consensus on the markers that should be assessed in longitudinal cohort studies in PD. However, controversy still exists on the specific type of assessment. To allow comparison of data and common analyses it will be essential to harmonize scales and assessment outcomes.

Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned

No significant improvement in 'off' time using preladenant... but the investigators raise questions about the study design and conduct, which may have obscured benefits...

JAMA Neurol. 2015 Nov 2:1-10. doi: 10.1001/jamaneurol.2015.2268. [Epub ahead of print]
Hauser RA, Stocchi F, Rascol O, Huyck SB, Capece R, Ho TW, Sklar P, Lines C, Michelson D, Hewitt D.


IMPORTANCE:
Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials.

OBJECTIVE:
To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations.

DESIGN, SETTING, AND PARTICIPANTS:
Two 12-week, phase 3, randomized, placebo-controlled, double-blind trials performed from July 15, 2010, to April 16, 2013. The setting included neurology clinics, clinical research centers, and hospitals in the Americas, the European Union, Eastern Europe, India, and South Africa. Participants included patients with moderate to severe PD taking levodopa who were experiencing motor fluctuations.

INTERVENTIONS:
In trial 1, a total of 778 eligible patients were randomized to the addition of preladenant (2 mg, 5 mg, or 10 mg twice daily), placebo, or rasagiline mesylate (1 mg/d) in a 1:1:1:1:1 ratio. In trial 2, a total of 476 eligible patients were randomized to the addition of preladenant (2 mg or 5 mg twice daily) or placebo in a 1:1:1 ratio.

MAIN OUTCOMES AND MEASURES:
The primary outcome measure was change in off time from baseline to week 12.

RESULTS:
In trial 1, neither preladenant nor rasagiline was superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.10 hour (95% CI, -0.69 to 0.46 hour) for preladenant 2 mg twice daily, -0.20 hour (95% CI, -0.75 to 0.41 hour) for preladenant 5 mg twice daily, -0.00 hour (95% CI, -0.62 to 0.53 hour) for preladenant 10 mg twice daily, and -0.30 hour (95% CI, -0.90 to 0.26 hour) for rasagiline mesylate 1 mg/d. In trial 2, preladenant was not superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.20 hour (95% CI, -0.72 to 0.35 hour) for preladenant 2 mg twice daily and -0.30 hour (95% CI, -0.86 to 0.21 hour) for preladenant 5 mg twice daily. Preladenant was well tolerated, with the most common adverse event that showed an increase over placebo in both trials being constipation (6%-8% for preladenant vs 1%-3% for placebo).

CONCLUSIONS AND RELEVANCE:

In these phase 3 trials, preladenant did not significantly reduce off time compared with placebo. That the active control rasagiline also failed to demonstrate a significant reduction in off time suggests that issues of study design or conduct may have affected these trials.

Saturday, 31 October 2015

Pathogenesis of Parkinson disease-the gut-brain axis and environmental factors

Interesting article... that said there is plenty of evidence in favour of genetics explaining much of the risk and heterogeneity of PD... time to stop considering genes and the environment independently...?

Nat Rev Neurol. 2015 Oct 27. doi: 10.1038/nrneurol.2015.197. [Epub ahead of print]
Klingelhoefer L, Reichmann H.

Abstract

Parkinson disease (PD) follows a defined clinical pattern, and a range of nonmotor symptoms precede the motor phase. The predominant early nonmotor manifestations are olfactory impairment and constipation. The pathology that accompanies these symptoms is consistent with the Braak staging system: α-synuclein in the dorsal motor nucleus of the vagus nerve, the olfactory bulb, the enteric nervous system (ENS) and the submandibular gland, each of which is a gateway to the environment. The neuropathological process that leads to PD seems to start in the ENS or the olfactory bulb and spreads via rostrocranial transmission to the substantia nigra and further into the CNS, raising the intriguing possibility that environmental substances can trigger pathogenesis. Evidence from epidemiological studies and animal models supports this hypothesis. For example, in mice, intragastric administration of the pesticide rotenone can almost completely reproduce the typical pathological and clinical features of PD. In this Review, we present clinical and pathological evidence to support the hypothesis that PD starts in the gut and spreads via trans-synaptic cell-to-cell transfer of pathology through the sympathetic and parasympathetic nervous systems to the substantia nigra and the CNS. We also consider how environmental factors might trigger pathogenesis, and the potential for therapeutically targeting the mechanisms of these initial stages.

Friday, 30 October 2015

Increased risk of brain tumor in patients with Parkinson's disease: a nationwide cohort study in Taiwan

Unfortunately from what I can see, the paper doesn't tell us what proportion of these subjects had brain scans. One can imagine that although a brain scan is not essential for the diagnosis of PD, people with PD are still more likely to have a brain scan than those in the background population. This could explain the excess numbers observed...

Acta Neurol Scand. 2015 Oct 28. doi: 10.1111/ane.12524. [Epub ahead of print]
Tang CF, Lu MK, Muo CH, Tsai CH, Kao CH.

OBJECTIVES:
Parkinson's disease (PD) is a neurodegenerative disease. A decreased risk of cancer, except for melanoma, has been observed in patients with PD. The aim of this study was to evaluate the association between brain tumor and PD in a Taiwanese population.

MATERIALS AND METHODS:
We used data from the National Health Insurance program of Taiwan. The PD cohort contained 2998 patients, and each patient was frequency-matched, based on age and sex, with 4 people without PD, who were randomly selected from the general population. Cox's proportional hazard regression analysis was conducted to estimate the effects of PD on the risk of brain tumor.

RESULTS:
The risk of developing brain tumor was significantly higher in patients with PD than in those without PD (adjusted hazard ratio = 2.11; 95% confidence interval (CI) = 1.24-3.59), and benign brain tumor exhibited a particularly elevated risk of 2.16-fold (95% CI = 1.26-3.68). The hazard ratio (HR) for developing a benign brain tumor was higher in female patients with PD than in female patients without PD, with the risk being 2.65-fold (95% CI = 1.30-5.43). An analysis of the two age groups, 50-64 years and ≥65 years, showed that the HR of only the 50-64-year group was significantly higher between the PD and non-PD groups (HR = 2.77, 95% CI = 1.07-7.14).

CONCLUSION:

The present study showed that Taiwanese patients with PD are at a higher risk of developing brain tumor than the general population. The exact underlying etiologies require further investigation.

Wednesday, 28 October 2015

Pisa syndrome in Parkinson disease: An observational multicenter Italian study

More common than one would expect, but important insights into this disabling feature of PD. Risk factors, preventive measures and treatments are really important for patients and their relatives...

Neurology. 2015 Oct 21. pii: 10.1212/WNL.0000000000002122. [Epub ahead of print]
Tinazzi M, Fasano A, Geroin C, Morgante F, Ceravolo R, Rossi S, Thomas A, Fabbrini G, Bentivoglio A, Tamma F, Cossu G, Modugno N, Zappia M, Volontè MA, Dallocchio C, Abbruzzese G, Pacchetti C, Marconi R, Defazio G, Canesi M, Cannas A, Pisani A, Mirandola R, Barone P, Vitale C; Italian Pisa Syndrome Study Group.


OBJECTIVE:
To estimate the prevalence of Pisa syndrome (PS) in patients with Parkinson disease (PD) and to assess the association between PS and demographic and clinical variables.

METHODS:
In this multicenter cross-sectional study, consecutive outpatients with PD attending 21 movement disorders Italian tertiary centers were enrolled and underwent standardized clinical evaluation. PS was defined as trunk lateral deviation ≥10°. Patients with PD were compared according to the presence of PS for several demographic and clinical variables.

RESULTS:
Among 1,631 enrolled patients with PD, PS was detected in 143 patients (8.8%, 95% confidence interval 7.4%-10.3%). Patients with PS were older, had lower body mass index, longer disease duration, higher disease stages, and poorer quality of life. Falls were more frequent in the PS group as well as occurrence of "veering gait" (i.e., the progressive deviation toward one side when patient walked forward and backward with eyes closed). Patients with PS received higher daily levodopa equivalent daily dose and were more likely to be treated with combination of levodopa and dopamine agonists. Osteoporosis and arthrosis were significantly the most frequent associated medical conditions in patients with PS. Multiple explanatory variable logistic regression models confirmed the association of PS with the following variables: Hoehn and Yahr stage, ongoing combined treatment with levodopa and dopamine agonist, associated medical conditions, and presence of veering gait.

CONCLUSIONS:

Our results suggest that PS is a relatively frequent and often disabling complication in PD, especially in the advanced disease stages. The association is dependent on a number of potentially relevant demographic and clinical variables.

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

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