Alpha-synuclein immunoreactivity patterns in the enteric nervous system

Further evidence that some staining for alpha-syn can be seen resected GI tissue but that staining patterns may differ between patients and controls...and this in itself may hold more promise as a biomarker than simply the presence of alpha-syn alone...

Neurosci Lett. 2015 Jul 7. pii: S0304-3940(15)30023-9. doi: 10.1016/j.neulet.2015.07.005. [Epub ahead of print]

Aldecoa I, Navarro-Otano J, Stefanova N, Sprenger F, Seppi K, Poewe W, Cuatrecasas M, Valldeoriola F, Gelpi E, Tolosa E.

We aimed to compare immunoreactivity patterns of four different anti-α-syn antibodies in surgical specimens of the gastrointestinal tract of Parkinson disease and control cases. Surgical specimens from stomach, small and large bowel of 6 PD cases and 12 controls were studied. Primary antibodies: anti-α-syn clone KM51, anti-phosphorylated α-syn Ser129, anti-α-syn clone 15G7 and anti-nitrated α-syn505. We found different immunoreactivity patterns: a) coarse, Lewy-body-like aggregates labelled by the 4 antibodies and detected in 4/6 PD cases and in 1/12 controls; b) distinct punctate cytoplasmic staining of ganglion cells labelled by anti-phosphorylated-α-syn and detected in 3/6 PD cases and 3/12 controls; c) fine diffuse, synaptic-type staining of neural structures labelled by anti-α-syn-15G7 and anti-nitrated-α-syn505 and detected in all subjects. We conclude that different specific and non-specific immunoreactivity patterns are detected in surgical specimens of gastrointestinal tract when using different anti-α-syn antibodies, as they recognize different epitopes and states of alpha-synuclein protein. Coarse aggregates in neural structures seem to be the most promising marker for the diagnosis of Lewy-body parkinsonism when evaluating abnormal α-syn in the gastrointestinal tract.

Traffic-Related Air Pollution and Parkinson's Disease in Denmark: A Case-Control Study

Environ Health Perspect. 2015 Jul 7. [Epub ahead of print]

Ritz B, Lee PC, Hansen J, Funch Lassen C, Ketzel M, Sørensen M, Raaschou-Nielsen O.

OBJECTIVE:

Very little is currently known about air pollutants' adverse effects on neurodegenerative diseases even though recent studies have linked particulate exposures to brain pathologies associated with Parkinson's and Alzheimer's disease. Here we investigate long-term exposure to traffic-related air pollution and Parkinson's disease.

METHODS:

In a case-control study of 1,696 Parkinson's disease (PD) patients identified from Danish hospital registries and diagnosed 1996-2009 and 1,800 population controls matched by gender and year of birth we assessed long-term traffic-related air pollutant exposures (NO2) from a dispersion model, using residential addresses from 1971 to the date of diagnosis or first cardinal symptom for cases and the corresponding index date for their matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with logistic regression adjusting for matching factors and potential confounders.

RESULTS:

We found ambient air pollution from traffic sources to be associated with risk of PD, with a 9% higher risk (95% CI: 3, 16.0%) per interquartile range increase (2.97 μg/m3) in modeled NO2. For participants living for 20 years or more in the capital city odds ratios were larger (OR= 1.21; 95% CI: 1.11, 1.31) than in provincial towns (OR=1.10; 95% CI: 0.97, 1.26), while there was no association among rural residents.

CONCLUSIONS:

Our findings raise concerns about potential effects of air pollution from traffic and other sources on the risk of PD, particularly in populations with high or increasing exposures.

Increased oligomerization and phosphorylation of α-synuclein are associated with decreased activity of glucocerebrosidase and protein phosphatase 2A in aging monkey brains

I don't post many basic science articles and even fewer animal studies, but I do feel this is important. The interplay between GCase and oligomeric alpha-syn may be very important for the molecular basis of Parkinson's... Targeting therapies against GCase may be relevant to GBA associated-Parkinson's and idiopathic Parkinson's...

Neurobiol Aging. 2015 Jun 11. pii: S0197-4580(15)00315-2. doi: 10.1016/j.neurobiolaging.2015.06.004. [Epub ahead of print]

Liu G, Chen M, Mi N, Yang W, Li X, Wang P, Yin N, Li Y, Yue F, Chan P, Yu S.

Aging is associated with an increased risk for Parkinson's disease and dementia with Lewy bodies, in which α-synuclein (α-syn) oligomerization plays key pathogenic roles. Here, we show that oligomeric α-syn levels increase with age in the brain of cynomolgus monkeys and are accompanied by a decrease in the expression and activity of glucocerebrosidase (GCase), a lysosomal enzyme whose dysfunction is linked to accumulation of oligomeric α-syn. Besides, levels of α-syn phosphorylated at serine 129 (pS129 α-syn), a modification that promotes α-syn oligomerization also increase with age in the brain and is associated with a reduction in the activity of protein phosphatase 2A (PP2A), an enzyme that facilitates α-syn dephosphorylation. The inverse relationship between levels of oligomeric α-syn and pS129 α-syn and activity of GCase and PP2A was more evident in brain regions susceptible to neurodegeneration (i.e., the striatum and hippocampus) than those that are less vulnerable (i.e., cerebellum and occipital cortex). In vitro experiments showed that GCase activity was more potently inhibited by oligomeric than by monomeric α-syn in the lysosome-enriched fractions isolated from brain tissues and cultured neuronal cells. Inhibition of GCase activity induced an elevation of oligomeric α-syn levels, which was shown to increase pS129 α-syn levels and reduce PP2A activity in cultured neuronal cells. The alterations in oligomeric and pS129 α-syns and their association with GCase and PP2A in aging brains may explain the vulnerability of certain brain regions to neurodegeneration in Parkinson's disease and dementia with Lewy bodies.

Slides from my talk at Parkinson's 2015 conference in London

Parkinson's 2015 meeting 2nd July London from anoyce

Exercise Improves Cognition in Parkinson's Disease: The PRET-PD Randomized, Clinical Trial

Further support to suggest that exercise has effects beyond just keeping you fit in PD. 

This is a small study in subjects without dementia. It was well conducted - randomised and single blinded (investigators but not patients). At baseline, the treatment groups were similar, which suggests an even distribution of measured and unmeasured confounding factors. The effects are clinically meaningful and statistically significant despite the modest sample size... very interesting!

Mov Disord. 2015 Jul 6. doi: 10.1002/mds.26291. [Epub ahead of print]

David FJ, Robichaud JA, Leurgans SE, Poon C, Kohrt WM, Goldman JG, Comella CL, Vaillancourt DE, Corcos DM.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26291/full

BACKGROUND:

This article reports on the findings of the effect of two structured exercise interventions on secondary cognitive outcomes that were gathered as part of the Progressive Resistance Exercise Training in Parkinson's disease (PD) randomized, controlled trial.

METHODS:

This study was a prospective, parallel-group, single-center trial. Fifty-one nondemented patients with mild-to-moderate PD were randomly assigned either to modified Fitness Counts (mFC) or to Progressive Resistance Exercise Training (PRET) and were followed for 24 months. Cognitive outcomes were the Digit Span, Stroop, and Brief Test of Attention (BTA).

RESULTS:

Eighteen patients in mFC and 20 patients in PRET completed the trial. At 12 and at 24 months, no differences between groups were observed. At 12 months, relative to baseline, mFC improved on the Digit Span (estimated change: 0.3; interquartile range: 0, 0.7; P = 0.04) and Stroop (0.3; 0, 0.6; P = 0.04), and PRET improved only on the Digit Span (0.7; 0.3, 1; P < 0.01). At 24 months, relative to baseline, mFC improved on the Digit Span (0.7; 0.3, 1.7; P < 0.01) and Stroop (0.3; 0.1, 0.5; P = 0.03), whereas PRET improved on the Digit Span (0.5; 0.2, 0.8; P < 0.01), Stroop (0.2; -0.1, 0.6; P = 0.048), and BTA (0.3; 0, 0.8; P = 0.048). No neurological or cognitive adverse events were observed.

CONCLUSIONS:

This study provides class IV level of evidence that 24 months of PRET or mFC may improve attention and working memory in nondemented patients with mild-to-moderate Parkinson's disease. 

Cerebrospinal fluid tau and amyloid-β1-42 in patients with dementia

CSF based biomarkers are already being used in the Alzheimer's setting and this study suggests how they might be more widely used for other neurodegenerative disorders associated with cognitive decline...

Brain. 2015 Jun 30. pii: awv181. [Epub ahead of print]

Skillbäck T, Farahmand BY, Rosén C, Mattsson N, Nägga K, Kilander L, Religa D, Wimo A, Winblad B, Schott JM, Blennow K, Eriksdotter M, Zetterberg H.

http://brain.oxfordjournals.org/content/early/2015/06/30/brain.awv181.long

Abstract

Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-β1-42 and high levels of total tau and phosphorylated tau is typical of Alzheimer's disease. However, several neurodegenerative disorders may overlap with Alzheimer's disease both in regards to clinical symptoms and neuropathology. In a uniquely large cohort of dementia patients, we examined the associations of cerebrospinal fluid biomarkers for Alzheimer's disease molecular pathology with clinical dementia diagnoses and disease severity. We cross-referenced the Swedish Dementia Registry with the clinical laboratory database at the Sahlgrenska University Hospital. The final data set consisted of 5676 unique subjects with a clinical dementia diagnosis and a complete set of measurements for cerebrospinal fluid amyloid-β1-42, total tau and phosphorylated tau. In cluster analysis, disregarding clinical diagnosis, the optimal natural separation of this data set was into two clusters, with the majority of patients with early onset Alzheimer's disease (75%) and late onset Alzheimer's disease (73%) assigned to one cluster and the patients with vascular dementia (91%), frontotemporal dementia (94%), Parkinson's disease dementia (94%) and dementia with Lewy bodies (87%) to the other cluster. Frontotemporal dementia had the highest cerebrospinal fluid levels of amyloid-β1-42 and the lowest levels of total tau and phosphorylated tau. The highest levels of total tau and phosphorylated tau and the lowest levels of amyloid-β1-42 and amyloid-β1-42:phosphorylated tau ratios were found in Alzheimer's disease. Low amyloid-β1-42, high total tau and high phosphorylated tau correlated with low Mini-Mental State Examination scores in Alzheimer's disease. In Parkinson's disease dementia and vascular dementia low cerebrospinal fluid amyloid-β1-42 was associated with low Mini-Mental State Examination score. In the vascular dementia, frontotemporal dementia, dementia with Lewy bodies and Parkinson's disease dementia groups 53%, 34%, 67% and 53% of the subjects, respectively had abnormal amyloid-β1-42 levels, 41%, 41%, 28% and 28% had abnormal total tau levels, and 29%, 28%, 25% and 19% had abnormal phosphorylated tau levels. Cerebrospinal fluid biomarkers were strongly associated with specific clinical dementia diagnoses with Alzheimer's disease and frontotemporal dementia showing the greatest difference in biomarker levels. In addition, cerebrospinal fluid amyloid-β1-42, total tau, phosphorylated tau and the amyloid-β1-42:phosphorylated tau ratio all correlated with poor cognitive performance in Alzheimer's disease, as did cerebrospinal fluid amyloid-β1-42 in Parkinson's disease dementia and vascular dementia. The results support the use of cerebrospinal fluid biomarkers to differentiate between dementias in clinical practice, and to estimate disease severity.

Can clock drawing differentiate Alzheimer's disease from other dementias?

Perhaps expected results... parkinsonian patients not infrequently have problems with these types of task...

Int Psychogeriatr. 2015 Jul 3:1-12. [Epub ahead of print]

Tan LP, Herrmann N, Mainland BJ, Shulman K.

BACKGROUND:

Studies have shown the clock-drawing test (CDT) to be a useful screening test that differentiates between normal, elderly populations, and those diagnosed with dementia. However, the results of studies which have looked at the utility of the CDT to help differentiate Alzheimer's disease (AD) from other dementias have been conflicting. The purpose of this study was to explore the utility of the CDT in discriminating between patients with AD and other types of dementia.

METHODS:

A review was conducted using MEDLINE, PsycINFO, and Embase. Search terms included clock drawing or CLOX and dementia or Parkinson's Disease or AD or dementia with Lewy bodies (DLB) or vascular dementia (VaD).

RESULTS:

Twenty studies were included. In most of the studies, no significant differences were found in quantitative CDT scores between AD and VaD, DLB, and Parkinson's disease dementia (PDD) patients. However, frontotemporal dementia (FTD) patients consistently scored higher on the CDT than AD patients. Qualitative analyses of errors differentiated AD from other types of dementia.

CONCLUSIONS:

Overall, the CDT score may be useful in distinguishing between AD and FTD patients, but shows limited value in differentiating between AD and VaD, DLB, and PDD. Qualitative analysis of the type of CDT errors may be a useful adjunct in the differential diagnosis of the types of dementias.

When DLB, PD, and PSP masquerade as MSA: An autopsy study of 134 patients

Interesting report. The problem with all of these things is the heterogeneity in the clinical picture...further support for the need for biomarkers...

Neurology. 2015 Jul 2. pii: 10.1212/WNL.0000000000001807. [Epub ahead of print]

Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, Wszolek ZK, Langston JW, Dickson DW.

OBJECTIVE:

To determine ways to improve diagnostic accuracy of multiple system atrophy (MSA), we assessed the diagnostic process in patients who came to autopsy with antemortem diagnosis of MSA by comparing clinical and pathologic features between those who proved to have MSA and those who did not. We focus on likely explanations for misdiagnosis.

METHODS:

This is a retrospective review of 134 consecutive patients with an antemortem clinical diagnosis of MSA who came to autopsy with neuropathologic evaluation of the brain. Of the 134 patients, 125 had adequate medical records for review. Clinical and pathologic features were compared between patients with autopsy-confirmed MSA and those with other pathologic diagnoses, including dementia with Lewy bodies (DLB), Parkinson disease (PD), and progressive supranuclear palsy (PSP).

RESULTS:

Of the 134 patients with clinically diagnosed MSA, 83 (62%) had the correct diagnosis at autopsy. Pathologically confirmed DLB was the most common misdiagnosis, followed by PSP and PD. Despite meeting pathologic criteria for intermediate to high likelihood of DLB, several patients with DLB did not have dementia and none had significant Alzheimer-type pathology. Autonomic failure was the leading cause of misdiagnosis in DLB and PD, and cerebellar ataxia was the leading cause of misdiagnosis in PSP.

CONCLUSIONS:

The diagnostic accuracy for MSA was suboptimal in this autopsy study. Pathologically confirmed DLB, PD, and PSP were the most common diseases to masquerade as MSA. This has significant implications not only for patient care, but also for research studies in MSA cases that do not have pathologic confirmation.

Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations

These are really important data that shape our understanding particularly of GBA-associated PD... I am particularly interested in the results for 'benign' GBA variants as opposed to disease associated mutations. Moreover the fact that lower G-case activity is seen in PD non-carriers does (as the authors point out) make it an exciting therapeutic target!... 

Brain. 2015 Jun 27. pii: awv179. [Epub ahead of print]

Alcalay RN, Levy OA, Waters CC, Fahn S, Ford B, Kuo SH, Mazzoni P, Pauciulo MW, Nichols WC, Gan-Or Z, Rouleau GA, Chung WK, Wolf P, Oliva P, Keutzer J, Marder K, Zhang X.

http://brain.oxfordjournals.org/content/early/2015/06/27/brain.awv179.long

Abstract

Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometry-based assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P < 0.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 µmol/l/h versus 7.88 µmol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 µmol/l/h versus 11.93 µmol/l/h, P < 0.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P < 0.001; L444P, P < 0.001; 84GG, P = 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P < 0.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 µmol/l/h versus 11.85 µmol/l/h, P = 0.011). Difference compared to controls persisted in patients with idiopathic Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 µmol/l/h, versus 12.11 µmol/l/h, P = 0.036) and after adjustment for age and gender (P = 0.012). Interestingly, LRRK2 G2019S carriers (n = 36), most of whom had Parkinson's disease, had higher enzymatic activity than non-carriers (13.69 µmol/l/h versus 11.93 µmol/l/h, P = 0.002). In patients with idiopathic Parkinson's, higher glucocerebrosidase enzymatic activity was associated with longer disease duration (P = 0.002) in adjusted models, suggesting a milder disease course. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson's disease. The association of lower glucocerebrosidase activity in both GBA mutation carriers and Parkinson's patients without GBA mutations suggests that loss of glucocerebrosidase function contributes to the pathogenesis of Parkinson's disease. High glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. Taken together, these data suggest that glucocerebrosidase enzymatic activity could be a modifiable therapeutic target.

The diagnostic value of dopamine transporter imaging and olfactory testing in patients with parkinsonian syndromes

The problem with this study is the use of the B-SIT which is far more restricted than the UPSIT (12 items versus 40). Previous studies have shown comparable diagnostic accuracy between UPSIT and DaTSCAN, although one might perhaps expect imaging to perform better than objective smell testing. One needs to consider the costs here... UPSIT $25 and DaTSCAN over $1000. In my opinion both have a place in the clinical and research setting, and agree that in combination predictive value is likely to maximal...

J Neurol. 2015 Jun 30. [Epub ahead of print]

Georgiopoulos C, Davidsson A, Engström M, Larsson EM, Zachrisson H, Dizdar N.

Abstract

The aim of the study was to compare the efficacy of olfactory testing and presynaptic dopamine imaging in diagnosing Parkinson's disease (PD) and atypical parkinsonian syndromes (APS); to evaluate if the combination of these two diagnostic tools can improve their diagnostic value. A prospective investigation of 24 PD patients, 16 APS patients and 15 patients with non-parkinsonian syndromes was performed during an 18-month period. Single photon emission computed tomography with the presynaptic radioligand 123I-FP-CIT (DaTSCAN®) and olfactory testing with the Brief 12-item Smell Identification Test (B-SIT) were performed in all patients. DaTSCAN was analysed semi-quantitatively, by calculating two different striatal uptake ratios, and visually according to a predefined ranking scale. B-SIT score was significantly lower for PD patients, but not significantly different between APS and non-parkinsonism. The visual assessment of DaTSCAN had higher sensitivity, specificity and diagnostic accuracy compared to olfactory testing. Most PD patients (75 %) had visually predominant dopamine depletion in putamen, while most APS patients (56 %) had visually severe dopamine depletion both in putamen and in caudate nucleus. The combination of DaTSCAN and B-SIT led to a higher rate of correctly classified patients. Olfactory testing can distinguish PD from non-parkinsonism, but not PD from APS or APS from non-parkinsonism. DaTSCAN is more efficient than olfactory testing and can be valuable in differentiating PD from APS. However, combining olfactory testing and DaTSCAN imaging has a higher predictive value than these two methods separately.

Body Mass Index and Risk of Parkinson's Disease: A Dose-Response Meta-Analysis of Prospective Studies

No association with BMI and risk of Parkinson's overall, but confounding factors may be having a big role in this...

PLoS One. 2015 Jun 29;10(6):e0131778. doi: 10.1371/journal.pone.0131778. eCollection 2015.

Wang YL, Wang YT, Li JF, Zhang YZ, Yin HL, Han B.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131778

BACKGROUND:

A number of epidemiologic studies examining the relationship between body mass index (BMI) and the future occurrence of Parkinson's disease (PD) reported largely inconsistent findings. We conducted a dose-response meta-analysis of prospective studies to clarify this association.

METHODS:

Eligible prospective studies were identified by a search of PubMed and by checking the references of related publications. The generalized least squares trend estimation was employed to compute study-specific relative risks (RR) and 95% confidence intervals (CI) for an increase in BMI of 5 kg/m2, and the random-effects model was used to compute summary RR and 95% CI.

RESULTS:

A total of 10 prospective studies were included in the final analysis. An increase in BMI of 5 kg/m2 was not associated with PD risk, with a summary RR of 1.00 (95% CI = 0.89-1.12). Results of subgroup analysis found similar results except for a week positive association in studies that adjusted for alcohol consumption (RR = 1.13, 95% CI = 0.99-1.29), and a week inverse association in studies that did not (RR = 0.90, 95% CI = 0.78-1.04). In a separate meta-analysis, no significant association between overweight (25 kg/m2 ≤ BMI ≤29.9 kg/m2), obesity (BMI≥30 kg/m2) or excess weight (BMI≥25 kg/m2) and PD risk was observed.

CONCLUSION:

This meta-analysis does not support the notion that higher BMI materially increases PD risk. However, a week positive BMI-PD association that may be masked by confounders still cannot be excluded, and future prospective studies with a good control for potential confounding factors are needed.