Friday, 29 May 2015

Developments in the role of transcranial sonography for the differential diagnosis of parkinsonism

As one of the few people trained to do this examination on PD subjects in the UK I can vouch for the merits of its use in the both the clinical and research setting...

Curr Neurol Neurosci Rep. 2015 Jul;15(7):566. doi: 10.1007/s11910-015-0566-9.
Pilotto A, Yilmaz R, Berg D.


In the last two decades transcranial sonography (TCS) has developed as a valuable, supplementary tool in the diagnosis and differential diagnosis of movement disorders. In this review, we highlight recent evidence supporting TCS as a reliable method in the differential diagnosis of parkinsonism, combining substantia nigra (SN), basal ganglia and ventricular system findings. Moreover, several studies support SN hyperechogenicity as one of most important risk factors for Parkinson's disease (PD). The advantages of TCS include short investigation time, low cost and lack of radiation. Principal limitations are still the dependency on the bone window and operator experience. New automated algorithms may reduce the role of investigator skill in the assessment and interpretation, increasing TCS diagnostic reliability. Based on the convincing evidence available, the EFNS accredited the method of TCS a level A recommendation for supporting the diagnosis of PD and its differential diagnosis from secondary and atypical parkinsonism. An increasing number of training programmes is extending the use of this technique in clinical practice.

Thursday, 28 May 2015

Depression and subsequent risk of Parkinson disease: A nationwide cohort study

Interesting stuff indeed...dose dependent effect and significance differences observed up to two decades prior to diagnosis. To my knowledge this is the first study that has suggested depression precedes PD by this length of time but anxiety has been shown to antedate PD by a similar length of time...

Neurology. 2015 May 20. pii: 10.1212/WNL.0000000000001684. [Epub ahead of print]
Gustafsson H, Nordström A, Nordström P.


OBJECTIVE:
To investigate the long-term risk of Parkinson disease (PD) after depression and evaluate potential confounding by shared susceptibility to the 2 diagnoses.

METHODS:
The nationwide study cohort included 140,688 cases of depression, matched 1:3 using a nested case-control design to evaluate temporal aspects of study parameters (total, n = 562,631). Potential familial coaggregation of the 2 diagnoses was investigated in a subcohort of 540,811 sibling pairs. Associations were investigated using multivariable adjusted statistical models.

RESULTS:
During a median follow-up period of 6.8 (range, 0-26.0) years, 3,260 individuals in the cohort were diagnosed with PD. The multivariable adjusted odds ratio (OR) for PD was 3.2 (95% confidence interval [CI], 2.5-4.1) within the first year of depression, decreasing to 1.5 (95% CI, 1.1-2.0) after 15 to 25 years. Among participants with depression, recurrent hospitalization was an independent risk factor for PD (OR, 1.4; 95% CI, 1.1-1.9 for ≥5 vs 1 hospitalization). In family analyses, siblings' depression was not significantly associated with PD risk in index persons (OR, 1.1; 95% CI, 0.9-1.4).

CONCLUSIONS:

The time-dependent effect, dose-response pattern for recurrent depression, and lack of evidence for coaggregation among siblings all indicate a direct association between depression and subsequent PD. Given that the association was significant for a follow-up period of more than 2 decades, depression may be a very early prodromal symptom of PD, or a causal risk factor.

Wednesday, 27 May 2015

High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2* relaxometry

Interesting work... these kind of radiological markers may help define the pre-diagnostic stage of disease in asymptomatic gene carriers and perhaps more widely...

Mov Disord. 2015 May 22. doi: 10.1002/mds.26218. [Epub ahead of print]
Pyatigorskaya N, Sharman M, Corvol JC, Valabregue R, Yahia-Cherif L, Poupon F, Cormier-Dequaire F, Siebner H, Klebe S, Vidailhet M, Brice A, Lehéricy S.

The goal of this work was to investigate iron deposition in the basal ganglia and thalamus in symptomatic and asymptomatic leucine-rich repeat kinase 2 (LRRK2) and Parkin-associated Parkinson's disease (PD), using R2* relaxometry rate. Twenty subjects with genetic PD (four symptomatic and two asymptomatic Parkin subjects, nine symptomatic and five asymptomatic LRRK2 subjects) were compared with 20 patients with idiopathic PD (IPD) and 20 healthy subjects. Images were obtained at 3 teslas, using multi-echo T2 and T2* sequences. R2 and R2* values were calculated in the substantia nigra (SN), the striatum, the globus pallidus, and the thalamus. The R2* values in the SN were increased in IPD and mutation-carrying patients as compared with controls and in mutation-carrying patients as compared with IPD. Asymptomatic mutation carriers showed higher R2* values than controls and did not differ from IPD patients. No changes were seen in the other structures or in R2 values. These results are consistent with increased iron load in LRRK2- and Parkin-mutation carriers. The increased R2* in asymptomatic PD-mutation carriers suggests that iron deposition occurs early during the preclinical phase of the disease. R2* measurements may be used as markers for investigating nigrostriatal damage in preclinical mutation-carrying patients.
Mullin S, Schapira A. The genetics of Parkinson's disease. Br Med Bull. 2015
May 20. pii: ldv022. [Epub ahead of print] PubMed PMID: 25995343.

http://bmb.oxfordjournals.org/content/early/2015/05/20/bmb.ldv022.short?rss=1

Only 15 years ago in medical school Parkinson’s disease was said to be the very definition of a non genetically inherited disease. It’s taken a giant leap forward in our understanding of genetics to realise that, as is the case in Parkinson’s, genetic inheritance doesn’t have mean one gene giving rise to a disease, but rather many genes, modified possibly by environmental factors or even one another, interacting to cause it. This article describes the genetic causes which account for 30% or so of the inheritance of Parkinson’s disease and speculates on what underlies the 70% of genetic inheritance which is still unclear.    

The genetics of Parkinson's disease

Nice review on this topic by my colleague Stephen Mullin... well worth a read.
Our understanding of the contribution of genetics to PD grows all the time... whilst perhaps not a 'genetic' disorder in the classical sense, it is the very concept of 'genetic disorders' has changed dramatically as a result of Genome Wide Association Studies and will continue to unfold in the current era of Next Generation Sequencing. Things that were considered non-genetic are now increasingly recognised to have a an important and complex genetic contribution...

Br Med Bull. 2015 May 20. pii: ldv022. [Epub ahead of print]
Mullin S, Schapira A.

BACKGROUND:
Parkinson's disease (PD) was previously described as the prototypical sporadic disease; however, rapid advances in population and molecular genetics have revealed the existence of a significant number genetic risk factors, prompting its redefinition as a primarily genetic disorder.

SOURCES OF DATA:
Data for this review have been gathered from the published literature.

AREAS OF AGREEMENT:
Multiple haplotypes conveying variable but quantifiable genetic risk, acting concurrently and possibly interacting with one another, provide the basis for a new model of PD. The beginning of this revolution in our understanding came from the clinical observation of parkinsonism with a Mendelian pattern of inheritance in a number of families. The functional work that followed elucidated multiple disease pathways leading to the degeneration of the substantia nigra that characterizes PD. It is however only in recent years, with the emergence of large cohort genome-wide association studies (GWAS), that the relevance of these pathways to so-called sporadic PD has become apparent.

AREAS OF CONTROVERSY:
A substantial portion of the presumed genetic inheritance of PD remains at present undefined. Although it is likely that so-called intermediate risk genetic risk factors are the principal component of this 'missing heritability', this is yet to be proved.

GROWING POINTS:
Although the picture is by now means complete, the beginnings of rational basis for genetic screening of PD risk have begun to emerge. Equally, this enhanced understanding of the various genetic and in turn biochemical pathways shows promising signs of producing fruitful therapeutic strategies. Technological advances promise to reduce the costs associated with and further increase our capability to understand the complex influence of genetics on the pathogenesis of PD.

AREAS TIMELY FOR DEVELOPING RESEARCH:

The coming years will require the enhancement of current techniques and the development of new ones to define PD's missing heritability. It will also require functional work to define better and in turn potentially reverse the mechanisms that contribute with large effect sizes to the risk of sporadic PD.

Tuesday, 26 May 2015

External validation of a simple clinical tool used to predict falls in people with Parkinson disease

A different type of prediction for those with PD... one that predicts who might fall. This is really important because falls may be preventable and the sequelae of falls, namely fractures and head injuries can have profound negative effects on those with PD...

Parkinsonism Relat Disord. 2015 May 16. pii: S1353-8020(15)00210-2. doi: 10.1016/j.parkreldis.2015.05.008. [Epub ahead of print]
Duncan RP, Cavanaugh JT, Earhart GM, Ellis TD, Ford MP, Foreman KB, Leddy AL, Paul SS, Canning CG, Thackeray A, Dibble LE.


BACKGROUND:
Assessment of fall risk in an individual with Parkinson disease (PD) is a critical yet often time consuming component of patient care. Recently a simple clinical prediction tool based only on fall history in the previous year, freezing of gait in the past month, and gait velocity <1.1 m/s was developed and accurately predicted future falls in a sample of individuals with PD.

METHODS:
We sought to externally validate the utility of the tool by administering it to a different cohort of 171 individuals with PD. Falls were monitored prospectively for 6 months following predictor assessment.

RESULTS:
The tool accurately discriminated future fallers from non-fallers (area under the curve [AUC] = 0.83; 95% CI 0.76-0.89), comparable to the developmental study.

CONCLUSION:

The results validated the utility of the tool for allowing clinicians to quickly and accurately identify an individual's risk of an impending fall.

Monday, 25 May 2015

What do patients with scans without evidence of dopaminergic deficit (SWEDD) have? New evidence and continuing controversies

Agree to be honest... likely to represent two broad categories 1) those that are misdiagnosed as having PD and 2) those that are in the early stages and may develop DAT positivity at a later date...

J Neurol Neurosurg Psychiatry. 2015 May 19. pii: jnnp-2014-310256. doi: 10.1136/jnnp-2014-310256. [Epub ahead of print]
Erro R, Schneider SA, Quinn NP, Bhatia KP.


Abstract

The term SWEDD (scans without evidence for dopaminergic deficit) refers to the absence, rather than the presence, of an imaging abnormality in patients clinically presumed to have Parkinson's disease (PD). However, such a term has since been widely used in the medical literature, even as a diagnostic label. While many authors have suggested that different disorders of PD lookalikes may account for a proportion of SWEDD cases, others have claimed that some of them may have a benign subtype of PD. Thus, there has been ensuing controversy and confusion and the use of this term continues without clarity of what it represents. We have systematically reviewed all the studies involving patients with SWEDD with the aim of shedding light on what these patients actually have. It becomes clear from this systematic review that while most 'SWEDD' cases are due to a clinical misdiagnosis of PD, there exists a small proportion of patients with SWEDD who may have PD on the basis of a positive levodopa response, clinical progression, imaging and/or genetic evidence. The latter challenge the seemingly incontrovertible relationship between dopaminergic tracer binding and the diagnosis of nigrostriatal parkinsonism, particularly PD. Patients with SWEDD are unlikely to reflect a single clinical entity and we suggest that the term SWEDD should be abandoned.

Sunday, 24 May 2015

Fluid biomarkers in multiple system atrophy: A review of the MSA Biomarker Initiative

Neurobiol Dis. 2015 May 14. pii: S0969-9961(15)00166-7. doi: 10.1016/j.nbd.2015.05.004. [Epub ahead of print]
Laurens B, Constantinescu R, Freeman R, Gerhard A, Jellinger K, Jeromin A, Krismer F, Mollenhauer B, Schlossmacher MG, Shaw LM, Verbeek MM, Wenning GK, Winge K, Zhang J, Meissner WG.


Abstract

Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results suggest that combining several CSF fluid biomarkers may be more successful than using single markers, at least for the diagnosis. Currently, the clinically most useful markers may comprise a combination of the light chain of neurofilament (which is consistently elevated in MSA compared to controls and Parkinson's disease), metabolites of the catecholamine pathway and proteins such as α-synuclein, DJ-1 and total-tau. Beyond future efforts in biomarker discovery, the harmonization of standard operating procedures will be crucial for future success.

Saturday, 23 May 2015

Olfactory function combined with morphology distinguishes Parkinson's disease

Interesting to see that this battery can differentiate PD from atypical Parkinson's which can be very tricky. What about PD versus controls does MRI of the bulbs and tracts differentiate these two groups??

Parkinsonism Relat Disord. 2015 May 11. pii: S1353-8020(15)00197-2. doi: 10.1016/j.parkreldis.2015.05.001. [Epub ahead of print]


Sengoku R, Matsushima S, Bono K, Sakuta K, Yamazaki M, Miyagawa S, Komatsu T, Mitsumura H, Kono Y, Kamiyama T, Ito K, Mochio S, Iguchi Y.

OBJECTIVE:
This study aimed to examine whether the volume of the olfactory bulbs and tracts (OB & T) on magnetic resonance imaging (MRI) is useful for differentiating Parkinson's disease (PD) from PD-related disorders.

METHODS:
The study group comprised 13 patients with PD, 11 with multiple system atrophy (MSA), five with progressive supranuclear palsy, and five with corticobasal degeneration (PSP/CBD). All patients were evaluated using the odor stick identification test for Japanese (OSIT-J), 123I-meta-iodobenzylguanidine (MIBG) scintigraphy, and brain MRI. OB & T areas on 1-mm-thick coronal images were measured and summed for volumes. We examined relationships between olfactory function and volume, and cardiovascular dysautonomia. We defined the cut-off values for OSIT-J score or MIBG uptake and OB & T volume to discriminate PD from PD-related disorders and calculated the proportional rate of PD in four categorized groups.

RESULTS:
OB & T volume was smaller in PD than in MSA or PSP/CBD (p < 0.05 each). The cut-off for detecting PD patients was OSIT-J score <8, heart/mediastinum ratio <1.6, and OB & T volume <270 mm3. In the group with OSIT-J score <8 and OB & T volume <270 mm3, the proportion of PD patients among all patients with PD-related disorders was 91%. The rate of probable PD gradually increased as OSIT-J score and OB & T volume decreased (p < 0.001).

CONCLUSIONS:

Although preliminary, these data obtained from a combined morphological and functional evaluation of OB or cardiovascular dysautonomia could be useful for further differential of PD and other PD-related disorders.

Friday, 22 May 2015

Neuropathobiology of non-motor symptoms in Parkinson disease

This is important and may underpin efforts to define biomarkers (tissue markers at least) of pre-diagnostic PD... knowing the pathological substrate for these symptoms is essential to characterise and make objective measurement to monitor the pre-diagnosis stage...

J Neural Transm. 2015 May 15. [Epub ahead of print]
Jellinger KA.


Abstract

Parkinson disease (PD) is a multisystem disorder associated with α-synuclein aggregates throughout the central, autonomic, and peripheral nervous system, clinically characterized by motor and non-motor (NM) symptoms. The NMS in PD, many of which antedating motor dysfunction and representing a preclinical phase spanning 20 or more years, are linked to widespread distribution of α-synuclein pathology not restricted to the dopaminergic nigrostriatal system that is responsible for core motor features of PD. The pathologic substrate of NM manifestations such as olfactory, autonomic (gastrointestinal, urogenital, cardia, respiratory), sensory, skin, sleep, visual, neuropsychiatric dysfunctions (cognitive, mood, dementia), and others are critically reviewed. In addition to non-nigral brainstem nuclei, α-synuclein pathology involves sympathetic and parasympathetic, enteric, cardiac and pelvic plexuses, and many other organs indicating a topographical and chronological spread, particularly in the prodromal stages of the disease. Few animal models recapitulate NMS in PD. The relationship between regional α-synuclein/Lewy pathology, neurodegeneration and the corresponding clinical deficits awaits further elucidation. Controlled clinicopathologic studies will refine the correlations between presymptomatic and late-developing NM features of PD and neuropathology, and new premotor biomarkers will facilitate early diagnosis of PD as a basis for more effective preventive and therapeutic options of this devastating disease.

Thursday, 21 May 2015

Gastrointestinal dysfunction in Parkinson's disease

Nice Lancet Neurology review of GI dysfunction in PD...

Lancet Neurol. 2015 Jun;14(6):625-639. doi: 10.1016/S1474-4422(15)00007-1.
Fasano A, Visanji NP, Liu LW, Lang AE, Pfeiffer RF.



Our understanding of dysfunction of the gastrointestinal system in patients with Parkinson's disease has increased substantially in the past decade. The entire gastrointestinal tract is affected in these patients, causing complications that range from oral issues, including drooling and swallowing problems, to delays in gastric emptying and constipation. Additionally, small intestinal bacterial overgrowth and Helicobacter pylori infection affect motor fluctuations by interfering with the absorption of antiparkinsonian drugs. The multifaceted role of the gastrointestinal system in Parkinson's disease necessitates a specific and detailed assessment and treatment plan. The presence of pervasive α-synuclein deposition in the gastrointestinal tract strongly implicates this system in the pathogenesis of Parkinson's disease. Future studies elucidating the role of the gastrointestinal tract in the pathological progression of Parkinson's disease might hold potential for early disease detection and development of neuroprotective approaches.

Amyloid-β and α-synuclein cerebrospinal fluid biomarkers and cognition in early Parkinson's disease

More on CSF biomarkers and cognition in PD... nearly time for a meta-analysis!

Parkinsonism Relat Disord. 2015 May 2. pii: S1353-8020(15)00193-5. doi: 10.1016/j.parkreldis.2015.04.027. [Epub ahead of print]
Stav AL, Aarsland D, Johansen KK, Hessen E, Auning E, Fladby T.

INTRODUCTION:
Cognitive impairment in early Parkinson's disease (PD) is common and distinct from early Alzheimer's disease. Predictors and mechanisms are only partially known, but α-synuclein, amyloid-β and tau dysmetabolism may be involved. Our aim was to study associations between cerebrospinal fluid biomarkers (CSF) and cognition in non-dementia PD compared to normal controls (NC) and non-PD patients with mild cognitive impairment (MCI non-PD).

METHODS:
Patients were classified as having normal, subjective or mild cognitive impairment after cognitive screening. CSF levels of total α-synuclein (t-α-syn), amyloid-β (Aβ) 38, 40 and 42, total tau (T-tau) and phosphorylated tau (P-tau) were measured in 34 NC, 31 early, non-dementia PD and 28 MCI non-PD patients. A well validated neuropsychological test battery was administered.

RESULTS:
In the PD group, 13 had normal cognition, 4 had subjective and 14 mild cognitive impairment. PD patients had significantly lower CSF biomarker levels of t-α-syn, Aβ38, 40 and 42, T-tau and P-tau compared to NC. Compared to MCI non-PD, t-α-syn, Aβ38 and 40, T-tau and P-tau were also lower, while Aβ42 was significantly higher in the PD group. Aβ38 and 40 correlated strongly with t-α-syn levels in PD. Lower Aβ42 was associated with decreased verbal learning, delayed verbal recall and response inhibition in PD.

CONCLUSION:

While Aβ38, 40 and t-α-syn levels are strongly correlated, only lower Aβ42 was associated with reduced cognitive functions in early PD, mainly connected to medial temporal lobe-based cognitive functions.

Wednesday, 20 May 2015

Olfaction and Aging: A Mini-Review

Building cohorts of subjects with truly idiopathic anosmia is a worthwhile endeavour... but it must be based on objective rather than subjective measurement...

Gerontology. 2015 May 9. [Epub ahead of print]
Attems J, Walker L, Jellinger KA.



Decreased olfactory function is very common in the older population, being present in >50% of individuals aged between 65 and 80 years and in 62-80% of those >80 years of age. Smell dysfunction significantly influences physical well-being, quality of life, nutritional status as well as everyday safety and is associated with increased mortality. Multiple factors contribute to age-related olfactory sensory loss, including nasal engorgement, cumulative damage of the olfactory epithelium from environmental insults, a reduction in mucosal metabolizing enzymes, sensory loss of receptor cells to odorants, and changes in neurotransmitter and neuromodulator systems. In addition, structural and functional abnormalities of the olfactory epithelium, olfactory bulb, central olfactory cortex, and basic olfactory circuitry, which are related to the neuronal expression of aberrant proteins in these areas, may result in olfactory sensory impairment in aging and neurodegenerative diseases. Impaired odour identification is associated with a decrease in cognitive abilities and memory decline. A reduction in the sense of smell is considered to potentially represent an early and important warning of neurodegenerative disorders, particularly of Parkinson's disease and Alzheimer's disease, and, in mild cognitive impairment, olfactory impairment may herald progression to dementia. Further investigations of the potential role of olfactory dysfunction in the early diagnosis and treatment of neurodegenerative diseases are warranted.

Monday, 18 May 2015

Occupational history of night shift work and Parkinson's disease in Denmark

Previous studies have shown some association between PD and night shift work...

Scand J Work Environ Health. 2015 May 7. pii: 3502. doi: 10.5271/sjweh.3502. [Epub ahead of print]
Schernhammer ES, Lassen CF, Kenborg L, Ritz B, Olsen JH, Hansen J.

OBJECTIVES:
We investigated whether working night shifts was associated with the risk of Parkinson's disease (PD).

METHODS:
Between January 2008 and December 2010, we recruited 1808 patients with a confirmed diagnosis of idiopathic PD from Denmark and 1876 population controls matched by year of birth and gender. Information on lifelong occupational history, including information on night work, smoking, caffeine and alcohol consumption habits, and family history of PD was collected through structured telephone interviews.

RESULTS:
Overall, there was no association between a history of night shift work and PD [odds ratio (OR) for any type of night work (ie, either permanent or rotating night work) 1.01, 95% confidence interval (95% CI) 0.86-1.21]. Compared with persons who never worked night shifts, risks of those with longer durations of night work did not appear to differ (OR <10 years=0.95, 95% CI 0.75-1.19, OR 10-19 years= 1.09, 95% CI 0.77-1.53, OR ≥20 years=1.05, 95% CI 0.81-1.37, P for trend=0.23). Associations were similar among men and women.

CONCLUSIONS:

These data suggest that working night shifts is not associated with PD or that low tolerance for night shift work is an early marker of PD. Due to the novel and exploratory nature of these findings, confirmation is needed.

Sunday, 17 May 2015

Disclosure of research results in genetic studies of Parkinson's disease caused by LRRK2 mutations

Helpful recommendations...

Mov Disord. 2015 May 7. doi: 10.1002/mds.26250. [Epub ahead of print]
Pont-Sunyer C, Bressman S, Raymond D, Glickman A, Tolosa E, Saunders-Pullman R.

Abstract

With the advent of large genetic studies examining both symptomatic and asymptomatic individuals, whether and how to disclose genetic research results have become pressing questions. The need is particularly acute in the case of LRRK2 research: Movement centers worldwide are recruiting cohorts of individuals with Parkinson's disease (PD) and their family members, including asymptomatic carriers. Clinical features and treatment are complex and evolving, and disclosure policies vary at different sites and have been modified during the course of some studies. We present the major ethical principles of autonomy, beneficence, nonmaleficence, and honesty that should guide disclosure policies in studies of families with LRRK2 mutations. We make recommendations regarding genetic counseling, policies of either active or passive disclosure, responsibilities of funders to budget for genetic counseling, clinical genetic testing where locally required for disclosure, and aspects of study design to avoid mandatory disclosure whenever feasible.

Thursday, 14 May 2015

Plasma Oligomeric Alpha-Synuclein Is Associated With Glucocerebrosidase Activity in Gaucher Disease

There is some mounting evidence for an association between these two important proteins that play a role in PD pathogenesis...

Mov Disord. 2015 May 12. doi: 10.1002/mds.26200. [Epub ahead of print]
Nuzhnyi E, Emelyanov A, Boukina T, Usenko T, Yakimovskii A, Zakharova E, Pchelina S.

BACKGROUND:
The link between Parkinson's disease (PD) and Gaucher disease (GD), the most common lysosomal storage disease associated with loss of glucocerebrosidase (GBA) activity, can be explained by abnormal accumulation of oligomeric alpha-synuclein (α-Syn) species resulting from mutations in the GBA gene. However, in GD, the relationship between GBA activity and α-Syn accumulation in biological fluids has not been investigated.

METHODS:
We analyzed plasma oligomeric α-Syn levels, leucocyte GBA activity, and plasma chitotriosidase activity in 21 patients with GD.

RESULTS:
Negative correlation between plasma oligomeric α-Syn levels, and leucocyte GBA activity was observed in patients with GD (R2  = 0.487; P < 0.001).

CONCLUSION:

The decrease in GBA activity may influence α-Syn oligomerization, explaining the high risk of PD development in GD patients.

Wednesday, 13 May 2015

Our new letter in Movement Disorders - GBA variants in PREDICT-PD

This was cut down from a brief report because we only had data on the first ~185 subjects. In brief, we show that those deemed to be at higher risk, according to early non-motor features and risk factors, were significantly more likely to carry variants in the GBA gene compared to those at lower risk. This supports the notion that the algorithm enriches for Parkinson's risk.

Letter is Open Access and available via the link below: 
http://onlinelibrary.wiley.com/doi/10.1002/mds.26249/abstract

Presenting symptoms of GBA-related Parkinson's disease

The rate of GBA mutations is about right in this cohort of sporadic PD subjects... perhaps surprising not to see some more differences...


Parkinsonism Relat Disord. 2015 May 1. pii: S1353-8020(15)00194-7. doi: 10.1016/j.parkreldis.2015.04.028. [Epub ahead of print]
Kresojević N, Janković M, Petrović I, Kumar KR, Dragašević N, Dobričić V, Novaković I, Svetel M, Klein C, Pekmezović T, Kostić VS.

BACKGROUND:
Mutations in the Glucocerebrosidase gene (GBA) are associated with Parkinson's disease (PD). It has been shown that GBA-related PD (PD-GBA) patients had an earlier age at PD onset and more prevalent non-motor symptoms when compared to "sporadic" PD patients without such mutations (sPD).

AIM:
To explore whether presenting symptoms differ between PD-GBA and sPD patients.

METHODS:
Demographic and clinical features (including presenting symptoms) were collected for 578 PD patients. Sequence analysis was performed for exons 8-11 of the GBA gene for all participants.

RESULTS:
39 PD patients (6.7%) with GBA mutations were compared to 539 PD patients without them. Although no statistically significant differences were found regarding the presenting symptoms, we observed that pain was more frequently reported as an initial problem in the PD-GBA (10.3%) than in the sPD group (3.0%) (chi square p = 0.039; logistic regression analysis OR = 3.74; p = 0.024).

CONCLUSIONS:

Overall, the presenting symptoms were similar in PD-GBA and sPD patients, with the exception that pain might be more frequent in PD-GBA.

Friday, 8 May 2015

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

Alzheimers Dement. 2015 Apr 29. pii: S1552-5260(15)00122-3. doi: 10.1016/j.jalz.2014.12.009. [Epub ahead of print]
Lill CM, Rengmark A, Pihlstrøm L, Fogh I, Shatunov A, Sleiman PM, Wang LS, Liu T, Lassen CF, Meissner E, Alexopoulos P, Calvo A, Chio A, Dizdar N, Faltraco F, Forsgren L, Kirchheiner J, Kurz A, Larsen JP, Liebsch M, Linder J, Morrison KE, Nissbrandt H, Otto M, Pahnke J, Partch A, Restagno G, Rujescu D, Schnack C, Shaw CE, Shaw PJ, Tumani H, Tysnes OB, Valladares O, Silani V, van den Berg LH, van Rheenen W, Veldink JH, Lindenberger U, Steinhagen-Thiessen E; SLAGEN Consortium, Teipel S, Perneczky R, Hakonarson H, Hampel H, von Arnim CA, Olsen JH, Van Deerlin VM, Al-Chalabi A, Toft M, Ritz B, Bertram L.

Abstract

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10-25). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction.

Thursday, 7 May 2015

Groundwater Pesticide Levels and the Association With Parkinson Disease

There is little doubt in my mind that pesticide exposure is associated with PD and a huge number of epidemiological studies support this observation...moreover animal models of PD are induced through pesticide analogues and Parkinsonism has been caused in humans too, through inadvertent and recreational exposure. The most important questions are what, which and how much???

Int J Toxicol. 2015 May 4. pii: 1091581815583561. [Epub ahead of print]
James KA, Hall DA.


It is unclear whether exposure to environmentally relevant levels of pesticides in groundwater is associated with an increased risk of Parkinson disease (PD). The purpose of this study was to examine the relationship between PD and pesticide levels in groundwater. This cross-sectional study included 332 971 Medicare beneficiaries, including 4207 prevalent cases of PD from the 2007 Colorado Medicare Beneficiary Database. Residential pesticide levels were estimated from a spatial model based on 286 well water samples with atrazine, simazine, alachlor, and metolachlor measurements. A logistic regression model with known PD risk factors was used to assess the association between residential groundwater pesticide levels and prevalent PD. We found that for every 1.0 µg/L of pesticide in groundwater, the risk of PD increases by 3% (odds ratio = 1.03; 95% confidence interval: 1.02-1.04) while adjusting for age, race/ethnicity, and gender suggesting that higher age-standardized PD prevalence ratios are associated with increasing levels of pesticides in groundwater.

Tuesday, 5 May 2015

Prevalence and timeline of nonmotor symptoms in idiopathic rapid eye movement sleep behavior disorder

J Neurol. 2015 May 1. [Epub ahead of print]
Aguirre-Mardones C, Iranzo A, Vilas D, Serradell M, Gaig C, Santamaría J, Tolosa E.


Parkinson disease (PD) patients may experience nonmotor symptoms (NMS) before Parkinsonism onset. Patients with idiopathic REM sleep behavior disorder (IRBD) eventually develop PD and may represent premotor PD. We aimed to evaluate the prevalence and perceived timeline of NMS in IRBD through validated scales and questionnaires used in PD research. In 44 IRBD patients and 40 matched controls, overall NMS evaluation was assessed by NMS questionnaire for Parkinson disease, olfaction by University of Pennsylvania Smell Identification Test, dysautonomia by scales for outcomes in Parkinson's disease-autonomic, constipation by Rome III criteria, depression by Hospital Anxiety and Depression Scale, cognitive impairment by Montreal cognitive assessment (MoCA) and hypersomnia by Epworth Sleepiness Scale. Patients were asked to report the perceived time of onset of hyposmia, constipation, and depression. Hyposmia (52.3 vs. 20.0 %, p = 0.002) and constipation (56.8 vs. 20.0 %, p = 0.001) were more frequent in patients than in controls. Patients reported more memory problems and showed a trend toward lower score in MoCA. Depression and hypersomnia were not more frequent in patients. The first symptom perceived was RBD in 38.6 % patients, hyposmia in 15.9 %, constipation in 11.4 %, and depression in 6.8 %. The temporal course of the NMS studied was heterogeneous. The three most common presentations were RBD followed by hyposmia; hyposmia followed by RBD; and hyposmia followed by RBD and constipation occurring at the same time span. IRBD patients frequently exhibit NMS that occur in premotor PD, particularly hyposmia and constipation. In IRBD, the perceived timeline of NMS is highly variable. This variability may suggest that pathological changes occurring in IRBD subjects are also heterogeneous and not restricted to the structures that regulate REM sleep.

Monday, 4 May 2015

Diffusion tensor imaging of the nigrostriatal fibers in Parkinson's disease

Novel applications of MRI may throw up imaging markers for PD in the next few years and studies like PPMI are the perfect opportunity to test them...


Mov Disord. 2015 Apr 29. doi: 10.1002/mds.26251. [Epub ahead of print]
Zhang Y, Wu IW, Buckley S, Coffey CS, Foster E, Mendick S, Seibyl J, Schuff N.


Parkinson's disease (PD) is histopathologically characterized by the loss of dopamine neurons in the substantia nigra pars compacta. The depletion of these neurons is thought to reduce the dopaminergic function of the nigrostriatal pathway, as well as the neural fibers that link the substantia nigra to the striatum (putamen and caudate), causing a dysregulation in striatal activity that ultimately leads to lack of movement control. Based on diffusion tensor imaging, visualizing this pathway and measuring alterations of the fiber integrity remain challenging. The objectives were to 1) develop a diffusion tensor tractography protocol for reliably tracking the nigrostriatal fibers on multicenter data; 2) test whether the integrities measured by diffusion tensor imaging of the nigrostriatal fibers are abnormal in PD; and 3) test whether abnormal integrities of the nigrostriatal fibers in PD patients are associated with the severity of motor disability and putaminal dopamine binding ratios. Diffusion tensor tractography was performed on 50 drug-naïve PD patients and 27 healthy control subjects from the international multicenter Parkinson's Progression Marker Initiative. Tractography consistently detected the nigrostriatal fibers, yielding reliable diffusion measures. Fractional anisotropy, along with radial and axial diffusivity of the nigrostriatal tract, showed systematic abnormalities in patients. In addition, variations in fractional anisotropy and radial diffusivity of the nigrostriatal tract were associated with the degree of motor deficits in PD patients. Taken together, the findings imply that the diffusion tensor imaging characteristic of the nigrostriatal tract is potentially an index for detecting and staging of early PD.

Sunday, 3 May 2015

Brainstem raphe and substantia nigra echogenicity in idiopathic REM sleep behavior disorder with comorbid depression

Using risk markers in subjects with early non-motor features of PD may get us closer to identifying those at highest risk of future PD...

J Neurol. 2015 May 1. [Epub ahead of print]
Vilas D, Iranzo A, Pont-Sunyer C, Serradell M, Gaig C, Santamaria J, Tolosa E.


In Parkinson disease (PD), REM sleep behavior disorder (RBD) and depression may occur before the onset of parkinsonism. Transcranial sonography (TCS) shows that hyperechogenicity of the substantia nigra (SN+) and hypoechogenicity of the brainstem raphe (BR+) are frequent in PD, particularly when depression is associated. Combined SN+ and BR+ identify PD subjects in whom depression antedates parkinsonism onset. It can be speculated that SN+ and BR+ may also identify idiopathic RBD (IRBD) subjects with comorbid depression, supporting the clinical diagnosis of this mood disorder. We aimed to study the brainstem raphe and substantia nigra echogenicity and their ability to predict comorbid depression in IRBD. Seventy-two IRBD patients and 71 age and sex-matched controls underwent TCS. Depression was diagnosed by means of DSM-IV criteria. Depression was more frequent in IRBD patients than in controls (44.4 vs. 18.3 %; p = 0.001). BR+ was more frequent in depressed than in nondepressed IRBD patients (32.0 vs. 11.4 %; p = 0.050). Sensitivity of BR+ to predict depression in IRBD was 32.0 %, specificity was 88.6 %, and relative risk was 1.88. Sensitivity of SN+ to predict depression in IRBD was 72.0 %, specificity was 44.1 %, and relative risk was 1.53. Sensitivity of combined BR+ and SN+ to predict depression in IRBD was 23.1 %, specificity 97.1 %, and relative risk was 2.31. Hypoechogenicity of the brainstem raphe, particularly when combined with hyperechogenicity of the substantia nigra, detects comorbid depression in IRBD. This finding suggests that dysfunction of the serotonergic dorsal raphe may be involved in the pathophysiology of depression in IRBD.

Saturday, 2 May 2015

Genetic risk of neurodegenerative diseases is associated with mild cognitive impairment and conversion to dementia

Alzheimers Dement. 2015 Apr 24. pii: S1552-5260(15)00118-1. doi: 10.1016/j.jalz.2014.12.008. [Epub ahead of print]
Adams HH, de Bruijn RF, Hofman A, Uitterlinden AG, van Duijn CM, Vernooij MW, Koudstaal PJ, Ikram MA.

Abstract
BACKGROUND:
Neurodegenerative diseases are a major cause of cognitive impairment and can ultimately lead to dementia. Genome-wide association studies have uncovered many genetic variants conferring risk of neurodegenerative diseases, but their role in cognitive impairment remains unexplored.

METHODS:
In the prospective, population-based Rotterdam Study, 3605 nondemented persons aged ≥55 years were genotyped, screened for mild cognitive impairment (MCI) in 2002 to 2005 and underwent continuous follow-up for dementia until 2012. Weighted polygenic risk scores of genetic variants for Alzheimer's disease (AD), Parkinson's disease (PD), and the frontotemporal lobar degeneration/amyotrophic lateral sclerosis disease spectrum (FTLD/ALS) were constructed and investigated for association with MCI and the subsequent conversion to dementia.

RESULTS:
In total, 360 (10.0%) persons had MCI, of whom 147 (4.1%) were amnestic and 213 (5.9%) nonamnestic. The AD risk score was associated with both MCI subtypes (odds ratio for all MCI 1.15 [95% CI, 1.03-1.28]), whereas PD and FTLD/ALS risk scores were associated only with nonamnestic MCI (odds ratios 1.15 [1.00-1.32] and 1.19 [1.03-1.37], respectively). The AD risk score, but not PD and FTLD/ALS risk scores, was associated with an increased risk of dementia (hazard ratio 1.55 [1.37-1.77]).

CONCLUSIONS:

Genetic evidence supports the view that multiple neurodegenerative pathways lead to MCI and that the subsequent conversion to dementia, primarily of the AD subtype, is mainly due to the AD pathway(s).

Friday, 1 May 2015

The olfactory bulb volume in patients with idiopathic Parkinson's disease

How disappointing... this is something I have been thinking and talking to others about for some time... sadly it hasn't show anything suggestive. 

Eur J Neurol. 2015 Apr 23. doi: 10.1111/ene.12709. [Epub ahead of print]
Paschen L, Schmidt N, Wolff S, Cnyrim C, van Eimeren T, Zeuner KE, Deuschl G, Witt K.

BACKGROUND AND PURPOSE:
This study addresses the question of whether the neuropathological findings on the olfactory bulb (OB) in idiopathic Parkinson's disease (IPD) correspond to a detectable change in volume of the OB. Additionally, the relationship between OB volume and residual olfactory function, clinical disease characteristics and age are investigated.

METHODS:
Fifty-two IPD patients were investigated and compared to 31 healthy age-matched controls. All participants were scanned using a 3 T magnetic resonance imaging MRI scanner including a T2 DRIVE sequence in coronal slices through the OB. The OB volumes were measured via manual segmentation of the OB. Olfactory testing was carried out using the Sniffin' Sticks test battery.

RESULTS:
The OB volume in the IPD group was 42.1 mm³ (SD ± 11.6) for the right and 41.5 mm³ (SD ± 11.7) for the left OB and showed no difference from the controls. Additionally, there were no significant correlations between OB volume and disease characteristics such as disease duration or Unified Parkinson's Disease Rating Scale motor score. Likewise, patients' residual smell function did not correlate with their OB volume. In contrast, controls indicated a correlation between smell function and OB volume.

CONCLUSION:

The study shows that high resolution MRI does not show a detectable volume loss of the OB in PD patients. It is concluded that OB measurement using in vivo high resolution MRI at 3 T is not helpful to identify IPD.

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...