Tuesday, 30 October 2012

Essential tremor is not a neurodegenerative disease

Neurodegener Dis Manag. 2012 Jun;2(3):259-268.
Rajput AH, Adler CH, Shill HA, Rajput A.

Movement Disorders Program, Neurology Division, University of Saskatchewan/Saskatoon Health Region, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada.

The pathophysiology of essential tremor (ET) remains unknown. Standard neuropathological studies have reported no consistent changes but a detailed study found neurodegeneration in all ET cases - 24% demonstrated lower brainstem Lewy body (LB) inclusions and 76% experienced a loss of cerebellar Purkinje cells (PCs) and its sequelae. We review the evidence on neurodegeneration in ET. The prevalence of LB inclusions in ET brains is similar to that in the asymptomatic general population. These incidental LB disease cases have evidence for reduced striatal tyrosine hydroxylase levels, as found in Parkinson's disease, but there is no evidence for reduced tyrosine hydroxylase levels in ET patients. Reduced mean PC counts in ET cases compared with the controls reported by some studies could not be replicated by others. Most ET cases have the same number of PCs as controls of a comparable age. Neither the lower brainstem LB inclusions nor the cerebellar PC loss represent the neurodegenerative basis of ET. Further studies are needed to determine the pathophysiology of ET.

Monday, 29 October 2012

Parkinson's disease: Evidence for environmental risk factors

Mov Disord. 2012 Oct 24. doi: 10.1002/mds.25150. [Epub ahead of print]
Kieburtz K, Wunderle KB.

Center for Human Experimental Therapeutics, University of Rochester Medical Center, Rochester, New York, USA.

Parkinson's disease (PD) has no known cause. Although recent research has focused particularly on genetic causes of PD, environmental causes also play a role in developing the disease. This article reviews environmental factors that may increase the risk of PD, as well as the evidence behind those factors. Enough evidence exists to suggest that age has a causal relationship to PD. Significant evidence exists that gender, tobacco use, and caffeine consumption are also associated with the development of PD. Other environmental factors (pesticide exposure, occupation, blood urate levels, NSAID use, brain injury, and exercise) have limited or conflicting evidence of a relationship to PD. Future research must not neglect the impact of these environmental factors on the development of PD, especially with respect to potential gene-environment interactions. 

Friday, 26 October 2012

PREDICT PD on tour!

Today PREDICT PD starts the home visits phase of the project. A proportion of our participants will be visited at home for some additional tests. Over the next three months I will be travelling around the UK by bike, car, rail, and some cases planes and boats. I can't wait to get started on this phase and I'll post updates along the way. Off to South East London today...

- Alastair Noyce

Thursday, 25 October 2012

Clinical features of Parkinson disease when onset of diabetes came first: A case-control study

Neurology [2012, 78(19):1507-1511]

Cereda E, Barichella M, Cassani E, Caccialanza R, Pezzoli G
Nutrition and Dietetics Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 


OBJECTIVE: Recent literature suggests that diabetes is a risk factor for Parkinson disease (PD). We investigated the clinical features of patients with idiopathic PD (IPD) in whom the onset of diabetes came first.

METHODS: We designed a case-control study. From the cohort of all new patients with IPD free of vascular disease (n = 783) admitted and evaluated at our institute over a 3-year period (2007-2010), we included all the patients with a diagnosis of diabetes prior to PD onset (n = 89) and a control group (n = 89) matched (1:1) for gender, body mass index (± 1 kg/m(2)), and duration of PD (± 1 year). The Unified Parkinson's Disease Rating Scale (UPDRS) motor score was the primary endpoint.

RESULTS: At study entry, patients with diabetes were similar to controls in terms of most demographic, lifestyle, and general medical features with exception of statins (18% vs 3.4%; p = 0.003). However, diabetes was associated with higher UPDRS motor (22.3 ± 9.0 vs 19.3 ± 7.9; p = 0.019) and activities of daily living (9.7 ± 5.1 vs 8.3 ± 4.3; p = 0.049) scores, more severe Hoehn & Yahr staging (p = 0.009), and higher treatment doses of levodopa (mg/day, 448 ± 265 vs 300 ± 213; p < 0.0001; mg/kg/day, 5.8 ± 4.0 vs 3.8 ± 2.9; p < 0.0001).

CONCLUSIONS: Onset of diabetes before the onset of PD appears to be a risk factor for more severe PD symptoms. These findings support the hypothesis that diabetes has a role in the etiopathogenesis of PD. Neurologists should be aware of the potential impact of diabetes on overall PD management.

The PREDICT-PD Website went down for 24 hours but is now fully operational again

Tuesday, 23 October 2012

600 and counting...

600 of our participants have now completed the year 1 follow up of PREDICT-PD.

- Alastair Noyce

Istradefylline, an adenosine A(2A) receptor antagonist, for patients with Parkinson's Disease: A meta-analysis

J Neurol Sci. 2012 Oct 18. pii: S0022-510X(12)00482-0. doi: 10.1016/j.jns.2012.08.030. [Epub ahead of print]
Chen W, Wang H, Wei H, Gu S, Wei H.

Department of Neurology, The Second People's Hospital of Gansu Province, Lanzhou, Gansu, China.

To assess the efficacy and safety of istradefylline as an adjunct to levodopa in patients with Parkinson's Disease (PD).
In this study, we searched the Cochrane Library, MEDLINE, Embase, China Academic Journal Full-text Database (CNKI), China Biomedical Literature Database (CBM), Chinese Scientific Journals Database (VIP), and Wanfang Database. The quality of included studies was strictly evaluated. Data analyses were performed by the Cochrane Collaboration's RevMan5.0 software.
Five randomized controlled trials (RCTs) were included. The result showed a significant reduction of the awake time per day spent in the OFF state and improvement of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III in the ON state when receiving istradefylline compared with patients receiving placebo. There was no significant difference between the istradefylline 20mg and the istradefylline 40mg groups in the UPDRS Part III in the ON state (WMD=1.27, 95% CI [-0.40, 2.95]). The results showed significant differences in dyskinesia (RR=1.63, 95% CI [1.16, 2.29]) compared to istradefylline 40mg with placebo. There was no significant statistical difference with regard to other adverse events.
The present study showed that istradefylline is safe and effective as an adjunct to levodopa in patients with PD. Future large-scale, higher-quality, long-treatment, and placebo-controlled trials are needed.

Thursday, 18 October 2012

Tuesday, 16 October 2012

Transcranial sonography and functional imaging in glucocerebrosidase mutation Parkinson disease

Parkinsonism Relat Disord. 2012 Oct 9. pii: S1353-8020(12)00348-3. doi: 10.1016/j.parkreldis.2012.09.007. [Epub ahead of print]
Barrett MJ, Hagenah J, Dhawan V, Peng S, Stanley K, Raymond D, Deik A, Gross SJ, Schreiber-Agus N, Mirelman A, Marder K, Ozelius LJ, Eidelberg D, Bressman SB, Saunders-Pullman R; The LRRK2 Ashkenazi Jewish Consortium.

Department of Neurology, Beth Israel Medical Center, NY 10003, USA.


Heterozygous glucocerebrosidase (GBA) mutations are the leading genetic risk factor for Parkinson disease, yet imaging correlates, particularly transcranial sonography, have not been extensively described.
To determine whether GBA mutation heterozygotes with Parkinson disease demonstrate hyperechogenicity of the substantia nigra, transcranial sonography was performed in Ashkenazi Jewish Parkinson disease subjects, tested for the eight most common Gaucher disease mutations and the LRRK2 G2019S mutation, and in controls. [(18)F]-fluorodeoxyglucose or [(18)F]-fluorodopa positron emission tomography is also reported from a subset of Parkinson disease subjects with heterozygous GBA mutations.
Parkinson disease subjects with heterozygous GBA mutations (n = 23) had a greater median maximal area of substantia nigral echogenicity compared to controls (n = 34, aSNmax = 0.30 vs. 0.18, p = 0.007). There was no difference in median maximal area of nigral echogenicity between Parkinson disease groups defined by GBA and LRRK2 genotype: GBA heterozygotes; GBA homozygotes/compound heterozygotes (n = 4, aSNmax = 0.27); subjects without LRRK2 or GBA mutations (n = 32, aSNmax = 0.27); LRRK2 heterozygotes/homozygotes without GBA mutations (n = 27, aSNmax = 0.28); and GBA heterozygotes/LRRK2 heterozygotes (n = 4, aSNmax = 0.32, overall p = 0.63). In secondary analyses among Parkinson disease subjects with GBA mutations, maximal area of nigral echogenicity did not differ based on GBA mutation severity or mutation number. [(18)F]-fluorodeoxyglucose (n = 3) and [(18)F]-fluorodopa (n = 2) positron emission tomography in Parkinson disease subjects with heterozygous GBA mutations was consistent with findings in idiopathic Parkinson disease.
Both transcranial sonography and positron emission tomography are abnormal in GBA mutation associated Parkinson disease, similar to other Parkinson disease subjects.

Dysfunction of the locus coeruleus-norepinephrine system and related circuitry in Parkinson's disease-related dementia

J Neurol Neurosurg Psychiatry. 2012 Oct 13. [Epub ahead of print]
Del Tredici K, Braak H.

Clinical Neuroanatomy, Center for Biomedical Research, Department of Neurology, University of Ulm, Ulm, Germany.

Although resting tremor, cogwheel rigidity, hypokinesia/bradykinesia and postural instability usually dominate the clinical picture of sporadic Parkinson's disease (PD), both clinical and epidemiological data reveal that a wide variety of additional symptoms impair patients' quality of life considerably, parallel to the chronic progressive neurodegenerative movement disorder. Autopsy based retrospective studies have shown that α-synuclein immunoreactive Lewy pathology (LP) develops in the locus coeruleus (LC) of patients with neuropathologically confirmed sporadic PD, as well as in individuals with incidental (prodromal or premotor) Lewy body disease but not in age and gender matched controls. Using five case studies, this review discusses the possible role of LP (axonopathy, cellular dysfunction and nerve cell loss) in the LC, catecholaminergic tract and related circuitry in the development of PD-related dementia. The contribution of noradrenergic deficit to cognitive dysfunction in PD has been underappreciated. Noradrenergic therapeutic interventions might not only alleviate depressive symptoms and anxiety but also delay the onset of cognitive decline.

Meta-Analysis of Early Nonmotor Features and Risk Factors for Parkinson Disease

Alastair J. Noyce, Jonathan P. Bestwick, Laura Silveira-Moriyama, Christopher H. Hawkes, Gavin Giovannoni, Andrew J. Lees, and Anette Schrag

ANN NEUROL 2012 (E-pub ahead of print)

Objective: To evaluate the association between diagnosis of Parkinson disease (PD) and risk factors or early symptoms amenable to population-based screening.

Methods: A systematic review and meta-analysis of risk factors for PD.

Results: The strongest associations with later diagnosis of PD were found for having a first-degree or any relative with PD (odds ratio [OR], 3.23; 95% confidence interval [CI], 2.65–3.93 and OR, 4.45; 95% CI, 3.39–5.83) or any relative with tremor (OR, 2.74; 95% CI, 2.10–3.57), constipation (relative risk [RR], 2.34; 95% CI, 1.55–3.53), or lack of smoking history (current vs never: RR, 0.44; 95% CI, 0.39–0.50), each at least doubling the risk of PD. Further positive significant associations were found for history of anxiety or depression, pesticide exposure, head injury, rural living, beta-blockers, farming occupation, and well-water drinking, and negative significant associations were found for coffee drinking, hypertension, nonsteroidal anti-inflammatory drugs, calcium channel blockers, and alcohol, but not for diabetes mellitus, cancer, oral contraceptive pill use, surgical menopause, hormone replacement therapy, statins, acetaminophen/paracetamol, aspirin, tea drinking, history of general anesthesia, or gastric ulcers. In the systematic review, additional associations included negative associations with raised serum urate, and single studies or studies with conflicting results.

Interpretation: The strongest risk factors associated with later PD diagnosis are having a family history of PD or tremor, a history of constipation, and lack of smoking history. Further factors also but less strongly contribute to risk of PD diagnosis or, as some premotor symptoms, require further standardized studies to demonstrate the magnitude of risk associated with them.

Here is the abstract for our comprehensive exploration of risk factors and early non-motor features for PD. This piece of work took 18-24 months to complete but is a strong foundation upon which the PREDICT-PD project is built. We are arranging for this to be made Open Access so that as many people as possible can see it.

- Alastair Noyce

Monday, 15 October 2012

300 complete the year 1 follow up

After sending out requests to undertake the year 1 survey and tapping test, I'm pleased to say that already 300 of our participants have done this. We will send further reminders after a few days.

- Alastair Noyce

RBD as a biomarker for neurodegeneration: The past 10 years

Sleep Med. 2012 Oct 8. pii: S1389-9457(12)00329-2. doi: 10.1016/j.sleep.2012.09.001. [Epub ahead of print]

Postuma RB, Gagnon JF, Montplaisir J.


Department of Neurology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada; Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur, Montreal, Canada.


Since its original description, idiopathic RBD has become a well-established risk factor for neurodegenerative disease. Studies from sleep centers have found that at least 40-65% of patients with idiopathic RBD will develop a defined neurodegenerative phenotype over 10years. This elevated risk of neurodegeneration has been recently confirmed in a population-based study of probable RBD. When a defined syndrome develops, it is almost always a 'synucleinopathy' (Parkinson's disease, Dementia with Lewy Bodies or multiple system atrophy). Often, manifestations of parkinsonism and cognitive impairment overlap. The ability of RBD to predict disease has major implications for development of neuroprotective therapy. First, RBD is a prodromal marker with a disease risk sufficiently high for design of neuroprotective trials. Second, study of idiopathic RBD allows prospective testing of other predictive markers of neurodegeneration. Third, it allows an unprecedented direct examination of the evolution of prodromal disease into defined neurodegenerative syndromes. This review summarizes what is known about the risk of neurodegeneration in idiopathic RBD, the utility of prodromal/predictive markers in synuclein-mediated neurodegeneration, and the evolution of motor and non-motor markers in prodromal stages.

Sunday, 14 October 2012

Feedback from PREDICT-PD - Length of survey

We asked our participants what they though about the length of our survey. This is what they told us...

Year 1 Follow Up Launched

Whatever way you look at it, the PREDICT-PD project has been a great success so far: exceeding recruitment expectations, exciting early results, and now, on the morning of the launch of year 1 follow up, another great response from our participants!

Over the next few months I will share the feedback we get from PREDICT-PD, explain more about our research and post abstracts from other studies that are relevant to the overall goal of identifying Parkinson's at the earliest possible stages. 

I hope to drive more comments on this blog because your opinions count. At a recent patients' meeting with the Cure Parkinson's Trust I heard again how patients are too often not regarded as the experts they are in their own disease. I would like to hear more from the experts and their friends and relatives.

- Alastair Noyce

Friday, 12 October 2012

The impact of autonomic dysfunction on survival in patients with dementia with lewy bodies and Parkinson's disease with dementia

PLoS One. 2012;7(10):e45451. doi: 10.1371/journal.pone.0045451. Epub 2012 Oct 1.
Stubendorff K, Aarsland D, Minthon L, Londos E.

Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Sweden.
Autonomic dysfunction is a well-known feature in neurodegenerative dementias, especially common in α-synucleinopathies like dementia with Lewy bodies and Parkinson's disease with dementia. The most common symptoms are orthostatic hypotension, incontinence and constipation, but its relevance in clinical practice is poorly understood. There are no earlier studies addressing the influence of autonomic dysfunction on clinical course and survival. The aim of this study was to investigate the frequency of the three most common features of autonomic dysfunction and analyze how it affects survival.
Thirty patients with dementia with Lewy bodies and Parkinson's disease with dementia were included in this prospective, longitudinal follow-up study. Presence of incontinence and constipation was recorded at baseline. Blood pressure was measured at baseline, after 3 months and after 6 months according to standardized procedures, with 5 measurements during 10 minutes after rising. Orthostatic hypotension was defined using consensus definitions and persistent orthostatic hypotension was defined as 5 or more measurements with orthostatic hypotension. Difference in survival was analyzed 36 months after baseline.
There was a high frequency of persistent orthostatic blood pressure (50%), constipation (30%) and incontinence (30%). Patients with persistent orthostatic hypotension had a significantly shorter survival compared to those with no or non-persistent orthostatic hypotension (Log rank x(2) = 4.47, p = 0.034). Patients with constipation and/or urinary incontinence, in addition to persistent orthostatic hypotension, had a poorer prognosis compared to those with isolated persistent orthostatic hypotension or no orthostatic hypotension (Log rank x(2) = 6.370, p = 0.041).
According to our findings, the identification of autonomic dysfunction seems to be of great importance in clinical practice, not only to avoid falls and other complications, but also as a possible predictor of survival.

Wednesday, 10 October 2012

Left hemispheric predominance of nigrostriatal dysfunction in Parkinson's disease

Brain. 2012 Oct 4. [Epub ahead of print]
Scherfler C, Seppi K, Mair KJ, Donnemiller E, Virgolini I, Wenning GK, Poewe W.

1 Department of Neurology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.

The aim of this study was to investigate the distribution and the degree of asymmetric putaminal dopamine transporter availability in right-handed patients with Parkinson's disease and its association with the severity of lateralized motor signs. Asymmetry of motor symptoms was defined by the difference between right- and left-sided scores for lateralized items assessed by the Unified Parkinson's Disease Rating Scale Motor Score in a series of 68 patients with Parkinson's disease (disease duration 2.1 ± 1.5 years; Unified Parkinson's Disease Rating Scale Motor Score 22.7 ± 9). Putaminal dopamine transporter availability was measured with the radioligand [(123)I]β-carboxymethyoxy-3 -β-(4-iodophenyl) tropane ([(123)I]β-CIT) and single photon emission computed tomography. We found that in the right-handed Parkinson's disease cohort, the number of patients who had lower dopamine transporter uptake in the left posterior putamen was significantly greater compared with those with lower uptake in the right posterior putamen (Parkinson's disease-left group, n = 49; Parkinson's disease-right group, n = 19; P < 0.001). In addition, one-way analysis of variance revealed significant reductions of mean total putaminal [(123)I]β-CIT binding of the Parkinson's disease-right patients compared with Parkinson's disease-left patients (P < 0.05).The preponderance of reduced left putaminal dopamine transporter availability strengthens clinical observations of a greater proportion of right-handed patients with Parkinson's disease with predominantly right-sided motor signs and argues against a randomly distributed asymmetric vulnerability of substantia nigra dopaminergic neurons. The coexistence of a subgroup of right-handed patients with Parkinson's disease with more severe and predominant ipsilateral putaminal dopamine transporter decline suggests that asymmetry of dopaminergic denervation and motor dysfunction in Parkinson's disease cannot be fully explained by hemispheric dominance alone, but that other factors must be involved.

Monday, 8 October 2012

GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology

Neurology. 2012 Oct 3. [Epub ahead of print]

Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Trojanowski JQ, Schellenberg GD, Yearout D, Huston H, Fritts-Penniman A, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP.

Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both.
We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD).
Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8-31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2-17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2-6.6; p = 0.92). There was a highly significant trend test across groups (χ(2)(1) = 19.3; p = 1.1 × 10(-5)), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB.
GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.

Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains

Ann Neurol. 2012 Sep;72(3):455-63. doi: 10.1002/ana.23614.
Gegg ME, Burke D, Heales SJ, Cooper JM, Hardy J, Wood NW, Schapira AH.

Department of Clinical Neurosciences, University College London Institute of Neurology.

Mutations in the glucocerebrosidase gene (GBA) represent a significant risk factor for developing Parkinson disease (PD). We investigated the enzymatic activity of glucocerebrosidase (GCase) in PD brains carrying heterozygote GBA mutations (PD+GBA) and sporadic PD brains.
GCase activity was measured using a fluorescent assay in cerebellum, frontal cortex, putamen, amygdala, and substantia nigra of PD+GBA (n = 9-14) and sporadic PD brains (n = 12-14). Protein expression of GCase and other lysosomal proteins was determined by western blotting. The relation between GCase, α-synuclein, and mitochondria function was also investigated in vitro.
A significant decrease in GCase activity was observed in all PD+GBA brain areas except the frontal cortex. The greatest deficiency was in the substantia nigra (58% decrease; p < 0.01). GCase activity was also significantly decreased in the substantia nigra (33% decrease; p < 0.05) and cerebellum (24% decrease; p < 0.05) of sporadic PD brains. GCase protein expression was lower in PD+GBA and PD brains, whereas increased C/EBP homologous protein and binding immunoglobulin protein levels indicated that the unfolded protein response was activated. Elevated α-synuclein levels or PTEN-induced putative kinase 1 deficiency in cultured cells had a significant effect on GCase protein levels.
GCase deficiency in PD brains with GBA mutations is a combination of decreased catalytic activity and reduced protein levels. This is most pronounced in the substantia nigra. Biochemical changes involved in PD pathogenesis affect wild-type GCase protein expression in vitro, and these could be contributing factors to the GCase deficiency observed in sporadic PD brains.

Friday, 5 October 2012

A study of subtle motor signs in early Parkinson's disease

Mov Disord. 2012 Oct 2. doi: 10.1002/mds.25161. [Epub ahead of print]
Schneider SA, Drude L, Kasten M, Klein C, Hagenah J.

Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Lübeck, Lübeck, Germany.


The UPDRS is the most widely used rating scale for Parkinson's disease (PD). However, subtle features of early disease stages may be missed.
We studied 25 early PD patients using a newly compiled battery of motor tests focusing on subtle motor features. Focal dystonia patients (n = 31) and healthy individuals (n = 26) served as controls. Specifically, asymmetric shoulder null position and delayed shoulder shrugs, reduced arm swing, subtle tremor, and timed finger taps were assessed. Spiral drawings and writing were also studied.
With a total mean of 9.8 ± 4.9 (possible range: 0-94), PD patients scored significantly higher than dystonia patients (2.9 ± 2.0) and healthy controls (1.9 ± 2.0) (P < 0.001). Reduced arm swing and tremor of individual fingers best distinguished PD from the other groups.
The battery was sensitive to detect subtle motor features missed by the UPDRS. For future revisions of an international motor score, further assessment of these items may be worthwhile. © 2012 Movement Disorder Society.

Neuroimaging over the course of Parkinson's disease: from early detection of the at-risk patient to improving pharmacotherapy of later-stage disease

Semin Nucl Med. 2012 Nov;42(6):406-14. doi: 10.1053/j.semnuclmed.2012.06.003.

Seibyl J, Russell D, Jennings D, Marek K.

Institute for Neurodegenerative Disorders, New Haven, CT; Molecular Neuroimaging, LLC, New Haven, CT; Yale University School of Medicine, New Haven, CT. 

Brain imaging of striatal dopamine terminal degeneration serves an important role in the clinical management of Parkinson's disease (PD). Imaging biomarkers for interrogating dopaminergic systems are used for clarifying diagnosis when only subtle motor symptoms are present. However, motor dysfunction is not the earliest symptom of PD. There is increasing interest in identifying premotor PD patients, particularly because potential disease-modifying therapies are developed and the clinical imperative becomes early and accurate diagnosis. On the other end of the spectrum of the disease course, during later stages of PD, significant clinical challenges like levo-dopa-induced dyskinesias and medication on-off phenomenon become more prevalent. In this instance, better understanding of altered PD motor pathways suggests the potential utility of novel treatments targeting neuronal systems that are impacted by degenerating dopamine neurons and chronic dopamine replacement treatment. Molecular neuroimaging serves unique roles in both very early PD and later-stage disease, in the former, potentially pushing back the time of diagnosis, and in the latter, elucidating pathology relevant to new drug development.

Wednesday, 3 October 2012

James Parkinson: The Man Behind the Shaking Palsy

Journal of Parkinson's Disease 

Patrick A. Lewis
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK


James Parkinson occupies a unique position in the history of Parkinson's disease. As the man responsible for originally identifying and describing the disease that he called the Shaking Palsy, his name is familiar to anybody with a connection with the disease – patients, carers, clinicians and members of the general public alike. This review summarises the life and career of one of the most recognizable names in neurology.

Tuesday, 2 October 2012

Different patterns of cardiac sympathetic denervation in tremor-type compared to akinetic-rigid-type Parkinson's disease: Molecular imaging with 123I-MIBG.

Mol Med Report. 2012 Sep 27. doi: 10.3892/mmr.2012.1104. [Epub ahead of print]

Chiaravalloti A, Stefani A, Tavolozza M, Pierantozzi M, Di Biagio D, Olivola E, Di Pietro B, Stampanoni M, Danieli R, Simonetti G, Stanzione P, Schillaci O.

Department of Biopathology and Diagnostic Imaging, University Tor Vergata, Rome, Italy.

The aim of this study was to evaluate the correlation between the clinical motor phenotypes of Parkinson's disease (PD) and 123I-MIBG myocardial uptake. In total, 53 patients with PD [31 males and 22 females, mean age 62±10 years; 19 Hoehn & Yahr (H&Y) stage 1, 9 stage 1.5, 15 stage 2 and 10 at stage 3] were examined and subdivided into different clinical forms on the basis of dominance of resting tremor (n=19, TDT) and bradykinesia plus rigidity (n=34, ART). This status was correlated with the semi-quantitative analysis of 123I-MIBG myocardial uptake. An age-matched control group of 18 patients was recruited (8 males and 10 females, mean age 62.4±16.3 years). 123I-MIBG myocardial uptake significantly correlated with disease duration in early (r2=0.1894; P=0.0028) and delayed images (r2=0.1795; P=0.0037) in PD patients, while no correlation was found when considering age at examination, UPDRS III motor examination section score and H&Y score. PD patients showed a reduced 123I‑MIBG myocardial uptake compared to the control group in early (P=0.0026) and delayed images (P=0.0040), and 123I-MIBG myocardial uptake was significantly lower in delayed images in TDT patients compared with ART patients (P=0.0167). A decrease was detected in the heart-to-mediastinum (H/M) ratio in delayed images compared to that of the early images in TDT patients (P=0.0040) and in the whole PD population (P=0.0012), while no differences were found in ART patients (P=0.1043). The results of the present study revealed that the cardiac sympathetic system is more severely impaired in TDT than in ART patients and 123I-MIBG molecular imaging has the potential help in improving therapeutic planning in these patients.

Recent data on rapid eye movement sleep behavior disorder in patients with Parkinson's disease: Analysis of behaviors, movements and periodic leg movements

Sleep Med. 2012 Sep 27. pii: S1389-9457(12)00307-3. doi: 10.1016/j.sleep.2012.07.005. [Epub ahead of print]
Cochen De Cock V.

Unité des Troubles du Sommeil, Service de Neurologie, Hôpital Gui de Chauliac, 80 Av. Augustin Fliche, 34235 Montpellier, France. 

Rapid eye movement (REM) sleep behavior disorder (RBD) is a fascinating parasomnia in which patients are able to enact their dreams because of a lack of muscle atonia during REM sleep. RBD represents a unique window into the dream world. Frequently associated with Parkinson's disease (PD), RBD raises various issues about dream modifications in this pathology and about aggressiveness during RBD episodes in placid patients during wakefulness. Studies on these behaviors have underlined their non-stereotyped, action-filled and violent characteristics but also their isomorphism with dream content. Complex, learnt behaviors may reflect the cortical involvement in this parasomnia but the more frequent elementary movements and the associated periodic limb movements during sleep also implicate the brainstem. Surprisingly, patients with PD have an improvement of their movements during their RBD as if they were disease-free. Also not yet understood, this improvement of movement during REM sleep raises issues about the pathways involved in RBD and about the possibility of using this pathway to improve movement in PD during the day.

Monday, 1 October 2012

Past exposure to neuroleptic drugs and risk of Parkinson disease in an elderly cohort

Neurology. 2012 Sep 26. [Epub ahead of print]
Foubert-Samier A, Helmer C, Perez F, Le Goff M, Auriacombe S, Elbaz A, Dartigues JF, Tison F.

From INSERM Unit 897 (A.F.-S., C.H., M.L., J.-F.D.), Bordeaux; University Bordeaux Segalen (A.F.-S., C.H., M.L., J.-F.D., F.T.), Bordeaux; Institut des Maladies Neurodégénératives (F.T.), Bordeaux; CMRR d'Aquitaine (A.F.-S., S.A., J.-F.D.) and Department of Neurology (F.P., F.T.), University Hospital of Bordeaux, Bordeaux; UMR CNRS 5293 (F.T.), Bordeaux; and Neuroepidemiology, UPMC University Paris, and INSERM Unit 708 (A.E.), Paris, France.

Neuroleptics and neuroleptic-like drugs are known to induce parkinsonism, which may reveal underlying Parkinson disease (PD) in some cases. We assessed the long-term risk of developing PD after past exposure to these drugs, in a 15-year prospective population-based elderly cohort study.
We used the Cox proportional hazards model to assess the relation between past exposure to neuroleptics and the risk of developing incident PD. All incident cases of parkinsonism were identified by standardized procedure and validated by a committee of experts.
Of 2,991 subjects followed, 117 developed parkinsonism and 43 developed probable PD during follow-up, of whom 22.2% and 32.6%, respectively, had been exposed to neuroleptics, compared to 16.6% for subjects without parkinsonism. About a third of subjects presented transient parkinsonism during drug exposure. After adjustment for gender and past occupation, past exposure to neuroleptics was associated with incident PD (relative risk, 3.16; 95% confidence interval [CI], 1.65-6.04). The relative risk was 3.65 (95% CI, 1.41-9.45) for benzamides and 2.59 (95% CI, 1.23-5.43) for phenothiazines. The population-attributable fraction of the risk for developing PD was 8.2% for benzamides and 12.2% for phenothiazines.
In a French elderly cohort, the risk of probable PD was increased by 3.2-fold after exposure to neuroleptics. This finding suggests the necessity of limiting the use of such drugs in elderly people.

Colonic inflammation in Parkinson's disease

Neurobiol Dis. 2012 Sep 24. pii: S0969-9961(12)00321-X. doi: 10.1016/j.nbd.2012.09.007. [Epub ahead of print]

Devos D, Lebouvier T, Lardeux B, Biraud M, Rouaud T, Pouclet H, Coron E, des Varannes SB, Naveilhan P, Nguyen JM, Neunlist M, Derkinderen P.

Inserm, U913, Nantes, F-44093, France; Inserm, CIC-04, Nantes, F-44093, France; University Nantes, Nantes, F-44093, France; CHU Nantes, Department of Neurology, Nantes, F-44093, France.

Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and data from recent genetic studies suggest a link between PD and gut inflammation. We therefore undertook the present survey to investigate whether gastrointestinal inflammation occurs in PD patients. Nineteen PD patients and 14 age-matched healthy controls were included. For each PD patients, neurological and gastrointestinal symptoms were assessed using the Unified Parkinson's Disease Rating Scale part III and the Rome III questionnaire, respectively and cumulative lifetime dose of L-dopa was calculated. Four biopsies were taken from the ascending colon during the course of a total colonoscopy in controls and PD patients. The mRNA expression levels of pro-inflammatory cytokines (tumor necrosis factor alpha, interferon gamma, interleukin-6 and interleukin-1 beta) and glial marker (Glial fibrillary acidic protein, Sox-10 and S100-beta) were analyzed using real-time PCR in two-pooled biopsies. Immunohistochemical analysis was performed on the two remaining biopsies using antibodies against phosphorylated alpha-synuclein to detect Lewy pathology. The mRNA expression levels of pro-inflammatory cytokines as well as of two glial markers (Glial fibrillary acidic protein and Sox-10) were significantly elevated in the ascending colon of PD patients with respect to controls. The levels of tumor necrosis factor alpha, interferon gamma, interleukin-6, interleukin-1 beta and Sox-10 were negatively correlated with disease duration. By contrast, no correlations were found between the levels of pro-inflammatory cytokines or glial markers and disease severity, gastrointestinal symptoms or cumulative lifetime dose of L-dopa. There was no significant difference in the expression of pro-inflammatory cytokines or glial marker between patients with and without enteric Lewy pathology. Our findings provide evidence that enteric inflammation occurs in PD and further reinforce the role of peripheral inflammation in the initiation and/or the progression of the disease.