Wednesday, 30 January 2013

Delayed emergence of a parkinsonian disorder or dementia in 81% of older males initially diagnosed with idiopathic REM sleep behavior disorder (RBD): 16year update on a previously reported series

Sleep Med. 2013 Jan 21. pii: S1389-9457(12)00381-4. doi: 10.1016/j.sleep.2012.10.009. [Epub ahead of print]
Schenck CH, Boeve BF, Mahowald MW.

Minnesota Regional Sleep Disorders Center, Departments of Psychiatry, Hennepin County Medical Center and University of Minnesota Medical School, Minneapolis, United States.

To provide a 16year update from the authors' 1996 report documenting a 38% conversion from idiopathic RBD (iRBD) to a parkinsonian disorder at a mean interval of nearly 13years after the onset of iRBD in a series of 29 males ⩾50years old.
The methods of evaluation, diagnosis and follow-up were previously described in the 1996 report. All patients had video-polysomnography (vPSG) confirmed RBD.
80.8% (21/26) of patients who were initially diagnosed with iRBD eventually developed parkinsonism/dementia (three of the original 29 patients were lost to follow-up). The distribution of diagnoses was as follows: n=13, Parkinson's disease (PD); n=3, dementia with Lewy bodies (DLB); n=1, dementia (unspecified; profound); n=2, multiple system atrophy (MSA); n=2, clinically diagnosed Alzheimer's Disease (AD) with autopsy-confirmed combined AD plus Lewy body disease pathology. Among the 21 iRBD "converters," the mean age (±SD) of iRBD onset was 57.7±7.7years; mean age (±SD) of parkinsonism/dementia onset was 71.9±6.6years; and mean interval (±SD) from iRBD onset to parkinsonism/dementia onset was 14.2±6.2years (range: 5-29years).
The vast majority of men ⩾50years old initially diagnosed with iRBD in this study eventually developed a parkinsonian disorder/dementia, often after a prolonged interval from onset of iRBD, with the mean interval being 14years while the range extended to 29years. Also, the specificity of iRBD converting to parkinsonism/dementia is striking. These findings carry important clinical and research implications in the convergent fields of sleep medicine, neurology, and neuroscience, and identify an optimal clinical group for conducting prospective research studies utilizing putative neuroprotective agents to delay the emergence of, or halt the progression to, parkinsonism and/or cognitive impairment as manifestations of either PD, DLB or MSA.

Tuesday, 29 January 2013

Manganese-induced parkinsonism in methcathinone abusers: bio-markers of exposure and follow-up

Eur J Neurol. 2013 Jan 24. doi: 10.1111/ene.12088. [Epub ahead of print]
Sikk K, Haldre S, Aquilonius SM, Asser A, Paris M, Roose A, Petterson J, Eriksson SL, Bergquist J, Taba P.

Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia.

Methcathinone abuse is a new cause of manganism. The psychostimulant is prepared from pseudoephedrine using potassium permanganate as an oxidant. We describe the clinical, biological, neuroimaging characteristics and follow-up results in a large Estonian cohort of intravenous methcathinone users.
During 2006-2012 we studied 38 methcathinone abusers with a mean age of 33 years. Subjects were rated by the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (HY), and Schwab and England (SE) rating scales. Twenty-four cases were reassessed 9-70 (20 ± 15) months after the initial evaluation. Manganese (Mn) in plasma and hair was analysed by inductively coupled plasma-atom emission spectrometry. Magnetic resonance imaging (MRI) was performed in 11, and single-photon emission computed tomography (SPECT) with iodobenzamide (IBZM) in eight subjects.
The average total UPDRS score was 43 ± 21. The most severely affected domains in UPDRS Part III were speech and postural stability, the least affected domain was resting tremor. At follow-up there was worsening of HY and SE rating scales. Subjects had a higher mean level of Mn in hair (2.9 ± 3.8 ppm) than controls (0.82 ± 1.02 ppm), P = 0.02. Plasma Mn concentrations were higher (11.5 ± 6.2 ppb) in active than in former users (5.6 ± 1.8 ppb), P = 0.006. Active methcathinone users had increased MRI T1-signal intensity in the globus pallidus, substantia nigra and periaquaductal gray matter. IBZM-SPECT showed normal symmetric tracer uptake in striatum.
Methcathinone abusers develop a distinctive hypokinetic syndrome. Though the biomarkers of Mn exposure are characteristic only of recent abuse, the syndrome is not reversible.

Sunday, 20 January 2013

The show must go on!!

Despite the snow fall in Hampshire and Wiltshire I took the opportunity to continue to see the study participants (snow chains were a necessity for much of the day). Unfortunately my trip to Gloucestershire and South Wales had to be postponed. 

- Alastair Noyce

The impassable...

Made passable!

Saturday, 19 January 2013

Palliative care and end-of-life planning in Parkinson's disease

J Neural Transm. 2013 Jan 18. [Epub ahead of print]
Walker RW.

Northumbria Healthcare NHS Foundation Trust, North Tyneside General Hospital, Rake Lane, North Shields, Tyne and Wear, NE29 8NH, UK

In Parkinson's disease (PD) typical "palliative care" type symptoms, such as pain, nausea, weight loss and breathlessness can occur throughout the condition, but become more prevalent in later disease stages. Pain may be specifically related to PD, e.g. dystonic pain with wearing off, but is more commonly due to other conditions. The cause can usually be elicited by a careful history and examination, and this guides intervention, both non-pharmaceutical, and pharmaceutical. For example, dystonic pain will respond best to appropriate changes to dopaminergic medication. In later disease stages people have increasing problems with swallowing, and also cognitive impairment. Impaired swallowing may lead to aspiration pneumonia, which is a common cause of hospital admission, and also death. Decisions about interventions towards the end of life, such as insertion of percutaneous endoscopic gastrostomy (PEG) tube for nutrition, can be very challenging, particularly if, as in most cases, the person with PD has not previously expressed their views upon this while they still maintained capacity to make decisions. Advance care planning (ACP) in PD should be encouraged in relation to interventions such as PEG tubes. It may also cover issues such as preferred place of death. Over recent years lower proportions of people have been dying at home, and this is especially true for PD, but home may well be where they would have preferred to die. However, there is little evidence to guide health professionals about how, when, and by whom, ACP should be approached.

Sunday, 13 January 2013

Stem cells and the treatment of Parkinson's disease

Exp Neurol. 2013 Jan 5. pii: S0014-4886(13)00004-6. doi: 10.1016/j.expneurol.2012.12.017. [Epub ahead of print]
Ali F, Stott SR, Barker RA.

Cambridge Centre for Brain Repair, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, England.

Progress in Parkinson's disease (PD) research has been hampered by the lack of an appropriate model which exhibits the core pathology seen in the human brain. Recent advances in deriving cells with neuronal phenotypes from patients with neurodegenerative disorders through cellular reprogramming offers a unique tool for disease modelling and may help shed light on the molecular pathogenesis the drives the progression of the disease. This technology may also help in establishing platforms for drug screening and open up exciting new prospects for cell grafting. In this review, we will discuss progress made in differentiating stem cells into authentic dopamine neurons and where we stand with respect to clinical trials with these cells in patients with PD. We will also examine the various approaches used in cellular reprogramming and their differentiation into patient-specific midbrain dopamine neurons, with an emphasis particularly on modelling familial cases of PD to recapitulate disease phenotypes. This review will highlight some of the challenges that need to be addressed for this technology to have any potential clinical application in cell therapy and personalised medicine.

Friday, 11 January 2013

α-Synuclein Levels in Blood Plasma from LRRK2 Mutation Carriers

PLoS One. 2012;7(12):e52312. doi: 10.1371/journal.pone.0052312. Epub 2012 Dec 27.
Gorostidi A, Bergareche A, Ruiz-Martínez J, Martí-Massó JF, Cruz M, Varghese S, Qureshi MM, Alzahmi F, Al-Hayani A, de Munáin AL, El-Agnaf OM.

Biodonostia Research Institute, Neurosciences area, Donostia, Gipuzkoa, Spain ; Hospital Donostia, Department of Neurology, Movement Disorders Unit, Donostia, Gipuzkoa, Spain ; Centro de investigación biomédica en Red para enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Madrid, Spain.

The diagnosis of Parkinson's disease (PD) remains primarily a clinical issue, based mainly on phenotypic patterns. The identification of biomarkers capable of permitting the preclinical detection of PD is critically needed. α-Synuclein is a key protein in PD, with missense and multiplication mutations in the gene encoding α-synuclein (SNCA) having been reported in familial cases of PD, and accumulation of the protein identified in Lewy bodies (LBs) and Lewy neurites (LNs) in affected brain regions. With the objective of validating the use of α-synuclein as a clinical or progressive biomarker in an accessible tissue, we used an enzyme-linked immunosorbent assay (ELISA) to measure α-synuclein levels in the peripheral blood plasma of idiopathic PD and LRRK2 mutation carrier patients and compared our findings with healthy control subjects. Compared to healthy controls, we found a significant decrease in plasma total α-synuclein levels in idiopathic PD (iPD) patients (n = 134, p = 0.010). However, the reduction was less significant in patients who were LRRK2 mutation carriers (n = 32, p = 0.133). This lack of significance could be due to the small number of individuals employed in this group. No predictive value of total α-synuclein in the diagnosis of PD was found in a receiver operating characteristic (ROC) curve analysis. Although this is a pilot study requiring corroboration on a larger cohort of patients, our results highlight the possible use of plasma α-synuclein as a biomarker for PD.

The Addenbrooke's Cognitive Examination for the differential diagnosis and longitudinal assessment of patients with parkinsonian disorders

J Neurol Neurosurg Psychiatry. 2013 Jan 8. [Epub ahead of print]
Rittman T, Ghosh BC, McColgan P, Breen DP, Evans J, Williams-Gray CH, Barker RA, Rowe JB.

Department of Clinical Neurosciences, University of Cambridge, , Cambridge, UK.

Differentiating idiopathic Parkinson's disease from atypical parkinsonian syndromes is challenging, especially in the early stages. We assessed whether the Revised Addenbrooke's Cognitive Examination (ACE-R) could differentiate between parkinsonian syndromes and reflect longitudinal changes in cognition in these disorders.
The ACE-R was administered at baseline and after approximately 18 months to 135 patients with parkinsonian disorders: 86 with idiopathic Parkinson's disease (PD), 30 with progressive supranuclear palsy (PSP), 19 with corticobasal degeneration (CBD). We assessed differences between groups for ACE-R, ACE-R subscores and Mini Mental State Examination (MMSE) scores at baseline (analyses of variance, receiver operating characteristics curves), and the interaction between diagnosis and change in ACE-R scores between visits (analyses of variance).
The ACE-R verbal fluency subscore distinguished between PSP and PD with a high sensitivity (0.92) and specificity (0.87); total ACE-R score and the visuospatial subscore were less specific (0.87 and 0.84 respectively) and sensitive (0.70 and 0.73). Significant group level differences were found between PD and PSP for MMSE and ACE-R (total score and subscores for attention and concentration, fluency, language, and visuospatial function), and between PD and CBD for the ACE-R visuospatial subscore. Performance worsened between visits for ACE-R score in PD (p=0.001) and CBD (p=0.001); visuospatial subscore in PD (p=0.003), PSP (p=0.022) and CBD (p=0.0002); and MMSE in CBD (p=0.004).
We propose the ACE-R, particularly the verbal fluency subscore, as a valuable contributor to the differential diagnosis of parkinsonian syndromes in the correct clinical context. The ACE-R may reflect disease progression in PD and CBD.

Tuesday, 8 January 2013

A Disruption Mechanism of the Molecular Clock in a MPTP Mouse Model of Parkinson's Disease

Neuromolecular Med. 2013 Jan 5. [Epub ahead of print]

Hayashi A, Matsunaga N, Okazaki H, Kakimoto K, Kimura Y, Azuma H, Ikeda E, Shiba T, Yamato M, Yamada KI, Koyanagi S, Ohdo S.


Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Fukuoka, Higashi-ku, 812-8582, Japan.


Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum. Although the motor symptoms are still regarded as the main problem, non-motor symptoms in PD also markedly impair the quality of life. Several non-motor symptoms, such as sleep disturbances and depression, are suggested to be implicated in the alteration in circadian clock function. In this study, we investigated circadian disruption and the mechanism in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP-treated mice exhibited altered 24-h rhythms in body temperature and locomotor activity. In addition, MPTP treatment also affected the circadian clock system at the genetic level. The exposure of human neuroblastoma cells (SH-SY5Y) to 1-metyl-4-phenylpyridinium (MPP(+)) increased or decreased the mRNA levels of several clock genes in a dose-dependent manner. MPP(+)-induced changes in clock genes expression were reversed by Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Most importantly, addition of ATP to the drinking water of MPTP-treated mice attenuated neurodegeneration in dopaminergic neurons, suppressed AMPK activation and prevented circadian disruption. The present findings suggest that the activation of AMPK caused circadian dysfunction, and ATP may be a novel therapeutic strategy based on the molecular clock in PD.

Wednesday, 2 January 2013

Reduced Body Mass Index in Parkinson's Disease: Contribution of Comorbid Depression

J Nerv Ment Dis. 2013 Jan;201(1):76-79.
Pilhatsch M, Kroemer NB, Schneider C, Ebersbach G, Jost WH, Fuchs G, Odin P, Reifschneider G, Bauer M, Reichmann H, Storch A.

*Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Dresden, Germany, †Department of Neurology, Technische Universität Dresden, Dresden, Germany, ‡Movement Disorders Clinic, Beelitz-Heilstätten, Germany; §Department of Neurology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany; ∥Parkinson Clinic Wolfach, Wolfach, Germany; ¶Department of Neurology, Klinikum-Bremerhaven, Bremerhaven, Germany; #Department of Neurology, University Hospital, Lund, Sweden; **Neuro Centrum Odenwald, Erbach, Germany; and ††German Center for Neurodegenerative Diseases (DZNE) Dresden, Germany.

ABSTRACT: Courses of Parkinson's disease (PD) that are complicated by weight loss result in poorer overall treatment outcome and lower quality of life. To determine the contribution of depression, which has not yet been specified in the etiology of weight loss in PD, symptomatology and anamnesis from 215 outpatients diagnosed with PD were assessed using a comprehensive battery of neuropsychiatric scales. A percentage of 31 comorbid depressed patients and a comparison with a control population allowed an accurate characterization of effect sizes, sex differences, and patterns of the contribution of comorbid depression to weight loss. Our study showed that comorbid depression had a clinically relevant effect concerning reduced body mass index in male (0.3; Hedges' g) but not in female PD patients. Although some possible confounders are not controlled here, our results support the need of monitoring depressive symptoms in the courses of PD, particularly in male patients.

Investigation of C9orf72 repeat expansions in Parkinson's disease

Neurobiol Aging. 2012 Dec 27. pii: S0197-4580(12)00613-6. doi: 10.1016/j.neurobiolaging.2012.11.025. [Epub ahead of print]

Daoud H, Noreau A, Rochefort D, Paquin-Lanthier G, Gauthier MT, Provencher P, Pourcher E, Dupré N, Chouinard S, Jodoin N, Soland V, Fon EA, Dion PA, Rouleau GA.

Centre of Excellence in Neuroscience of Université de Montréal (CENUM), CHUM Research Center and the Department of Medicine, Montreal, Quebec, Canada.

Large repeat expansions in the C9orf72 gene were recently reported to be a major cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Given some of the clinical and pathologic overlap between these 2 diseases and Parkinson's disease, we sought to evaluate the presence of these expansions in a cohort of French-Canadian patients with Parkinson's disease. No pathologic expansion was found in our cohort of patients suggesting that C9orf72 repeat expansions do not play a major role in the pathogenesis of Parkinson's disease.

Plain English - LRRK2 G2019S Parkinson's disease with more benign phenotype than idiopathic

This research study compared patients with Parkinson's who carry the commonest gene mutation associated with the disease (called LRRK2),...