Thursday, 26 July 2012

Alpha-synuclein: from secretion to dysfunction and death.

Cell Death Dis. 2012 Jul 19;3:e350. doi: 10.1038/cddis.2012.94.

Marques O, Outeiro TF.


Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisboa, Portugal.


The aggregation, deposition, and dysfunction of alpha-synuclein (aSyn) are common events in neurodegenerative disorders known as synucleinopathies. These include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. A growing body of knowledge on the biology of aSyn is emerging and enabling novel hypotheses to be tested. In particular, the hypothesis that aSyn is secreted from neurons, thus contributing to the spreading of pathology not only in the brain but also in other organs, is gaining momentum. Nevertheless, the precise mechanism(s) of secretion, as well as the consequences of extracellular aSyn species for neighboring cells are still unclear. Here, we review the current literature and integrate existing data in order to propose possible mechanisms of secretion, cell dysfunction, and death. Ultimately, the complete understanding of these processes might open novel avenues for the development of new therapeutic strategies.

Donepezil for dementia with Lewy bodies: A randomized, placebo-controlled trial.

Ann Neurol. 2012 Jul;72(1):41-52. doi: 10.1002/ana.23557.

Mori E, Ikeda M, Kosaka K; on behalf of the Donepezil-DLB Study Investigators.


Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai.



Because cholinergic deficits are prominent in dementia with Lewy bodies (DLB), we investigated the effects of a cholinesterase inhibitor, donepezil, in such patients in a randomized, double-blind, placebo-controlled exploratory phase 2 trial.


One-hundred forty patients with DLB, recruited from 48 specialty centers in Japan, were randomly assigned to receive placebo or 3, 5, or 10mg of donepezil hydrochloride daily for 12 weeks (n = 35, 35, 33, and 37, respectively). Effects on cognitive function were assessed using the Mini-Mental State Examination (MMSE) and several domain-specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Safety measures included the Unified Parkinson's Disease Rating Scale part III.


Donepezil at 5 and 10mg/day was significantly superior to placebo on both the MMSE (5mg: mean difference, 3.8; 95% confidence interval [CI], 2.3-5.3; p < 0.001; 10 mg: mean difference, 2.4; 95% CI, 0.9-3.9; p = 0.001) and CIBIC-plus (p < 0.001 for each); 3mg/day was significantly superior to placebo on CIBIC-plus (p < 0.001), but not on the MMSE (p = 0.017). Significant improvements were found also in behavioral measures (p < 0.001) at 5 and 10mg/day and caregiver burden (p = 0.004) at 10 mg/day. The safety results were consistent with the known profile of donepezil and similar among groups.


Donepezil at 5 and 10mg/day produces significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose. Donepezil is safe and well tolerated.

Wednesday, 25 July 2012

Decision making, impulsivity, and addictions: Do Parkinson's disease patients jump to conclusions?

Mov Disord. 2012 Jul 20. doi: 10.1002/mds.25105. [Epub ahead of print]

Djamshidian A, O'Sullivan SS, Sanotsky Y, Sharman S, Matviyenko Y, Foltynie T, Michalczuk R, Aviles-Olmos I, Fedoryshyn L, Doherty KM, Filts Y, Selikhova M, Bowden-Jones H, Joyce E, Lees AJ, Averbeck BB.

Department of Molecular Neuroscience and Reta Lila Weston Institute for Neurological Studies, University of London, London, United Kingdom.

Links between impulsive-compulsive behaviors (ICBs) in treated Parkinson's disease (PD), behavioral addictions, and substance abuse have been postulated, but no direct comparisons have been carried out so far. We directly compared patients with PD with and without ICBs with illicit drug abusers, pathological gamblers, and age-matched healthy controls using the beads task, a test of reflection impulsivity, and a working memory task. We found that all patients with PD made more impulsive and irrational choices than the control group. PD patients who had an ICB showed similar behavior to illicit substance abusers, whereas patients without ICBs more closely resembled pathological gamblers. In contrast, we found no difference in working memory performance within the PD groups. However, PD patients without ICBs remembered distractors significantly less than all other patients during working memory tests. We were able to correctly classify 96% of the PD patients with respect to whether or not they had an ICB by analyzing three trials of the 80/20 loss condition of the beads task with a negative prediction value of 92.3%, and we propose that this task may prove to be a powerful screening tool to detect an ICB in PD. Our results also suggest that intact cortical processing and less distractibility in PD patients without ICBs may protect them from developing behavioral addictions.

Prevalence of non-motor symptoms in young-onset versus late-onset Parkinson's disease

J Neurol. 2012 Jul 22. [Epub ahead of print]
Spica V, Pekmezović T, Svetel M, Kostić VS.

Institute of Neurology CCS, School of Medicine, University of Belgrade, Ul. Dr Subotića 6, 11000, Belgrade, Serbia.

Non-motor symptoms (NMS) of Parkinson's disease (PD) have only recently been increasingly recognized for their impact on a patient's quality of life. In this study, we applied the validated, comprehensive self-completed NMS questionnaire for PD (NMS Quest) to 101 patients with young-onset PD (onset between 21 and 45 years, YOPD) and 107 patients with late-onset PD (onset of PD ≥ 55 years, LOPD). The mean total NMS (NMSQ-T) was 11.9 ± 6.0 (range: 0 to of a maximum of 26) in LOPD and 7.7 ± 5.8 (range: 0 to of a maximum of 26) in YOPD (p < 0.05). Compared to YOPD, dribbling of saliva, loss of taste/smell, nocturia, forgetfulness, loss of interest, hallucinations, lack of concentration, anxiety, change in libido and difficulty in sexual activities, were significantly more prevalent in LOPD. The only NMS more prevalent in YOPD were restless legs and sweating, although such findings might be associated with drug effects. Among the nine NMS Quest domains, in both LOPD and YOPD patients the three most prevalent domains were depression/anxiety, urinary and sexual. Also, in both groups, hallucinations/delusions had the lowest frequency. In the multivariate linear regression model, the Hoehn and Yahr (HY) stage of the disease and activities of daily living scores in YOPD patients, while only the HY stage in LOPD patients appeared to be statistically significant predictors of increasing number of NMS. In contrast to a previous suggestion that YOPD patients might have an increased risk for NMS, we found a higher prevalence of NMS in LOPD patients than in those with YOPD.

The search for genetic mouse models of prodromal Parkinson's disease.

Exp Neurol. 2012 Jul 14. [Epub ahead of print]
Smith GA, Isacson O, Dunnett SB.

Neuroregeneration laboratories, McLean Hospital/Harvard Medical School, MA, USA.

Parkinson's disease is characterized and diagnosed by bradykinetic motor symptoms caused by the loss of dopamine neurons in the substantia nigra. The pathological and non-motor behavioral changes that occur prior to degeneration are less well characterized, although changes in gait, olfaction and cognition have been recognized in familial Parkinson's disease subjects. Gene mutations associated familial Parkinson's disease give rise to mitochondrial changes, altered energy homeostasis and intracellular trafficking deficits, and these can be modeled in transgenic mice. Here we discuss the recent finding of prodromal behavioral disturbances in a PINK1 deficient mouse that manifest prior to dopaminergic cell death and correlate to 5-HT fiber losses and mitochondrial morphological changes. We discuss the representation of the PINK1 deficient mouse and other genetic models to accurately recapitulate early Parkinson's disease. Prodromal symptoms and underlying pathology modeled in mice and cell lines from human subjects may have wide implications for earlier diagnosis. Current and emerging therapies need to be tailored to target both early cognitive and late stage motor symptoms.

Statin use and risk of Parkinson's disease: a meta-analysis of observational studies.

J Neurol. 2012 Jul 21. [Epub ahead of print]
Undela K, Gudala K, Malla S, Bansal D.

Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Sector 67, SAS Nagar, 160062, Punjab, India,

Inconsistent results regarding the association between statin use and risk of Parkinson's disease (PD) have been reported. We therefore examined the association between statin use and risk of PD by conducting a detailed meta-analysis of all observational studies published regarding this subject. A literature search in the PubMed database was undertaken through April 2012, looking for observational studies evaluating the association between statin use and risk of PD. Combined relative risk (RR) estimates and 95 % confidence intervals (CIs) were calculated using a random-effects model. Subgroup and sensitivity analyses were also performed. A total of eight (five case-control and three cohort) studies contributed to the analysis. There was heterogeneity and publication bias among the studies. Statin use significantly reduced the risk of PD by 23 % (RR 0.77, 95 % CI 0.64-0.92, p = 0.005). However, long-term statin use did not significantly affect the risk of PD (RR 0.72, 95 % CI 0.45-1.13, p = 0.15). Stratification of studies by age and smoking status significantly affected the final estimate (age-adjusted RR 0.61, 95 % CI 0.42-0.86, p = 0.005; age-not-adjusted RR 0.93, 95 % CI 0.83-1.05, p = 0.23 and smoking-adjusted RR 0.60, 95 % CI 0.42-0.87, p = 0.007; smoking-not-adjusted RR 0.92, 95 % CI 0.82-1.02, p = 0.10). Furthermore, sensitivity analysis confirmed the stability of results. Our meta-analysis supports the hypothesis that statin use reduced the risk of PD. Nevertheless, more randomized clinical trials and observational studies are required to confirm this association with underlying biological mechanisms in the future.

Frequencies of falls and associated features at different stages of Parkinson's disease.

Eur J Neurol. 2012 Jul 21. doi: 10.1111/j.1468-1331.2012.03821.x. [Epub ahead of print]
Hiorth YH, Lode K, Larsen JP.

Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.


To examine the frequencies and clinical characteristics of fallers and non-fallers at different stages of Parkinson's disease (PD).

The sample consisted of 232 patients in an unselected cross-sectional cohort of patients with PD, 207 newly diagnosed and drug naive patients and 175 controls. The examinations included the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr, Schwab and England, and Mini-Mental State Examination. According to item 13 of the UPDRS, the participants were classified as fallers, rare-fallers and non-fallers.

In the cross-sectional study cohort, 19% of the patients were classified as fallers and 25% as rare-fallers. Higher scores on activity of daily living (UPDRS ADL score) and motor complications (UPDRS complication of therapy score) were significantly and independently associated with falling. In the cohort of newly diagnosed patients with PD 2% were classified as fallers and 15% as rare-fallers. In the age- and sex-matched control group, none were fallers, and only 2% were rare-fallers. Patients with tremor-dominated PD subtype in both study populations did not fall.

Falls are a markedly increasing problem in patients with PD as the disease progresses. Healthcare workers should ask patients about falling, and specially focus on patients with motor complications or postural instability and gait disability (PIGD)-dominated subtype of parkinsonism.

Sunday, 22 July 2012

Cognitive impairment in patients with Parkinson's disease: diagnosis, biomarkers, and treatment.

Lancet Neurol. 2012 Aug;11(8):697-707.

Svenningsson P, Westman E, Ballard C, Aarsland D.



Centre for Molecular Medicine, Department of Neurology and Clinical Neuroscience, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.


Dementia is one of the most common and important aspects of Parkinson's disease and has consequences for patients and caregivers, and has health-related costs. Mild cognitive impairment is also common and frequently progresses to dementia. The underlying mechanisms of dementia associated with Parkinson's disease are only partly known and no mechanism-based treatments are available. Both dysmetabolism of α-synuclein and amyloid-protein and cholinergic deficits contribute to cognitive impairment in Parkinson's disease, and preliminary findings show that imaging and neurophysiological and peripheral biomarkers could be useful in diagnosis and prognosis. Rivastigmine is the only licensed treatment for dementia in Parkinson's disease, but emerging evidence suggests that memantine might also be useful. Whether these or other treatments can delay the progression from mild cognitive impairment to dementia in Parkinson's disease is a key research question.

Friday, 20 July 2012

Functional brain imaging of cognitive dysfunction in Parkinson's disease.

J Neurol Neurosurg Psychiatry. 2012 Jul 17. [Epub ahead of print]

Hirano S, Shinotoh H, Eidelberg D.


Department of Neurology, Chiba University School of Medicine, Chiba, Japan.


Multiple factors are involved in the development of cognitive impairment in Parkinson's disease (PD) and related disorders. Notably, several underlying factors, such as monoaminergic dysfunction, Lewy body pathology, Alzheimer disease-like pathology and cerebrovascular disease are implied in the PD pathophysiology of cognitive impairment. The mesocortical dopaminergic system is associated with executive functions which are frequently affected in PD and are influenced by local levodopa concentration, dopamine metabolism and baseline performance status. The ventral striatum and frontal cortex are associated with impulse control disorders reported in PD patients treated with dopamine replacement therapy. Cholinergic impairment in PD plays a cardinal role in the development of dementia. Acetylcholinesterase positron emission tomography demonstrates that posterior brain areas are related to cognitive decline in PD patients. Amyloid radiotracer illustrates that patients with PD with severe cognitive impairment were prone to accompanied cortical amyloid deposition. Metabolism/perfusion change associated with cognitive impairment in PD, so-called PD related cognitive pattern, is characterised by reduced frontoparietal activity and is an effective way to differentiate and monitor cognitive function of individual PD patients. Cognitive impairment in PD cannot be explained by a single mechanism and is entangled by multiple factors. Imaging studies can unravel each pathological domain, further shed light on the interrelation between different pathomechanisms, not only in PD but also in other dementia related disorders, and thereby integrate its interpretation to apply to therapeutics in individual patients.

Below is an example of the kind of images that can be obtained through functional MRI.

Image from


Tuesday, 17 July 2012

Physiotherapy versus placebo or no intervention in Parkinson's disease

Cochrane Database Syst Rev. 2012 Jul 11;7:CD002817.
Tomlinson CLPatel SMeek CClarke CEStowe RShah LSackley CMDeane KHHerd CPWheatley KIves N.


Birmingham Clinical Trials Unit, University of Birmingham, Robert Aitken Institute, Edgbaston, Birmingham, UK, B15 2TT.


BACKGROUND: Despite medical therapies and surgical interventions for Parkinson's disease (PD), patients develop progressive disability. The role of physiotherapy aims to maximise functional ability and minimise secondary complications through movement rehabilitation within a context of education and support for the whole person. The overall aim is to optimise independence, safety and well-being, thereby enhancing quality of life.


To assess the effectiveness of physiotherapy intervention compared with no intervention in patients with PD.


We identified relevant trials by electronic searches of numerous literature databases (e.g. MEDLINE, EMBASE) and trial registers, plus handsearching of major journals, abstract books, conference proceedings and reference lists of retrieved publications. The literature search included trials published up to end of December 2010.


Randomised controlled trials of physiotherapy intervention versus no physiotherapy intervention in patients with PD.


Two review authors independently extracted data from each article. We used standard meta-analysis methods to assess the effectiveness of physiotherapy intervention compared with no physiotherapy intervention. Trials were classified into the following intervention comparisons: general physiotherapy, exercise, treadmill training, cueing, dance and martial arts. We used tests for heterogeneity to assess for differences in treatment effect across these different physiotherapy interventions.


We identified 33 trials with 1518 participants. Compared with no-intervention, physiotherapy significantly improved the gait outcomes of velocity (mean difference 0.05 m/s, 95% confidence interval (CI): 0.02 to 0.07, P = 0.0002), two- or six-minute walk test (16.40 m, CI: 1.90 to 30.90, P = 0.03) and step length (0.03 m, CI: 0 to 0.06, P = 0.04); functional mobility and balance outcomes of Timed Up & Go test (-0.61 s, CI: -1.06 to -0.17, P = 0.006), Functional Reach Test (2.16 cm, CI: 0.89 to 3.43, P = 0.0008) and Berg Balance Scale (3.36 points, CI: 1.91 to 4.81, P < 0.00001); and clinician-rated disability using the Unified Parkinson's Disease Rating Scale (UPDRS) (total: -4.46 points, CI -7.16 to -1.75, P = 0.001; activities of daily living: -1.36, CI -2.41 to -0.30, P = 0.01; and motor: -4.09, CI: -5.59 to -2.59, P < 0.00001). There was no difference between arms in falls or patient-rated quality of life. Indirect comparisons of the different physiotherapy interventions found no evidence that the treatment effect differed across the physiotherapy interventions for any of the outcomes assessed.


Benefit for physiotherapy was found in most outcomes over the short-term (i.e. < three months), but was only significant for velocity, two- or six-minute walk test, step length, Timed Up & Go, Functional Reach Test, Berg Balance Scale and clinician-rated UPDRS. Most of the observed differences between the treatments were small. However, for some outcomes (e.g. velocity, Berg Balance Scale and UPDRS), the differences observed were at, or approaching, what are considered minimally clinical important changes.The review illustrates that a wide range of approaches are employed by physiotherapists to treat PD. However, there was no evidence of differences in treatment effect between the different types of physiotherapy interventions being used, though this was based on indirect comparisons. There is a need to develop a consensus menu of 'best-practice' physiotherapy, and to perform large well-designed randomised controlled trials to demonstrate the longer-term efficacy and cost-effectiveness of 'best practice' physiotherapy in PD.

Occupational Exposure to Whole-Body Vibration and Parkinson's Disease: Results From a Population-based Case-Control Study

Am J Epidemiol. 2012 Jul 12. [Epub ahead of print]

Harris MA, Marion SA, Spinelli JJ, Tsui JK, Teschke K.


Mechanical stress producing head injury is associated with Parkinson's disease, suggesting that relations with other physical hazards such as whole-body vibration (WBV) should be tested. In this study, the authors evaluated the relation between occupational exposure to WBV and Parkinson's disease. A population-based case-control study with 403 cases and 405 controls was conducted in British Columbia, Canada, between 2001 and 2008. From detailed occupational histories and published measurements, metrics of occupational WBV exposure were constructed and tested for associations with Parkinson's disease using logistic regression and adjusting for age and sex first, and then also for smoking and history of head injury. While ever being occupationally exposed to WBV was inversely associated with Parkinson's disease (odds ratio = 0.67, 95% confidence interval: 0.48, 0.94), higher intensities had consistently elevated odds ratios, with a statistically significant effect being noted for intermediate intensities when exposures were restricted to the 10 years or more prior to diagnosis. Possible mechanisms of an inverse relation between low levels of WBV exposure and Parkinson's disease could include direct protective effects or correlation with other protective effects such as exercise. Higher intensities of WBV could result in micro-injury, leading to vascular or inflammatory pathology in susceptible neurons.

Thursday, 12 July 2012

Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial

The Lancet Neurology, Volume 11, Issue 7, Pages 589 - 596, July 2012


Published Online: 01 June 2012

Caroline Moreau MD, Arnaud Delval MD , Luc Defebvre MD, et al for the Parkgait-II study



Despite optimum medical management, many patients with Parkinson's disease are incapacitated by gait disorders including freezing of gait. We aimed to assess whether methylphenidate—through its combined action on dopamine and noradrenaline reuptake—would improve gait disorders and freezing of gate in patients with advanced Parkinson's disease without dementia who also received subthalamic nucleus stimulation.


This multicentre, parallel, double-blind, placebo-controlled, randomised trial was done in 13 movement disorders departments in France between October, 2009, and December, 2011. Eligible patients were younger than 80 years and had Parkinson's disease, severe gait disorders, and freezing of gate despite optimised treatment of motor fluctuations with dopaminergic drugs and subthalamic stimulation. We randomly assigned patients (1:1 with a computer random-number generator in blocks of four) to receive methylphenidate (1 mg/kg per day) or placebo capsules for 90 days. Patients, their carers, study staff, investigators, and data analysts were masked to treatment allocation. To control for confounding effects of levodopa we assessed patients under standardised conditions with an acute levodopa challenge. Our primary outcome was a change in the number of steps during the stand-walk-sit (SWS) test without levodopa. We compared the respective mean numbers of steps at day 90 in the methylphenidate and placebo groups in a covariance analysis and adjusted for baseline differences. This trial is registered with, number NCT00914095.


We screened 81 patients and randomly assigned 35 to receive methylphenidate and 34 to receive placebo. 33 patients in the methylphenidate group and 32 patients in the placebo group completed the study. Efficacy outcomes were assessed in the patients who completed the study. Compared with patients in the placebo group (median 33 steps [IQR 26—45]), the patients in the methylphenidate group made fewer steps at 90 days (31 [26—42], F(1, 62)=6·1, p=0·017, adjusted size effect 0·61). Adverse events were analysed in all randomly assigned patients. There were significantly more adverse events in the methylphenidate group compared with placebo. Patients on methylphenidate had a significant increase in heart rate (mean 3·6 [SD 7·2] beats per min) and decrease in weight (mean 2·2 [SD 1·8] kg) compared with the placebo group.


Methylphenidate improved gait hypokinesia and freezing in patients with advanced Parkinson's disease receiving subthalamic nucleus stimulation. Methylphenidate represents a therapeutic option in the treatment of gait disorders at the advanced stage of Parkinson's disease. The long term risk—benefit balance should be further studied.


French Ministry of Health and Novartis Pharma.


Some time away from PD to highlight two large bits of news from the Alzheimer's world

A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline

  • Thorlakur Jonsson,
  • Jasvinder K. Atwal,
  • Stacy Steinberg,
  • Jon Snaedal,
  • Palmi V. Jonsson,
  • Sigurbjorn Bjornsson,
  • Hreinn Stefansson,
  • Patrick Sulem,
  • Daniel Gudbjartsson,
  • Janice Maloney,
  • Kwame Hoyte,
  • Amy Gustafson,
  • Yichin Liu,
  • Yanmei Lu,
  • Tushar Bhangale,
  • Robert R. Graham,
  • Johanna Huttenlocher,
  • Gyda Bjornsdottir,
  • Ole A. Andreassen,
  • Erik G. Jönsson,
  • Aarno Palotie,
  • Timothy W. Behrens,
  • Olafur T. Magnusson,
  • Augustine Kong,
  • Unnur Thorsteinsdottir
  • et al.
Nature (2012) doi:10.1038/nature11283
  14 March 2012 
Accepted 06 June 2012
Published online
 11 July 2012

The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer’s disease. The age-specific prevalence of Alzheimer’s disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90. Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer’s disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer’s disease and cognitive decline in the elderly without Alzheimer’s disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer’s disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer’s disease, the two may be mediated through the same or similar mechanisms.

Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease

Randall J. Bateman, M.D., Chengjie Xiong, Ph.D., Tammie L.S. Benzinger, M.D., Ph.D., Anne M. Fagan, Ph.D., Alison Goate, Ph.D., Nick C. Fox, M.D., Daniel S. Marcus, Ph.D., Nigel J. Cairns, Ph.D., Xianyun Xie, M.S., Tyler M. Blazey, B.S., David M. Holtzman, M.D., Anna Santacruz, B.S., Virginia Buckles, Ph.D., Angela Oliver, R.N., Krista Moulder, Ph.D., Paul S. Aisen, M.D., Bernardino Ghetti, M.D., William E. Klunk, M.D., Eric McDade, M.D., Ralph N. Martins, Ph.D., Colin L. Masters, M.D., Richard Mayeux, M.D., John M. Ringman, M.D., Martin N. Rossor, M.D., Peter R. Schofield, Ph.D., D.Sc., Reisa A. Sperling, M.D., Stephen Salloway, M.D., and John C. Morris, M.D. for the Dominantly Inherited Alzheimer Network

New England Journal of Medicine
July 11, 2012 (10.1056/NEJMoa1202753)


The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.


In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.


Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.


We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN number, NCT00869817.)

Wednesday, 11 July 2012

Exploring the electrocardiogram as a potential tool to screen for premotor Parkinson's disease

Mov Disord. 2010 Oct 30;25(14):2296-303.
Valappil RA, Black JE, Broderick MJ, Carrillo O, Frenette E, Sullivan SS, Goldman SM, Tanner CM, Langston JW.


Clinical Research Department, The Parkinson's Institute and Clinical Center, Sunnyvale, California, USA.


The aim of this study was to test the hypothesis that patients with REM sleep behavior disorder, many of whom will develop Parkinson's disease (PD) or a related synucleinopathy, will demonstrate decreased heart rate variability (HRV) compared with a group of age-matched controls as measured by an electrocardiogram during wakefulness. We compared HRV in 11 untreated idiopathic REM sleep behavior disorder patients (9 men and 2 women; mean age, 63.3 years; SD, 7.5 years) and 11 control subjects with idiopathic insomnia without REM sleep behavior disorder (7 men and 4 women; mean age, 59.5 years; SD, 8.7 years). Subjects with other causes of reduced HRV were excluded. HRV was determined from 5-minute presleep segments of a single channel electrocardiogram recorded during polysomnographic evaluations, using R-R intervals during wakefulness. Time domain, geometric measures, and spectral analysis of the R-R intervals were significantly different between cases and controls. A discriminant function analysis correctly classified 95.5% of subjects (overall model fit, P = 0.016). Leave-one-out cross-validation correctly classified 77.3% of subjects. HRV during wakefulness is significantly decreased in patients with idiopathic REM sleep behavior disorder compared with control subjects, suggesting abnormalities of both sympathetic and parasympathetic function. Patients with RBD may later develop motor and cognitive features of a Lewy body disorder, such as PD. Cardiac autonomic dysfunction is also impaired in PD, suggesting that impaired HRV may be an early sign of PD. HRV measured by routine electrocardiograms could be used to screen for Lewy body disorders such as PD.

Reduced sympathetically driven heart rate variability during sleep in Parkinson's disease: a case-control polysomnography-based study

Mov Disord. 2011 Feb 1;26(2):234-40. doi: 10.1002/mds.23479. Epub 2011 Jan 31.
Sauvageot N, Vaillant M, Diederich NJ.


Centre de Recherche Publique Santé, Centre d'Etudes en Santé, Strassen, Luxembourg.



To study heart rate variability during nocturnal sleep in idiopathic Parkinson's disease.


Retrospective study, using part of the data set accumulated in an earlier study, in which polysomnography was performed in 35 idiopathic Parkinson's disease patients under their usual medication and in 35 non-idiopathic Parkinson's disease controls, matched for age, gender, and amount of apneas/hypopneas per hour. R-R intervals were calculated separately for non-rapid eye movements and rapid eye movements sleep stages. R-R variability was analyzed for time and frequency domains. Selected variables considered were high frequency band (0.15-0.40 Hz) influenced by parasympathetic input and low frequency band (0.04-0.15 Hz) influenced by sympathetic input. Both frequency bands were considered in normalized units (low frequency and high frequency normalized units). Low frequency/high frequency ratio was calculated as an estimate of sympathicovagal balance.


All respiratory and sleep stage characteristics were similar in both groups. Low frequency normalized unit was reduced in idiopathic Parkinson's disease patients, both for non-rapid eye movements and rapid eye movements sleep (P = 0.005). Low frequency/high frequency was smaller in idiopathic Parkinson's disease for both sleep portions (P = 0.02).


Idiopathic Parkinson's disease patients show reduced sympathetic influence on heart rate variability in both non-rapid eye movements and rapid eye movements sleep stages. We speculate that these findings are a consequence of the postganglionic noradrenergic cardiac denervation found in idiopathic Parkinson's disease patients.

Image from

Tuesday, 10 July 2012

“Disease-modification” trials in Parkinson disease: Target populations, endpoints and study design

Olivier Rascol, MD, PhD

doi: 10.1212/WNL.0b013e318199049e
Neurology February 17, 2009 vol. 72 no. 7 Supplement 2 S51-S58

“Neuroprotective” compounds that block dopamine cell death are expected to slow the progression of the neurologic symptoms of Parkinson disease (PD) and therefore “modify” the disease course. However, presently, no fully satisfying efficacy “disease-modification” study design exists, and no drug has yet been approved for that indication. This is inherent to the slow progression of PD with respect to the limited time for patient follow-up and exposure to placebo, the modest effects of investigated drugs, and the confounding effects of symptomatic medications used to treat patients with PD. Disease-modification trials assessing drug efficacy on PD progression are currently prospective, randomized, parallel-group, placebo-controlled, long-term (1–3 year) studies. Untreated patients with early PD represent the main target population because more neurons remain for protection, PD may progress faster, and symptomatic medications are not needed at this stage. “Long lasting” prevention/postponement of disability is a relevant objective for such trials and two main types of outcome and analysis are proposed: slopes analysis of cardinal clinical feature progression (Unified PD Rating Scale, UPDRS) or survival curve analysis of “time to emergence” of clinically relevant milestones (time to dopaminergic therapy, Hoehn and Yahr stage III, etc.). The use of biomarkers remains investigational. Wash-out and delayed-start designs have been proposed to disentangle symptomatic and neuroprotective mechanisms, although this clarification might not be so important practically, as long as the effect on disability is large and long-lasting. To observe clinically relevant changes, several years of follow-up is required, and controlled, randomized, pragmatic trials should be

An exploratory analysis on gene-environment interactions for Parkinson disease.

Neurobiol Aging. 2012 Jul 2. [Epub ahead of print]
Gao J, Nalls MA, Shi M, Joubert BR, Hernandez DG, Huang X, Hollenbeck A, Singleton AB, Chen H.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

Little is known about gene-environment interactions in Parkinson disease (PD). We examined potential interactions of smoking and caffeine intake with 10 genome-wide association studies single nucleotide polymorphisms (SNPs) at or near the SNCA, MAPT, LRRK2, and HLA loci among 584 PD patients and 1571 controls. The main effects of these SNPs and environmental exposures were consistent with previous reports. Family history of PD was associated with PD risk (odds ratio = 2.71, 95% confidence interval, 1.97-3.74), which was little affected by further adjustment for these SNPs and environmental exposures. Overall, we did not find significant interactions of either smoking or caffeine intake with these SNPs. However, with a combined smoking and caffeine intake exposure, we found a significant interaction with rs2896905 at SLC2A13, near LRRK2 (p uncorrected = 0.0008). Each A allele was associated with a 35% higher PD risk among never smokers with low caffeine intake, but with a 32% lower risk among smokers with high caffeine intake. This study provides preliminary evidence of a potential gene-environment interaction for PD, which should be investigated in future studies.

Parkinson’s Researcher Fabricated Data

The findings of two studies are retracted that looked into the role of pesticides and neurodegeneration.

In San Francisco

I've arrived in San Francisco for a series of meetings that relate to the PREDICT-PD project. Here's hoping for a productive time.

Friday, 6 July 2012

Subjective sleep problems in patients with early Parkinson's disease

Eur J Neurol. 2012 Jun 30. doi: 10.1111/j.1468-1331.2012.03791.x. [Epub ahead of print]

Stefansdottir S, Gjerstad MD, Tysnes OB, Larsen JP.

Department of Clinical Neurophysiology, Stavanger University Hospital, Stavanger, Norway; Department of Neurology, Stavanger University Hospital, Stavanger, Norway.


Sleep problems are common in Parkinson's disease (PD) and increasingly so with disease progression. The frequency of these problems and the influence of dopaminergic treatment on sleep in early stages of PD remain unclear. We have therefore in this study examined the subjective experience of sleep problems in drug-naïve patients with early PD and how these problems developed after 1 year on dopaminergic treatment using the Parkinson's Disease Sleep Scale (PDSS).

Of 138 drug-naïve patients with early PD derived from a population-based incident cohort and 138 age and gender-matched control subjects were thoroughly assessed for Parkinsonism, cognition, depressive symptoms and sleep by structured interviews and clinical examination at the time of diagnosis and 1 year later on medication. Sleep problems were assessed using the PDSS.

The total PDSS score for patients with PD was lower compared with controls, 119 vs. 127 ( P  < 0.05) at baseline and 121 vs. 128 ( P  < 0.005) after 1 year on drugs. Analyses of PDSS subdomains showed more nocturnal motor off symptoms both at baseline and after 1 year (P < 0.005), and increased daytime somnolence in patients compared with control subjects ( P  < 0.005 at baseline and after 1 year P  < 0.05). Only minor changes in sleep scores were seen after the introduction of dopaminergic treatment.

Patients with early PD report only modestly increased subjective sleep problems at the time of diagnosis compared with control subjects and dopaminergic treatment during the first year did in general only slightly change the experienced sleep problems.

Prevalence and phenomenology of olfactory hallucinations in Parkinson's disease

J Neurol Neurosurg Psychiatry. 2012 Jun 29. [Epub ahead of print]
Bannier S, Berdagué JL, Rieu I, de Chazeron I, Marques A, Derost P, Ulla M, Llorca PM, Durif F.

CHU Clermont-Ferrand, Neurology Department, Clermont-Ferrand, France.


Although visual hallucinations in Parkinson's disease (PD) have been described in several major studies, little is known about olfactory hallucinations (OHs).

The authors performed a detailed analysis of OHs in a cohort of 87 Parkinsonian patients to estimate the prevalence of OHs and describe their phenomenology. They also evaluated smelling abilities in terms of detection and identification. Assessment of both, OHs and olfactory function, was also performed using a control group of 40 normal subjects.

Nine patients exhibited OHs compared with none of the controls, giving a prevalence of 10% for OHs in patients. OHs were described as rare, short-lasting, unpleasant odours which are not frightening since clearly identified by the patient as hallucinations. Parkinsonian patients with OHs exhibited olfactory impairment of detection and identification compared with controls, but there was no difference in their olfactory abilities from Parkinsonian patients without OHs.

In conclusion, OHs should be added to the list of non-motor PD symptoms that can occur early or late in the course of PD. The authors' study did not reveal any significant difference in terms of olfactory abilities between patients with or without OHs. However, olfactory impairment is well documented in Parkinsonian patients and cannot be totally ruled out as a risk factor for OHs. The authors recognise that complex mechanisms are probably involved in this phenomenon.

Association of Parkinson's disease with infections and occupational exposure to possible vectors

Mov Disord. 2012 Jul 2. doi: 10.1002/mds.25077. [Epub ahead of print]
Harris MA, Tsui JK, Marion SA, Shen H, Teschke K.

University of British Columbia, School of Population and Public Health, Vancouver, British Columbia, Canada; Cancer Care Ontario, Occupational Cancer Research Centre, Toronto, Ontario, Canada. 

The ultimate causes of idiopathic Parkinson's disease (PD) are not fully known, but environmental and occupational causes are suspected. Postencephalitic parkinsonism has been linked to influenza, and other viral infections have also been suspected to relate to PD. We estimated the relationship between PD and both infections and possible vectors of infection (i.e., animal and human) in a population-based, case-control study in British Columbia, Canada. We recruited 403 cases detected by their use of antiparkinsonian medications and 405 controls from the registrants of the provincial universal health insurance plan. Severe influenza was associated with PD (odds ratio [OR]: 2.01; 95% confidence interval [CI]: 1.16-3.48), although this effect was attenuated when reports were restricted to those occurring 10 or more years before diagnosis. Childhood illnesses were inversely associated with PD, particularly red measles (OR: 0.65; 95% CI: 0.48-0.90). Several animal exposures were associated with PD, with statistically significant effects for cats (OR: 2.06; 95% CI: 1.09-3.92) and cattle (OR: 2.23; 95% CI: 1.22-4.09). Influenza infection may be associated with PD. The inverse relationships with childhood infections may suggest an increased risk with subclinical or asymptomatic childhood infections. Occupational exposure to animals may increase risk through transmission of infections or may indicate exposure to another agent of interest (e.g., bacterial endotoxin).

Image of 3D rendered infleunza virion from