Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson's disease

Mov Disord. 2014 Feb 26. doi: 10.1002/mds.25838. [Epub ahead of print]

Nuytemans K, Inchausti V, Beecham GW, Wang L, Dickson DW, Trojanowski JQ, Lee VM, Mash DC, Frosch MP, Foroud TM, Honig LS, Montine TJ, Dawson TM, Martin ER, Scott WK, Vance JM.

BACKGROUND:

We have reported that intermediate repeat lengths of the C9ORF72 repeat are a risk factor for Parkinson's disease (PD) in a clinically diagnosed data set. Because 10% to 25% of clinically diagnosed PD have different diagnoses upon autopsy, we hypothesized that this may reflect phenotypic heterogeneity or concomitant pathology of other neurodegenerative disorders.

METHODS:

We screened 488 autopsy-confirmed PD cases for expansion haplotype tag rs3849942T. In 196 identified haplotype carriers, the C9ORF72 repeat was genotyped using the repeat-primed polymerase chain reaction assay.

RESULTS:

No larger (intermediate or expanded) repeats were found in these autopsy-confirmed PD samples. This absence of larger repeats is significantly different from the frequency in clinically diagnosed datasets (P = 0.002).

CONCLUSIONS:

Our results suggest that expanded or intermediate C9ORF72 repeats in clinically diagnosed PD or parkinsonism might be an indication of heterogeneity in clinically diagnosed PD cases. Further studies are needed to elucidate the potential contribution of the C9ORF72 repeat to autopsy-confirmed PD.

Accuracy of the Microsoft Kinect sensor for measuring movement in people with Parkinson's disease

Gait Posture. 2014 Jan 22. pii: S0966-6362(14)00024-1. doi: 10.1016/j.gaitpost.2014.01.008. [Epub ahead of print]

Galna B, Barry G, Jackson D, Mhiripiri D, Olivier P, Rochester L.

Author information

• Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
• Culture Lab, School of Computing Science, Newcastle University, Newcastle upon Tyne, United Kingdom.
• Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.

Abstract

BACKGROUND:

The Microsoft Kinect sensor (Kinect) is potentially a low-cost solution for clinical and home-based assessment of movement symptoms in people with Parkinson's disease (PD). The purpose of this study was to establish the accuracy of the Kinect in measuring clinically relevant movements in people with PD.

METHODS:

Nine people with PD and 10 controls performed a series of movements which were measured concurrently with a Vicon three-dimensional motion analysis system (gold-standard) and the Kinect. The movements included quiet standing, multidirectional reaching and stepping and walking on the spot, and the following items from the Unified Parkinson's Disease Rating Scale: hand clasping, finger tapping, foot, leg agility, chair rising and hand pronation. Outcomes included mean timing and range of motion across movement repetitions.

RESULTS:

The Kinect measured timing of movement repetitions very accurately (low bias, 95% limits of agreement <10% of the group mean, ICCs >0.9 and Pearson's r>0.9). However, the Kinect had varied success measuring spatial characteristics, ranging from excellent for gross movements such as sit-to-stand (ICC=.989) to very poor for fine movement such as hand clasping (ICC=.012). Despite this, results from the Kinect related strongly to those obtained with the Vicon system (Pearson's r>0.8) for most movements.

CONCLUSIONS:

The Kinect can accurately measure timing and gross spatial characteristics of clinically relevant movements but not with the same spatial accuracy for smaller movements, such as hand clasping.

Olfactory bulb involvement in neurodegenerative diseases

Acta Neuropathol. 2014 Feb 20. [Epub ahead of print]

Attems J, Walker L, Jellinger KA.

Author information

Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.

Abstract

Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Parkinson's disease and other synucleinopathies, Alzheimer's disease (AD), and mild cognitive impairment heralding its progression to dementia. The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve the olfactory epithelium, olfactory bulb/tract, primary olfactory cortices, and their secondary targets. Olfactory dysfunction is related to deposition of pathological proteins, α-synuclein, hyperphosphorylated tau protein, and neurofilament protein in these areas, featured by neurofibrillary tangles, Lewy bodies and neurites inducing a complex cascade of molecular processes including oxidative damage, neuroinflammation, and cytosolic disruption of cellular processes leading to cell death. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with severe anosmia. Recent studies of olfactory dysfunction have focused its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Here, we summarize the current knowledge on neuropathological and pathophysiological changes of the olfactory system in the most frequent neurodegenerative diseases, in particular AD and synucleinopathies. We also present neuropathological findings in the olfactory bulb and tract in a large autopsy cohort (n = 536, 57.8 % female, mean age 81.3 years). The severity of olfactory bulb HPτ, Aβ, and αSyn pathology correlated and increased significantly (P < 0.001) with increasing neuritic Braak stages, Thal Aβ phases, and cerebral Lewy body pathology, respectively. Hence, further studies are warranted to investigate the potential role of olfactory biopsies (possibly restricted to the olfactory epithelium) in the diagnostic process of neurodegenerative diseases in particular in clinical drug trials to identify subjects showing early, preclinical stages of neurodegeneration and to stratify clinically impaired cohorts according to the underlying cerebral neuropathology.

Exenatide as a potential treatment for patients with Parkinson's disease: First steps into the clinic

It is an exciting time for Exenatide

Alzheimers Dement. 2014 Feb;10(1S):S38-S46. doi: 10.1016/j.jalz.2013.12.005.

Foltynie T, Aviles-Olmos I.

Author information

Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK. 

Abstract

BACKGROUND:

There is an increasing number of approaches to try and relieve the motor symptoms of Parkinson's disease (PD) that focus predominantly on strategies of dopaminergic replacement or deep brain stimulation. There remains, however, a major need to slow down or reverse the relentless progression of the disease to prevent the evolution of disabling motor and nonmotor features that continue to cause disability despite the existing symptomatic approaches. Data emerging from the laboratory suggest that agonists for the glucagonlike peptide 1 (GLP-1) receptor may have biological properties relevant to PD pathogenesis and progression.

METHODS:

Future progress in the evaluation of GLP-1 agonists such as exenatide as potential disease-modifying treatments in PD can be facilitated by collection of proof-of-concept data to mitigate against the risk associated with major financial investments into these agents. There are, nevertheless, multiple issues that must be considered in the planning, setup, and conduct of pilot trials of potential disease-modifying drugs.

RESULTS:

Open-label proof-of-concept data have been collected in a small cohort of patients with moderate severity PD that suggest that this agent is well tolerated. Patients randomized to receive exenatide showed advantages on validated motor and nonmotor scales of PD that persisted after a 2-month drug washout period.

CONCLUSIONS:

Although data must be interpreted with caution, given the strong possibility of placebo effects, the clinical evaluation of these patients supports additional investment into double-blind trials of the GLP-1 agonists in PD.

Anxiety and depression in Parkinson's disease

This is an excellent overview and I say that without bias.

Curr Treat Options Neurol. 2014 Apr;16(4):285. doi: 10.1007/s11940-014-0285-6.

Djamshidian A, Friedman JH.

Author information

Department of Molecular Neuroscience and Reta Lila Weston Institute for Neurological Studies, University of London, London, 1 Wakefield Street, WC1N1PJ, London, UK,

Abstract

OPINION STATEMENT:

Anxiety and depression, while very common problems in Parkinson's disease (PD), have not been subject to adequate treatment trials. While a handful of double blind placebo-controlled trials of depression have been published, only a small number of subjects have been enrolled in most of these. There have been no adequate treatment trials of anxiety. Thus, most practitioners base their treatments on what has been published in the general population and their own personal experience. The data suggest that depression is probably treatable in some cases, but there are no data to support any drug treatment of anxiety. Much of the rationale for treating these disorders is based primarily on side effect profiles rather than efficacy and is almost entirely based on anecdotal experience. Although we lack convincing data, we do believe in the pharmacologic treatment of depression and anxiety and choose medications based on side effect profiles, some of which may be useful. We favor the selective serotonin reuptake inhibitors (SSRIs) in general for both depression and anxiety because of their relative freedom from side effects but will often choose mirtazapine if insomnia or weight loss is a problem, clonazepam for anxiety without depression if an SSRI is insufficient or if REM sleep behavior disorder is a problem, or a tricyclic antidepressant if drooling is troubling and the patient is not demented. Alternatively, we use the serotonin and noradrenaline reuptake inhibitor venlafaxine in those who do not tolerate an SSRI. SSRIs cannot be used for anxiety on an as needed basis, whereas short-acting benzodiazepines may be useful for this purpose. Psychosocial treatments of both depression and anxiety have also been under-studied, with probable benefits and a benign adverse effect profile.

Practical approach to freezing of gait in Parkinson's disease

Practical advice for one of the trickiest features of PD.

Pract Neurol. 2014 Feb 14. doi: 10.1136/practneurol-2013-000743. [Epub ahead of print]

Okuma Y.

Abstract

Freezing of gait in Parkinson's disease and related disorders is common and very disabling. It usually occurs in the advanced stages, although mild forms may develop earlier. Freezing can occur on turning, in narrow spaces, immediately before reaching a destination, and in stressful situations. Dual tasking (motor or cognitive load) aggravates the problem. Freezing of gait in Parkinson's disease usually occurs in the 'off' rather than in the 'on' state. It is, therefore, not entirely drug-resistant; the first step in medical treatment is to ensure adequate dopaminergic stimulation to reduce the 'off' state. There is no good evidence for any specific drug to alleviate freezing. Visual or auditory cues are very helpful as behavioural therapy. Assistive devices, such as a wheeled walker sometimes help. Deep brain stimulation of the subthalamic nucleus may alleviate freezing in the 'off' state. Because of the complexity of freezing, individual patients need a careful assessment-particularly in relation to motor fluctuation-to optimise their treatment.

Optical Coherence Tomography in Parkinson's Disease: Is the Retina a Biomarker?

This seems to be gaining momentum.

J Parkinsons Dis. 2014 Feb 11. [Epub ahead of print]

Lee JY, Ahn J, Kim TW, Jeon BS.

Abstract

Visual symptoms are a common feature in patients with Parkinson's disease (PD), and retinal dopamine loss and dysfunctions in foveal vision have been described in PD patients. Because visual hallucination (VH) is a specific feature of PD which is differentiated from other parkinsonian disorders, defective visual information processing from both the central and peripheral pathways is suggested to be the pathophysiological mechanisms of VH in PD. Decreased visual acuity as well as impaired contrast sensitivity and color vision is known to be related to the appearance of VH in PD. However, these functional studies were also affected by cognitive or cortical dysfunctions; thus, structural imaging can more reliably reflect visual afferent dysfunction. Recently, optical coherence tomography (OCT) scans have been used to investigate the structural changes in the retina in vivo. Segmental measures of the vertical retinal layers by OCT provide structural evidence for retinal dopamine loss and foveal dysfunction in PD. Retinal nerve fiber layer (RNFL) thinning in PD was shown to be significantly associated with VH and correlated with PD duration and severity. Thus, there is a possibility that the retina could be a biomarker for disease progression and risk of VH in PD. A standard protocol for OCT studies in PD with more accurate measures of the retinal layers needs to be developed in the future.

Randomized clinical trial of topiramate for levodopa-induced dyskinesia in Parkinson's disease

Parkinsonism Relat Disord. 2014 Jan 28. pii: S1353-8020(14)00031-5. doi: 10.1016/j.parkreldis.2014.01.016. [Epub ahead of print]

Kobylecki C, Burn DJ, Kass-Iliyya L, Kellett MW, Crossman AR, Silverdale MA.

Abstract

BACKGROUND:

The antiepileptic drug topiramate reduces levodopa-induced dyskinesia without exacerbating parkinsonism in animal models. We report a randomized, double-blind, placebo-controlled crossover trial in patients with Parkinson's disease and levodopa-induced dyskinesia.

METHODS:

Fifteen patients with Parkinson's disease and stable levodopa-induced dyskinesia were enrolled into the study, of whom 13 were randomized to topiramate or placebo. The study medication was titrated to 100 mg/day over four weeks, and assessments were carried out after a further two weeks. Dyskinesia severity assessed by a blinded rater from video recordings was the primary outcome measure.

RESULTS:

Seven patients (mean age 58.9 ± 12.8 years) completed the study. Patients taking topiramate vs. placebo showed a significant increase in dyskinesia severity compared to baseline (Wilcoxon signed rank test, P = 0.043). Five patients withdrew from the study whilst taking topiramate due to adverse effects.

CONCLUSIONS:

Topiramate tended to worsen dyskinesia in patients with Parkinson's disease, and was poorly tolerated.

Association of Parkinson Disease Risk Loci With Mild Parkinsonian Signs in Older Persons

This is an interesting study which turns the traditional way of doing things upside down. Starting with the hard outcome and working back to the variable phenotype, rather than starting with a heterogenous phenotype and trying to achieve a hard outcome.


JAMA Neurol. 2014 Feb 10. doi: 10.1001/jamaneurol.2013.6222. [Epub ahead of print]
Shulman JM, Yu L, Buchman AS, Evans DA, Schneider JA, Bennett DA, De Jager PL.

• 
  
IMPORTANCE Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored. OBJECTIVE To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons. DESIGN, SETTING, AND PARTICIPANTS Eighteen candidate single-nucleotide polymorphisms from PD genome-wide association studies were evaluated in a joint clinicopathologic cohort. Participants included 1698 individuals and a nested autopsy collection of 821 brains from the Religious Orders Study and the Rush Memory and Aging Project, 2 prospective community-based studies. MAIN OUTCOMES AND MEASURES The primary outcomes were a quantitative measure of global parkinsonism or component measures of bradykinesia, rigidity, tremor, and gait impairment that were based on the motor Unified Parkinson's Disease Rating Scale. In secondary analyses, we examined associations with additional quantitative motor traits and postmortem indices, including substantia nigra Lewy bodies and neuronal loss. RESULTS Parkinson disease risk alleles in the MAPT (rs2942168; P = .0006) and CCDC62 (rs12817488; P = .004) loci were associated with global parkinsonism, and these associations remained after exclusion of patients with a PD diagnosis. Based on motor Unified Parkinson's Disease Rating Scale subscores, MAPT (P = .0002) and CCDC62 (P = .003) were predominantly associated with bradykinesia, and we further discovered associations between SREBF1 (rs11868035; P = .005) and gait impairment, SNCA (rs356220; P = .04) and rigidity, and GAK (rs1564282; P = .03) and tremor. In the autopsy cohort, only NMD3 (rs34016896; P = .03) was related to nigral neuronal loss, and no associations were detected with Lewy bodies. CONCLUSIONS AND RELEVANCE In addition to the established link to PD susceptibility, our results support a broader role for several loci in the development of parkinsonian motor signs and nigral pathology in older persons.

A practical approach to remote longitudinal follow-up of Parkinson's disease: The FOUND study.

"Following patients up by telephone interview is cheaper (and can therefore be done more frequently) than seeing patients in clinic. This study demonstrates that telephone interviews can be quite accurate for diagnosis, assessing disease features and adequacy of medications for patients with PD. However, face-to-face interaction between doctor and patient has many advantages which telephone consultations cannot replicate. Therefore, the telephone interview should be considered a useful addition to - but not a substitute for - in-person visits." - Joe Masters

Abstract:

The objective of this study was to examine a remote method for maintaining long-term contact with Parkinson's disease (PD) patients participating in clinical studies. Long-term follow-up of PD patients is needed to fill critical information gaps on progression, biomarkers, and treatment. Prospective in-person assessment can be costly and may be impossible for some patients. Remote assessment using mail and telephone contact may be a practical follow-up method. Patients enrolled in the multi-center Longitudinal and Biomarker Study in Parkinson's Disease (LABS-PD) in-person follow-up study in 2006 were invited to enroll in Follow-up of Persons With Neurologic Diseases (FOUND), which is overseen by a single center under a separate, central institutional review board protocol. FOUND uses mailed questionnaires and telephone interviews to assess PD status. FOUND follow-up continued when LABS-PD in-person visits ended in 2011. Retention and agreement between remote and in-person assessments were determined. In total, 422 of 499 (84.5%) of eligible patients volunteered, AND 96% of participants were retained. Of 60 patients who withdrew consent from LABS-PD, 51 were retained in FOUND. Of 341 patients who were active in LABS-PD, 340 were retained in FOUND (99.7%) when the in-person visits ceased. Exact agreement between remote and in-person assessments was ≥ 80% for diagnosis, disease features (eg, dyskinesias), and PD medication. Correlation between expert-rated and self-reported Unified Parkinson's Disease Rating Scale and Movement Disorder Society Unified Parkinson's Disease Rating Scale, which were examined at times separated by several months, was moderate or substantial for most items. Retention was excellent using remote follow-up of research participants with PD, providing a safety net when combined with in-person visits, and also is effective as a stand-alone assessment method, providing a useful alternative when in-person evaluation is not feasible. © 2014 International Parkinson and Movement Disorder Society

Authors:

Tanner CM, Meng CC, Ravina B, Lang A, Kurlan R, Marek K, Oakes D, Seibyl J, Flagg E, Gauger L, Guest DD, Goetz CG, Kieburtz K, Dieuliis D, Fahn S, Elliott RA, Shoulson I.

 Mov Disord. 2014 Feb 11. doi: 10.1002/mds.25814. [Epub ahead of print]

PMID:

 24515275
 

Deep brain stimulation in Parkinson's disease: meta-analysis of randomized controlled trials

J Neurol. 2014 Feb 2. [Epub ahead of print]

Perestelo-Pérez L, Rivero-Santana A, Pérez-Ramos J, Serrano-Pérez P, Panetta J, Hilarion P.

Author information

Evaluation Unit of the Canary Islands Health Service (SESCS), Tenerife, Spain

Abstract

Until recent years there has been no evidence from randomized controlled trials (RCTs) on the efficacy of deep brain stimulation (DBS) for Parkinson's disease (PD). This review and meta-analysis of RCTs describes the efficacy of DBS in improving motor signs, functionality and quality of life of PD patients. Several electronic databases were consulted up to April 2013. RCTs that compared DBS plus medication versus medication (alone or plus sham DBS) in PD patients were included. Outcome measures were motor function, waking time on good functioning without troublesome dyskinesias, levodopa-equivalent dose reduction, medication-induced complications, activities of daily living, health-related quality of life, and neurocognitive and psychiatric effects. Six RCTs (n = 1,184) that compared DBS plus medication versus medication alone were included. The results show that DBS significantly improves patients' symptoms, functionality and quality of life. Effects sizes are intense for the reduction of motor signs and improvement of functionality in the off-medication phase, in addition to the reduction of the required medication dose and its associated complications. Moderate effects were observed in the case of motor signs and time in good functionality in the on-medication phase, in addition to the quality of life. Although the number of RCTs obtained is small, the total sample size is relatively large, confirming the efficacy of DBS in the control of motor signs and improvement of patients' functionality and quality of life. More controlled research is required on the neurocognitive and psychiatric effects of DBS.

Neuropathology of prodromal Lewy body disease

Mov Disord. 2014 Jan 31. doi: 10.1002/mds.25825. [Epub ahead of print]

Iranzo A, Gelpi E, Tolosa E, Molinuevo JL, Serradell M, Gaig C, Santamaria J.

Author information

Neurology Service, Hospital Clínic de Barcelona, Institut d'Investigacións Biomédiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.

Abstract

BACKGROUND:

Current evidence suggests that there is a prodromal stage in Parkinson disease characterized by a variety of nonmotor symptoms.

METHODS AND RESULTS:

A 69-year-old man presented to our sleep center with isolated rapid eye movement sleep behavior disorder. During a 10-year follow-up period, longitudinal clinical and laboratory assessments indicated the development of hyposmia, depression, mild cognitive impairment, and constipation. Parkinsonism was absent, but dopamine transporter imaging showed subclinical substantia nigra damage. Postmortem examination demonstrated neuronal loss and Lewy body pathology in the peripheral autonomic nervous system (eg, cardiac and myenteric plexus), olfactory bulb, medulla, pons, substantia nigra pars compacta (estimated cell loss, 20%-30%), nucleus basalis of Meynert, and amygdala, sparing the neocortex.

CONCLUSIONS:

Our observations indicate that nonmotor symptoms plus widespread peripheral and central nervous system pathological changes occur before parkinsonism and dementia onset in diseases associated with Lewy pathology. The current diagnostic criteria for Parkinson's disease miss these patients, who present only with nonmotor symptoms. © 2014 International Parkinson and Movement Disorder Society.

Emerging Candidate Biomarkers for Parkinson's Disease: a Review

Aging Dis. 2013 Oct 9;5(1):27-34. eCollection 2014.

Saracchi E, Fermi S, Brighina L.

Author information

Department of Neurology, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy.

Neurology Department, Azienda Ospedaliera di Lodi, 26900 Lodi, Italy.

Abstract

Parkinson's disease is a chronic neurodegenerative disorder leading to progressive motor impairment affecting more than 1% of the over-65 population. In spite of considerable progress in identifying the genetic and biochemical basis of PD, to date the diagnosis remains clinical and disease-modifying therapies continue to be elusive. A cornerstone in recent PD research is the investigation of biological markers that could help in identifying at-risk population or to track disease progression and response to therapies. Although none of these parameters has been validated for routine clinical practice yet, however some biochemical candidates hold great promise for application in PD patients, especially in the early stages of disease, and it is likely that in the future the diagnosis of PD will require a combination of genetic, imaging and laboratory data. In this review we discuss the most interesting biochemical markers for PD (including the "-omics" techniques), focusing on the methodological challenges in using ex vivo blood/CSF/tissue-based biomarkers and suggesting alternative strategies to overcome the difficulties that still prevent their actual use.

Visuoperceptive region atrophy independent of cognitive status in patients with Parkinson's disease with hallucinations

Brain. 2014 Jan 29. [Epub ahead of print]

Goldman JG, Stebbins GT, Dinh V, Bernard B, Merkitch D, Detoledo-Morrell L, Goetz CG.

Author information

Rush University Medical Center, Department of Neurological Sciences, Chicago, IL, USA.

Abstract

Visual hallucinations are frequent, disabling complications of advanced Parkinson's disease, but their neuroanatomical basis is incompletely understood. Previous structural brain magnetic resonance imaging studies suggest volume loss in the mesial temporal lobe and limbic regions in subjects with Parkinson's disease with visual hallucinations, relative to those without visual hallucinations. However, these studies have not always controlled for the presence of cognitive impairment or dementia, which are common co-morbidities of hallucinations in Parkinson's disease and whose neuroanatomical substrates may involve mesial temporal lobe and limbic regions. Therefore, we used structural magnetic resonance imaging to examine grey matter atrophy patterns associated with visual hallucinations, comparing Parkinson's disease hallucinators to Parkinson's disease non-hallucinators of comparable cognitive function. We studied 50 subjects with Parkinson's disease: 25 classified as current and chronic visual hallucinators and 25 as non-hallucinators, who were matched for cognitive status (demented or non-demented) and age (±3 years). Subjects underwent (i) clinical evaluations; and (ii) brain MRI scans analysed using whole-brain voxel-based morphometry techniques. Clinically, the Parkinson's disease hallucinators did not differ in their cognitive classification or performance in any of the five assessed cognitive domains, compared with the non-hallucinators. The Parkinson's disease groups also did not differ significantly in age, motor severity, medication use or duration of disease. On imaging analyses, the hallucinators, all of whom experienced visual hallucinations, exhibited grey matter atrophy with significant voxel-wise differences in the cuneus, lingual and fusiform gyri, middle occipital lobe, inferior parietal lobule, and also cingulate, paracentral, and precentral gyri, compared with the non-hallucinators. Grey matter atrophy in the hallucinators occurred predominantly in brain regions responsible for processing visuoperceptual information including the ventral 'what' and dorsal 'where' pathways, which are important in object and facial recognition and identification of spatial locations of objects, respectively. Furthermore, the structural brain changes seen on magnetic resonance imaging occurred independently of cognitive function and age. Our findings suggest that when hallucinators and non-hallucinators are similar in their cognitive performance, the neural networks involving visuoperceptual pathways, rather than the mesial temporal lobe regions, distinctively contribute to the pathophysiology of visual hallucinations and may explain their predominantly visual nature in Parkinson's disease. Identification of distinct structural MRI differences associated with hallucinations in Parkinson's disease may permit earlier detection of at-risk patients and ultimately, development of therapies specifically targeting hallucinations and visuoperceptive functions.

Olfactory-related cortical atrophy is associated with olfactory dysfunction in Parkinson's disease

Mov Disord. 2014 Jan 30. doi: 10.1002/mds.25829. [Epub ahead of print]

Lee EY, Eslinger PJ, Du G, Kong L, Lewis MM, Huang X.

Author information

Departments of Neurology, Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA.

Abstract

BACKGROUND:

Olfactory dysfunction is often associated with Parkinson's disease (PD) and can precede characteristic motor symptoms by several years. Olfactory-related cortical atrophy has been reported in PD, although the extent and association between cortical atrophy and olfactory dysfunction have been controversial. The present study examined whether olfactory dysfunction is associated with gray matter (GM) volume in brain regions subserving primary and secondary olfactory processing.

METHODS:

High-resolution T1-weighted brain MRIs were acquired from 40 PD without dementia and 40 matched controls along with smell identification scores. Brain volumes were compared using voxel-based morphometry.

RESULTS:

Compared to controls, PD patients sustained greater GM loss localized to bilateral piriform cortex (PC) and orbitofrontal cortex (OFC). Reduced olfactory performance in PD was significantly associated with lower GM volumes in PC and OFC.

CONCLUSIONS:

Both primary and secondary olfactory cortical atrophy occurred in PD and were associated with olfactory dysfunction.

Extracellular α-synuclein-a novel and crucial factor in Lewy body diseases

Nat Rev Neurol. 2014 Jan 28. doi: 10.1038/nrneurol.2013.275. [Epub ahead of print]

Lee HJ, Bae EJ, Lee SJ.

Author information

1 Department of Anatomy, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 143-701, Korea.

2 Department of Biomedical Science and Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 143-701, Korea.

Abstract

Misfolding and intracellular aggregation of α-synuclein are thought to be crucial factors in the pathogenesis of Lewy body diseases (LBDs), such as Parkinson disease. However, the pathogenic modifications of this protein and the mechanisms underlying its activity have not been fully characterized. Recent studies suggest that small amounts of α-synuclein are released from neuronal cells by unconventional exocytosis, and that this extracellular α-synuclein contributes to the major pathological features of LBD, such as neurodegeneration, progressive spreading of α-synuclein pathology, and neuroinflammation. In this article, we review a rapidly growing body of literature on possible mechanisms by which extracellular α-synuclein contributes to LBD pathology, and discuss therapeutic approaches to target this form of α-synuclein to halt disease progression.

Diabetes and risk of Parkinson's disease: an updated meta-analysis of case-control studies

PLoS One. 2014 Jan 21;9(1):e85781. doi: 10.1371/journal.pone.0085781. eCollection 2014.

Lu L, Fu DL, Li HQ, Liu AJ, Li JH, Zheng GQ.

Author information

Department of Neurology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Abstract

BACKGROUND:

Whether diabetes increases the risk of Parkinson's disease (PD) is still inconclusive. The objective of this updated meta-analysis is to synthesize evidence from case-control studies that evaluated the association between diabetes and the risk of PD.

METHODS:

Seven databases were searched to identify case-control studies that evaluated the association between diabetes and PD. The methodological quality of included studies was assessed using Newcastle-Ottawa scale. All data were analyzed using Review Manager 5.1 software. Subgroup analyses were also adopted, according to stratification on gender, geographic location, source of the control group, smoking, anti-diabetes drug prescription and duration of DM.

RESULTS:

Fourteen studies fulfilled inclusion criteria for meta-analysis, yielding a total of 21395 PD patients and 84579 control subjects. Individuals with diabetes were found to have a negative association with future PD (OR 0.75; 95% CI 0.58-0.98) in spite of significant heterogeneity. In subgroup analyses, the negative correlation was still found in studies from North America, non-PD control groups from general population, never smoking individuals, and DM ascertainment based on questionnaire or self-report. Stratification of gender and DM duration showed no significant association. No association was also found in European and Asian individuals, hospital-based controls, ever smoking subjects, DM assessment by medical record or physician diagnosis, and insulin prescription for DM.

CONCLUSION:

Evidence from case-control studies suggested that diabetic individuals may have a decreased incidence of PD despite significant heterogeneity. More researches are warranted to clarify an understanding of the association between diabetes and risk of PD.