Brit Mollenhauer

Diagnostic Criteria for Mild Cognitive Impairment in Parkinson’s Disease: Movement Disorder Society Task Force Guidelines

Mild cognitive impairment is common in nondemented Parkinsons disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long‐term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.

A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease.

To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.

Diagnosis and management of dementia with Lewy bodies Fourth consensus report of the DLB Consortium

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

The Parkinson Progression Marker Initiative (PPMI)

The Parkinson Progression Marker Initiative (PPMI) is a comprehensive observational, international, multi-center study designed to identify PD progression biomarkers both to improve understanding of disease etiology and course and to provide crucial tools to enhance the likelihood of success of PD modifying therapeutic trials. The PPMI cohort will comprise 400 recently diagnosed PD and 200 healthy subjects followed longitudinally for clinical, imaging and biospecimen biomarker assessment using standardized data acquisition protocols at twenty-one clinical sites. All study data will be integrated in the PPMI study database and will be rapidly and publically available through the PPMI web site- www.ppmi-info.org. Biological samples including longitudinal collection of blood, cerebrospinal fluid (CSF) and urine will be available to scientists by application to an independent PPMI biospecimen review committee also through the PPMI web site. PPMI will rely on a partnership of government, PD foundations, industry and academics working cooperatively. This approach is crucial to enhance the potential for success of this ambitious strategy to develop PD progression biomarkers that will accelerate research in disease modifying therapeutics.

α-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study

BACKGROUND Parkinsons disease, dementia with Lewy bodies, and multiple system atrophy are brain disorders characterised by intracellular α-synuclein deposits. We aimed to assess whether reduction of α-synuclein concentrations in CSF was a marker for α-synuclein deposition in the brain, and therefore diagnostic of synucleinopathies. METHODS We assessed potential extracellular-fluid markers of α-synuclein deposition in the brain (total α-synuclein and total tau in CSF, and total α-synuclein in serum) in three cohorts: a cross-sectional training cohort of people with Parkinsons disease, multiple system atrophy, dementia with Lewy bodies, Alzheimers disease, or other neurological disorders; a group of patients with autopsy-confirmed dementia with Lewy bodies, Alzheimers disease, or other neurological disorders (CSF specimens were drawn ante mortem during clinical investigations); and a validation cohort of patients who between January, 2003, and December, 2006, were referred to a specialised movement disorder hospital for routine inpatient admission under the working diagnosis of parkinsonism. CSF and serum samples were assessed by ELISA, and clinical diagnoses were made according to internationally established criteria. Mean differences in biomarkers between diagnostic groups were assessed with conventional parametric and non-parametric statistics. FINDINGS In our training set, people with Parkinsons disease, multiple system atrophy, and dementia with Lewy bodies had lower CSF α-synuclein concentrations than patients with Alzheimers disease and other neurological disorders. CSF α-synuclein and tau values separated participants with synucleinopathies well from those with other disorders (p<0·0001; area under the receiver operating characteristic curve [AUC]=0·908). In the autopsy-confirmed cases, CSF α-synuclein discriminated between dementia with Lewy bodies and Alzheimers disease (p=0·0190; AUC=0·687); in the validation cohort, CSF α-synuclein discriminated Parkinsons disease and dementia with Lewy bodies versus progressive supranuclear palsy, normal-pressure hydrocephalus, and other neurological disorders (p<0·0001; AUC=0·711). Other predictor variables tested in this cohort included CSF tau (p=0·0798), serum α-synuclein (p=0·0502), and age (p=0·0335). CSF α-synuclein concentrations of 1·6 pg/μL or lower showed 70·72% sensitivity (95% CI 65·3-76·1%) and 52·83% specificity (39·4-66·3%) for the diagnosis of Parkinsons disease. At this cutoff, the positive predictive value for any synucleinopathy was 90·7% (95% CI 87·3-94·2%) and the negative predictive value was 20·4% (13·7-27·2%). INTERPRETATION Mean CSF α-synuclein concentrations as measured by ELISA are significantly lower in Parkinsons disease, dementia with Lewy bodies, and multiple system atrophy than in other neurological diseases. Although specificity was low, the high positive predictive value of CSF α-synuclein concentrations in patients presenting with synucleinopathy-type parkinsonism might be useful in stratification of patients in future clinical trials. FUNDING American Parkinson Disease Association, Stifterverband für die Deutsche Wissenschaft, Michael J Fox Foundation for Parkinsons Research, National Institutes of Health, Parkinson Research Consortium Ottawa, and the Government of Canada.

MDS Task Force on Mild Cognitive Impairment in Parkinson’s disease: Critical Review of PD-MCI

There is controversy regarding the definition and characteristics of mild cognitive impairment in Parkinsons disease. The Movement Disorder Society commissioned a Task Force to critically evaluate the literature and determine the frequency and characteristics of Parkinsons disease–mild cognitive impairment and its association with dementia. A comprehensive PubMed literature review was conducted using systematic inclusion and exclusion criteria. A mean of 26.7% (range, 18.9%–38.2%) of nondemented patients with Parkinsons disease have mild cognitive impairment. The frequency of Parkinsons disease–mild cognitive impairment increases with age, disease duration, and disease severity. Impairments occur in a range of cognitive domains, but single domain impairment is more common than multiple domain impairment, and within single domain impairment, nonamnestic is more common than amnestic impairment. A high proportion of patients with Parkinsons disease–mild cognitive impairment progress to dementia in a relatively short period of time. The primary conclusions of the Task Force are that: (1) Parkinsons disease–mild cognitive impairment is common, (2) there is significant heterogeneity within Parkinsons disease–mild cognitive impairment in the number and types of cognitive domain impairments, (3) Parkinsons disease–mild cognitive impairment appears to place patients at risk of progressing to dementia, and (4) formal diagnostic criteria for Parkinsons disease–mild cognitive impairment are needed.

Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration

Because accumulation of alpha-synuclein (alphaS) in the brain is a hallmark of Parkinson disease (PD) and related disorders, we examined its occurrence in human cerebrospinal fluid (CSF). Following affinity enrichment and trypsin digestion of CSF collected from a neurologically healthy donor, we identified several alphaS-derived peptides by mass spectrometry. The concentration of alphaS amounted to <0.001% of the CSF proteome. We then built, validated and optimized a sandwich-type, enzyme-linked immunoadsorbent assay (ELISA) to measure total alphaS levels in unconcentrated CSF. In a cross-sectional study of 100 living donors, we examined cell-free CSF samples from subjects clinically diagnosed with advanced PD, dementia with Lewy bodies (DLB), Alzheimer disease (AD), and a group of non-neurodegenerative disease controls (NCO). In these four groups the CSF alphaS concentrations ranged from 0.8 to 16.2 pg/microl. Mean CSF alphaS values were lower in donors with a primary synucleinopathy (PD, DLB: n=57) than in the other two groups (AD, NCO: n=35; p=0.025). By contrast, living Creutzfeldt-Jakob disease patients showed markedly elevated CSF alphaS levels (n=8; mean, 300 pg/microl; p<0.001). Our results unequivocally confirm the presence of alphaS in adult human CSF. In a first feasibility study employing a novel ELISA, we found relatively low CSF alphaS concentrations in subjects with parkinsonism linked to synucleinopathy, PD and DLB. In definite prion disease cases, we recorded a marked rise in total CSF alphaS resulting from rapid cell death. Our results will likely aid future biomarker explorations in neurodegenerative conditions and facilitate target validation studies.

Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt–Jakob disease

Background: Diagnosis of Creutzfeldt–Jakob disease (CJD) is made according to the typical clinical picture and can be supported by a positive 14-3-3 CSF immunoblot. Promising results for the diagnostic sensitivity and specificity of tau-protein measurement in CSF already have been described in a smaller group of patients. Both tests in a larger group of patients with the differential diagnosis of CJD were evaluated. Methods: CSF of 297 patients under the differential diagnosis of CJD (109 definite, 55 probable, 39 possible; 85 others, 1 iatrogenic, 8 genetic), 23 nondemented control subjects, and 15 non-CJD patients with positive 14-3-3 immunoblots were analyzed. The 14-3-3 immunoblot bands were semiquantitatively rated as strong, medium, and weak. Tau-protein was analyzed using a commercially available ELISA. In addition, patients were neuropathologically classified according to prion protein type and polymorphism at codon 129. Results: A diagnostic sensitivity of 94%, a diagnostic specificity of 90%, and a positive predictive value of 92% were achieved for tau-protein at a cut-off of 1,300 pg/mL. These results are comparable with those of the 14-3-3 immunoblot. For patients with type II prion protein and methionine/valine or valine/valine polymorphism at codon 129, tau-protein has a higher diagnostic sensitivity than 14-3-3 protein. Tau-protein levels were significantly higher in patients with higher-rated 14-3-3 immunoblot bands. Conclusion: The differential diagnostic significance of the 14-3-3 immunoblot is similar to that of the tau-protein ELISA. The advantage of the tau-protein ELISA is that it is easy to use in routine laboratories. Patients with a negative 14-3-3 immunoblot already have measurable tau-protein levels. This increases information on 14-3-3—negative patients with CJD and especially on patients with other diseases.

Associated factors for REM sleep behavior disorder in Parkinson disease

Objective: To investigate the frequency, phenomenology, and associated risk factors of REM sleep behavior disorder (RBD) in Parkinson disease (PD). Methods: An unselected cohort of sleep-disturbed patients with PD (n=457) was investigated with video-supported polysomnography. We determined the frequency of RBD and analyzed the influence of age, clinical disease features, disease duration, cognitive and physical impairment, medication, comorbidity, and sleep architecture. Results: The overall frequency of RBD was 46%. According to our cohort and modified definition, there was no preferred PD subtype for RBD (p=0.142). There was no gender preference (p=0.770). RBD was associated with older age (p=0.000). Adjusted for age and gender, patients with PD and RBD had longer disease duration (p=0.024), higher Hoehn & Yahr stages (p=0.002), more falls (p=0.018), more fluctuations (p=0.005), more psychiatric comorbidity (p=0.026), and a higher dose of levodopa (p=0.002). The presence of RBD was related to slightly increased sleep efficiency (p=0.007), a higher amount of REM sleep (p=0.000), and more periodic leg movements during sleep (p=0.019). Conclusion: RBD is a frequent and clinically relevant nocturnal disturbance for all stages of PD. It increases with age and disease duration and may contribute to the nocturnal problems of patients with PD and their bed partners.

Characterizing mild cognitive impairment in incident Parkinson disease: The ICICLE-PD Study

Objective: To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers. Methods: Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria. Results: The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1–42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1–42 and 1–40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold. Conclusions: In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1–42 and 1–40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.