Benjamin Roeben

Prodromal Markers in Parkinson's Disease: Limitations in Longitudinal Studies and Lessons Learned

A growing body of evidence supports a prodromal neurodegenerative process preceding the clinical onset of Parkinson’s disease (PD). Studies have identified several different prodromal markers that may have the potential to predict the conversion from healthy to clinical PD but use considerably different approaches. We systematically reviewed 35 longitudinal studies reporting prodromal PD features and evaluated the methodological quality across 10 different predefined domains. We found limitations in the following domains: PD diagnosis (57% of studies), prodromal marker assessments (51%), temporal information on prodromal markers or PD diagnosis (34%), generalizability of results (17%), statistical methods (accounting for at least age as confounder; 17%), study design (14%), and sample size (9%). However, no limitations regarding drop-out (or bias investigation), or report of inclusion/exclusion criteria or prodromal marker associations were revealed. Lessons learned from these limitations and additional aspects of current prodromal marker studies in PD are discussed to provide a basis for the evaluation of findings and the improvement of future research in prodromal PD. The observed heterogeneity of studies, limitations and analyses might be addressed in future longitudinal studies using a, yet to be established, modular minimal set of assessments improving comparability of findings and enabling data sharing and combined analyses across studies.

Methods in Neuroepidemiology Characterization of European Longitudinal Cohort Studies in Parkinson's Disease - Report of the JPND Working Group BioLoC-PD

Background: Enormous effort is being put into the identification and characterization of symptoms that may be used as predictive and progression markers in Parkinsons disease (PD). An impressive number of PD patients and individuals at risk for or in the prodromal stage of PD are currently followed in longitudinal studies; however, there does not exist an overview on the kind of markers evaluated and the assessments used. Methods: Information on the design, sample size, evaluated markers and assessments of 21 studies of the Joint Programme - Neurodegenerative Disease Research BioLoC-PD working group were collected by questionnaire. The studies were classified into at risk/prodromal or clinical PD cohorts. The assessments were grouped into quantitative assessments, investigator-rated assessments, investigator interviews, patient-rated questionnaires and caregiver-rated questionnaires. Results: Compilation of these data revealed an interesting consensus on evaluated markers, but there was an enormous variability of assessments. Furthermore, there is a remarkable similarity in the markers assessed and evaluation methods applied in the risk/prodromal and clinical PD cohorts. Conclusions: The inventory of the longitudinal cohorts that are part of the BioLoC-PD consortium reveals that there is a growing consensus on the markers that should be assessed in longitudinal cohort studies in PD. However, controversy still exists on the specific type of assessment. To allow comparison of data and common analyses it will be essential to harmonize scales and assessment outcomes.

A neurodegenerative vascular burden index and the impact on cognition.

A wide range of vascular burden factors has been identified to impact vascular function and structure as indicated by carotid intima–media thickness (IMT). On the basis of their impact on IMT, vascular factors may be selected and clustered in a vascular burden index (VBI). Since many vascular factors increase the risk of Alzheimer’s disease (AD), a multifactorial neurodegenerative VBI may be related to early pathological processes in AD and cognitive decline in its preclinical stages. We investigated an elderly cohort at risk for neurodegeneration (TREND study, n = 1102) for the multifactorial influence of vascular burden factors on IMT measured by ultrasound. To create a VBI for this cohort, vascular factors and their definitions (considering medical history, medication, and/or blood marker data) were selected based on their statistical effects on IMT in multiple regressions including age and sex. The impact of the VBI on cognitive performance was assessed using the Trail-Making Test (TMT) and the consortium to establish a registry for Alzheimer’s disease (CERAD) neuropsychological battery. IMT was significantly predicted by age (standardized β = 0.26), sex (0.09; males > females) and the factors included in the VBI: obesity (0.18), hypertension (0.14), smoking (0.08), diabetes (0.07), and atherosclerosis (0.05), whereas other cardiovascular diseases or hypercholesterolemia were not significant. Individuals with 2 or more VBI factors compared to individuals without had an odds ratio of 3.17 regarding overly increased IMT ( ≥ 1.0 mm). The VBI showed an impact on executive control [log(TMT B−A), p = 0.047] and a trend toward decreased global cognitive function (CERAD total score, p = 0.057) independent of age, sex, and education. A VBI established on the basis of IMT may help to identify individuals with overly increased vascular burden linked to decreased cognitive function indicating neurodegenerative processes. The longitudinal study of this risk cohort will reveal the value of the VBI as prodromal marker for cognitive decline and AD.

Application of the movement disorder society prodromal Parkinson's disease research criteria in 2 independent prospective cohorts: Application of Research Criteria For Prodromal PD

Background: The research criteria for prodromal PD of the MDS propose a new approach for the assessment of the individual probability of prodromal PD. These criteria require a testing of their reliability in different prospective cohorts.

Reasons for mild parkinsonian signs - Which constellation may indicate neurodegeneration?

INTRODUCTION Mild parkinsonian signs (MPS) are common in the elderly population. Several factors including physical decline and comorbidities in addition to neurodegeneration may be possible sources for MPS. The objective was to examine whether MPS are associated with a history of orthopedic disturbances, vascular diseases or prodromal markers for neurodegeneration. METHODS The TREND study is a prospective longitudinal cohort study in individuals >50 years with biennial assessments designed to identify prodromal markers for neurodegeneration. In this substudy, 1091 elderly individuals were evaluated for a possible association of MPS with prodromal markers for neurodegeneration, orthopedic disturbances, vascular diseases, as well as cerebral abnormalities. These factors were assessed by self-administered questionnaires, with a structured health interview, a neurological examination and by transcranial sonography. RESULTS 82 participants showed MPS. They were found to have more often hyposmia and RBD, had a higher autonomic dysfunction score and they more frequently showed hyperechogenicity of the substantia nigra compared to controls. Neither orthopedic disturbances nor vascular diseases were significantly associated with the prevalence of MPS. CONCLUSION MPS might be a sign of early neurodegeneration rather than caused by other motor influencing diseases.

Insulin-Like Growth Factor 1 (IGF-1) in Parkinson's Disease: Potential as Trait-, Progression- and Prediction Marker and Confounding Factors.

Introduction Biomarkers indicating trait, progression and prediction of pathology and symptoms in Parkinsons disease (PD) often lack specificity or reliability. Investigating biomarker variance between individuals and over time and the effect of confounding factors is essential for the evaluation of biomarkers in PD, such as insulin-like growth factor 1 (IGF-1). Materials and Methods IGF-1 serum levels were investigated in up to 8 biannual visits in 37 PD patients and 22 healthy controls (HC) in the longitudinal MODEP study. IGF-1 baseline levels and annual changes in IGF-1 were compared between PD patients and HC while accounting for baseline disease duration (19 early stage: ≤3.5 years; 18 moderate stage: >4 years), age, sex, body mass index (BMI) and common medical factors putatively modulating IGF-1. In addition, associations of baseline IGF-1 with annual changes of motor, cognitive and depressive symptoms and medication dose were investigated. Results PD patients in moderate (130±26 ng/mL; p = .004), but not early stages (115±19, p>.1), showed significantly increased baseline IGF-1 levels compared with HC (106±24 ng/mL; p = .017). Age had a significant negative correlation with IGF-1 levels in HC (r = -.47, p = .028) and no correlation in PD patients (r = -.06, p>.1). BMI was negatively correlated in the overall group (r = -.28, p = .034). The annual changes in IGF-1 did not differ significantly between groups and were not correlated with disease duration. Baseline IGF-1 levels were not associated with annual changes of clinical parameters. Discussion Elevated IGF-1 in serum might differentiate between patients in moderate PD stages and HC. However, the value of serum IGF-1 as a trait-, progression- and prediction marker in PD is limited as IGF-1 showed large inter- and intraindividual variability and may be modulated by several confounders.

Aiming for Study Comparability in Parkinson's Disease: Proposal for a Modular Set of Biomarker Assessments to be Used in Longitudinal Studies

Parkinsons disease (PD) is an example for a complex field of research, which is driven by the multifactorial etiology, the heterogeneity in phenotype and the variability in disease progression, as well as the presence of a long pre-diagnostic period, called prodromal PD, lasting up to decades (Postuma et al., 2010). The very slow, so far inevitably progressive, neurodegenerative process and the multidimensional heterogeneity of symptoms in kind (motor and non-motor), time of onset and speed of progression call for prediction markers and progression markers to understand the onset of neurodegeneration and its course. These markers would also help to establish endpoints for neuroprotective treatment strategies aiming to modify disease progression. Because of the complexity, heterogeneity, and the progressive nature of PD, such predictive and progression markers can only be identified in large cohorts and in studies with a longitudinal design. A considerable number of longitudinal cohort studies in PD patients, as well as in individuals at risk, are currently being performed, and extensive effort has gone into the characterization of the individuals assessed. Although each study has its own value and merits, many important research questions cannot be answered as the numbers of participants are too small (e.g., when studying conversion to PD in at-risk populations). Moreover, the pivotal combination of data and findings across studies is hampered by the lack of comparability of symptoms/factors that are being assessed and the specific assessments that are being applied. Therefore, a common approach is needed to enable harmonization and combination of data across studies to define and validate predictive and progression markers. Based on the need for harmonized assessments of symptoms/markers in PD, the working group: Harmonization of biomarker assessment in longitudinal cohort studies in Parkinsons Disease (BioLoC-PD) of the Joint Programme for Neurodegenerative Diseases (JPND), set out to develop an assessment battery that includes the most useful clinical, laboratory, and brain imaging assessments for (longitudinal) studies in PD. We here describe the result of the process to find a way to harmonize assessments across studies and propose a modular set of biomarker assessments agreed upon by the group of experts who were included in the working group (all authors of this manuscript).

Substantia nigra hyperechogenicity is related to decline in verbal memory in healthy elderly adults.

Deficits in cognition have been reported in Parkinsons disease (PD) already in the early and even in the pre‐motor stages. Whilst substantia nigra hyperechogenicity measured by transcranial B‐mode sonography (TCS) represents a strong PD marker and is associated with an increased risk for PD in still healthy individuals, its association with cognitive performance in prodromal PD stages is not well established.

Erratum: Structural Ultrasound of the Medial Temporal Lobe in Alzheimer’s Disease

Purpose One of the anatomical hallmarks of Alzheimer’s disease (AD) is the atrophy of the medial temporal lobe (MTL), yet cost-effective and broadly available methodological alternatives to the current imaging tools for screening of this brain area are not currently available. Materials and Methods Using structural transcranial ultrasound (TCS), we attempted to visualize and measure the MTL, and compared the results of 32 AD patients and 84 healthy controls (HC). The MTL and the surrounding space were defined in the coronal plane on TCS. A ratio of the height of the MTL/height of the choroidal fissure (M/F) was calculated in order to obtain a regional proportion. Results An insufficient temporal bone window was identified in 22 % of the AD patients and 12 % of the HCs. The results showed that the ratio of M/F was significantly smaller in the AD group on both sides (p = 0.004 right, p = 0.007 left side). Furthermore, the M/F ratio made it possible to discriminate AD patients from HCs with a sensitivity of 83 % (right)/73 % (left) and a specificity of 76 % (right)/72 % (left) which is basically comparable to results published for magnetic resonance imaging. The measurements showed substantial intra/interrater reliability (ICC:0.79/0.69). Conclusion These results suggest that utilization of structural TCS may possibly constitute a cheap and easy-to-use supplement to other techniques for the diagnosis of AD. It may be especially useful as a screening tool in the large population of individuals with cognitive decline. Further studies are needed to validate this novel method.

Cognitive Performance Patterns in Healthy Individuals with Substantia Nigra Hyperechogenicity and Early Parkinson's Disease.

Introduction: Hyperechogenicity of the substantia nigra (SN+) is a risk marker for Parkinson’s disease (PD) which can be detected before the diagnosis. In healthy individuals, SN+ has been associated with slight deficits in specific cognitive functions, suggesting cognitive impairment as a possible pre-diagnostic marker for PD. However, the pattern of cognitive deficits associated with SN+ has not yet been compared with those present in PD. Methods: Data of 262 healthy individuals with normal echogenicity (SN-) and 48 healthy individuals with SN+ were compared with 82 early stage PD patients using the “Consortium to Establish a Registry for Alzheimer’s disease” test battery. First, the test clusters (factors) were identified using a principal component analysis (PCA). Mean group performance of cognitive tests belonging to distinct factors, according to the PCA, and single subtest performances were compared using analyses of variance. Second, the number of individuals with abnormal cognitive performances (z-score < -1.0) were compared between groups. Results: Verbal memory, semantic and executive function, and praxis were identified as components of cognitive performances. The SN+ group performed significantly worse than the SN- group in tests assessing semantic and executive function, with a non-significant decrease in verbal memory. On the subtest level, individuals of the SN+ group scored significantly lower than the SN- group on the Boston Naming Test (BNT; p = 0.008). In all subtests, the percentages of PD patients with values below the cut-off for abnormal performance were higher than in the SN- group. Moreover, more individuals from the SN+ group scored below the cut-off in the BNT (SN- = 8.4%, SN+ = 20.8%, p = 0.01) and TMT-B (SN- = 6.9%, SN+ = 16.7%, p = 0.02), compared to the SN- group. Conclusion: This study confirms poorer performance of healthy individuals with SN+ compared to SN- in specific cognitive domains. However, against the SN- group, the cognitive profile of the SN+ group was not fully consistent with the profile of early PD patients. Our data argues that cognitive impairment associated with SN+ might differ slightly from that seen in early PD. Compensational mechanisms in the early phases of neurodegeneration, and the fact that only a subgroup of SN+ will develop PD, may partly explain these differences.