The Five Best Parkinson’s Research Projects 2019:
A. Fanciulli, T. Foki, N. Homayoon, F. Krismer, P. Mahlknecht
1 Early Distinction of Parkinson-Variant Multiple System Atrophy from Parkinson’s Disease
Alessandra Fanciulli, MD PhD, et al
Distinguishing the Parkinson variant of MSA (MSA-P) from Parkinson’s disease (PD) is often difficult at disease onset. This is a major drawback for counseling of patients and timely enrollment into disease-modifying clinical trials.
Clinicopathological studies consistently report that postural instability and autonomic failure emerge earlier in MSA-P than in PD,2,3 but it remains to be determined how this information can be integrated into the diagnostic work-up of patients with early parkinsonism.
Here, we aimed at (1) quantifying the diagnostic yield of early-onset postural instability as well as cardiovascular and urological autonomic failure in differentiating MSA-P from PD and (2) merging early MSA-P distinctive features into a MSA-P diagnostic probability score.
For this purpose, we retrospectively studied 161 PD and 29 MSA-P patients, who had undergone tilt-table testing at early disease, defined as Hoehn & Yahr (H&Y) stage <3 and/or disease duration <2 years. In the absence of neuropathological confirmation, established PD4 and MSA-P5 criteria were applied at last available visit by senior investigators and served as the clinical diagnostic gold standard. The diagnosis was further supported by cerebral MRI volumetry6 in all MSA-P patients with available MRI (n = 21) and in those PD patients with a follow-up time < 24 months and disease duration <5 years (n = 19): patients with a mismatch between the final clinical and MRI diagnosis were excluded from further analysis (n = 4). Clinical features at early disease, associated with a diagnosis of MSA-P at last available visit, were investigated by means of χ2, parametric, and nonparametric tests, followed by binary logistic regression analysis. An MSA-P diagnostic probability score was generated on the basis of early MSA-P discriminant variables. The study protocol was approved by the local ethical committee and performed according to the Declaration of Helsinki. Because of the retrospective design, no written informed consent was due. Processing of data followed the current Austrian regulation for data protection. By taking into account all significantly different clinicaldemographic traits at early disease, logistic regression analysis showed the following features to be associated with a final diagnosis of MSA-P: (1) postural instability (H&Y stage ≥3) within 2 years from disease onset; (2) orthostatic hypotension7; (3) symptoms of overactive bladder (urge and/or urinary incontinence); and (4) urinary retention (i.e., postvoid residual urine volume > 100 mL).
By assigning 1 point per above-mentioned feature, a cumulative score ≥ 2 (score range: 0-4) showed 78% sensitivity (95% confidence interval [CI]: 58-91), 86% specificity (95% CI: 80-91), 50% positive predictive value (95% CI: 39-61), and 96% negative predictive value (95% CI: 91-98) for a final diagnosis of MSA-P. The area under the receiver operating characteristic (ROC) curve was 0.884 (95% CI: 0.823-0.946).
We conclude that postural instability and autonomic failure manifest in both PD and MSA-P, but their early development indicates MSA-P.
The 4-points MSA-P diagnostic probability score shows a balanced sensitivity and specificity for early MSA-P and represents an easily accessible, cost- and time-effective tool for screening parkinsonian patients with low or absent MSA risk (0–1 point) from those with high MSA-risk (2–4 points). The latter may benefit from referral to specialized movement disorder centers and, ultimately, recruitment in ongoing neuroprotective studies.
2 Individual Cognitive Change After DBS-Surgery in Parkinson’s Disease Patients Using Reliable Change Index Methodology
Thomas Foki, MD, et al
Long-term therapy of Parkinson’s disease (PD) with levodopa (L-DOPA) is associated with a high risk of developing motor fluctuations and dyskinesia. Deep brain stimulation (DBS) in PD patients of the subthalamic nucleus can improve these motor complications. Although the positive effect on motor symptoms has been proven, postoperative cognitive decline has been documented. To tackle the impact of PD-DBS on cognition, 18 DBS patients were compared to 25 best medically treated Parkinson’s patients, 24 Mild Cognitive Impairment (MCI) patients and 12 healthy controls using the Neuropsychological Test Battery Vienna-long (NTBV-long) for cognitive outcome 12 months after first examination. Reliable change index methodology was used. Overall, there was cognitive change in individual patients, but the change was very heterogeneous with gains and losses. Further research is needed to identify the mechanisms that lead to improvement or deterioration of cognitive functions in individual cases.
3 Nigral Iron Deposition in Common Tremor Disorders
Nina Homayoon, MD, et al
We investigated R2* relaxation rates as a marker of iron content in the substantia nigra in patients with common tremor disorders and explored their diagnostic properties.
Mean nigral R2* rates were measured in 40 patients with tremor-dominant Parkinson’s disease (PD), 15 with tremor in dystonia, 25 with essential tremor, and 25 healthy controls.
Tremor-dominant PD patients had significantly higher nigral R2* values (34.1 5.7) than those with tremor in dystonia (30.0 3.9), essential tremor (30.6 4.8), and controls (30.0 2.8). An R2* threshold of 31.15 separated tremor-dominant PD from controls with a sensitivity and specificity of 67.5% and 72%. The sensitivity and specificity for discrimination between PD and non-PD tremor patients was 67.5% and 60%.
Iron content in the substantia nigra is significantly higher in tremor-dominant PD than in tremor in dystonia, essential tremor, and controls. Because of the considerable overlap, nigral R2* cannot be suggested as a useful diagnostic tool.
4 Morphometric MRI Profiles of Multiple System Atrophy Variants and Implications for Differential Diagnosis
Florian Krismer, PhD, et al
Manual width measurements of the middle cerebellar peduncle on MRI were shown to improve the accuracy of an imaging‐guided diagnosis of multiple system atrophy (MSA). Recently, automated volume segmentation algorithms were able to reliably differentiate patients with Parkinson’s disease (PD) and the parkinsonian variant of MSA. The objective of the current study was to integrate probabilistic information of the middle cerebellar peduncle into an existing MRI atlas for automated subcortical segmentation and to evaluate the diagnostic properties of the novel atlas for the differential diagnosis of MSA (parkinsonian and cerebellar variant) versus PD.
Three Tesla MRI scans of 48 healthy individuals were used to establish an automated whole‐brain segmentation procedure that includes the volumes of the putamen, cerebellar gray and white matter, and the middle cerebellar peduncles. Classification accuracy of segmented volumes were tested in early‐stage MSA patients (18 MSA‐parkinsonism, 13 MSA‐cerebellar) and 19 PD patients using a C4.5 classifier.
Putaminal and infratentorial atrophy were present in 77.8% and 61.1% of MSA‐parkinsonian patients, respectively. Four of 18 MSA‐parkinsonian patients (22.2%) had infratentorial atrophy without evidence of putaminal atrophy. Infratentorial atrophy was present in all MSA‐cerebellar patients, with concomitant putaminal atrophy in 46.2% of these cases. The diagnostic algorithm using putaminal and infratentorial volumetric information correctly classified all PD patients and 96.8% of MSA patients.
The middle cerebellar peduncle was successfully integrated into a subcortical segmentation atlas, and its excellent diagnostic accuracy outperformed existing volumetric MRI processing strategies in differentiating MSA patients with variable atrophy patterns from PD patients.
5 Performance of the Movement Disorders Society Criteria for Prodromal Parkinson’s Disease: A Population-Based 10-Year Study
Philipp Mahlknecht, MD PhD, et al
We aimed to identify prodromal Parkinson’s disease (PD) and its predictive accuracy for incident PD in an unselected elderly population and to estimate the relevance of this approach for future neuroprotection trials.
We applied the recently published Movement Disorders Society (MDS) research criteria for prodromal PD to participants of the prospective population-based Bruneck Study of the 2005 assessment (n 5 574, ages 55-94 years). Cases of incident PD were identified at 3-year, 5-year, and 10-year follow-up visits. We calculated predictive accuracies of baseline prodromal PD status for incident cases, and, based on them, estimated sample sizes for neuroprotection trials with conversion to PD as the primary outcome.
Baseline status of probable prodromal PD (n 5 12) had a specificity in predicting incident PD of 98.8% (95% confidence interval, 97.3%-99.5%), a sensitivity of 66.7% (29.6%-90.8%), and a positive predictive value of 40.0% (16.7%-68.8%) over 3 years.
Specificity remained stable with increasing follow-up time, sensitivity decreased to 54.6% (28.0%-78.8%) over 5 years and to 35.0% (18.0%-56.8%) over 10 years, whereas positive predictive value rose to 60.0% (31.2%-83.3%) and 77.8% (44.3%-94.7%), respectively. Sample size estimates at 80% power in an intention-to-treat approach ranged from 108 to 540 patients with probable prodromal PD depending on trial duration (3-5 years) and effect size of the agent (30%-50%). Conclusions: Our findings show that the MDS criteria for prodromal PD yield moderate to high predictive power for incident PD in a community-based setting and may thus be helpful to define target populations of future neuroprotection trials.
© 2019 the authors