Aristide Merola

Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials

Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: A single‐mechanism therapy can affect most of those sharing the classic pathological hallmark. From a systems‐biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine‐neuron degeneration, exhibit unique genetic, biological, and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker‐defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker‐discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers), rather than clinical definitions, are used to define disease phenotypes. Successful development of disease‐modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision‐medicine approach will likely yield smaller, but well‐defined, subsets of PD amenable to successful neuroprotection.

Essential pitfalls in "essential" tremor.

Although essential tremor has been considered the most common movement disorder, it has largely remained a diagnosis of exclusion: many tremor and nontremor features must be absent for the clinical diagnosis to stand. The clinical features of “essential tremor” overlap with or may be part of other tremor disorders and, not surprisingly, this prevalent familial disorder has remained without a gene identified, without a consistent natural history, and without an acceptable pathology or pathophysiologic underpinning. The collective evidence suggests that under the rubric of essential tremor there exists multiple unique diseases, some of which represent cerebellar dysfunction, but for which there is no intrinsic “essence” other than a common oscillatory behavior on posture and action. One approach may be to use the term essential tremor only as a transitional node in the deep phenotyping of tremor disorders based on historical, phenomenological, and neurophysiological features to facilitate its etiologic diagnosis or serve for future gene‐ and biomarker‐discovery efforts. This approach deemphasizes essential tremor as a diagnostic entity and facilitates the understanding of the underlying disorders to develop biologically tailored diagnostic and therapeutic strategies.

Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration

Idiopathic normal pressure hydrocephalus (NPH) remains both oversuspected on clinical grounds and underconfirmed when based on immediate and sustained response to cerebrospinal fluid diversion. Poor long‐term postshunt benefits and findings of neurodegenerative pathology in most patients with adequate follow‐up suggest that hydrocephalic disorders appearing in late adulthood may often result from initially unapparent parenchymal abnormalities. We critically review the NPH literature, highlighting the near universal lack of blinding and controls, absence of specific clinical, imaging, or pathological features, and ongoing dependence for diagnostic confirmation on variable cutoffs of gait response to bedside fluid‐drainage testing. We also summarize our long‐term institutional experience, in which postshunt benefits in patients with initial diagnosis of idiopathic NPH persist in only 32% of patients at 36 months, with known revised diagnosis in over 25% (Alzheimers disease, dementia with Lewy bodies, and progressive supranuclear palsy). We postulate that previously reported NPH cases with “dual” pathology (ie, developing a “second” disorder) more likely represent ventriculomegalic presentations of selected neurodegenerative disorders in which benefits from shunting may be short‐lived, with a consequently unfavorable risk‐benefit ratio. Ann Neurol 2017;82:503–513

Autonomic dysfunction in Parkinson's disease: A prospective cohort study: Prospective PD Autonomic Function Assessment

Background: Dysautonomia is a frequent and disabling complication of PD, with an estimated prevalence of 30‐40% and a significant impact on the quality of life.

Thalamic Deep Brain Stimulation for Orthostatic Tremor: A Multicenter International Registry

We report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor.

Prevalence and burden of dysautonomia in advanced Parkinson's disease

We sought to examine the prevalence and burden of dysautonomia in patients with advanced Parkinson’s disease (PD) treated with subthalamic deep brain stimulation (STNDBS) and levodopa-carbidopa intestinal gel infusion (LCIG). Using a standardized battery of autonomic tests, blood pressure measurement protocol, and the Scale for Outcomes in Parkinson’s Disease-Autonomic (SCOPA-AUT), 60 consecutive PD patients treated with STN-DBS (n 5 30) and LCIG (n 5 30) were classified according to the presence or absence of dysautonomia. We evaluated the impairment in activities of daily living/instrumental activities of daily living (ADL/iADL), adjusting for cognitive impairment, as measured by the Montreal Cognitive Assessment (MoCA), age, and motor severity using the motor subscale of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS-III). Additional measures included SCOPA-AUT, Orthostatic Hypotension Symptom Assessment, and the PD Quality-of-Life Questionnaire (PDQ-8). Binary logistic regression was used to estimate the impact (odds ratio [OR]) of dysautonomia on ADL/iADL, adjusting for cognitive impairment, age, and motor severity. A multiple linear regression model was used to estimate the correlation between SCOPA-AUT and PDQ-8. In addition, analysis of covariance was used to estimate the extent to which the dependent variables, ADL/iADL, adjusted for MoCA, age, and MDS-UPDRS-III, were influenced by (1) symptomatic state (symptomatic vs asymptomatic orthostatic hypotension); and (2) therapy (STN-DBS vs LCIG). Mann-Whitney and Fisher’s tests were used for comparisons between groups. The overall prevalence of dysautonomia in this unselected population was 48.3% (29 of 60 patients), similar to that in the STN-DBS (50%) and LCIG (46.7%) cohorts (P 5 0.796). Adjusted analysis showed that dysautonomia was independently associated with a threefold impairment in ADL/iADL (OR, 2.850; 95% CI, 1.044-10.326; P 5 0.042). There was a robust correlation between autonomic symptoms (SCOPA-AUT) and quality-of-life impairment (P< 0.001). The strongest correlation was for gastrointestinal (P< 0.001), urinary/sexual (P 5 0.01), and cardiovascular (P 5 0.017) domains. Adjusted ADL/iADL scores differed between patients with and without orthostatic hypotension (P 0.047). In post hoc analyses, symptomatic (15.0%) and asymptomatic (11.7%) orthostatic hypotension worsened ADL/iADL to a similar extent (P 0.045) compared with patients without orthostatic hypotension (Fig. 1). The adjusted ADL/iADL scores was similar in the STN-DBS and LCIG cohorts (P 0.473). Subanalysis of autonomic domains (Fig. 1) revealed worse cardiovascular impairment in the LCIG cohort (P 5 0.039), potentially because of higher dopaminergic dosage (Supplementary Table) and worse pupillomotor impairment in the STN-DBS cohort (P 5 0.026), plausibly associated with electrical spread to the optic tract.

Functional neurological disorders in Parkinson disease

Objective To ascertain demographic and clinical features of Parkinson disease (PD) associated with functional neurological features. Methods A standardised form was used to extract data from electronic records of 53 PD patients with associated functional neurological disorders (PD-FND) across eight movement disorders centres in the USA, Canada and Europe. These subjects were matched for age, gender and disease duration to PD patients without functional features (PD-only). Logistic regression analysis was used to compare both groups after adjusting for clustering effect. Results Functional symptoms preceded or co-occurred with PD onset in 34% of cases, nearly always in the most affected body side. Compared with PD-only subjects, PD-FND were predominantly female (68%), had longer delay to PD diagnosis, greater prevalence of dyskinesia (42% vs 18%; P=0.023), worse depression and anxiety (P=0.033 and 0.025, respectively), higher levodopa-equivalent daily dose (972±701 vs 741±559 mg; P=0.029) and lower motor severity (P=0.019). These patients also exhibited greater healthcare resource utilisation, higher use of [(123)I]FP-CIT SPECT and were more likely to have had a pre-existing psychiatric disorder (P=0.008) and family history of PD (P=0.036). Conclusions A subtype of PD with functional neurological features is familial in one-fourth of cases and associated with more psychiatric than motor disability and greater use of diagnostic and healthcare resources than those without functional features. Functional manifestations may be prodromal to PD in one-third of patients.

Reverse blood pressure dipping as marker of dysautonomia in Parkinson disease

INTRODUCTION We sought to evaluate if the presence of abnormal circadian loss of nocturnal blood pressure dipping (reverse dipping) is associated with cardiovascular dysautonomia, a major source of morbidity in Parkinson disease. METHODS Consecutive Parkinson disease patients were enrolled in this cross-sectional study between January 2015 and June 2017. All subjects underwent same-day autonomic testing and 24-h ambulatory blood pressure monitoring. Cardiovascular dysautonomia was defined by the presence of at least one moderate or severe cardiovagal and adrenergic test abnormality. RESULTS We recruited 114 PD patients (79 males; mean age 64 ± 10 years; disease duration 6 ± 4 years). Cardiovascular dysautonomia was present in 32% (36/114). The blood pressure patterns were normal dipping in 28.9% (n = 33), extreme dipping in 6.1% (n = 7), reduced dipping in 32.5% (n = 37), and reverse dipping in 32.5% (n = 37). Reverse dipping was disproportionately prevalent in subjects with cardiovascular dysautonomia (69% vs 15%, p < 0.001). The diagnostic accuracy of reverse dipping in discriminating cardiovascular dysautonomia (AUC 0.791, specificity 84%, sensitivity 69%) was higher than that of bedside blood pressure ascertainment of neurogenic orthostatic hypotension (0.681, 66%, 69%) and supine hypertension (0.641, 78%, 50%). CONCLUSIONS Reverse nocturnal blood pressure dipping is a marker of cardiovascular dysautonomia in Parkinson disease, which can be screened for with ease and affordability using ambulatory blood pressure monitoring.

Effects of intestinal Levodopa infusion on freezing of gait in Parkinson disease

OBJECTIVE To determine the impact of levodopa-carbidopa intestinal gel (LCIG) infusion on different subtypes of freezing of gait (FoG) classified according to levodopa responsiveness in advanced Parkinson disease (PD) patients. METHODS We retrospectively assessed the presence and severity of FoG in 32 advanced PD patients based on the Unified PD Rating Scale (UPDRS) item 14 score. Different FoG subtypes were inferred from the score variation with oral dopaminergic medications. Modifications following long-term LCIG infusion were analysed. Motor symptoms and motor complications were assessed by UPDRS part III and IV respectively. RESULTS FoG related UPDRS score varied from 2.6±0.9 in OFF condition to 0.9±0.8 in the ON condition at baseline and improved to 0.6±0.7 with LCIG infusion (p=0.027). After a mean of 2.59±1.12years of continuous LCIG infusion, Pseudo-ON-FoG improved to a greater extent with LCIG infusion than with oral therapy in 12 patients (38%) and equally well in 8 patients (25%), OFF-type-FoG was controlled equally well in 8 patients (25%) and worsened slightly in 3 patients (9%). Unresponsive-FoG, present in one patient (3%), was unmodified by LCIG infusion. CONCLUSIONS Even though limited by the subjective simple measure of FoG, this study suggests that patients undergoing LCIG infusion maintain a good long-term control of FoG. Pseudo-on-FoG improves in a considerable percentage of patients and OFF-type-FoG remains well controlled with LCIG infusion. Further studies with a larger number of patients and objective measures of FoG are needed to confirm these findings.

Levodopa-Induced Neuropathy: A Systematic Review: Levodopa-induced neuropathy

Clinical, neurophysiological, and pathological evidence suggest an association between Parkinsons disease (PD) and peripheral neuropathy (PNP), with a possible causative role of levodopa metabolic products, such as homocysteine and methylmalonic acid.