Faculty Bibliography

Background/UNASSIGNED:Freezing of gait (FOG) is one of the most disabling symptoms of Parkinson disease (PD). It has been found that different land-based rehabilitation approaches based on motor and cognitive strategies could be effective for treating FOG. At the same time, there are data about the efficacy of aquatic therapy (AT) in ameliorating this phenomenon. No 1 study has explored the combined effect of land plus AT in patients with PD who have FOG. Objective/UNASSIGNED:The objective was to investigate the effectiveness of a multidisciplinary, intensive, motor-cognitive rehabilitation treatment (MIRT) in improving FOG and whether the implementation with AT (MIRT-AT) adds further benefits. Design/UNASSIGNED:The design consisted of a single-blind, parallel group, 1:1 allocation ratio, randomized trial. Setting/UNASSIGNED:Department of Parkinson disease, Movement Disorders and Brain Injury Rehabilitation - "Moriggia-Pelascini" Hospital (Gravedona ed Uniti, Como-Italy) was used as the setting. Participants/UNASSIGNED:60 hospitalized patients with PD who had FOG in Hoehn & Yahr (H&Y) stage 2 or 5-3 were included. Intervention/UNASSIGNED:60 patients with PD + FOG were randomly assigned to 2 groups. 30 underwent a 4-week MIRT and 30 underwent a 4-week MIRT plus AT (MIRT-AT). Measurements/UNASSIGNED:The primary outcome measure was the Freezing of Gait Questionnaire (FOGQ); secondary outcome measures were total Unified Parkinson Disease Rating Scale (UPDRS), UPDRS II, UPDRS III, Berg Balance Scale (BBS), Timed Up and Go Test (TUG) and 6-Minute Walk Test (6MWT). These measures were assessed both at admission and discharge. Results/UNASSIGNED:Patients in the two groups had similar age, gender distribution, H&Y stage, and most-affected side. At baseline, no difference in outcome measures was observed between the two groups. After treatment, a significant time effect was observed for all variables in both groups. No significant time x-group interaction was observed. A between-group analysis showed non-significant differences between values at T1 and values at T0 for all variables. Limitations/UNASSIGNED:A limitation is that control group and follow-up are lacking. Conclusions/UNASSIGNED:We showed that a multidisciplinary, intensive, and goal-based rehabilitation treatment, such as MIRT, improve FOG in patients with PD. Even though AT could be considered as a useful approach for treating FOG, it does not add further benefits to this kind of motor-cognitive rehabilitation.

Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.

Systemic and localized vasculitis affects the skin and subcutis, due to large vascular beds and hemodynamic factors, such as stasis in lower extremities, and environmental influences, as occur in cold exposure. Initial cutaneous manifestations of vasculitides include diverse and dynamic patterns of discoloration, swelling, hemorrhage, and necrosis. One-half of affected patients present with localized, self-limited disease to the skin without any known trigger or associated systemic disease, known as idiopathic cutaneous leukocytoclastic vasculitis. Skin biopsy and dermatopathology contribute relevant information; however, they require correlation with clinical history, physical examination, and laboratory findings to reach an accurate diagnosis.

Granulomatous inflammation, the prototypical histopathology of adult and childhood vasculitis, is characterized by inflammation of blood vessels accompanied by giant cells and epithelioid cells in the walls of cerebral vessels ranging from small leptomeningeal veins to large named cerebral arteries. Headache, hemiparesis, mental changes, abnormal cerebrospinal fluid protein content, and pleocytosis are suggestive features that warrant brain and leptomeningeal biopsy to make the diagnosis certain and begin cytotoxic therapy to improve outcome.

Objective/UNASSIGNED:The amyotrophic lateral sclerosis (ALS) trial outcome measures are clinic based. Active and passive smartphone data can provide important longitudinal information about ALS progression outside the clinic. Methods/UNASSIGNED:We used Beiwe, a research platform for smartphone-based digital phenotyping, to collect active (self-report ALSFRS-R surveys and speech recordings) and passive (phone sensors and logs) data from patients with ALS for approximately 24 weeks. In clinics, at baseline and every 3 months, we collected vital capacity, ALSFRS-R, and ALS-CBS at enrollment, week 12, and week 24. We also collected ALSFRS-R by telephone at week 6. Results/UNASSIGNED: < 0.001). ALSFRS-R slopes were equivalent and within-subject standard deviation was smaller for smartphone-based self-report (0.26 vs. 0.56). Use of Beiwe afforded weekly collection of speech samples amenable to a variety of analyses, and we found mean pause time to increase by 0.02 sec per month across the sample. Interpretation/UNASSIGNED:Smartphone-based digital phenotyping in people with ALS is feasible and informative. Self-administered smartphone ALSFRS-R scores correlate highly with clinic-based ALSFRS-R scores, have low variability, and could be used in clinical trials. More research is required to fully analyze speech recordings and passive data, and to identify optimal digital markers for use in future ALS clinical trials.

BACKGROUND AND PURPOSE/OBJECTIVE:Patients with ischemic stroke of cardioembolic origin are at risk of visceral (renal or splenic) infarction. We hypothesized that serum troponin level at time of ischemic stroke would be associated with presence of visceral infarction. METHODS:Data were abstracted from a single center prospective stroke database over 18 months and included all patients with ischemic stroke who underwent contrast-enhanced computerized tomography (CT) of the abdomen and pelvis for clinical purposes within 1 year of stroke. The primary predictor was troponin concentration ≥.1 ng/mL. The primary outcome was visceral infarct (renal and/or splenic) on CT abdomen and pelvis. Univariate and multivariable logistic regression models were used to estimate the odds ratio and 95% confidence intervals (OR, 95% CI) for the association of troponin with visceral infarction. RESULTS:Of 1233 patients with ischemic stroke, 259 patients had a qualifying visceral CT. Serum troponin level on admission was measured in 237 of 259 patients (93.3%) and 41 of 237 (17.3%) had positive troponin. There were 25 patients with visceral infarcts: 16 renal, 7 splenic, and 2 both. In univariate models, patients with a positive troponin level (versus negative) were more likely to have visceral infarcts (39.1% [9/23] versus 15.0% [32/214], P = .008) and this association persisted in multivariable models (adjusted OR 3.83; 95% CI 1.42-10.31, P = .006). CONCLUSIONS:In ischemic stroke patients, elevated serum troponin levels may help identify patients with visceral infarcts. This suggests that troponin in the acute stroke setting is a biomarker of embolic risk. Larger studies with systematic visceral imaging are needed to confirm our findings.

Interactions between axons and Schwann cells are essential for the acquisition of Schwann cell radial and longitudinal polarity and myelin sheath assembly. In the internode, the largest of these longitudinal domains, axon-Schwann cell interactions are mediated by the Nectin-like (Necl) cell adhesion proteins, also known as SynCAMs or Cadms. In particular, Necl-1/Cadm3 expressed on the axon surface binds to Necl-4/Cadm4 expressed along the adaxonal membrane of myelinating Schwann cells. Necl-4 promotes myelination in vitro and is required for the timely onset of myelination and the fidelity of the organization of the myelin sheath and the internode in vivo. A key question is the identity of the downstream effectors of Necl-4 that mediate its effects. The cytoplasmic terminal region (CTR) of Necl-4 contains a PDZ-domain binding motif. Accordingly, we used the CTR of Necl-4 in an unbiased proteomic screen of PDZ-domain proteins. We identify Par-3, a multi-PDZ domain containing protein of the Par-aPKC polarity complex previously implicated in myelination, as an interacting protein. Necl-4 and Par-3 are colocalized along the inner Schwann cell membrane and coprecipitate from Schwann cell lysates. The CTR of Necl-4 binds to the first PDZ domain of Par-3 thereby recruiting Par-3 to sites of Necl-4/Necl-1 interaction. Knockdown of Necl-4 perturbs Par-3 localization to the inner membrane of Schwann cells in myelinating co-cultures. These findings implicate interactions of Necl-1/Necl-4 in the recruitment of Par-3 to the Schwann cell adaxonal membrane and the establishment of Schwann cell radial polarity.

The systemic vasculitides are heterogeneous clinicopathologic disorders that share the common feature of vascular inflammation. The resulting disorder can vary depending on involvement of specific organs, caliber of blood vessels, the underlying inflammatory process, and individual host factors. The cumulative result is diminished blood flow, vascular alterations, and eventual occlusion with variable ischemia, necrosis, and tissue damage. An international revised nomenclature system provides the necessary nosology and findings relevant to classify each of the vasculitides. This article is an introduction and overview of the clinical presentation, differential diagnosis, laboratory evaluation, and treatment of systemic and nervous system vasculitides.

Illicit drug abuse is a common differential diagnosis of acquired central nervous system vasculitis even though there are only a handful of histopathologically confirmed patients in the literature from among the many potential classes of abused drugs traditionally implicated in this disease. This article considers the major classes of illicit drugs in those with and without human immunodeficiency virus type-1 infection and acquired immune deficiency syndrome.

The diagnosis of primary central and peripheral nerve vasculitides should be established with certainty if suspected before commencing potent immunosuppressive therapy. The aim of induction therapy is to rapidly control the underlying inflammatory response and stabilize the blood-brain and blood-nerve barriers, followed by maintenance immunosuppression tailored to the likeliest humoral and cell-mediated autoimmune inflammatory vasculitic processes.