Anticholinergic Medication Burden and Cognitive Subtypes in Parkinson's Disease without Dementia.

OBJECTIVE: Cognitive changes are heterogeneous in Parkinson's disease (PD). This study compared whether anticholinergic burden drives differences in cognitive domain performance and empirically-derived PD-cognitive phenotypes. METHOD: A retrospective chart review contained participants (n = 493) who had idiopathic PD without dementia. Participants' medications were scored (0-3) and summed based on the anticholinergic cognitive burden scale (ACBS). We examined the ACBS' relationship to five cognitive domain composites (normative z-scores) and three (K-means clustering based) cognitive phenotypes: cognitively intact, low executive function (EF), and predominately impaired EF/memory. Analyses included Spearman correlations, analysis of covariance, and Pearson chi-squared test. RESULTS: Overall, phenotypes did not differ in anticholinergic burden, and (after false-discovery-rate corrections) no cognitive domains related. When comparing those above and below the clinically relevant ACBS cutoff (i.e., score ≥3), no significant phenotype or domain differences were found. CONCLUSIONS: Anticholinergic medication usage did not drive cognitive performance in a large clinical sample of idiopathic PD without dementia.

Identification and Management of Persistent Stimulation-Induced Dyskinesia Associated with STN DBS: The See-Saw Dilemma.

Clinical vignette: A 73-year-old woman with Parkinson's disease (PD) underwent implantation of bilateral subthalamic nucleus deep brain stimulators (STN-DBS) to address bilateral upper extremity medication-refractory tremor. Post-operatively, she experienced a "see-saw effect" where small increases in stimulation resulted in improvement in one symptom (tremor) with concurrent worsening in another (dyskinesia). Clinical dilemma: SID is usually considered a positive predictor of DBS outcome. However, there are cases where SID cannot be optimized. Lead location and pre-operative characteristics may contribute to this adverse effect. If the combination of programming and medication adjustments fails to resolve SID, what can be done to "rescue" the outcome? Clinical solution: Management of SID requires a gradual and steadfast programming approach. Post-operative lead localization can guide advanced programming and decision-making. Rescue surgical interventions may be considered. Gap in knowledge: In cases where SID is persistent despite deploying persistent optimization strategies, there is limited guidance on next steps.

Illusory Responses across the Lewy Body Disease Spectrum.

OBJECTIVE: This study was undertaken to study pareidolias, or perceived meaningful objects in a meaningless stimulus, in patients across the Lewy body (LB) disease spectrum, where most do not report hallucinations or delusions. METHODS: We studied illusory responses on the Noise Pareidolia Task in 300 participants (38 cognitively impaired LB, 65 cognitively unimpaired LB, 51 Alzheimer disease spectrum [AD-s], 146 controls). Pairwise between-group comparisons examined how diagnosis impacts the number of illusory responses. Ordinal regression analysis compared the number of illusory responses across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions. RESULTS: Cognitively impaired LB participants were 12.3, 4.9, and 4.6 times more likely than control, cognitively unimpaired LB, and AD-s participants, respectively, to endorse illusory responses. After adjusting for age, sex, and education, the probability of endorsing 1 or more illusory responses was 61% in the cognitively impaired LB group, compared to 26% in AD-s, 25% in cognitively unimpaired LB, and 12% in control participants. All results were similar after repeated analysis only in participants without hallucinations or delusions. In LB without hallucinations or delusions, 52% with mild cognitive impairment and 66.7% with dementia endorsed at least 1 illusory response. INTERPRETATION: We found illusory responses are common in cognitively impaired LB patients, including those without any reported psychosis. Our data suggest that, prior to the onset of hallucinations and delusions, the Noise Pareidolia Task can easily be used to screen for unobtrusive pareidolias in all LB patients. ANN NEUROL 2023;93:702-714.

Surgical Therapies for Parkinson Disease.

PURPOSE OF REVIEW: Parkinson disease (PD) is a progressive neurodegenerative disorder that is often difficult to manage with medications alone. This article reviews the current therapeutic surgical interventions for PD, patient selection criteria, timing of patient referral to surgical services, procedure overview, and future directions. RECENT FINDINGS: Adaptive, or closed-loop, deep brain stimulation is a promising therapy that can detect ongoing circuit changes and deliver appropriate stimulation based on the patient's dominant symptom and level of dopaminergic medication. SUMMARY: Patients with PD can benefit from surgical interventions that can be added to their medication regimen. These patients should be referred to comprehensive centers that offer complete multidisciplinary screening evaluation to ensure appropriate patient selection and intervention selection. With the appropriate surgical intervention and continued management from their care team, patients with PD can maximize their quality of life.

The chromatin repressors EZH2 and Suv4-20h coregulate cell fate specification during hippocampal development.

The cell fate transition from radial glial-like (RGL) cells to neurons and astrocytes is crucial for development and pathological conditions. Two chromatin repressors-the enhancer of zeste homolog 2 and suppressor of variegation 4-20 homolog-are expressed in RGL cells in the hippocampus, implicating these epigenetic regulators in hippocampal cell fate commitment. Using a double knockout mouse model, we demonstrated that loss of both chromatin repressors in the RGL population leads to deficits in hippocampal development. Single-nuclei RNA-Seq revealed differential gene expression and provided mechanistic insight into how the two chromatin repressors are critical for the maintenance of cycling cells in the dentate gyrus as well as the balance of cell trajectories between neuronal and astroglial lineages.

Rare Etiology of Bow Hunter's Syndrome and Systematic Review of Literature.

BACKGROUND: Bow Hunter's Syndrome is a mechanical occlusion of the vertebral artery which leads to a reduction in blood flow in posterior cerebral circulation resulting in transient reversible symptomatic vertebrobasilar insufficiency. CASE DESCRIPTION: We present a case of Bow Hunter's syndrome in a 53-year-old male that occurred after the patient underwent surgical correction of a proximal left subclavian artery aneurysm. Shortly after the surgery, the patient began to complain of transient visual changes, presyncopal spells, and dizziness upon turning his head to the left. A transcranial doppler ultrasound confirmed the diagnosis of Bow Hunter's syndrome. SYSTEMIC REVIEW: We analyzed the data on 153 patients with Bow Hunter's syndrome from the literature. An osteophyte was the most common cause of vertebral artery occlusion, and left vertebral artery was more commonly involved in patients with Bow Hunter's syndrome. Dynamic angiography was the definitive imaging modality to confirm the diagnosis, and surgery was most successful in alleviating symptoms. CONCLUSION: We believe that this is the first case of iatrogenic Bow Hunter's syndrome after surgical intervention for an aneurysm repair, and the largest review of literature of Bow Hunter's syndrome. Dynamic angiography is the gold standard for the diagnosis of Bow Hunter's syndrome. Surgery should be considered as the primary treatment approach in these patients, especially those who have bony compression as the etiology.

Repeated administrations of human umbilical cord blood cells improve disease outcomes in a mouse model of Sanfilippo syndrome type III B.

Sanfilippo syndrome type III B (MPS III B) is an inherited disorder characterized by a deficiency of α-N-acetylglucosaminidase (Naglu) enzyme leading to accumulation of heparan sulfate in lysosomes and severe neurological deficits. We have previously shown that a single administration of human umbilical cord mononuclear cells (hUCB MNCs) into Naglu knockout mice decreased behavioral abnormalities and tissue pathology. In this study, we tested whether repeated doses of hUCB MNCs would be more beneficial than a single dose of cells. Naglu mice at 3 months of age were randomly assigned to either a Media-only group or one of three hUCB MNC treatment groups--single low dose (3 × 10(6) cells), single high dose (1.8 × 10(7) cells), or multiple doses (3 × 10(6) cells monthly for 6 months) delivered intravenously; cyclosporine was injected intraperitoneally to immune suppress the mice for the duration of the study. An additional control group of wild-type mice was also used. We measured anxiety in an open field test and cognition in an active avoidance test prior to treatment and then at monthly intervals for 6 months. hUCB MNCs restored normal anxiety-like behavior in these mice (p < 0.001). The repeated cell administrations also restored hippocampal cytoarchitecture, protected the dendritic tree, decreased GM3 ganglioside accumulation, and decreased microglial activation, particularly in the hippocampus and cortex. These data suggest that the neuroprotective effect of hUCB MNCs can be enhanced by repeated cell administrations.

Blood-brain barrier impairment in an animal model of MPS III B.

BACKGROUND: Sanfilippo syndrome type B (MPS III B) is caused by a deficiency of α-N-acetylglucosaminidase enzyme, leading to accumulation of heparan sulfate within lysosomes and eventual progressive cerebral and systemic multiple organ abnormalities. However, little is known about the competence of the blood-brain barrier (BBB) in MPS III B. BBB dysfunction in this devastating disorder could contribute to neuropathological disease manifestations. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we investigated structural (electron microscope) and functional (vascular leakage) integrity of the BBB in a mouse model of MPS III B at different stages of disease, focusing on brain structures known to experience neuropathological changes. Major findings of our study were: (1) endothelial cell damage in capillary ultrastructure, compromising the BBB and resulting in vascular leakage, (2) formation of numerous large vacuoles in endothelial cells and perivascular cells (pericytes and perivascular macrophages) in the large majority of vessels, (3) edematous space around microvessels, (4) microaneurysm adjacent to a ruptured endothelium, (6) Evans Blue and albumin microvascular leakage in various brain structures, (7) GM3 ganglioside accumulation in endothelium of the brain microvasculature. CONCLUSIONS/SIGNIFICANCE: These new findings of BBB structural and function impairment in MPS III B mice even at early disease stage may have implications for disease pathogenesis and should be considered in current and future development of treatments for MPS III B.