Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder.

Purpose: De novo variants in CUL3 (Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism. Methods: Genetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells. Results: We assembled a cohort of 35 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro . Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells. Conclusion: Our study further refines the clinical and mutational spectrum of CUL3 -associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism.

Neocortical Lewy Body Pathology Parallels Parkinson's Dementia, but Not Always.

OBJECTIVE: The objective of this study was to evaluate the relationship between Parkinson's disease (PD) with dementia and cortical proteinopathies in a large population of pathologically confirmed patients with PD. METHODS: We reviewed clinical data from all patients with autopsy data seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2019. All patients with a diagnosis of PD based on neuropathology were included. We used logistic regression and multivariate analysis of covariance (MANCOVA) to investigate the relationship between neuropathology and dementia. RESULTS: A total of 165 patients with PD met inclusion criteria. Among these, 128 had clinical dementia. Those with dementia had greater mean ages of motor onset and death but equivalent mean disease duration. The delay between motor symptom onset and dementia was 1 year or less in 14 individuals, meeting research diagnostic criteria for possible or probable dementia with Lewy bodies (DLB). Braak Lewy body stage was associated with diagnosis of dementia, whereas severities of Alzheimer's disease neuropathologic change (ADNC) and small vessel pathology did not. Pathology of individuals diagnosed with DLB did not differ significantly from that of other patients with PD with dementia. Six percent of individuals with PD and dementia did not have neocortical Lewy bodies; and 68% of the individuals with PD but without dementia did have neocortical Lewy bodies. INTERPRETATION: Neocortical Lewy bodies almost always accompany dementia in PD; however, they also appear in most PD patients without dementia. In some cases, dementia may occur in patients with PD without neocortical Lewy bodies, ADNC, or small vessel disease. Thus, other factors not directly related to these classic neuropathologic features may contribute to PD dementia. ANN NEUROL 2023;93:184-195.

Excellent Outcome of Acute Necrotizing Encephalopathy in an Adult With Bacterial Infections, Case Report.

Acute necrotizing encephalopathy (ANE) is a rare para-infectious encephalopathy that classically occurs in children. However, ANE should be considered in the differential diagnosis of adults with symmetric brain lesions after a prodromal illness given recent reports of coronavirus disease of 2019 (COVID-19) to presumably cause ANE in adults. We report a case of a 29-year-old male presenting with fever, malaise, and rapid deterioration into coma. Brain magnetic resonance imaging revealed multifocal symmetric areas of diffusion restriction and surrounding vasogenic edema involving bilateral thalami, pons and cerebellar hemispheres with a core of susceptibility artifact, and minimal thalamic contrast enhancement, most consistent with ANE. Extensive infectious workup revealed isolated Escherichia coli and Neisseria gonorrhoeae in his urine. Despite the severe encephalopathy on initial presentation, the patient improved with intravenous antibiotics and supportive management with minimal residual deficits at 9 months follow-up. We aim to provide an overview of the radiological features, differential diagnosis, treatment and prognosis of ANE. Becoming familiarized with this rare but devastating disease will improve detection, treatment, and ultimately prognosis, especially in the era of a new pandemic.

Resting-State Functional Connectivity Predicts STN DBS Clinical Response.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus is a widely used adjunctive therapy for motor symptoms of Parkinson's disease, but with variable motor response. Predicting motor response remains difficult, and novel approaches may improve surgical outcomes as well as the understanding of pathophysiological mechanisms. The objective of this study was to determine whether preoperative resting-state functional connectivity MRI predicts motor response from deep brain stimulation of the subthalamic nucleus. METHODS: We collected preoperative resting-state functional MRI from 70 participants undergoing subthalamic nucleus deep brain stimulation. For this cohort, we analyzed the strength of STN functional connectivity with seeds determined by stimulation-induced (ON/OFF) 15 O H2 O PET regional cerebral blood flow differences in a partially overlapping group (n = 42). We correlated STN-seed functional connectivity strength with postoperative motor outcomes and applied linear regression to predict motor outcomes. RESULTS: Preoperative functional connectivity between the left subthalamic nucleus and the ipsilateral internal globus pallidus correlated with postsurgical motor outcomes (r = -0.39, P = 0.0007), with stronger preoperative functional connectivity relating to greater improvement. Left pallidal-subthalamic nucleus connectivity also predicted motor response to DBS after controlling for covariates. DISCUSSION: Preoperative pallidal-subthalamic nucleus resting-state functional connectivity predicts motor benefit from deep brain stimulation, although this should be validated prospectively before clinical application. These observations suggest that integrity of pallidal-subthalamic nucleus circuits may be critical to motor benefits from deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society.

Bilateral Subthalamic Nucleus Deep Brain Stimulation in Elderly Patients With Parkinson Disease: A Case-Control Study.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) is an effective adjunctive therapy for Parkinson disease. Studies have shown improvement of motor function but often exclude patients older than 75 yr. OBJECTIVE: To determine the safety and effectiveness of STN DBS in patients 75 yr and older. METHODS: A total of 104 patients (52 patients >75 yr old, 52 patients <75 yr old) with STN DBS were paired and retrospectively analyzed. The primary outcome was change in Unified Parkinson Disease Rating Scale (UPDRS) subscale III at 1 yr postoperatively, OFF medication. Secondary outcomes were changes in UPDRS I, II, and IV subscales and levodopa equivalents. Complications and all-cause mortality were assessed at 30 d and 1 yr. RESULTS: Both cohorts had significant improvements in UPDRS III at 6 mo and 1 yr with no difference between cohorts. Change in UPDRS III was noninferior to the younger cohort. The cohorts had similar worsening in UPDRS I at 1 yr, no change in UPDRS II, similar improvement in UPDRS IV, and similar levodopa equivalent reduction. There were similar numbers of postoperative intracerebral hemorrhages (2/52 in each cohort, more severe in the older cohort) and surgical complications (4/52 in each cohort), and mortality in the older cohort was similar to an additional matched cohort not receiving DBS. CONCLUSION: STN DBS provides substantial motor benefit and reduction in levodopa equivalents with a low rate of complications in older patients, which is also noninferior to the benefit in younger patients. STN DBS remains an effective therapy for those over 75 yr.

A Systematic Review and Case Series of Ziprasidone for Psychosis in Parkinson's Disease.

The atypical antipsychotic ziprasidone has been considered inappropriate for use in patients with Parkinson's disease (PD), as most atypical antipsychotics worsen parkinsonism. However, the current evidence for safety and efficacy of ziprasidone in PDP has not been evaluated in a systematic fashion. We review published experience with ziprasidone for treating psychosis in PD via systematic search of MEDLINE, Embase, Cochrane CENTRAL, and Clinicaltrials.gov with terms related to "ziprasidone" and "Parkinson's disease", inclusive of case reports and prospective studies. We also add seven cases of ziprasidone exposure in patients in our center with idiopathic PD or Lewy body dementia (DLB), selected by retrospective query of all clinical data since 1996. In our review, two prospective trials and 11 case reports or series were found, with ziprasidone found to be generally effective for treatment of psychosis and with few adverse events reported. Our case series did not support efficacy of ziprasidone; it was generally safe in PD, but two patients with DLB had adverse motor events. We conclude that, although ziprasidone occasionally can produce substantial worsening of motor signs, it usually is well tolerated, and may provide in some cases a useful alternative to quetiapine, clozapine and pimavanserin, particularly in the acute care setting. Further randomized controlled studies are needed.

Thalamic and ventricular volumes predict motor response to deep brain stimulation for Parkinson's disease.

BACKGROUND: Brain atrophy frequently occurs with Parkinson's disease (PD) and relates to increased motor symptoms of PD. The predictive value of neuroimaging-based measures of global and regional brain volume on motor outcomes in deep brain stimulation (DBS) remains unclear but potentially could improve patient selection and targeting. OBJECTIVES: To determine the predictive value of preoperative volumetric MRI measures of cortical and subcortical brain volume on motor outcomes of subthalamic nucleus (STN) DBS in PD. METHODS: Preoperative T1 3D MP-RAGE structural brain MRI images were analyzed for each participant to determine subcortical, ventricular, and cortical volume and thickness. Change in Unified Parkinson's Disease Rating Scale (UPDRS) scores for subsection 3, representing motor outcomes, was computed preoperatively and postoperatively following DBS programming in 86 participants. A multiple linear regression analysis was performed to investigate the relationship between volumetric data and the effect of DBS on UPDRS 3 scores. RESULTS: Larger ventricular and smaller thalamic volumes predicted significantly less improvement of UPDRS 3 scores after STN DBS. CONCLUSIONS: Our findings demonstrate in PD that regional brain volumes, in particular thalamic and ventricular volumes, predict motor outcomes after DBS. Differences in regional brain volumes may alter electrode targeting, reflect a specific disease trait such as postoperative progression of subclinical dementia, or directly interfere with the action of DBS.

Clinical Problem-Solving: Fever and Rapidly Progressive Weakness in an Immunocompromised Patient.

Here we report the challenging case of a 41-year-old man with HIV complicated by AIDS and a history of prior neurologic injury from progressive multifocal leukoencephalopathy who presented with headache, fevers, lower extremity weakness, hyperreflexic upper extremities, and diminished lower extremity reflexes. We review the clinical decision-making and differential diagnosis for this presentation as the physical examination evolved and diagnostic testing changed over time.

Robust deep brain stimulation functional MRI procedures in rats and mice using an MR-compatible tungsten microwire electrode.

PURPOSE: To develop a series of robust and readily adoptable protocols for the application of deep brain stimulation (DBS)-functional MRI (fMRI) in rodents. METHODS: DBS-fMRI procedures were conducted in rat and mouse under varying anesthetic conditions (isoflurane in rat and mouse, α-chloralose in rat). A homemade two-channel tungsten microwire electrode was used to minimize magnetic susceptibility artifacts, and was targeted to the ventral posteromedial (VPM) thalamus for DBS-fMRI scanning procedures. RESULTS: Compared with a commercially available MR-compatible electrode, the tungsten microwire generated greatly reduced magnetic-susceptibility artifacts. In the rat, VPM-DBS using the microwire electrode resulted in robust positive blood-oxygen-level-dependent signal changes in somatosensory cortex that were relatively independent of anesthetic type. In the mouse, VPM-DBS similarly generated large, positive neurovascular responses in somatosensory cortex that were detected using cerebral blood volume measurements. CONCLUSION: Collectively, this work describes reasonable and easily adoptable procedures for conducting DBS-fMRI studies in rodent models. The protocols developed herein may be extended to study DBS effects under numerous experimental conditions and at varying stimulation targets.

Functional MRI reveals frequency-dependent responses during deep brain stimulation at the subthalamic nucleus or internal globus pallidus.

Deep brain stimulation (DBS) represents a widely used therapeutic tool for the symptomatic treatment of movement disorders, most commonly Parkinson's disease (PD). High frequency stimulation at both the subthalamic nucleus (STN) and internal globus pallidus (GPi) has been used with great success for the symptomatic treatment of PD, although the therapeutic mechanisms of action remain elusive. To better understand how DBS at these target sites modulates neural circuitry, the present study used functional blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to map global brain responses to DBS at the STN and GPi of the rat. Robust activation centered in the ipsilateral motor cortex was observed during high frequency stimulation at either target site, with peak responses observed at a stimulation frequency of 100Hz. Of note, frequency tuning curves were generated, demonstrating that cortical activation was maximal at clinically-relevant stimulation frequencies. Divergent responses to stimulation were noted in the contralateral hemisphere, with strong cortical and striatal negative BOLD signal during stimulation of the GPi, but not STN. The frequency-dependence of the observed motor cortex activation at both targets suggests a relationship with the therapeutic effects of STN and GPi DBS, with both DBS targets being functionally connected with motor cortex at therapeutic stimulation frequencies.