Faculty Bibliography

Early-onset parkinsonism (EO parkinsonism), defined as subjects with disease onset before the age of 40 or 50 years, can be the main clinical presentation of a variety of conditions that are important to differentiate. Although rarer than classical late-onset Parkinson's disease (PD) and not infrequently overlapping with forms of juvenile onset PD, a correct diagnosis of the specific cause of EO parkinsonism is critical for offering appropriate counseling to patients, for family and work planning, and to select the most appropriate symptomatic or etiopathogenic treatments. Clinical features, radiological and laboratory findings are crucial for guiding the differential diagnosis. Here we summarize the most important conditions associated with primary and secondary EO parkinsonism. We also proposed a practical approach based on the current literature and expert opinion to help movement disorders specialists and neurologists navigate this complex and challenging landscape.

Studies of epilepsy patients provide insight into the neuroscience of human memory. Patients with remote memory deficits may learn new information but have difficulty recalling events from years past. The processes underlying remote memory impairment are unclear and likely result from the interaction of multiple factors, including hippocampal dysfunction. The hippocampus likely has a continued role in remote semantic and episodic memory storage over time, and patients with mesial temporal lobe epilepsy (TLE) are at particular risk for deficits. Studies have focused on lateralization of remote memory, often with greater impairment in left TLE, which may relate to verbal task demands. Remote memory testing is restricted by methodological limitations. As a result, deficits have been difficult to measure. This review of remote memory focuses on evidence for its underlying neurobiology, theoretical implications for hippocampal function, and methodological difficulties that complicate testing in epilepsy patients.

The APOE gene is diversified by three alleles ε2, ε3, and ε4 encoding corresponding apolipoprotein (apo) E isoforms. Possession of the ε4 allele is signified by increased risks of age-related cognitive decline, Alzheimer's disease (AD), and the rate of AD dementia progression. ApoE is secreted by astrocytes as high-density lipoprotein-like particles and these are internalized by neurons upon binding to neuron-expressed apoE receptors. ApoE isoforms differentially engage neuronal plasticity through poorly understood mechanisms. We examined here the effects of native apoE lipoproteins produced by immortalized astrocytes homozygous for ε2, ε3, and ε4 alleles on the maturation and the transcriptomic profile of primary hippocampal neurons. Control neurons were grown in the presence of conditioned media from Apoe ^-/- astrocytes. ApoE2 and apoE3 significantly increase the dendritic arbor branching, the combined neurite length, and the total arbor surface of the hippocampal neurons, while apoE4 fails to produce similar effects and even significantly reduces the combined neurite length compared to the control. ApoE lipoproteins show no systemic effect on dendritic spine density, yet apoE2 and apoE3 increase the mature spines fraction, while apoE4 increases the immature spine fraction. This is associated with opposing effects of apoE2 or apoE3 and apoE4 on the expression of NR1 NMDA receptor subunit and PSD95. There are 1,062 genes differentially expressed across neurons cultured in the presence of apoE lipoproteins compared to the control. KEGG enrichment and gene ontology analyses show apoE2 and apoE3 commonly activate expression of genes involved in neurite branching, and synaptic signaling. In contrast, apoE4 cultured neurons show upregulation of genes related to the glycolipid metabolism, which are involved in dendritic spine turnover, and those which are usually silent in neurons and are related to cell cycle and DNA repair. In conclusion, our work reveals that lipoprotein particles comprised of various apoE isoforms differentially regulate various neuronal arbor characteristics through interaction with neuronal transcriptome. ApoE4 produces a functionally distinct transcriptomic profile, which is associated with attenuated neuronal development. Differential regulation of neuronal transcriptome by apoE isoforms is a newly identified biological mechanism, which has both implication in the development and aging of the CNS.

Background/UNASSIGNED:. Methods/UNASSIGNED:Patients with PoMS (N=215; aged 10-<18 years) were randomised to once-daily oral fingolimod (N=107) or once-weekly intramuscular IFN β-1a (N=108). HRQoL outcomes were assessed using the 23-item Pediatric Quality of Life (PedsQL) scale that comprises Physical and Psychosocial Health Summary Scores (including Emotional, Social and School Functioning). A post hoc inferential analysis evaluated changes in self-reported or parent-reported PedsQL scores from baseline up to 2 years between treatment groups using an analysis of covariance model. Results/UNASSIGNED:Treatment with fingolimod showed improvements versus IFN β-1a on the PedsQL scale in both the self-reported and parent-reported Total Scale Scores (4.66 vs -1.16, p≤0.001 and 2.71 vs -1.02, p≤0.05, respectively). The proportion of patients achieving a clinically meaningful improvement in the PedsQL Total Scale Score was two times higher with fingolimod versus IFN β-1a per the self-reported scores (47.5% vs 24.2%, p=0.001), and fingolimod was favoured versus IFN β-1a per the parent-reported scores (37.8% vs 24.7%, p=non-significant). Group differences in self-reported Total Scale Scores in favour of fingolimod were most pronounced among patients who had ≥2 relapses in the year prior to study entry or who showed improving or stable Expanded Disability Status Scale scores during the study. Conclusion/UNASSIGNED:Fingolimod improved HRQoL compared with IFN β-1a in patients with PoMS as evidenced by the self-reported and parent-reported PedsQL scores.

Posthypoxic myoclonus (PHM) is a possible sequela of acute hypoxic events. An acute form and a chronic form (the latter also referred to as Lance-Adams syndrome, LAS) have been described. Acute PHM is usually associated with a poor prognosis. LAS, instead, is characterized by myoclonus presenting or persisting as patients regain consciousness. It can improve over time, and when additional neurological symptoms are present those are usually mild. Differentiating these two phenotypes based on clinical and neurophysiological assessments (such as electroencephalogram recordings and somatosensory evoked potentials) is not always straightforward, although very important because of the different prognostic implications. There are differences in therapeutic approaches for acute and chronic PHM because of the different nature of the myoclonus (cortical vs. subcortical or a combination of the two) and concurrent events. Multidrug approaches are usually required in both settings, mostly leveraging antiepileptic medications. In patients with persistent and debilitating LAS, multistep and even surgical approaches, such as deep brain stimulation, can be attempted to maximize functional recovery.
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BACKGROUND:As the Hispanic/Latino (HL) population grows, so too does the need for HL family caregivers for persons with dementia. HL caregivers tend to have less education, lower health literacy, and lower income, each uniquely compounding burden. Research is needed to appropriately tailor interventions for this population. OBJECTIVE:A systematic review and meta-analysis was conducted to 1) provide an updated review of non-pharmacologic intervention studies for HL dementia caregivers, 2) characterize promising interventions, and 3) highlight opportunities for future research. METHODS:Databases were searched for articles evaluating non-pharmacologic interventions for HL dementia caregivers. Studies were excluded if target populations did not include HLs or if no intervention was delivered. Data were extracted and random effects meta-analysis was performed on two primary outcomes: caregiver depression and burden. Effect sizes were calculated as pre- and post-intervention standardized mean differences (SMD), and further depression subgroup meta-analysis was performed. Other secondary outcome measures (e.g., perceived social support, caregiver knowledge, anxiety) were evaluated qualitatively. RESULTS:Twenty-three studies were identified. Most included multiple components pertaining to psychosocial support, caregiver education, and community resource facilitation. Many studies were successful in improving caregiver outcomes, though intervention design varied. Meta-analysis revealed minimal to moderate heterogeneity and small effect size in improving depressive symptoms (SMD = -0.31, 95% CI -0.46 to -0.16; I2 = 50.16%) and burden (SMD = -0.28, 95% CI -0.37 to -0.18; I2 = 11.06%). CONCLUSION/CONCLUSIONS:Although intervention components varied, many reported outcome improvements. Future studies may benefit from targeting physical health, addressing sociocultural and economic contexts of caregivers, and leveraging technology.