COVID-19: Brain Effects.

Severe acute respiratory syndrome coronavirus 2, the novel coronavirus responsible for the coronavirus disease (COVID-19), affects the brain. Neurologic and neuropsychiatric symptoms may manifest in the acute and post-acute phases of illness. The vulnerability of the brain with aging further increases the burden of disease in the elderly, who are at the highest risk of complications and death from COVID-19. The mechanisms underlying the effects of COVID-19 on the brain are not fully known. Emerging evidence vis-à-vis pathogenesis and etiologies of COVID-19 brain effects is promising and may pave the way for future research and development of interventions.

Regional fluorodeoxyglucose metabolism and instrumental activities of daily living across the Alzheimer's disease spectrum.

BACKGROUND: Impairment in instrumental activities of daily living (IADL) begins as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer's disease (AD) dementia. IADL impairment in AD dementia has been associated with inferior parietal, inferior temporal, and superior occipital hypometabolism using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). OBJECTIVE: To investigate the relationship between regional FDG metabolism and IADL in clinically normal (CN) elderly, MCI, and mild AD dementia subjects cross-sectionally and longitudinally. METHODS: One hundred and four CN, 203 MCI, and 95 AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative underwent clinical assessments every 6 to 12 months for up to three years and baseline FDG PET. The subjective, informant-based Functional Activities Questionnaire was used to assess IADL. General linear models and mixed effects models were used, covarying for demographics, cognition, and behavior. RESULTS: The cross-sectional analysis revealed middle frontal and orbitofrontal hypometabolism were significantly associated with greater IADL impairment. Additionally, the interaction of diagnosis with posterior cingulate and with parahippocampal hypometabolism showed a greater decline in IADL performance as metabolism decreased for the AD dementia relative to the MCI group, and the MCI group relative to the CN group. The longitudinal analysis showed that baseline middle frontal and posterior cingulate hypometabolism were significantly associated with greater rate of increase in IADL impairment over time. CONCLUSION: These results suggest that regional synaptic dysfunction, including the Alzheimer-typical medial parietal and less typical frontal regions, relates to daily functioning decline at baseline and over time across the early AD spectrum.

Development of a psychometrically equivalent short form of the Face-Name Associative Memory Exam for use along the early Alzheimer's disease trajectory.

Neuropsychologists are developing more challenging and specific tests to detect early and subtle changes in cognition related to preclinical Alzheimer's disease (AD). The 16-item Face-Name Associative Memory Exam (FNAME-16) is a challenging paired associative memory test able to detect subtle memory changes associated with biomarker evidence of preclinical AD. However, as individuals progress along the AD trajectory, measures that are sensitive at the preclinical stage may become too challenging by the stage of Mild Cognitive Impairment (MCI). Our goal was to develop a modified version of the face-name and face-occupation paired associative memory task (FNAME-12) with fewer stimuli and additional learning trials suitable for use in MCI. We administered the FNAME-12A, an alternate version FNAME 12B, the original FNAME-16, and a series of other neuropsychological measures to 65 clinically normal (CN) older adults (aged 65 to 85) and a subsample characterized by MCI (n = 18). The FNAME-12 exhibited psychometric equivalence with the FNAME-16 (r = .77, p < .001) and was correlated with other measures of episodic and semantic memory. The alternate form, FNAME-12B, was highly correlated with FNAME-12A (r = .76, p < .001). Mean performance on the FNAME 12A, stratified by education, was generated. The task could be completed by our MCI group yet remained challenging in the CN group, providing evidence for its utility along the AD trajectory.

Clinical gene therapy for the treatment of RPE65-associated Leber congenital amaurosis.

INTRODUCTION: The positive results of pioneering clinical trials using gene therapy as treatment for patients with Leber congenital amaurosis (LCA) have ushered in a new era of molecular retinal therapeutics for LCA, other blinding retinal disorders and gene therapy applications. AREAS COVERED: This review describes the role of retinal pigment epithelium-specific 65 kDa protein (RPE65) in the visual cycle and how RPE65 deficiency results in LCA; the extensive preclinical studies with recombinant adeno-associated virus (rAAV)-RPE65 gene vectors; and the human rAAV-RPE65 and related gene therapy clinical trials and studies. The literature search included a review of primary sources (e.g., journal articles) that reported study data results and key secondary sources such as meta-reviews available through PubMed, as well as reviews of clinical trial descriptions and results as reported in clinicaltrials.gov, conference publications and news releases. EXPERT OPINION: LCA-RPE65 gene therapy is an example of successful, innovative, translational research. Further research is needed regarding how retinal gene therapy can be improved.

Ocular gene therapy: an evaluation of recombinant adeno-associated virus-mediated gene therapy interventions for the treatment of ocular disease.

Both gene replacement therapy and alteration of host gene expression are playing increasingly important roles in the treatment of ocular diseases. Ocular gene therapy may provide alternatives to current treatments for eye diseases that are either greatly invasive and thus run the risk of complications, that offer only short-term relief from disease symptoms, or that are unable to directly treat vision loss. The success of three separate phase I clinical trials investigating a gene therapy intervention for the treatment of the retinal degenerative disorder Leber's congenital amaurosis (LCA) has unveiled the therapeutic potential of gene therapy. Preliminary results have demonstrated ocular gene transfer, using nonpathogenic recombinant adeno-associated viral (rAAV) vectors specifically, to be a safe, effective, and long-term treatment for LCA, a previously untreatable disorder. Nonpathogenic rAAV vectors offer the potential for long-term treatment. Many of the genes implicated in human ocular diseases have been identified, and animal models for such diseases have been developed, which have greatly facilitated the application of experimental rAAV-mediated gene therapy. This review highlights the key features of rAAV-mediated gene therapy that make it the most suitable gene therapy treatment approach for ocular diseases. Furthermore, it summarizes the current progress of rAAV-mediated gene therapy interventions/applications for a wide variety of ophthalmologic disorders.