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Objective: Seizure clusters require prompt medical treatment to minimize possible progression to status epilepticus, increased health care use, and disruptions to daily life. Isolated seizures may exhibit cyclical patterns, including circadian and longer rhythms. However, little is known about the cyclical patterns in seizure clusters. This post hoc analysis of data from a long‐term, phase 3, open‐label, repeat‐dose safety study of diazepam nasal spray modeled the periodicity of treated seizure clusters. Methods: Mixed‐effects cosinor analysis evaluated circadian rhythmicity, and single component cosinors using 12 and 24 h were used to calculate cosinor parameters (e.g., midline statistic of rhythm, wave ampitude, and acrophase [peak]). Analysis was completed for the full cohort and a consistent cohort of participants with two or more seizure clusters in each of four, 3‐month periods. The influence of epilepsy type on cosinor parameters was also analyzed. Results: Seizure‐cluster events plotted across 24 h showed a bimodal distribution with acrophases (peaks) at ~06:30 and ~18:30. A 12‐h plot showed a single peak at ~06:30. Cosinor analyses of the full and consistent cohort aligned, with acrophases for both models predicting peak seizure activity at ~23:30 on a 24‐h scale and ~07:30 on a 12‐h scale. The consistent cohort was associated with increases in baseline and peak seizure‐cluster activity. Analysis by epilepsy type identified distinct trends. Seizure clusters in the focal epilepsy group peaked in the evening (acrophase 19:19), whereas events in the generalized epilepsy group peaked in the morning (acrophase 04:46). Together they compose the bimodal clustering observed over 24 h. Significance: This analysis of seizure clusters treated with diazepam nasal spray demonstrated that seizure clusters occur cyclically in 12‐ and 24‐h time frames similar to that reported with isolated seizures. Further elucidation of these patterns may provide important information for patient care, ranging from improved patient‐centered outcomes to seizure‐cluster prediction. [ABSTRACT FROM AUTHOR]

Proteomic studies using postmortem human brain tissue samples have yielded robust assessments of the aging and neurodegenerative disease(s) proteomes. While these analyses provide lists of molecular alterations in human conditions, like Alzheimer's disease (AD), identifying individual proteins that affect biological processes remains a challenge. To complicate matters, protein targets may be highly understudied and have limited information on their function. To address these hurdles, we sought to establish a blueprint to aid selection and functional validation of targets from proteomic datasets. A cross-platform pipeline was engineered to focus on synaptic processes in the entorhinal cortex (EC) of human patients, including controls, preclinical AD, and AD cases. Label-free quantification mass spectrometry (MS) data (n=2260 proteins) was generated on synaptosome fractionated tissue from Brodmann area 28 (BA28; n=58 samples). In parallel, dendritic spine density and morphology was measured in the same individuals. Weighted gene co-expression network analysis was used to construct a network of protein co-expression modules that were correlated with dendritic spine metrics. Module-trait correlations were used to guide unbiased selection of Twinfilin-2 (TWF2), which was the top hub protein of a module that positively correlated with thin spine length. Using CRISPR-dCas9 activation strategies, we demonstrated that boosting endogenous TWF2 protein levels in primary hippocampal neurons increased thin spine length, thus providing experimental validation for the human network analysis. Collectively, this study describes alterations in dendritic spine density and morphology as well as synaptic proteins and phosphorylated tau from the entorhinal cortex of preclinical and advanced stage AD patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Vascular comorbidity (VC) is associated with multiple sclerosis (MS) disease progression and visual dysfunction. The longitudinal effect of VC in people with secondary progressive MS (SPMS) is unclear. This study explored the impact of VC on standard clinical, MRI, and visual outcomes in people with SPMS enrolled in a clinical trial. METHODS: Data were extracted from a 2-year randomized controlled trial (N = 51) testing the supplement lipoic acid in people with SPMS who underwent annual Expanded Disability Status Scales, Timed 25-Foot Walk tests, MRIs, visual acuity testing, and retinal nerve fiber layer (RNFL) and ganglion cell/inner plexiform layer (GCIPL) thicknesses per optical coherence tomography (OCT). Post hoc linear mixed-effects regression analysis compared baseline and annualized outcomes between participants without VC (VC-) and with 1 or more VCs (VC+) (hypertension, dyslipidemia, obesity, diabetes, peripheral or cardiovascular disease, tobacco use). RESULTS: The VC- (n = 19) and VC+ (n = 28) participants were similar in age, sex, and MS disease duration and had comparable MS disability, mobility, and brain atrophy at baseline and throughout the 2-year parent study. The VC+ participants had worse baseline visual acuity than those in the VC- group by 0.13 logMAR (P = .041). No significant differences were detected in RNFL or GCIPL baseline thickness or atrophy between groups. CONCLUSIONS: In an SPMS cohort, VC had an inconsistent effect on standard clinical, MRI, and exploratory OCT outcomes, suggesting that the effect of VC may not be evident in smaller cohort studies. Using a more refined definition of VC in future, adequately powered investigations may help effectively elucidate and account for the interaction between vascular risk burden and MS disability. [ABSTRACT FROM AUTHOR]

Background: Accurate longitudinal modelling of cognitive decline is a major goal of Alzheimer's disease and related dementia (ADRD) research. However, the impact of subject-specific effects is not well characterized and may have implications for data generation and prediction.Objective: This study seeks to address the impact of subject-specific effects, which are a less well-characterized aspect of ADRD cognitive decline, as measured by the Alzheimer's Disease Assessment Scale's Cognitive Subscale (ADAS-Cog).Methods: Prediction errors and biases for the ADAS-Cog subscale were evaluated when using only population-level effects, robust imputation of subject-specific effects using model covariances, and directly known individual-level effects fit during modelling as a natural control. Evaluated models included pre-specified parameterizations for clinical trial simulation, analogous mixed-effects regression models parameterized directly, and random forest ensemble models. Assessment used a meta-database of Alzheimer's disease studies with validation in simulated synthetic cohorts.Results: All models observed increases in variance under imputation leading to increased prediction error. Bias decreased with imputation except under the pre-specified parameterization, which increased in the meta-database, but was attenuated under simulation. Known fitted subject effects gave the best prediction results.Conclusion: Subject-specific effects were found to have a profound impact on predicting ADAS-Cog. Reductions in bias suggest imputing random effects assists in calculating results on average, as when simulating clinical trials. However, reduction in error emphasizes population-level effects when attempting to predict outcomes for individuals. Forecasting future observations greatly benefits from using known subject-specific effects. [ABSTRACT FROM AUTHOR]

Background: The Alabama Brief Cognitive Screener (ABCs) was developed as a nonproprietary replacement for the MMSE (Mini‐Mental State Examination) in order to screen for cognitive deficits. It requires 5‐10 minutes to complete and participants can score up to 30 points. Method: To assess the clinical correspondence of Alabama Brief Cognitive Screener (ABCs) scores relative to both the Montreal Cognitive Assessment (MoCA) and Dementia Rating Scale (DRS‐2) and also compare score differences by education attainment and the subject's clinical diagnosis‐ of either Normal Cognition (NC), Mild Cognitive Impairment (MCI), or Dementia. Participants from the UAB Alzheimer's Disease Center (ADC) from 2018 to 2022 were analyzed retrospectively. The ABCs, MoCA, and DRS‐2 were administered at the initial visit to subjects (n = 116) and their scores were compared to each other using Spearman's rank correlation along with their clinical diagnosis which included NC (n = 47), MCI (n = 41) and Dementia (n = 28) and their previous education using the Kruskal‐Wallis test. Result: Median scores for all three assessments were found to be associated with clinical diagnosis (MoCA: χ2 = 62.3, p = <.0001; ABCs: χ2 = 51.3, p = <.0001; DRS‐2: χ2 = 56.5, p = <.0001) and education level (MoCA: χ2 = 24.8 p = <.0001; ABCs: χ2 = 18.1, p = 0.0001; DRS‐2: χ2 = 11.15, p = 0.0038). Cognitive differences observed higher scores in the cognitively unimpaired relative to either MCI or subjects with dementia and in subjects with college or graduate degrees compared to those with only a high school education. Strong correspondence was observed between all assessments with significant correlations for all pairwise comparisons (MoCA v ABCs: ρ = 0.73; MoCA v DRS‐2: ρ = 0.72; ABCs v DRS‐2: ρ = 0.61, p = <.0001). When comparing sub‐types of the ABCs and DRS‐2, significant correlations were observed in the domains of memory (ρ = 0.61, p<0.001), attention (ρ = 0.26, p = 0.0054), construction (ρ = 0.37, p<0.001), and conceptualization (ρ = 0.30, p = 0.011). Conclusion: ABCs correlates proportionally with MoCA and DRS‐2 scores while also varying appropriately by diagnosis. ABCs shows promise as a non‐proprietary alternative to the MMSE for use as a screening instrument to identify and assess severity of cognitive deficits in medical practice, as well as measure progression of those deficits in patients with neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Background: African Americans are at increased risk for Alzheimer's disease (AD) but barriers to optimal clinical care are unclear.Objective: To comprehensively evaluate potential racial differences in the diagnosis and treatment of AD in an academic medical center.Methods: We used the clinical informatics tool, i2b2, to analyze all patient encounters for AD or mild cognitive impairment (MCI) in the University of Alabama at Birmingham Health System over a three-year period, examining neuroimaging rates and dementia-related medication use by race and clinic site using ratio tests on contingency tables of stratified patient counts.Results: Enterprise-wide, African Americans were not underrepresented among outpatients seen for AD/MCI. However, there were differences in the clinic setting where visits occurred, with African Americans overrepresented in Geriatrics and primary care clinics and underrepresented in Memory Disorders specialty clinics. There were no racial differences in the rates at which any clinic ordered PET neuroimaging tests or dementia-related medications. However, unsurprisingly, specialty clinics ordered both PET neuroimaging and dementia-related medications at a higher rate than primary care clinics, and overall across the medical enterprise, African Americans were statistically less likely to have PET neuroimaging or dementia-related medications ordered.Conclusion: African Americans with AD/MCI were not underrepresented at this academic medical center but were somewhat less likely to have PET neuroimaging or to be on dementia-related medications, potentially in part from underrepresentation in the specialty clinics where these orders are more likely. The reasons for this underrepresentation in specialty clinics are likely multifactorial and important to better understand. [ABSTRACT FROM AUTHOR]

Objective: The goal of this study was to investigate the effect of progranulin insufficiency on extracellular vesicles (EVs), a heterogeneous population of vesicles that may contribute to progression of neurodegenerative disease. Loss‐of‐function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD), and brains from GRN carriers with FTD (FTD‐GRN) exhibit signs of lysosomal dysfunction. Lysosomal dysfunction may induce compensatory increases in secretion of exosomes, EVs secreted from the endolysosomal system, so we hypothesized that progranulin insufficiency would increase EV levels in the brain. Methods: We analyzed levels and protein contents of brain EVs from Grn–/– mice, which model the lysosomal abnormalities of FTD‐GRN patients. We then measured brain EVs in FTD‐GRN patients. To assess the relationship of EVs with symptomatic disease, we measured plasma EVs in presymptomatic and symptomatic GRN mutation carriers. Results: Grn–/– mice had elevated brain EV levels and altered EV protein contents relative to wild‐type mice. These changes were age‐dependent, occurring only after the emergence of pathology in Grn–/– mice. FTD‐GRN patients (n = 13) had elevated brain EV levels relative to controls (n = 5). Symptomatic (n = 12), but not presymptomatic (n = 7), GRN carriers had elevated plasma EV levels relative to controls (n = 8). Interpretation: These data show that symptomatic FTD‐GRN patients have elevated levels of brain and plasma EVs, and that this effect is modeled in the brain of Grn–/– mice after the onset of pathology. This increase in EVs could influence FTD disease progression, and provides further support for EVs as potential FTD biomarkers. [ABSTRACT FROM AUTHOR]

Background Clinical practice for rehabilitation after mild traumatic brain injury (mTBI) is variable, and guidance on when to initiate physical therapy is lacking. Wearable sensor technology may aid clinical assessment, performance monitoring, and exercise adherence, potentially improving rehabilitation outcomes during unsupervised home exercise programs. Objective The objectives of this study were to: (1) determine whether initiating rehabilitation earlier than typical will improve outcomes after mTBI, and (2) examine whether using wearable sensors during a home-exercise program will improve outcomes in participants with mTBI. Design This was a randomized controlled trial. Setting This study will take place within an academic hospital setting at Oregon Health & Science University and Veterans Affairs Portland Health Care System, and in the home environment. Participants This study will include 160 individuals with mTBI. Intervention The early intervention group (n = 80) will receive one-on-one physical therapy 8 times over 6 weeks and complete daily home exercises. The standard care group (n = 80) will complete the same intervention after a 6- to 8-week wait period. One-half of each group will receive wearable sensors for therapist monitoring of patient adherence and quality of movements during their home exercise program. Measurements The primary outcome measure will be the Dizziness Handicap Inventory score. Secondary outcome measures will include symptomatology, static and dynamic postural control, central sensorimotor integration posturography, and vestibular-ocular-motor function. Limitations Potential limitations include variable onset of care, a wide range of ages, possible low adherence and/or withdrawal from the study in the standard of care group, and low Dizziness Handicap Inventory scores effecting ceiling for change after rehabilitation. Conclusions If initiating rehabilitation earlier improves primary and secondary outcomes post-mTBI, this could help shape current clinical care guidelines for rehabilitation. Additionally, using wearable sensors to monitor performance and adherence may improve home exercise outcomes. [ABSTRACT FROM AUTHOR]

Background: Cerebrovascular disease is a common cause of dementia in older adults, and potentially preventable with early intervention. Oxylipins are produced from the oxidation of long-chain polyunsaturated fatty acids (PUFA) possessing potent vascular effects. Oxylipins generated from the cytochrome P450 pathway are enzymatically converted to diols by soluble epoxide hydrolase (sEH); sEH products have been associated with small vessel ischemic disease. Little is known about oxylipins' impact on markers of dementia risk.Objective: An exploratory examination of the association between omega-6 and omega-3 derived oxylipins, brain MRI, and cognition.Methods: Thirty-seven non-demented participants with controlled hypertension (mean age 65.6 years) were enrolled in a dementia prevention study investigating fish oil and lipoic acid on preserving cognitive function. Baseline associations between plasma oxylipins, white matter hyperintensity (WMH), and Trails-B were examined using linear regression. P450-derived diol/epoxide ratio was an indirect measure of sEH activity.Results: Omega-6 derived 9-HODE was associated with increased WMH (p = 0.017) and reduced grey matter volume (p = 0.02). Omega-6 P450-derived diol/epoxide ratio 9,10-DiHOME/9,10-EpOME was associated with increased WMH (p = 0.035) and poorer performance on Trails-B (p = 0.05); ratio14,15-DHET/14,15-EET was associated with increased WMH (p = 0.045). Omega-3 P450-derived diol/epoxide ratio 19,20-DiHDPE/19,20-EpDPE was associated with increased WMH (p = 0.04) and poorer performance on Trails-B (p = 0.04). Arachidonic acid was associated with better performance on Trails-B (p = 0.012); Omega-3 derived 16,17-EpDPE was associated with decreased WMH (p = 0.005).Conclusions: With the exception of arachidonic acid, it was specific oxylipin products, not their parent PUFAs, that were associated with unfavorable and favorable MRI and cognitive markers of dementia risk. [ABSTRACT FROM AUTHOR]

Norepinephrine plays a major role in memory retrieval, when signaled through the beta1-adrenergic receptor in the hippocampus. The results of study on the above can be used in treatment of cardiac failure and neuropsychiatric disorders.

Background: Tools for efficient evaluation of amyloid- and tau-PET images are needed in both clinical and research settings.Objective: This study was designed to validate a semi-automated image analysis methodology, called Biomarker Localization, Analysis, Visualization, Extraction, and Registration (BLAzER). We tested BLAzER using two different segmentation platforms, FreeSurfer (FS) and Neuroreader (NR), for regional brain PET quantification in participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset.Methods: 127 amyloid-PET and 55 tau-PET studies with volumetric MRIs were obtained from ADNI. The BLAzER methodology utilizes segmentation of MR images by FS or NR, then visualizes and quantifies regional brain PET data using FDA-cleared software (MIM), enabling quality control to ensure optimal registration and to detect segmentation errors.Results: BLAzER analysis required ∼5 min plus segmentation time. BLAzER using FS segmentation showed strong agreement with ADNI for global amyloid-PET standardized uptake value ratios (SUVRs) (r = 0.9922, p < 0.001) and regional tau-PET SUVRs across all Braak staging regions (r > 0.97, p < 0.001) with high inter-operator reproducibility (ICC > 0.97) and nearly identical dichotomization as amyloid-positive or -negative (2 discrepant cases out of 127). Comparing FS versus NR segmentation with BLAzER, global SUVRs were strongly correlated for amyloid-PET (r = 0.9841, p < 0.001), but were systematically higher (4% on average) with NR, likely due to more inclusion of white matter with NR-defined regions.Conclusions: BLAzER provides an efficient methodology for regional brain PET quantification. FDA-cleared components and visualization of registration reduce barriers between research and clinical applications. [ABSTRACT FROM AUTHOR]

Background: Lipoic acid, an antioxidant, has beneficial effects in experimental acute optic neuritis and autoimmune encephalomyelitis. Optical coherence tomography can detect retinal nerve fiber layer thinning, representing axonal degeneration, approximately 3-6 months after acute optic neuritis. Objective: To determine whether lipoic acid is neuroprotective in acute optic neuritis. Methods: A single-center, double-blind, randomized, placebo controlled, 24-week trial. Intervention included 6 weeks of once daily lipoic acid (1200 mg) or placebo within 14 days of acute optic neuritis diagnosis. The primary outcome was the mean difference in affected eye retinal nerve fiber layer (RNFL) thickness from baseline to 24 weeks. Results: We enrolled 31 subjects (placebo n=16; lipoic acid n=15; average age 38.6 years (standard deviation (SD) 10.3)). Affected eye mean global RNFL thickness (μm) in the lipoic acid group decreased from 108.47 (SD 26.11) at baseline to 79.31 (SD 19.26) at 24 weeks. The affected eye RNFL in the placebo group decreased from 103.67 (SD 18.04) at baseline to 84.43 (SD 20.94) at 24 weeks. Unaffected eye RNFL thickness did not significantly change in either group over 24 weeks. Conclusion: Six weeks of oral lipoic acid supplementation after acute optic neuritis is safe and well tolerated; however, because of insufficient recruitment, we could not conclude that lipoic acid treatment was neuroprotective in acute optic neuritis. [ABSTRACT FROM AUTHOR]

Context: In longitudinal studies tracking recovery after concussion, researchers often have not considered the timing of return to play (RTP) as a factor in their designs, which can limit the understanding of how RTP may affect the analysis and resulting conclusions. Objective: To evaluate the recovery of balance and gait in concussed athletes using a novel linear mixed-model design that allows an inflection point to account for changes in trend that may occur after RTP. Design: Cohort study. Setting: University athletics departments, applied field setting. Patients or Other Participants: Twenty-three concussed (5 women, 18 men; age= 20.1 ± 1.3 years) and 25 healthy control (6 women, 19 men; age = 20.9 ± 1.4 years) participants were studied. Participants were referred by their team athletic trainers. Main Outcome Measure(s): Measures consisted of the Balance Error Scoring System (BESS) total score, sway (instrumented root mean square of mediolateral sway), singletask gait speed, gait speed while simultaneously reading a handheld article (dual-task gait speed), dual-task cost of reading on gait speed, and dual-task cost of walking on reading. Results: We observed no significant effects or interactions for the BESS. Instrumented sway was worse in concussed participants, and a change in the recovery trend occurred after RTP. We observed group and time effects and groupXtime and groupXRTP change interactions (P ≤ .046). No initial betweengroups differences were found for single-task or dual-task gait. Both groups increased gait speed initially and then leveled off after the average RTP date. We noted time and RTP change effects and positive groupXtime interactions for both conditions (P ≤ .042) and a groupXRTP change interaction for single-task gait speed (P =.005). No significant effects or interactions were present for the dual-task cost of reading on gait speed or the dual-task cost of walking on reading. Conclusions: Changes in the rate of recovery were coincident with the timing of RTP. Although we cannot suggest these changes were a result of the athletes returning to play, these findings demonstrate the need for further research to evaluate the effects of RTP on concussion recovery. [ABSTRACT FROM AUTHOR]

Background: Limited prospective information exists regarding spectral-domain optical coherence tomography (SD-OCT) in secondary progressive multiple sclerosis (SPMS). Objective: Document cross-sectional and longitudinal retinal nerve fiber layer (RNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) features of an SPMS clinical trial cohort. Methods: Prospective, observational study using a 2-year randomized placebo-controlled SPMS trial cohort with yearly SD-OCT testing. Post hoc analysis determined influences of optic neuritis (ON), disease duration, and baseline SD-OCT on annualized atrophy rates and on correlations between OCT and brain atrophy. Results: Mean RNFL and GCIPL values of patients (n = 47, mean age = 59 years, mean disease duration = 30 years) were significantly lower among eyes with prior ON than those without (no history of ON (NON)). Annualized RNFL (−0.31 µm/year) and GCIPL (−0.29 µm/year) atrophy rates did not differ between ON and NON eyes. Baseline RNFL thickness >75 µm was associated with greater annualized RNFL atrophy (−0.85 µm/year). Neither RNFL nor GCIPL atrophy correlated with whole-brain atrophy. Conclusion: This study suggests that eyes with and without ON history may be pooled for atrophy analysis in SPMS clinical trials using SD-OCT. Low baseline RNFL, small retinal atrophy rates, and lack of correlation with whole-brain atrophy in this population are important trial design considerations. [ABSTRACT FROM AUTHOR]

Background: Loss‐of‐function mutations in progranulin (GRN) are an autosomal dominant cause of frontotemporal dementia (FTD). Progranulin is critical for maintenance of lysosomal function. Patients with FTD due to GRN mutations (FTD‐GRN) exhibit signs of lysosomal dysfunction, which may contribute to FTD‐GRN pathogenesis. To assess the potential involvement of lysosomal dysfunction in FTD of sporadic origin, we investigated whether the lysosomal abnormalities of FTD‐GRN are also present in patients with sporadic frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP) type A, the same FTLD subtype found in patients with FTD‐GRN. Method: We used enzyme activity assays, western blot, immunostaining, and Nanostring analysis to assess changes in lysosomal protein and gene expression in orbital and occipital cortex of patients with FTD‐GRN, sporadic FTLD‐TDP type A, or controls. We measured lipofuscin using autofluorescence and staining with Sudan Black B. In follow‐up studies, we assessed these lysosomal markers in a transgenic mouse line expressing wild‐type human TDP‐43 under the Thy1 promoter. Result: We found similar lysosomal abnormalities in orbital cortex of patients with FTD‐GRN or sporadic FTLD‐TDP type A. Both FTD patient groups exhibited elevated levels of lysosomal enzymes and membrane proteins, higher expression of many lysosomal genes, and greater lipofuscin accumulation than controls. These changes were largely absent in occipital cortex from both groups. Analysis of frontal cortex from a transgenic mouse model of TDP‐opathy also revealed elevated levels of some lysosomal proteins and elevated lipofuscin levels. Conclusion: These studies indicate that the lysosomal abnormalities of patients with FTD‐GRN may be more closely associated with TDP‐opathy or neurodegeneration than with progranulin insufficiency. Orbital cortex, an affected brain region in FTD‐GRN, exhibited elevated lysosomal protein levels and lipofuscin accumulation, which were also found in patients with sporadic FTLD‐TDP type A. In contrast, the occipital cortex, a relatively spared brain region in FTD‐GRN, exhibited much milder lysosomal abnormalities. Future studies will assess signs of lysosomal dysfunction in patients with other classes of FTLD pathology to determine whether these changes are limited to patients with FTLD‐TDP or may be found throughout the FTLD spectrum. [ABSTRACT FROM AUTHOR]

Objectives: To explore if short term, high dose vitamin D supplementation is safe and improves balance in persons with Parkinson's disease (PD). Methods: A pilot randomized, double-blind intervention trial to measure the effects of 16 weeks of high dose vitamin D (10,000 IU/day) on balance as well as other motor and non-motor features of PD. We measured balance, gait, strength, falls, cognition, mood, PD severity, and quality of life before and after 16 weeks of high dose vitamin D supplementation or placebo. All participants also received 1000 mg calcium once daily. Results: Fifty-one randomized participants completed sixteen weeks of high dose vitamin D supplementation or placebo. The intervention resulted in a rise in serum concentrations of vitamin D (25-OH) (30.2 ng/ml to 61.1 ng/ml) and was well tolerated with no serious adverse events. Serum vitamin D (25-OH) levels rose steadily and did not suggest a leveling off at the end of the 16 weeks. There was not an improvement in the primary endpoint, balance as measured by the Sensory Organization Test (p = 0.43). A post hoc analysis examining treatment effects in younger (ages 52–66) versus older (ages 67–86) participants found a significant improvement in the SOT of 10.6 points in the younger half of the cohort (p = 0.012). Conclusions: Short term, high dose vitamin D supplementation appears safe in persons with PD, but did not significantly improve balance as measured with the Sensory Organization Test in this pilot study population. A post hoc analysis suggests that vitamin D may have potential for improving balance in a younger population with PD. High dose vitamin D supplementation in PD needs further study especially in light of new research suggesting that mega doses and even moderate doses (as low as 4000IU a day) may increase falls in an older populations. Trial registration: ClinicalTrials.gov: . [ABSTRACT FROM AUTHOR]

Abstract: Background: The goal of this study was to validate an objective method of measuring levodopa induced dyskinesia in Parkinson's disease (PD). Methods: To characterize agreement between the clinician‐based measure and a force plate, we assessed dyskinesia in PD subjects participating in a randomized and blinded clinical trial of an adenosine A2A anatagonist. Convergent validity and intra‐class correlations were evaluated between the objective force plate measure and clinician assessments. Results: All measures correlated across time and detected differences in treatments. Conclusion: Our results indicate that objective measure from a force plate is in scale agreement with clinical ratings of dyskinesia severity, indicating it as a reliable method to measure LID objectively but with greater resolution to detect changes in LID. [ABSTRACT FROM AUTHOR]

Introduction In preclinical studies, surgery/anesthesia contribute to cognitive decline and enhance neuropathologic changes underlying Alzheimer's disease (AD). Nevertheless, the link between surgery, anesthesia, apolipoprotein E ε4 ( APOE ε4), and AD remains unclear. Methods We performed a retrospective cohort analysis of two prospective longitudinal aging studies. Mixed-effects statistical models were used to assess the relationship between surgical/anesthetic exposure, the APOE genotype, and rate of change in measures of cognition, function, and brain volumes. Results The surgical group (n = 182) experienced a more rapid rate of deterioration compared with the nonsurgical group (n = 345) in several cognitive, functional, and brain magnetic resonance imaging measures. Furthermore, there was a significant synergistic effect of anesthesia/surgery exposure and presence of the APOE ε4 allele in the decline of multiple cognitive and functional measures. Discussion These data provide insight into the role of surgical exposure as a risk factor for cognitive and functional decline in older adults. [ABSTRACT FROM AUTHOR]

Background: Blood levels of marine n‐3 PUFA (20:5; 22:6) are inversely associated with cerebral white matter lesion volume (WML), suggesting that n‐3 may offer one approach to reduce this major vascular contributor to cognitive impairment and dementia. This trial determined whether n‐3 slows WML progression and sustains white matter integrity over 3‐years in older non‐demented adults with suboptimum n‐3 status and WML (NCT01953705). Methods: Double‐blind, placebo‐controlled trial in non‐demented adults age 75 and older with plasma omega‐3 (20:5 + 22:6) < 110 ug/mL and total WML ≥ 5 cm3. Participants were randomized to 1.65 g of n‐3 (975 mg‐20:5, 675 mg‐22:6) or placebo. Primary outcome was the annual WML progression with biomarker‐based ITT, per‐protocol (PP) and APOE4 stratified analysis. Total brain, medial temporal lobe, and diffusion tensor imaging (DTI) of white matter integrity were secondary outcomes. Linear mixed‐effects models were used. Result: 102 participants randomized (51 per group; mean age 81; 60% female, 28% APOE4+), 78 completed 3‐year visit (39 per group). Under mITT, annual WML change was 1.34 cm3 (95%CI: 0.80‐1.88) vs. 1.19 (0.64‐1.74) (p = 0.303) and annual DTI fractional anisotropy (FA) change was ‐0.002718 vs ‐0.001352 (p = 0.069) in the placebo and active, respectively. PPA comparing participants with study exit plasma omega‐3 ≤ 110 ug/mL vs above this threshold exhibited WML change of 1.71 cm3 vs. 0.99 (p = 0.026) and DTI radial diffusivity change of 5.412e06 mm2/sec vs. 3.143e06 (p = 0.047). No effects on WML were observed by APOE genotype (e4 p = 0.196; non‐carriers p = 0.785), however, e4 carriers on placebo had annual DTI FA change of ‐0.005 vs. ‐0.002 in the active arm (p = 0.037). Conclusion: Omega‐3 did not slow total WML progression in all randomized participants; however, those that superseded the plasma n‐3 threshold established in preliminary studies (110 ug/mL) had 50% and 43% reduction in annual WML and annual DTI RD progression, respectively. These results highlight responders and macro‐and microscopic structural features sensitive to omega‐3 that warrant more extensive studies powered to detect cognitive effects and dementia incidence. NIH‐National Institute on Aging R01 AG043398 (GLB). [ABSTRACT FROM AUTHOR]

Background: The n‐3 PUFA may modulate risk for age‐related cognitive impairment through vascular mechanisms. MRI derived cerebral white matter hyperintensities (WMH) presumptively reflect small vessel disease and their accumulation increases risk for age‐related cognitive decline and dementia. Blood n‐3 PUFA are consistently associated with reduced WMH and stroke. The primary aim here was to evaluate n‐3 PUFA supplementation on WMH accumulation over 3 years in an older population with evidence of WMH and absence of n‐3 PUFA supplementation. Methods: The study was a double‐blind, placebo‐controlled trial, with participants randomized to a daily dose of fish oil (1650 mg combined eicosapentaenoic acid‐EPA and docosahexaenoic acid‐DHA) or placebo oil (soybean) for a 3‐year intervention. Main inclusion criteria were: non‐demented (MMSE > 24), age > 74 years, WMH volume > 5.0 cc, and plasma n‐3 PUFA (EPA+DHA) < 110 umol/L (or < 5.5 percent of total fatty acids). The primary endpoint was 3‐year change in total WMH volume. Secondary endpoints include changes in regional brain volumes and white matter integrity. Exploratory endpoints include measures of cerebral blood flow, domain‐specific and global cognitive measures with subgroup analyses by APOE4 genotype. A linear mixed‐effects model was used to assess the outcomes. Results: 102 subjects were enrolled (mean age 81±4.4, MMSE 27.8±1.7; 60% female, 27.5% APOE4 positive) and a total of 78 participants completed the trial. Supplementation had no beneficial effect on rate of WMH progression, which increased by a mean of 1.07 cc per year in the n‐3 PUFA group vs 1.12 cc per year in the placebo group (p = 0.30 for time*trial arm interaction). Three‐year changes in executive cognitive function z‐scores were not different between treatment groups (p = 0.24). No differences in adverse events between groups were observed. Conclusion: N‐3 PUFA compared with placebo, failed to slow 3‐year WMH accumulation and executive function decline in older non‐demented adults presenting with evidence of WMH. N‐3 PUFA at the 1.65‐gram dose appears safe in older adults over 3‐years. Additional MRI and cognitive outcomes with detailed safety profiles are planned for presentation. [ABSTRACT FROM AUTHOR]

Background: Individuals with AD may be healthier than the general older adult population. Clinical trials for AD have been known to enroll individuals who are not representative of the general population, but it is unclear to what extent comorbidity affects cognitive outcomes in clinical trials. Methods: We included 10 studies with 4,002 subjects with AD from our meta‐database of 18 ADCS studies and ADNI. Comorbidity was measured using the RxRisk‐V, which provides a count of the total number of comorbid conditions based on medication data. Cognition was measured using the Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog). We used linear mixed effects models to examine the rate of cognitive decline by total comorbidity count, by individual disorders, and by presence of hypertension plus diabetes as known AD risk factors. Results: Across all participants, the mean RxRisk comorbidity score was 1.90 (SD 2.04). Approximately 27% had 0 comorbidities, 27% had 1 comorbidity, and 46% had 2+ comorbidities. Across all studies, for each additional comorbidity, the rate of progression on the ADAS‐cog increased by 0.11 point/year (95% CI ‐0.05, 0.26), reflecting a non‐significant worsening of cognition (Figure). After adjusting for other comorbidities, the rate of progression was not significant for congestive heart failure (‐0.5 point/year, 95% CI ‐1.3, 0.3), COPD (‐0.1 point/year, 95% CI ‐1.6, 1.3), diabetes (‐1.2 point/year, 95% CI ‐2.5, 0.1), hypertension (0.7 point/year, 95% CI ‐0.1, 1.6), or ischemic heart disease (‐0.3 point/year, 95% ‐0.9, 0.4). The rate of progression was also not significant for the combination of hypertension plus diabetes (0.1 point/year, 95% ‐0.7, 0.9). Conclusions: Comorbidity did not have a significant effect on rate of cognitive decline across AD clinical trials. As several comorbidities are known to affect the rate of AD progression, these findings suggest that AD clinical trials enroll participants with less severe comorbidities that do not affect cognitive decline. Further study of the effects of comorbidities on AD clinical trial outcomes are warranted, particularly study of severity of comorbidities. [ABSTRACT FROM AUTHOR]

Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer's disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ − 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW's impact on amyloid-β plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition. [ABSTRACT FROM AUTHOR]

Vascular risk factors for age-related cognitive decline are significant, and their management may ultimately prove the most successful strategy for reducing risk and sustaining cognitive health. This randomized, double-blinded, placebo-controlled trial with parallel group allocation to either marine n-3 polyunsaturated fatty acids (n-3 PUFA) or soybean oil placebo assesses the effects on the total volume of accumulation in cerebral white matter hyperintensities (WMH), a potentially modifiable neurovascular component of age-related cognitive decline. Total WMH accumulation over 3 years is the primary endpoint. The safety and efficacy of n-3 PUFA is evaluated in older adults with significant WMH and suboptimum plasma n-3 PUFA as inclusion criteria. One hundred and two non-demented older adults were enrolled with a mean age of 81.1 (±4.4) years, WMH of 19.4 (±16.1) cm3, and a plasma n-3 PUFA of 86.64 (±29.21) µg/mL. 61% were female, 28% were apolipoprotein E epsilon 4 carriers, and the mean mini-mental state exam (MMSE) was 27.9 (±1.7). This trial provides an initial evaluation of n-3 PUFA effects on WMH, a reproducible and valid risk biomarker for cognitive decline, as well as on inflammatory biomarkers thought to play a role in WMH accumulation. We present the baseline results and operational experience of enriching a study population on advanced age, blood n-3 PUFA, and magnetic resonance imaging (MRI) derived WMH with biomarker outcomes (WMH, inflammation markers) in a dementia prevention paradigm. [ABSTRACT FROM AUTHOR]

Highlights • Epilepsy, but not onchocerciasis (OC), is associated with cognition deficits. • OC, but not epilepsy, is associated with severe stunting in OC endemic areas. • Future studies should consider the immunomodulatory effects of OC on epilepsy risk. Abstract Increased epilepsy prevalence is reported in onchocerciasis (OC) endemic areas and is associated with the occurrence of distinct syndromes such as nodding disease and Nakalanga syndrome. To date, a causal relationship between OC and epilepsy is still a matter of controversy. We conducted a case-control study of participants with epilepsy and age- and gender-matched presumably healthy controls to elucidate the relationships between OC and epilepsy and explore the role of inflammation and growth factors in an OC endemic area in the Democratic Republic of Congo (DRC). Eighty-two participants with epilepsy (mean age ± SD: 23.2 ± 8.7 years) and 27 controls (mean age ± SD: 22.3 ± 12.0 years) underwent snip skin biopsies to determine Onchocerca volvulus infection status. Serum concentrations of cytokines, chemokines, and growth factors were measured using a Luminex Multiplex Assay kit. Children <19 years of age underwent neurocognitive assessments using the Kaufman Assessment Battery for Children, 2nd edition (KABC-II). Overall, epilepsy was associated with OC (OR = 4.51, z = 3.11, p = 0.0019), and children with OC were more likely to be severely stunted (OR = 11.67, z = 2.62, p = 0.0087). The relationship between epilepsy and OC was no longer significant (z = 1.27, p = 0.20) when stunting was included as a correcting covariate. Epilepsy was associated with poor KABC-II test scores, high serum levels of IL-17, and low levels of IL-1RA, IL-8, and EGF. KABC-II testing scores correlated with serum levels of IL-10, MCP-1 and HGF. Familial history of epilepsy occurred frequently. Future studies should consider cytokines and/or growth factors when assessing susceptibility to epilepsy in OC endemic areas. Additional investigations, preferentially in low-prevalence OC areas, may provide further insights into the concept, risk, and burden of river epilepsy. [ABSTRACT FROM AUTHOR]