Vitamin D (VitD) deficiency is associated with brain structural abnormalities, cognitive decline, and incident dementia.
To assess associations between VitD status and trajectories of change in ...subdomains of cognitive function in a cohort of ethnically diverse older adults.
Longitudinal multiethnic cohort study of 382 participants in an outpatient clinic enrolled between February 2002 and August 2010 with baseline assessment and yearly follow-up visits. Serum 25-hydroxyvitamin D (25-OHD) was measured, with VitD status defined as the following: deficient, less than 12 ng/mL (to convert to nanomoles per liter, multiply by 2.496); insufficient, 12 to less than 20 ng/mL; adequate, 20 to less than 50 ng/mL; or high, 50 ng/mL or higher. Subdomains of cognitive function were assessed using the Spanish and English Neuropsychological Assessment Scales. Associations were evaluated between 25-OHD levels (as continuous and categorical deficient, insufficient, or adequate) and trajectories of cognitive decline.
Serum 25-OHD levels, cognitive function, and associations between 25-OHD levels and trajectories of cognitive decline.
Participants (N = 382 at baseline) had a mean (SD) age of 75.5 (7.0) years; 61.8% were women; and 41.4% were white, 29.6% African American, 25.1% Hispanic, and 3.9% other race/ethnicity. Diagnosis at enrollment included 17.5% with dementia, 32.7% with mild cognitive impairment, and 49.5% cognitively normal. The mean (SD) 25-OHD level was 19.2 (11.7) ng/mL, with 26.2% of participants being VitD deficient and 35.1% insufficient. The mean (SD) 25-OHD levels were significantly lower for African American and Hispanic participants compared with white participants (17.9 15.8 and 17.2 8.4 vs 21.7 10.0 ng/mL, respectively; P < .001 for both). The mean (SD) 25-OHD levels were similarly lower in the dementia group compared with the mild cognitive impairment and cognitively normal groups (16.2 9.4 vs 20.0 10.3 and 19.7 13.1 ng/mL, respectively; P = .006). The mean (SD) follow-up was 4.8 (2.5) years. Rates of decline in episodic memory and executive function among VitD-deficient (episodic memory: β = -0.04 SE = 0.02, P = .049; executive function: β = -0.05 SE = 0.02, P = .01) and VitD-insufficient (episodic memory: β = -0.06 SE = 0.02, P < .001; executive function: β = -0.04 SE = 0.02, P = .008) participants were greater than those with adequate status after controlling for age, sex, education, ethnicity, body mass index, season of blood draw, vascular risk, and apolipoprotein E4 genotype. Vitamin D status was not significantly associated with decline in semantic memory or visuospatial ability. Exclusion of participants with dementia did not substantially affect the associations between VitD status and rates of cognitive decline.
Low VitD status was associated with accelerated decline in cognitive function domains in ethnically diverse older adults, including African American and Hispanic individuals who exhibited a high prevalence of VitD insufficiency or deficiency. It remains to be determined whether VitD supplementation slows cognitive decline.
Current medical countermeasures for organophosphate (OP)-induced status epilepticus (SE) are not effective in preventing long-term morbidity and there is an urgent need for improved therapies. Rat ...models of acute intoxication with the OP, diisopropylfluorophosphate (DFP), are increasingly being used to evaluate therapeutic candidates for efficacy in mitigating the long-term neurologic effects associated with OP-induced SE. Many of these therapeutic candidates target neuroinflammation and oxidative stress because of their implication in the pathogenesis of persistent neurologic deficits associated with OP-induced SE. Critical to these efforts is the rigorous characterization of the rat DFP model with respect to outcomes associated with acute OP intoxication in humans, which include long-term electroencephalographic, neurobehavioral, and neuropathologic effects, and their temporal relationship to neuroinflammation and oxidative stress. To address these needs, we examined a range of outcomes at later times post-exposure than have previously been reported for this model. Adult male Sprague-Dawley rats were given pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), which was immediately followed by atropine sulfate (2 mg/kg, im) and pralidoxime (25 mg/kg, im). This exposure paradigm triggered robust electroencephalographic and behavioral seizures that rapidly progressed to SE lasting several hours in 90% of exposed animals. Animals that survived DFP-induced SE (~70%) exhibited spontaneous recurrent seizures and hyperreactive responses to tactile stimuli over the first 2 months post-exposure. Performance in the elevated plus maze, open field, and Pavlovian fear conditioning tests indicated that acute DFP intoxication reduced anxiety-like behavior and impaired learning and memory at 1 and 2 months post-exposure in the absence of effects on general locomotor behavior. Immunohistochemical analyses revealed significantly increased expression of biomarkers of reactive astrogliosis, microglial activation and oxidative stress in multiple brain regions at 1 and 2 months post-DFP, although there was significant spatiotemporal heterogeneity across these endpoints. Collectively, these data largely support the relevance of the rat model of acute DFP intoxication as a model for acute OP intoxication in the human, and support the hypothesis that neuroinflammation and/or oxidative stress represent potential therapeutic targets for mitigating the long-term neurologic sequelae of acute OP intoxication.
The western blacklegged tick, Ixodes pacificus, an important vector in the western United States of two zoonotic spirochetes: Borrelia burgdorferi (also called Borreliella burgdorferi), causing Lyme ...disease, and Borrelia miyamotoi, causing a relapsing fever-type illness. Human cases of Lyme disease are well-documented in California, with increased risk in the north coastal areas and western slopes of the Sierra Nevada range. Despite the established presence of B. miyamotoi in the human-biting I. pacificus tick in California, clinical cases with this spirochete have not been well studied. To assess exposure to B. burgdorferi and B. miyamotoi in California, and to address the hypothesis that B. miyamotoi exposure in humans is similar in geographic range to B. burgdorferi, 1,700 blood donor sera from California were tested for antibodies to both pathogens. Sampling was from high endemic and low endemic counties for Lyme disease in California. All sera were screened using the C6 ELISA. All C6 positive and equivocal samples and nine randomly chosen C6 negative samples were further analyzed for B. burgdorferi antibody using IgG western blot and a modified two ELISA test system and for B. miyamotoi antibody using the GlpQ ELISA and B. miyamotoi whole cell sonicate western blot. Of the 1,700 samples tested in series, eight tested positive for antibodies to B. burgdorferi (0.47%, Exact 95% CI: 0.20, 0.93) and two tested positive for antibodies to B. miyamotoi (0.12%, Exact 95% CI: 0.01, 0.42). There was no statistically significant difference in seroprevalence for either pathogen between high and low Lyme disease endemic counties. Our results confirm a low frequency of Lyme disease and an even lower frequency of B. miyamotoi exposure among adult blood donors in California; however, our findings reinforce public health messaging that there is risk of infection by these emerging diseases in the state.
Many adults accumulate considerable time in screen-based behaviours, some of which have been associated with negative physical and psychological health outcomes. The aims of this study were to ...characterise contemporary patterns of screen-based behaviours and describe their temporal trends by global region, age, sex and education. Data covering the period 2012–2019 were obtained in aggregated form from GWI (previously known as Global Web Index), a global market research company. Temporal trends in the duration of adults' (16–64 years) self-reported personal computer, laptop and tablet use, mobile phone use, broadcast television viewing, online television viewing and games console use were described using data from over 2 million participants from 46 countries. For each activity, participants selected from response options ranging from less than 30 min to more than 10 h. Internationally, daily screen time increased from approximately 9 h in 2012 to 11 h in 2019, with notable increases in mobile phone use (approx. 2 h), online television viewing (approx. 37 min) and games console use (approx. 26 min). Differences were seen in the duration of time spent engaging in screen-based behaviours across regions and between socio-demographic groups, with Latin America, the Middle East and Africa and younger age groups seeing greater increases in overall screen time. The findings have important implications for health behaviour surveillance and for research exploring the links between screen-based behaviours and health.
•Daily screen time increased between 2012 and 2019 particularly in Latin America.•Screen use was highest in 16–24 and 25–34 age groups across all survey years.•Traditional TV viewing has decreased while mobile phone use has increased.•Industry data on technology use can provide insights for public health research.
We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD and LOAD).
Plasma was ...analyzed using ultra-sensitive immuno-based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults.
Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL-6, IP-10, IL-10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age.
Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD.
•Plasma biomarkers offer a noninvasive means of studying pathological differences in Alzheimer's disease (AD).•Plasma markers of neuronal injury, astrocytic activation, systemic inflammation, and cellular plasticity were quantified in EOAD and LOAD.•Markers of neuronal injury and astrocytic activation were elevated in AD groups in comparison with controls, with larger effect sizes in EOAD.•Markers of cellular plasticity were elevated in AD and especially associated with functional decline in EOAD.•Systemic inflammation correlated with age across groups, reflecting the well-described phenomenon of age-associated sterile chronic inflammation.
Abstract The Functional Activities Questionnaire (FAQ) and Alzheimer's Disease Assessment Scale—cognitive subscale (ADAS-cog) are frequently used indices of cognitive decline in Alzheimer's disease ...(AD). The goal of this study was to compare FDG-PET and clinical measurements in a large sample of elderly subjects with memory disturbance. We examined relationships between glucose metabolism in FDG-PET regions of interest (FDG-ROIs), and ADAS-cog and FAQ scores in AD and mild cognitive impairment (MCI) patients enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Low glucose metabolism at baseline predicted subsequent ADAS-cog and FAQ decline. In addition, longitudinal glucose metabolism decline was associated with concurrent ADAS-cog and FAQ decline. Finally, a power analysis revealed that FDG-ROI values have greater statistical power than ADAS-cog to detect attenuation of cognitive decline in AD and MCI patients. Glucose metabolism is a sensitive measure of change in cognition and functional ability in AD and MCI, and has value in predicting future cognitive decline.
Older adults with early forms of neurodegenerative disease are at risk for functional disability, which is often defined by the loss of independence in instrumental activities of daily living ...(IADLs). The current study investigated the influence of mild changes in everyday functional abilities (referred to as functional limitations) on risk for development of incident functional disability. A total of 407 participants, who were considered cognitively normal or diagnosed with mild cognitive impairment (MCI) at baseline, were followed longitudinally over an average 4.1 years (range=0.8-9.2 years). Informant-based ratings from the Everyday Cognition (ECog; Farias et al., 2008) and the Instrumental Activities of Daily Living (Lawton & Brody, 1969) scales assessed the degree of functional limitations and incident IADL disability, respectively. Cox proportional hazards models revealed that more severe functional limitations (as measured by the Total ECog score) at baseline were associated with approximately a four-fold increased risk of developing IADL disability a few years later. Among the ECog domains, functional limitations in Everyday Planning, Everyday Memory, and Everyday Visuospatial domains were associated with the greatest risk of incident functional disability. These results remained robust even after controlling for participants' neuropsychological functioning on tests of executive functions and episodic memory. Current findings indicate that early functional limitations have prognostic value in identifying older adults at risk for developing functional disability. Findings highlight the importance of developing interventions to support everyday abilities related to memory, executive function, and visuospatial skills in an effort to delay loss of independence in IADLs.
White matter hyperintensities (WMHs) are associated with progressive age-related cognitive decline and cardiovascular risk factors, but their biological relevance as indicators of generalized white ...matter injury is unclear. Diffusion tensor imaging provides more sensitive indications of subtle white matter disruption and can therefore clarify whether WMHs represent foci of generalized white matter damage that extends over a broader neighborhood.
Two hundred eight participants from the University of California, Davis Alzheimer's Disease Center received a comprehensive clinical evaluation and brain MRI including fluid-attenuated inversion recovery and diffusion tensor imaging sequences. Voxelwise maps of WMHs were produced from fluid-attenuated inversion recovery using a standardized WMH detection protocol. Fractional anisotropy maps were calculated from diffusion tensor imaging. All WMH and fractional anisotropy maps were coregistered to a standardized space. For each normal-appearing white matter voxel in each subject fluid-attenuated inversion recovery scan, a neighborhood white matter injury score was calculated that increased with increasing number and proximity of WMH in the vicinity of the normal-appearing white matter voxel. Fractional anisotropy was related to neighborhood white matter injury using a nonlinear mixed effect model controlling for relevant confounding factors.
Fractional anisotropy was found to decrease as neighborhood white matter injury increased (β = -0.0017/%, P < 0.0001) with an accelerated rate (P < 0.0001) for neighborhood white matter injury >0.4. An increase of 1% in neighborhood white matter injury score was associated with a decrease in mean fractional anisotropy of 0.012 (P < 0.001).
WMH may represent foci of more widespread and subtle white matter changes rather than distinct, sharply delineated anatomic abnormalities. We use the term white matter hyperintensities penumbra to explain this phenomenon.
Glycosylation has been found to be altered in the brains of individuals with Alzheimer's disease (AD). However, it is unknown which specific glycosylation-related pathways are altered in AD dementia. ...Using publicly available RNA-seq datasets covering seven brain regions and including 1724 samples, we identified glycosylation-related genes ubiquitously changed in individuals with AD. Several differentially expressed glycosyltransferases found by RNA-seq were confirmed by qPCR in a different set of human medial temporal cortex (MTC) samples (n = 20 AD vs. 20 controls). N-glycan-related changes predicted by expression changes in these glycosyltransferases were confirmed by mass spectrometry (MS)-based N-glycan analysis in the MTC (n = 9 AD vs. 6 controls). About 80% of glycosylation-related genes were differentially expressed in at least one brain region of AD participants (adjusted p-values < 0.05). Upregulation of MGAT1 and B4GALT1 involved in complex N-linked glycan formation and galactosylation, respectively, were reflected by increased concentrations of corresponding N-glycans. Isozyme-specific changes were observed in expression of the polypeptide N-acetylgalactosaminyltransferase (GALNT) family and the alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase (ST6GALNAC) family of enzymes. Several glycolipid-specific genes (UGT8, PIGM) were upregulated. The critical transcription factors regulating the expression of N-glycosylation and elongation genes were predicted and found to include STAT1 and HSF5. The miRNA predicted to be involved in regulating N-glycosylation and elongation glycosyltransferases were has-miR-1-3p and has-miR-16-5p, respectively. Our findings provide an overview of glycosylation pathways affected by AD and potential regulators of glycosyltransferase expression that deserve further validation and suggest that glycosylation changes occurring in the brains of AD dementia individuals are highly pathway-specific and unique to AD.
Background/Objectives
To examine the association between white matter hyperintensities (WMH) and cognitive domains such as memory and executive function (EF) across different clinical and biomarker ...categories of Alzheimer's disease (AD).
Design
Cross‐sectional study.
Setting
Alzheimer's Disease Neuroimaging Initiative.
Participants
A total of 216 cognitively normal (CN) participants and 407 participants with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) at baseline.
Measurements
Based on the 2018 research framework, participants were classified using AT(N) (amyloid‐β deposition A, pathologic tau T, and neurodegeneration (N)) biomarkers into one of three categories: biomarker negative A − T− (N)−, amyloid negative but other biomarker positive A − T ± (N)+ or A – T + (N)± or amyloid positive A + T ± (N)±. Linear regression models were then used to examine the association between WMH and memory composite scores and EF composite scores.
Results
Higher WMH burden was associated with worse EF in both CN and MCI subgroups while a significant association between WMH and memory was only found in the MCI subgroup. Furthermore, WMH was associated with EF in the group with A − T ± (N)+ or A – T + (N)± biomarker category, but not for A − T − (N)− (normal biomarker) and A + T ± (N) ± (AD pathology). The association between higher WMH and worse memory was independent of amyloid levels in individuals with MCI with evidence of AD pathology.
Conclusion
Vascular disease, as indexed by WMH, independent of AD pathology affects cognitive function in both CN and MCI subgroups. Future studies using the AT(N) research framework should consider white matter lesions as a key biomarker contributing to the clinical presentation of AD.
PDF
