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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: 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]

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]