Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aß phase = 0 (lacking detectable Aß plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

Cerebrospinal fluid dynamics and discordant amyloid biomarkers.

Do MRI-based metrics of a CSF-dynamics disorder, disproportionately enlarged subarachnoid-space hydrocephalus (DESH), correlate with discordant amyloid biomarkers (low CSF ß-amyloid 1-42, normal Aß-PET scan)? Individuals ≥50 years from the Mayo Clinic Study of Aging, with MRI, 11C-Pittsburgh compound B (Aß) PET scans, and CSF phosphorylated-tau protein and Aß42, were categorized into 4 groups: normal and/or abnormal by CSF ß-amyloid 1-42 and Aß amyloid PET. Within groups, we noted MRI patterns of CSF-dynamics disorders and Aß-PET accumulation-change rate. One-hundred participants (21%) in the abnormal-CSF and/or normal-PET group had highest DESH-pattern scores and lowest CSF-phosphorylated-tau levels. Among normal amyloid-PET individuals, a 1-unit DESH-pattern score increase correlated with 30%-greater odds of abnormal amyloid CSF after age, and sex adjustment. Mean rate over time of amyloid-PET accumulation in abnormal-CSF and/or normal-PET individuals approximated individuals with normal amyloid values. Adjusting for phosphorylated-tau, abnormal CSF-amyloid and/or normal amyloid-PET individuals had higher mean amyloid-PET accumulation rates than normal individuals. CSF dynamics disorders confound ß-amyloid and phosphorylated-tau CSF-biomarker interpretation.

Gait Speed and Instrumental Activities of Daily Living in Older Adults After Hospitalization: A Longitudinal Population-Based Study.

BACKGROUND: Hospitalization can impair physical and functional status of older adults, but it is unclear whether these deficits are transient or chronic. This study determined the association between hospitalization of older adults and changes in long-term longitudinal trajectories of 2 measures of physical and functional status: gait speed (GS) and instrumental activities of daily living measured with Functional Activities Questionnaire (FAQ). METHOD: Linear mixed-effects models assessed the association between hospitalization (nonelective vs elective, and surgical vs medical) and outcomes of GS and FAQ score in participants (older than 60 years) enrolled in the Mayo Clinic Study of Aging who had longitudinal assessments. RESULTS: Of 4902 participants, 1879 had ≥1 hospital admission. Median GS at enrollment was 1.1 m/s. The slope of the annual decline in GS before hospitalization was -0.015 m/s. The parameter estimate (95% CI) for additional annual change in GS trajectory after hospitalization was -0.009 (-0.011 to -0.006) m/s, p < .001. The accelerated GS decline was greater for medical versus surgical hospitalizations (-0.010 vs -0.003 m/s, p = .005), and nonelective versus elective hospitalizations (-0.011 vs -0.006 m/s, p = .067). The odds of a worsening FAQ score increased on average by 4% per year. Following hospitalization, odds of FAQ score worsening further increased (multiplicative annual increase in odds ratio per year [95% CI] following hospitalization was 1.05 [1.03, 1.07], p < .001). CONCLUSIONS: Hospitalization of older adults is associated with accelerated long-term decline in GS and functional limitations, especially after nonelective admissions and those for medical indications. However, for most well-functioning participants, these changes have little clinical significance.

Association of Hospitalization with Long-Term Cognitive Trajectories in Older Adults.

IMPORTANCE: Hospitalizations are associated with cognitive decline in older adults. OBJECTIVE: To determine the association between hospitalization characteristics and the trajectory of cognitive function in older adults. DESIGN: Population-based longitudinal study of cognitive aging. SETTING: Olmsted Medical Center and Mayo Clinic, the only centers in Olmsted County, Minnesota, with hospitalization capacity. PARTICIPANTS: Individuals without dementia at baseline, with consecutive cognitive assessments from 2004 through 2017, and at least one visit after the age of 60. MEASUREMENTS: The primary outcome was longitudinal changes in global cognitive z-score. Secondary outcomes were changes in four cognitive domains: memory, attention/executive function, language, and visuospatial skills. Hospitalization characteristics analyzed included elective versus nonelective, medical versus surgical, critical care versus no critical care admission, and long versus short duration admissions. RESULTS: Of 4,587 participants, 1,622 had 1 and more hospital admission. Before hospitalization, the average slope of the global z-score was -0.031 units/year. After hospitalization, the rate of annual global z-score accelerated by -0.051 (95% CI = -0.057, -0.045) units, P < .001, resulting in an estimated annual slope after the first hospitalization of -0.082. The accelerated decline was found in all four cognitive domains (memory, visuospatial, language, and executive, all P < .001). The acceleration of the decline in global z-score following hospitalization was greater for medical compared to surgical hospitalizations (slope change following hospitalization = -0.064 vs -0.034 for medical vs surgical, P < .001), and nonelective compared to elective admissions (slope change following hospitalization = -0.075 vs -0.037 for nonelective vs elective, P < .001). The acceleration of cognitive decline was not different for hospitalization with intensive care unit admission versus not. CONCLUSIONS: Hospitalization of older adults is associated with accelerated decline of global and domain-specific cognitive domains, with the rate of decline dependent upon type of admission. The clinical impact of this accelerated decline will depend on the individual's baseline cognitive reserve and expected longevity.

Exposure to surgery with general anaesthesia during adult life is not associated with increased brain amyloid deposition in older adults.

BACKGROUND: Exposure to surgery with general anaesthesia (surgery/GA) is associated with cortical atrophy, but the aetiology remains unknown. Amyloid-ß (Aß) deposition is one of the hallmark pathological characteristics of Alzheimer's disease (AD). We examined brain Aß burden in study participants exposed to surgery/GA. METHODS: We performed a cross-sectional analysis of residents of Olmsted County, MN, USA, in the Mayo Clinic Study of Aging who were aged 70-97 yr and underwent measurement of (i) brain Aß with Pittsburgh compound B positron emission tomography (PiB PET), (ii) brain glucose metabolism with 18-fluorodeoxyglucose (FDG) PET, and (iii) temporal cortical thickness with MRI. Separate analyses were performed with exposure to surgery/GA, defined as occurring after age 40 yr, and with exposure to surgery/GA, defined as occurring within 20 yr before neuroimaging. Imaging measurements were compared between participants who were exposed to surgery/GA vs not exposed. RESULTS: Of the 2563 participants, 585 had PET scans. Regardless of the definition used to quantify exposure, no significant associations were detected between exposure and either global PiB PET or FDG PET. In contrast, exposure to surgery/GA was associated with an increased likelihood of abnormal cortical thinning: odds ratio (OR)=1.98 (95% confidence interval [CI]: 1.19-3.31); P=0.010 in those exposed after age 40 yr, and OR=1.64 (95% CI: 1.05-2.55); P=0.029 in those exposed in the prior 20 yr. CONCLUSIONS: Exposure to surgery/GA is not associated with increases in cortical amyloid deposition. This finding suggests that the modest cortical thinning associated with surgery/GA is not related to AD pathology, but rather is caused by other processes.

Cognitive function after surgery with regional or general anesthesia: A population-based study.

INTRODUCTION: Our aim was to examine whether surgery with regional anesthesia (RA) is associated with accelerated long-term cognitive decline comparable with that previously reported after general anesthesia (GA). METHODS: Longitudinal cognitive function was analyzed in a cohort of 1819 older adults. Models assessed the rate of change in global and domain-specific cognition over time in participants exposed to RA or GA. RESULTS: When compared with those unexposed to anesthesia, the postoperative rate of change of the cognitive global z-score was greater in those exposed to both RA (difference in annual decline of -0.041, P = .011) and GA (-0.061, P < .001); these rates did not differ. In analysis of the domain-specific scores, an accelerated decline in memory was observed after GA (-0.065, P < .001) but not RA (-0.011, P = .565). CONCLUSIONS: Older adults undergoing surgery with RA experience decline of global cognition similar to those receiving GA; however, memory was not affected.

Population-Based Evaluation of Lumbar Puncture Opening Pressures.

Importance: Prior studies evaluating opening pressure (OP) have mostly involved lumbar puncture (LP) for diagnosis of neurologic disease or small cohorts of healthy volunteers and therefore the normal OP is not well-defined. Objective: The goal of this study was to establish the normal range of OP in a community-based population using the Mayo Clinic Study of Aging (MCSA) and to evaluate factors that contribute to OP variability. Design: LP OP were obtained from participants aged 32-95 years between 11/1/07 and 10/1/17, as part of routine data collection for the MCSA, a longitudinal, population-based study of residents of Olmsted County, Minnesota. Setting: A longitudinal, population-based study of residents of Olmsted County, Minnesota. Participants: There were 639 participants (56.8% male; 98.5% white) who underwent LP with recorded OP as part of the MCSA. Intervention: LP. Main Outcome(s) and Measure(s): LP OP was recorded along with variables that could possibly influence its variability, including age, body mass index (BMI), and obstructive sleep apnea (OSA). Results: Six hundred thirty-nine participants (56.8% men) underwent LP with recorded OP; average age was 71.0 years (SD 10.9) with a mean BMI of 28.0 (SD 4.6). Mean OP was 155.4 mmH2O (SD 41.9) with a 95% reference interval of 82-242 mmH2O (range 60-314; Q1, Q3: 124, 182). Increasing age was associated with lower OP (p < 0.001), while increasing BMI was associated with higher OP (p < 0.001). Twelve (2%) participants had OP ≥ 250 mmH2O; they were younger [58.5 (SD 8.2), p < 0.001], had higher BMI [33.6 (SD 4.6), p < 0.001], and were more likely to have OSA (75%, p < 0.001). Among the 79 participants with repeat LPs within 2.5 years, the coefficient of repeatability (CR) was 64.9. Ten (12.7%) had an OP difference ≥50 mmH2O between serial LPs. Conclusions and Relevance: This large population-based study showed that LP OP can vary significantly among individuals. Higher OPs were associated with higher BMI and younger age.

Chronic obstructive pulmonary disease and association with mild cognitive impairment: the Mayo Clinic Study of Aging.

OBJECTIVE: To investigate the association of chronic obstructive pulmonary disease (COPD) with mild cognitive impairment (MCI) and MCI subtype: amnestic MCI and nonamnestic MCI, in a population-based study of elderly patients. PATIENTS AND METHODS: Participants included 1927 individuals aged 70 to 89 years enrolled in the population-based Mayo Clinic Study of Aging. Participants were evaluated by using a nurse assessment, neurological evaluation, and neuropsychological testing, and the diagnosis of MCI was made by a consensus panel according to the standardized criteria. Chronic obstructive pulmonary disease was identified by the review of medical records. The study was conducted from October 1, 2004, through July 31, 2007. The associations of COPD and disease duration with MCI and its subtypes were evaluated by using logistic regression models adjusted for potential covariates. RESULTS: Of 1927 participants, 288 had COPD (men vs women: 18% vs 12%; P<.001). As compared with patients without COPD, patients with COPD had a higher prevalence of MCI (27% vs 15%; P<.001). The odds ratio (OR) for MCI was almost 2 times higher in patients with COPD than in those without (OR, 1.87; 95% CI, 1.34-2.61), with a similar effect in men and women. The OR for MCI increased from 1.60 (95% CI, 0.97-2.57) in patients with a COPD duration of 5 years or less to 2.10 (95% CI, 1.38-3.14) in patients with a COPD duration of more than 5 years. CONCLUSION: This population-based study suggests that COPD is associated with increased odds of having MCI and its subtypes. There was a dose-response relationship with the duration of COPD after controlling for the potential covariates.