Neuropathologic changes at age 90+ related to sleep duration 19 to 40 years earlier: The 90+ Study.

INTRODUCTION: We investigated the association between sleep duration and neuropathologic changes 19 to 40 years later in oldest-old (age 90+) participants of The 90+ Study. METHODS: Participants self-reported sleep duration and underwent neuropathologic evaluation. We categorized sleep duration as < 7, 7 to 8 = reference, > 8 hours and dichotomized neuropathologic changes as present/absent. We estimated odds ratio (OR) and 95% confidence intervals (CI) using logistic regression. RESULTS: In 264 participants, mean age at sleep self-report was 69 years, mean age at autopsy was 98 years, and mean interval between sleep self-report and autopsy was 29 years (range: 19-40). Those reporting > 8 hours of sleep had lower likelihood of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) inclusions (OR = 0.18; CI = 0.04-0.82) and amyloid beta deposits (OR = 0.34; 95% CI = 0.12-0.94). DISCUSSION: Long self-reported sleep is associated with lower odds of neurodegenerative neuropathologic changes 19 to 40 years later in the oldest-old, suggesting a potential role of sleep in accumulation of dementia-related neuropathologies. HIGHLIGHTS: Association of self-reported sleep with non-Alzheimer's disease neuropathologic changes has not been explored. Whether sleep duration is related to dementia neuropathologic changes decades later is unclear. Long self-reported sleep is associated with lower odds of Alzheimer's disease neuropathologic change 19 to 40 years later in the oldest-old. Long self-reported sleep is associated with lower odds of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change 19 to 40 years later in the oldest-old.

Follow-up care compliance among patients diagnosed with unruptured intracranial aneurysms.

OBJECTIVES: Periodic imaging follow-up for patients with unruptured intracranial aneurysms (UIA) is crucial, as studies indicate higher rupture risk with aneurysm growth. However, few studies address patient adherence to follow-up recommendations. This study aims to identify compliance rates and factors influencing follow-up adherence. METHODS: Patients with a UIA were identified from our institution's database from 2011-2021. Follow-up imaging (CT/MR Angiogram) was advised at specific intervals. Patients were categorized into compliant and non-compliant groups based on first-year compliance. Factors contributing to compliance were assessed through multivariate logistic regression. Phone interviews were conducted with non-compliant patients to understand reasons for non-adherence. RESULTS: Among 923 UIA diagnosed patients, 337 were randomly selected for analysis. The median follow-up period was 1.4 years, with a 42% first-year compliance rate. The mean aneurysm size was 3.3 mm. Five patients had a rupture during follow-up, of which 4 died. Compared with patients consulting specialists at the initial diagnosis, those seen by non-specialists exhibited lower compliance (OR 0.25, p < 0.001). Loss to follow-up was greatest during transition from emergency service to specialist appointments. Patients who spoke languages other than English exhibited poorer compliance than those speaking English (OR 0.20, p = 0.01). CONCLUSIONS: Significant amounts of UIA patients at low rupture risk were lost to follow-up before seeing UIA specialists. Main non-compliance factors include inadequate comprehension of follow-up instructions, poor care transfer from non-specialists to specialist, and insurance barriers.

Chronic kidney disease promotes cerebral microhemorrhage formation.

BACKGROUND: Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD. METHODS: CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier. RESULTS: CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels (p < 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r = 0.37, p < 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% (p < 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood-brain barrier (BBB) by 34% (p < 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) (p < 0.01) and increased sodium fluorescein permeability (p < 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group (p < 0.0001). CONCLUSIONS: CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease.

Alzheimer's Disease Neuropathologic Change and Vitamin Supplement Use Decades Earlier: The 90+ Study.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. AD neuropathologic change (ADNC) likely begins decades before clinical manifestations. One mechanism implicated in AD is oxidative stress. We explored the potential association of ADNC with antioxidant vitamin supplements taken about 30 years before death. METHODS: The 264 brain-autopsied participants were part of The 90+ Study, a longitudinal study of aging among people aged 90+ years, and originally members of the Leisure World Cohort Study, a population-based health study established in the 1980s. Intake of supplemental vitamins A, C, and E was collected by the Leisure World Cohort Study about 30 years before ADNC assessment. Odds ratios of ADNC (intermediate/high vs. none/low) for vitamin intake were estimated using logistic regression. RESULTS: The adjusted odds ratio (95% CI) of ADNC was 0.52 (0.29-0.92) for vitamin E supplements and 0.51 (0.27-0.93) for vitamin C supplements. Supplemental vitamin E intake was the first variable, after education, to enter the stepwise model. Intake of vitamin A or C did not improve the model fit. CONCLUSIONS: The observed association of ADNC and supplemental vitamin E intake decades earlier suggests a beneficial effect and supports further investigation into a nutritional approach to preventing AD with vitamin supplementation.

Self-reported sleep in relation to risk of dementia a quarter of a century later at age 90+: The 90+ Study.

OBJECTIVE: To examine sex-specific associations of sleep duration and napping self-reported at mean age of 69 years (range: 53-81) with risk of incident dementia 24 years later at age 90 +. METHOD: Analytic sample included individuals from a population-based study who reported sleep and napping once in the 1980s and 24 years later (range: 16-38) joined The 90+ Study and were evaluated in-person. Those without dementia at baseline of The 90+ Study were prospectively followed. Hazard ratios [HR] and 95% confidence intervals [CI] of dementia risk were estimated by Cox regression. RESULTS: Of 574 participants 71% were women, mean age at start of dementia follow-up with The 90+ Study was 93 years (range: 90-102). After 3.3 years (range: 0.4-13.8) of follow-up 47% developed dementia. Higher risk of dementia at age 90+ was seen in women with <6 hours of self-reported sleep per night (adjusted HR = 2.00; 95% CI = 1.15-3.50; p = .01) compared with 8 hours. Lower risk of dementia at 90+ was seen in men with short-to-moderate (<60 minutes) self-reported naps compared with no naps (HR = 0.33; 95% CI = 0.18-0.63; p < .01). CONCLUSIONS: Sleep and nap 24 years earlier are important risk factors for dementia after age 90.

Study of neuropathological changes and dementia in 100 centenarians in The 90+ Study.

INTRODUCTION: The association between neuropathological changes and dementia among centenarians and nonagenarians remains unclear. METHODS: We examined brain tissue from 100 centenarians and 297 nonagenarians from The 90+ Study, a community-based longitudinal study of aging. We determined the prevalence of 10 neuropathological changes and compared their associations with dementia and cognitive performance between centenarians and nonagenarians. RESULTS: A total of 59% of centenarians and 47% of nonagenarians had at least four neuropathological changes. In centenarians, neuropathological changes were associated with higher odds of dementia and, compared to nonagenarians, the odds were not attenuated. For each additional neuropathological change, the Mini-Mental State Examination score was lower by 2 points for both groups. DISCUSSION: Neuropathological changes continue to be strongly related to dementia in centenarians, highlighting the importance of slowing or preventing the development of multiple neuropathological changes in the aging brain to maintain cognitive health. HIGHLIGHTS: Individual and multiple neuropathological changes are frequent in centenarians. These neuropathological changes are strongly associated with dementia. There is no attenuation of this association with age.

Neuropsychological Test Norms in Cognitively Intact Oldest-Old.

OBJECTIVES: Individuals aged 90 or older (oldest-old), the fastest growing segment of the population, are at increased risk of developing cognitive impairment compared with younger old. Neuropsychological evaluation of the oldest-old is important yet challenging in part because of the scarcity of test norms for this group. We provide neuropsychological test norms for cognitively intact oldest-old. METHODS: Test norms were derived from 403 cognitively intact participants of The 90+ Study, an ongoing study of aging and dementia in the oldest-old. Cognitive status of intact oldest-old was determined at baseline using cross-sectional approach. Individuals with cognitive impairment no dementia or dementia (according to DSM-IV criteria) were excluded. Participants ranged in age from 90 to 102 years (mean=94). The neuropsychological battery included 11 tests (Mini-Mental Status Examination, Modified Mini-Mental State Examination, Boston Naming Test - Short Form, Letter Fluency Test, Animal Fluency Test, California Verbal Learning Test-II Short Form, Trail Making Tests A/B/C, Digit Span Forward and Backwards Test, Clock Drawing Test, CERAD Construction Subtests), and the Geriatric Depression Scale. RESULTS: Data show significantly lower scores with increasing age on most tests. Education level, sex, and symptoms of depression were associated with performance on several tests after accounting for age. CONCLUSIONS: Provided test norms will help to distinguish cognitively intact oldest-old from those with cognitive impairment. (JINS, 2019, 25, 530-545).

Aging exacerbates development of cerebral microbleeds in a mouse model.

BACKGROUND: Cerebral microhemorrhages (CMH) are commonly found in the aging brain. CMH are also the neuropathological substrate of cerebral microbleeds (CMB), demonstrated on brain MRI. Recent studies demonstrate the importance of systemic inflammation in CMH development, but the relationships among inflammation, aging, and CMH development are not well-defined. In the current study, we hypothesized that the pathogenesis of inflammation-induced CMH in mice differs by age. METHODS: We studied young (3 months, n = 20) and old (18 months, n = 25) C57BL/6 mice injected with low-dose lipopolysaccharide (LPS; 1 mg/kg, i.p.) or saline at 0, 6, and 24 h. Seven days after the first LPS/saline injection, brains were harvested, sectioned, and stained with hematoxylin and eosin (H&E) and Prussian blue (PB) to estimate acute/fresh and sub-acute CMH development, respectively. The relationships between microglial/macrophage activation (ionized calcium-binding adapter molecule-1), astrocyte activation (glial fibrillary acidic protein), blood-brain barrier (BBB) disruption (brain immunoglobulin G), aging, and CMH development were examined using immunohistochemistry. RESULTS: Aging alone did not increase spontaneous H&E-positive CMH development but significantly increased the number, size, and total area of LPS-induced H&E-positive CMH in mice. LPS- and saline-treated aged mice had significantly larger PB-positive CMH compared with young mice, but the total area of PB-positive CMH was increased only in LPS-treated aged mice. Aged mice had significantly increased microglial/macrophage activation, which correlated with H&E- and PB-positive CMH development. Aged mice treated with LPS had significantly increased astrocyte activation and BBB disruption compared with young LPS-treated mice. CONCLUSIONS: Aging makes the brain more susceptible to inflammation-induced CMH in mice, and this increase in CMH with aging is associated with microglial/macrophage activation.

Effects of phosphodiesterase 3A modulation on murine cerebral microhemorrhages.

BACKGROUND: Cerebral microbleeds (CMB) are MRI-demonstrable cerebral microhemorrhages (CMH) which commonly coexist with ischemic stroke. This creates a challenging therapeutic milieu, and a strategy that simultaneously protects the vessel wall and provides anti-thrombotic activity is an attractive potential approach. Phosphodiesterase 3A (PDE3A) inhibition is known to provide cerebral vessel wall protection combined with anti-thrombotic effects. As an initial step in the development of a therapy that simultaneously treats CMB and ischemic stroke, we hypothesized that inhibition of the PDE3A pathway is protective against CMH development. METHODS: The effect of PDE3A pathway inhibition was studied in the inflammation-induced and cerebral amyloid angiopathy (CAA)-associated mouse models of CMH. The PDE3A pathway was modulated using two approaches: genetic deletion of PDE3A and pharmacological inhibition of PDE3A by cilostazol. The effects of PDE3A pathway modulation on H&E- and Prussian blue (PB)-positive CMH development, BBB function (IgG, claudin-5, and fibrinogen), and neuroinflammation (ICAM-1, Iba-1, and GFAP) were investigated. RESULTS: Robust development of CMH in the inflammation-induced and CAA-associated spontaneous mouse models was observed. Inflammation-induced CMH were associated with markers of BBB dysfunction and inflammation, and CAA-associated spontaneous CMH were associated primarily with markers of neuroinflammation. Genetic deletion of the PDE3A gene did not alter BBB function, microglial activation, or CMH development, but significantly reduced endothelial and astrocyte activation in the inflammation-induced CMH mouse model. In the CAA-associated CMH mouse model, PDE3A modulation via pharmacological inhibition by cilostazol did not alter BBB function, neuroinflammation, or CMH development. CONCLUSIONS: Modulation of the PDE3A pathway, either by genetic deletion or pharmacological inhibition, does not alter CMH development in an inflammation-induced or in a CAA-associated mouse model of CMH. The role of microglial activation and BBB injury in CMH development warrants further investigation.

Lower likelihood of falling at age 90+ is associated with daily exercise a quarter of a century earlier: The 90+ Study.

Objective: to explore the relationship between risk of falling at age 90+ and prior physical activity at age 60-70s. Design: population-based cohort study (The 90+ Study). Setting: California retirement community. Participants: of 1596 cohort members, 1536 had both falls and prior activity data. Mean age = 94 years; 78% female; 99% Caucasian. Methods: time spent in active physical activity was self-reported in 1980s; medical history, medication, assistive devices, residence type, and falls (outcome) was collected in 2000s. Activity/fall relationships were assessed using logistic regression. Results: falls were reported by 52% of participants, recurrent falls by 32%, and severe injury by 21% of fallers. In univariate analyses risk of falling at age 90+ was significantly related to medical history (heart disease, TIA/stroke, arthritis, vision disease, depression, dementia), medication use (hypnotics, anti-psychotics, anti-depressants), use of assistive devices (cane, walker, wheelchair), residence type (living with relatives, sheltered living), and source of information (self-report vs informant). Risks of falling and recurrent falls at age 90+ were 35-45% lower in those reporting 30+ minutes/day of active physical activity at age 60-70s compared with no activity. The odds ratio of falling was 0.65 (95% CI = 0.44-0.97) for 30-45 minutes/day and 0.64 (0.44-0.94) for 1+ hour/day adjusting for age, sex, medical history (stroke/TIA, vision disease, depression), use of assistive devices, and source of information. Conclusions and Relevance: falls are extremely common among the oldest-old and a significant proportion lead to severe injury. This work is the first to show an association between exercise at age 60-70s and lower risk of falling at age 90+.

Age of onset of hypertension and risk of dementia in the oldest-old: The 90+ Study.

INTRODUCTION: We investigated the association between age of onset of hypertension and dementia risk in an oldest-old cohort. METHODS: Participants are from The 90+ Study, a population-based longitudinal study of people aged 90+ who are survivors from the Leisure World Cohort Study. We estimated hypertension onset age using self-reported information from The 90+ Study and Leisure World Cohort Study, collected about 20 years earlier. A total of 559 participants without dementia were followed every 6 months for up to 10 years. RESULTS: A total of 224 participants developed dementia during follow-up (mean = 2.8 years). Compared with those without hypertension, participants whose hypertension onset age was 80 to 89 years had a lower dementia risk (hazard ratio = 0.58, P = .04) and participants with an onset age of 90+ years had the lowest risk (hazard ratio = 0.37, P = .004). DISCUSSION: Developing hypertension at older ages may protect against dementia. Understanding the mechanisms for this lower risk is important for determining ways to prevent dementia in the very elderly.

A murine model of inflammation-induced cerebral microbleeds.

BACKGROUND: Cerebral microhemorrhages (CMH) are tiny deposits of blood degradation products in the brain and are pathological substrates of cerebral microbleeds. The existing CMH animal models are ß-amyloid-, hypoxic brain injury-, or hypertension-induced. Recent evidence shows that CMH develop independently of hypoxic brain injury, hypertension, or amyloid deposition and CMH are associated with normal aging, sepsis, and neurodegenerative conditions. One common factor among the above pathologies is inflammation, and recent clinical studies show a link between systemic inflammation and CMH. Hence, we hypothesize that inflammation induces CMH development and thus, lipopolysaccharide (LPS)-induced CMH may be an appropriate model to study cerebral microbleeds. METHODS: Adult C57BL/6 mice were injected with LPS (3 or 1 mg/kg, i.p.) or saline at 0, 6, and 24 h. At 2 or 7 days after the first injection, brains were harvested. Hematoxylin and eosin (H&E) and Prussian blue (PB) were used to stain fresh (acute) hemorrhages and hemosiderin (sub-acute) hemorrhages, respectively. Brain tissue ICAM-1, IgG, Iba1, and GFAP immunohistochemistry were used to examine endothelium activation, blood-brain barrier (BBB) disruption, and neuroinflammation. MRI and fluorescence microscopy were used to further confirm CMH development in this model. RESULTS: LPS-treated mice developed H&E-positive (at 2 days) and PB-positive (at 7 days) CMH. No surface and negligible H&E-positive CMH were observed in saline-treated mice (n = 12). LPS (3 mg/kg; n = 10) produced significantly higher number, size, and area of H&E-positive CMH at 2 days. LPS (1 mg/kg; n = 9) produced robust development of PB-positive CMH at 7 days, with significantly higher number and area compared with saline (n = 9)-treated mice. CMH showed the highest distribution in the cerebellum followed by the sub-cortex and cortex. LPS-induced CMH were predominantly adjacent to cerebral capillaries, and CMH load was associated with indices of brain endothelium activation, BBB disruption, and neuroinflammation. Fluorescence microscopy confirmed the extravasation of red blood cells into the brain parenchyma, and MRI demonstrated the presence of cerebral microbleeds. CONCLUSIONS: LPS produced rapid and robust development of H&E-positive (at 2 days) and PB-positive (at 7 days) CMH. The ease of development of both H&E- and PB-positive CMH makes the LPS-induced mouse model suitable to study inflammation-induced CMH.

Lifestyle Factors and Dementia in the Oldest-old: The 90+ Study.

Dementia incidence increases exponentially with age even in people aged 90 years and above. Because therapeutic regimens are limited, modification of lifestyle behaviors may offer the best means for disease control. To test the hypotheses that lifestyle factors are related to lower risk of dementia in the oldest-old, we analyzed data from The 90+ Study, a population-based longitudinal cohort study initiated in 2003. This analysis included 587 participants (mean age=93 y) seen in-person and determined not to have dementia at enrollment. Information on lifestyle factors (smoking, alcohol, caffeine, vitamin supplements, exercise, and other activities) was obtained at enrollment and was available from data collected 20 years previously. After an average follow-up of 36 months, 268 participants were identified with incident dementia. No variable measured 20 years previously was associated with risk. Engagement in specific social/mental activities and intakes of antioxidant vitamin supplements and caffeine at time of enrollment were, associated with significantly reduced risks. When these variables were analyzed together, the HRs changed little and remained significant for reading (0.54, P=0.01) and going to church/synagogue (HR=0.66, P<0.05) but not for caffeine (HR=0.61, P=0.15) and vitamin C (HR=0.68, P=0.07). While lifestyle behaviors around age 70 did not modify risk of late-life dementia, participation in activities and caffeine and supplemental vitamin intake around age 90 warrant further investigation.

Impact of interventions to reduce Alzheimer's disease pathology on the prevalence of dementia in the oldest-old.

INTRODUCTION: The number of persons aged >90 years will grow significantly in coming decades. This group has the highest rates of dementia, most commonly Alzheimer's disease (AD). METHODS: Using The 90+ Study, we developed a statistical model for dementia risk based on brain pathologies. Intervention scenarios which reduce or eliminate AD pathology were considered, and the numbers of dementia cases among the U.S. oldest-old that could be prevented were estimated. RESULTS: The U.S. dementia prevalence among the oldest-old will increase from 1.35 million in 2015 to 4.72 million in 2050. If interventions eliminate AD pathology, dementia prevalence would be reduced by approximately 50%, averting nearly 2.4 million cases in 2050. However, large numbers of dementia cases would still remain. DISCUSSION: Reducing AD pathology would significantly decrease the public health burden of dementia. However, other interventions are needed to address the burden associated with other dementing pathologies prevalent in the oldest-old.

Antioxidant vitamin intake and mortality: the Leisure World Cohort Study.

To assess the relationship between antioxidant vitamin intake and all-cause mortality in older adults, we examined these associations using data from the Leisure World Cohort Study, a prospective study of residents of the Leisure World retirement community in Laguna Hills, California. In the early 1980s, participants (who were aged 44-101 years) completed a postal survey, which included details on use of vitamin supplements and dietary intake of foods containing vitamins A and C. Age-adjusted and multivariate-adjusted (for factors related to mortality in this cohort­smoking, alcohol intake, caffeine consumption, exercise, body mass index, and histories of hypertension, angina, heart attack, stroke, diabetes, rheumatoid arthritis, and cancer) hazard ratios for death were calculated using Cox regression for 8,640 women and 4,983 men (median age at entry, 74 years). During follow-up (1981-2013), 13,104 participants died (median age at death, 88 years). Neither dietary nor supplemental intake of vitamin A or vitamin C nor supplemental intake of vitamin E was significantly associated with mortality after multivariate adjustment. A compendium that summarizes previous findings of cohort studies evaluating vitamin intake and mortality is provided. Attenuation in the observed associations between mortality and antioxidant vitamin use after adjustment for confounders in our study and in previous studies suggests that such consumption identifies persons with other mortality-associated lifestyle and health risk factors.

Effects of PDE4 pathway inhibition in rat experimental stroke.

PURPOSE: The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS: Rats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model. RESULTS: Global inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (p<0.01) and 138% (p<0.05) of control in the ligation and embolic models, respectively. PDE4D knockout rats subjected to embolic stroke showed no change in infarct size compared to wild-type control. CONCLUSIONS: Despite increase in infarct size after global inhibition of the PDE4 pathway with rolipram, specific inhibition of the PDE4D isoform had no effect on experimental stroke. These findings support a role for the PDE4 pathway, independent of the PDE4D isoform, in ischemic stroke pathogenesis.

Characterization of cerebellar amyloid-ß deposits in Alzheimer disease.

Cerebellar amyloid-ß (Aß) plaques are a component of the diagnostic criteria used in Thal staging and ABC scoring for Alzheimer disease (AD) neuropathologic change. However, Aß deposits in this anatomic compartment are unique and under-characterized; and their relationship with other pathological findings are largely undefined. In 73 cases of pure or mixed AD with an A3 score in the ABC criteria, parenchymal (plaques) and vascular (cerebral amyloid angiopathy [CAA]) cerebellar Aß-42 deposits were characterized with respect to localization, morphology, density, and intensity. Over 85% of cases demonstrated cerebellar Aß-42 parenchymal staining that correlated with a Braak stage V-VI/B3 score (p < 0.01). Among the 63 with cerebellar Aß-42 deposits, a diffuse morphology was observed in 75% of cases, compact without a central dense core in 32%, and compact with a central dense core in 16% (all corresponding to plaques evident on hematoxylin and eosin staining). Cases with Purkinje cell (PC) loss showed higher proportions of PC layer Aß-42 staining than cases without PC loss (88% vs 44%, p = 0.02), suggesting a link between Aß-42 deposition and PC damage. Among all 73 cases, CAA was observed in the parenchymal vessels of 19% of cases and in leptomeningeal vessels in 44% of cases.

Responders versus nonresponders in a dementia study of the oldest old: the 90+ study.

Because of difficulties in finding, recruiting, and diagnosing dementia in the oldest old (ages ≥90 years), most incidence studies include few very elderly persons, and little is known about the characteristics of those who refuse participation. In a California longitudinal study of dementia and aging (The 90+ Study, 2003-2011), we compared nonresponders with responders with regard to information collected 20 years earlier and the impression of dementia as determined during telephone recruitment. Of 1,815 eligible subjects, 1,514 (83%) joined the study, 182 refused, and 119 could not be contacted. Responders did not differ from nonresponders by sex or previously collected medical history or lifestyle behaviors. Recruiters' impressions of dementia were similar in responders and nonresponders who refused (35% and 38%), and among responders, impressions of dementia showed high positive predictive value (95%) but low sensitivity (51%) for a diagnosis of dementia made during the study. Although epidemiologic studies among the very old have the potential for significant nonresponse bias due to a high proportion of frail, ill, and cognitively impaired persons, strategies can improve response rates to over 80%. Classifying nonresponders on cognitive ability at recruitment, though crude, will give some idea of the selective bias in dementia prevalence and incidence estimates introduced by nonresponse due to cognitive status.

Apolipoprotein E genotype, dementia, and mortality in the oldest old: the 90+ Study.

BACKGROUND: Although the apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer's disease (AD), it is not clear whether this relationship persists among the oldest old. Several European studies suggest that the effect of the APOE ε4 allele on dementia and mortality disappears in very old age. We describe the APOE allele and genotype frequencies and examine whether the presence of the APOE ε4 or APOE ε2 alleles is related to prevalent dementia, incident dementia, and mortality in a population-based cohort of oldest-old participants in the United States. METHODS: We studied 904 participants aged 90 years and older from The 90+ Study. Eight hundred two (89%) participants were genotyped and included in the prevalent dementia and mortality analyses. The 520 initially nondemented participants were included in the incident dementia analyses and were evaluated for dementia every 6 months. RESULTS: The APOE ε4 allele was significantly associated with prevalent dementia (odds ratio = 2.06) and AD (odds ratio = 2.37) in women but not in men. The APOE ε2 allele was not related to prevalent dementia in either sex. After an average follow-up of 2.4 years, 188 incident dementia cases were identified. Neither the APOE ε4 nor the APOE ε2 allele was related to incident dementia or AD. Five hundred ten (64%) participants died after an average follow-up of 2.3 years, and their mortality was not related to the presence of either the APOE ε2 or APOE ε4 allele. CONCLUSIONS: Our findings suggest that the associations between APOE ε4, dementia, and mortality are age dependent, and that APOE ε4 no longer plays a role in dementia and mortality at very old ages.

Aging in Place in a Retirement Community: 90+ Year Olds.

Aging in place, an image of growing old in one's home and maintaining one's daily routine, is desired by most older adults. To identify variables promoting such independent living in the oldest-old, we examined the association between living situation of a population-based cohort of 90+ year olds with health and lifestyle variables. Of 1485 participants, 53% still lived in their home at a retirement community designed to foster wellness. Those living at home tended to be healthier, with smaller proportions having chronic diseases or hospitalizations in the preceding year and a greater proportion having normal functional ability. Dementia was the chronic disease most significantly related to living situation. In addition to not having dementia, not using a wheelchair or bath aid, receiving meals on wheels, and being married were jointly related to living at home. With the help of family and friends and with a medical and social support system, many 90+ year olds can age in place. This is often because they have a caregiving spouse or paid caregiver.