Sleep disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women

Poster Presentations P3 Background: Constriction of life space, the extent of spatial movement through the environment covered during daily functioning, is common for many older adults and associated with adverse health outcomes. Little is known about the relationship between life space and Alzheimer’s disease (AD). We tested the hypothesis that a constricted life space is associated with an increased risk of incident Alzheimer’s disease (AD), incident mild cognitive impairment (MCI), and more rapid cognitive decline in older adults. Methods: Participants included 1,294 community-dwelling elders without baseline clinical dementia. Self-report life space (ranging from the bedroom to outside of town) was measured at baseline, and a detailed clinical evaluation administered annually and used to diagnose incident AD and MCI. Results: During an average follow-up of 4 years, 180 (13.9%) persons developed AD. In a proportional hazards model which controlled for age, sex, race, and education, a more constricted life space was associated with an increased risk of AD (HR ¼ 1.21, 95% CI 1.08, 1.36, p < 0.001), such that a person with a life space constricted to their immediate home environment (score ¼ 3) was almost twice as likely to develop AD than a person with the largest life space (score ¼ 0, out of town). The association did not vary along demographic lines and persisted after the addition of terms for performance-based physical function, disability, depressive symptoms, social network size, vascular disease burden, and vascular risk factors. The association persisted after excluding persons with the lowest levels of cognitive function. A constricted life space was also associated with an increased risk of MCI (HR ¼ 1.17, 95% CI 1.06, 1.28, p ¼ 0.001), and a more rapid rate of cognitive decline (life space * time estimate: -0.012 (S.E., 0.003), p < 0.001). Conclusions: A constricted life space is associated with an increased risk of AD, MCI, and cognitive decline among community-dwelling older persons. P3-086

UNRAVELLING EARLIEST NEUROPATHOLOGY OF MEMORY IMPAIRMENT DURING NORMAL SENESCENCE AND ALZHEIMER’S DISEASE

Mak Adam Daulatzai, University of Melbourne, Melbourne, Australia. Contact e-mail: [email protected] Background: Age is the main risk factor for AD. Pinpointing the earliest pathogenetic mechanism(s) that lead to dementia is a challenge. This is the first study that claims to have accomplished this. Aging decreases neuronal - size, dendrites, and cell bodies in different brain regions including the basal forebrain (BFB), entorhinal (EC) and parietal cortices, hippocampus, and the brainstem. Extensive decrements occur in various sensory modalities, thalamocortical system (TCS), and cholinergic neurotransmission during senescence. Further, aging increases repetitive pharyngeal collapse, tongue atrophy, and intermittent hypoxia/hypoxemia. Here unambiguous evidence is presented emphasizing declines in TCS, ongoing atrophy of brainstem nuclei, and increasing nocturnal hypoxia/hypoxemia during normal senescence cause memory dysfunction. Methods: The fMRI data during normal senescence and prodromal AD encompasses: (A) somatosensory and special sensory functional alterations, and dysfunctional BFB, hippocampus, ERC, Parietal and temporal cortices; (B) role of neurotrophins from skin, olfactory bulb, and hippocampus in cholinergic neuronal viability/neurotransmission; (C) brainstem nuclei - ambiguous, solitarius (NST), hypoglossal, reticular, and motor nucleus of the 10th cranial nerve (MN10) during aging, (D) apnea hypopnea index (AHI); (E) hypoglossal nucleus, nocturnal dysfunction of genioglossus, UA sensorymotor reflex, pharyngeal collapse, respiratory disturbances, hypoxia/hypoxemia, (F) regional brain glucose metabolism and blood flow (rCBF). Results: Volumetry has documented lower volumes of the hippocampus, EC, BFB, and brainstem nuclei ambiguus, NST, and MN10 during normal aging. Reduced glucose hypometabolism exists in hippocampus and parietal cortex, as does the rCBF during normal aging. The age related decline in olfactory and other senses, and damages to thalamocortical system, BFB cholinergic neurotransmission, and EC, and hippocampal foci are ascribed to persistent cortical hypometabolism and decreased rCBF and decreases in neocortical and brainstem neurons. Conclusions: Normal aging-related

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sensory decline, in conjunction with hypotrophy of strategic brainstem nuclei subserving sensory modalities and respiration, constitute the initial neuropathological insults. During senescence, ongoing nocturnal hypoxia/hypoxemia are detrimental to viability of neurons in BFB, EC, thalamosensory system, PFC, amygdala, hippocampus and indeed brainstem. The abovementioned diurnal neuropathology increases with increasing age, results in intraneuronal neurofibrillary tangles, and deposition of extracellular b amyloid thus causing cognitive functions.

P3-087

CENTRAL NERVOUS SYSTEM (CNS) COMORBIDITIES AND CONCOMITANT DRUG USE IN A MEDICAID ALZHEIMER POPULATION

Lisa Mucha1, Trent McLaughlin2, Jill Racketa1, Machaon Bonafede3, Robert Fowler3, 1Pfizer, Inc., Collegeville, PA, USA; 2Janssen Alzheimer’s Immunotherapy Research & Development, South San Francisco, CA, USA; 3 Thomson Reuters, Cambridge, MA, USA. Contact e-mail: lisa.mucha@ pfizer.com Background: Agents such as atypical antipsychotics, antidepressants, or benzodiazepines are commonly used to treat neuropsychiatric symptoms in Alzheimer’s Disease (AD) patients. What has not been fully characterized is the incremental effect that central nervous system (CNS) comorbidities and prescription drug use contribute to the burden of AD to the Medicaid program. The objective of this study is to examine the differential in CNS comorbidities and concomitant drug use in a Medicaid AD cohort relative to a matched cohort without AD. Methods: Data are from a large multi-state Medicaid claims database 2000-2008. AD patients were identified via the first instance (index date) of ICD-9 code 331.0 or AD-related dementia (290.1x, 294.1x, 331.1x, 331.82). AD patients had to have a second AD claim or a prescription for a cholinesterase inhibitor or memantine. Patients with AD were matched to those without AD on age, gender, state/region, Charlson-Deyo Comorbidity Index (modified to remove dementia) and Medicare dual eligibility status. Primary outcomes measures were medical and pharmacy utilization and costs the first year after index. Univariate results are presented as percents or mean 6 standard deviation; t-tests for continuous variables or chi-square for categorical tests used alpha ¼ 0.05. Results: 13,927 AD patients were matched to controls. There were significantly (all differences p < 0.0001) higher numbers of AD patients with any CNS diagnosis including psychosis (57% vs 4%), depression (15% vs 6%), major depression (7% vs 3%). Atypical antipsychotics were the most commonly utilized drug class by AD patients (51% vs 9% non-AD) Atypicals also represented the highest drug expenditure category for AD patients ($951 {$1536 SD} vs $152 {$725 SD} for non-AD), followed by SSRIs ($239 {$440 SD} vs $124 {$326 SD} for non-AD). Drug expenditures were also higher for antidepressants and benzodiazepines. Conclusions: Due to the prevalence of CNS comorbidities and treatment in AD, it is expected that the use and cost of CNS agents would be higher for the AD cohort. However, the scale of the difference between the two cohorts is marked, highlighting the substantial expense to Medicaid and pointing to the need to assess the level of utilization of these agents in AD.

P3-088

SLEEP DISORDERED BREATHING, HYPOXIA, AND RISK OF MILD COGNITIVE IMPAIRMENT AND DEMENTIA IN OLDER WOMEN

Kristine Yaffe, University of California San Francisco, San Francisco, CA, USA. Contact e-mail: [email protected] Background: Sleep-disordered breathing (SDB), a disorder characterized by recurrent arousals from sleep and intermittent hypoxemia, is common among older adults. Cross-sectional studies have linked SDB and cognition; however it remains unclear whether SDB precedes cognitive impairment in community-dwelling elders. We prospectively examined the association between prevalent SDB and subsequent diagnosis of mild cognitive

Poster Presentations P3

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impairment (MCI) and dementia. Methods: We studied 298 dementia free women (mean age 82.3 6 3.2 years at baseline) participating in the SOFWISE study with overnight polysomnography (PSG) and clinically adjudicated cognitive status approximately 5 years later. An apnea-hypopnea index (AHI) score  15 events/hr was used to define SDB. Arousal index (arousals per hour of sleep) was used as a marker of sleep disruption and hypoxia was measured using oxygen desaturation (deSat) index (ODI), percent sleep time in apnea or hypopneas with  3% oxyhemoglobin deSat, and percent sleep time with < 90% Sa02. These predictors were analyzed in separate multivariate-adjusted logistic regression models (adjusted for age, race, education, BMI, myocardial infarction, diabetes, and baseline cognitive score) for likelihood of developing MCI or dementia. Results: At baseline, 105 (35.2%) women had SDB and after 5-years of follow-up 47 (44.8%) developed MCI/dementia, while MCI or dementia was observed in only 31.1% (60/ 193) of women without SDB. Presence of SDB doubled the odds of developing MCI/dementia (odds ratio [OR] ¼ 2.33, 95% confidence interval [CI] 1.28 - 4.25) compared to women without SDB. MCI or dementia was not related arousal index (OR 0.90, 95% CI 0.44 - 1.84 for highest tertile  22.6 vs. lowest terile <14.6). Of the hypoxia markers, ODI ( 15 events/ hr of sleep) and percent sleep time in apnea and hypopnea (highest tertile  7.04% vs. lowest tertile < 2.26%) increased odds of developing MCI/dementia (OR 2.05, 95% CI 1.15 - 3.67 and OR 2.23, 95% CI 1.10 - 4.54, respectively) but percent sleep time with < 90% Sa02 did not. Conclusions: The presence of SDB greatly increased the risk of developing cognitive impairment 5-years later in older women. These findings suggest that hypoxia is the likely mechanism through which SDB increases risk for cognitive changes in older adults. P3-089

participants with aMCI and OCIND were extremely high at 34.4% and 39.7% per year. Participants with naMCI had an incidence rate of 20.8% per year. Participants with normal cognition had a dementia incidence rate of 8.4% per year. Conclusions: The risk of developing dementia in the oldest-old is extremely high and increases to even higher rates once cognitive impairment is present. Similar to data from younger elderly, oldestold participants with aMCI and OCIND are more than four times more likely to become demented in a year than those with normal cognition. However, the magnitude of the incidence rate in all groups with cognitive impairment is astounding. Very high dementia incidence rates in cognitively impaired oldest-old emphasize the need to find effective preventions or treatments for cognitive decline. P3-090

HYPERTENSION AND RISK OF DEMENTIA IN THE OLDEST-OLD: THE 90+ STUDY

Maria M. Corrada, Daniel Berlau, Carrie B. Peltz, Claudia Kawas, University of California Irvine, Irvine, CA, USA. Contact e-mail: [email protected] Background: Hypertension has been reported as a risk factor for dementia in many studies but it is unknown if this association persists in the oldest-old. Because hypertension is a modifiable risk factor, it is important to know whether recommendations for healthy blood pressure (BP) in this group should be different from younger people for maintaining intact cognition. Here, we study the association between hypertension and risk of all-cause dementia in the oldest-old. Methods: Participants are from the 90+ Study,

INCIDENCE OF DEMENTIA IS VERY HIGH IN OLDEST-OLD PARTICIPANTS WITH AMNESTIC MCI AND OTHER COGNITIVE IMPAIRMENTS: RESULTS FROM THE 90+ STUDY

Carrie B. Peltz, Daniel J. Berlau, Maria M. Corrada, Claudia H. Kawas, University of California, Irvine, Irvine, CA, USA. Contact e-mail: cpeltz@ uci.edu Background: The incidence of dementia in those aged 90 and older is much higher than in younger elderly. In this study we examined the incidence of all-cause dementia in participants aged 90 and older stratified into four cognitive groups: normal, amnestic (aMCI) and non-amnestic mild cognitive impairment (naMCI), and other cognitive impairment not demented (OCIND). Methods: This study included 374 non-demented participants (mean age ¼ 93.8) in the 90+ Study, a large, population-based study of the oldest-old. The participants had follow-up assessments and evaluations for dementia (DSM-IV) every six months. The average follow-up was 2.3 years. Using data from the first visit, participants were categorized as normal, aMCI, naMCI, or OCIND (too impaired to meet MCI criteria but not demented). All-cause dementia incidence rates were calculated separately for each group using a person-years analysis. Results: Overall, 131 cases of incident all-cause dementia were identified in 861 person-years, resulting in an incidence rate of 15.2% per year. Dementia incidence rates for

Cognitive Groups

Baseline N (%)

Incident Cases / Person Years

Incidence of Dementia per 100 person years (95% CI)

31 (8.3) 17 / 50 34.4 (19.8-54.4) aMCI 70 (18.7) 49 / 123 39.7 (29.5-52.7) OCIND naMCI 30 (8) 12 / 58 20.8 (10.7-36.1) Normal 243 (65) 53 / 630 8.4 (6.3-11) Total 374 131 / 861 15.2 (12.7-18.1) aMCI ¼ amnestic MCI; OCIND ¼ other cognitive impairment not demented; naMCI ¼ non-amnestic MCI

a population based longitudinal study of people aged 90 and older. At baseline, self-reported history of hypertension was assessed from 325 non-demented participants. Systolic (SBP) and diastolic blood pressure (DBP) measurements (in mm Hg) were taken in 259 of the participants, and were categorized as normal (<120 SBP and <80 DBP), pre-hypertension (120139 SBP or 80-89 DBP), and hypertension (>140 SBP or >90 DBP). Participants were followed every 6 months for up to 5 years. Presence or absence of dementia (DSM-IV) was determined at each visit. Results: Participants had a mean age of 94 years (range: 90-103) and were mostly women (70%). 137 incident cases were detected during follow-up. At baseline, 53% reported a history of hypertension, and BP measurements were classified as 7% normal, 34% pre-hypertensive, and 59% hypertensive. History of hypertension was associated with a 29% lower risk of dementia (HR ¼ 0.71). In contrast, hypertension defined by direct BP measurements was not associated with dementia risk (pre-hypertensives: HR ¼ 1.20; hypertensives: HR ¼ 0.90). Conclusions: Hypertension, either by history or direct measurement, was very common in this sample. History of hypertension was associated with a reduced risk of dementia, suggesting that the relationship between hypertension and dementia may be reversed in the oldest-old compared to younger old. In contrast, hypertension defined by direct measurement was not associated with dementia risk. It is possible that hypertension at older ages is beneficial for maintaining intact cognition. However, as the inconsistent association found here may be related to treatment and duration of hypertension, further studies taking into account these factors are warranted to elucidate the complex association between hypertension and dementia in this age group.