Faculty Bibliography

Although there is an increasing agreement that hypertension is associated with cerebrovascular compromise, relationships between blood pressure (BP) and cerebral blood flow are not fully understood. It is not known what BP level, and consequently what therapeutic goal, is optimal for brain perfusion. Moreover, there is limited data on how BP affects hippocampal perfusion, a structure critically involved in memory. We conducted a cross-sectional (n=445) and longitudinal (n=185) study of adults and elderly without dementia or clinically apparent stroke, who underwent clinical examination and brain perfusion assessment (age 69.2±7.5 years, 62% women, 45% hypertensive). Linear models were used to test baseline BP-blood flow relationship and to examine how changes in BP influence changes in perfusion. In the entire group, systolic BP (SBP) was negatively related to cortical (β=-0.13, P=0.005) and hippocampal blood flow (β=-0.12, P=0.01). Notably, this negative relationship was apparent already in subjects without hypertension. Hypertensive subjects showed a quadratic relationship between SBP and hippocampal blood flow (β=-1.55, P=0.03): Perfusion was the highest in subjects with mid-range SBP around 125 mm Hg. Longitudinally, in hypertensive subjects perfusion increased with increased SBP at low baseline SBP but increased with decreased SBP at high baseline SBP. Cortical and hippocampal perfusion decrease with increasing SBP across the entire BP spectrum. However, in hypertension, there seems to be a window of mid-range SBP which maximizes perfusion.

Epidemiologic and mechanistic evidence is increasingly supporting the notion that obstructive sleep apnea is a risk factor for dementia. Hence, the identification of patients at risk of cognitive decline due to obstructive sleep apnea may significantly improve preventive strategies and treatment decision-making. Cerebrospinal fluid and blood biomarkers obtained through genomic, proteomic and metabolomic approaches are improving the ability to predict incident dementia. Therefore, fluid biomarkers have the potential to predict vulnerability to neurodegeneration in individuals with obstructive sleep apnea, as well as deepen our understanding of pathophysiological processes linking obstructive sleep apnea and dementia. Many fluid biomarkers linked to Alzheimer's disease and vascular dementia show abnormal levels in individuals with obstructive sleep apnea, suggesting that these conditions share common underlying mechanisms, including amyloid and tau protein neuropathology, inflammation, oxidative stress, and metabolic disturbances. Markers of these processes include amyloid-β, tau proteins, inflammatory cytokines, acute-phase proteins, antioxydants and oxidized products, homocysteine and clusterin (apolipoprotein J). Thus, these biomarkers may have the ability to identify adults with obstructive sleep apnea at high risk of dementia and provide an opportunity for therapeutic intervention. Large cohort studies are necessary to establish a specific fluid biomarker panel linking obstructive sleep apnea to dementia risk.

OBJECTIVE:F-FDG PET and neurodegeneration via structural MRI) and global cognition in middle-aged asymptomatic participants at risk for AD. DESIGN/METHODS:Prospective, longitudinal. SETTING/METHODS:The study was conducted at New York University Langone/Weill Cornell Medical Centres in New York City. PARTICIPANTS/METHODS:Seventy cognitively normal participants from multiple community sources, aged 30-60 years with lifestyle measures (diet, intellectual activity and physical activity), vascular risk measures and two imaging biomarkers visits over at least 2 years, were included in the study. OUTCOME MEASURES/METHODS:We examined MRI-based cortical thickness, fluoro-deoxy-glucose (FDG) glucose metabolism and PiB beta-amyloid in AD-vulnerable regions. A global cognitive z-score served as our summary cognition measure. We used regression change models to investigate the associations of clinical, lifestyle and vascular risk measures with changes in AD biomarkers and global cognition. RESULTS:. Higher baseline plasma homocysteine was associated with faster rates of decline in global cognition, with and without accounting for lifestyle and biomarker measures (p=0.048). None of the lifestyle variables were associated with cognition. CONCLUSIONS:Diet influenced brain glucose metabolism in middle-aged participants, while plasma homocysteine explained variability in cognitive performance. These findings suggest that these modifiable risk factors affect AD risk through different pathways and support further investigation of risk reduction strategies in midlife.

With 10% of adults over the age of 65 suffering from dementia and this number projected to double by 2050, understanding the factors responsible for cognitive impairment is of critical importance. Amyloid beta (Abeta) plaques and neurofibrillary tangles (NFT) are two key pathological processes that lead to cognitive deterioration in Alzheimer's disease (AD). Cerebrospinal fluid (CSF) Abeta and tau concentrations have been used extensively as biomarkers of AD pathology and found to correlate with amyloid plaques and NFT at post-mortem. Emerging evidence suggests that the sleep-wake cycle directly influences their levels. Specifically, low NREM stage 3 (NREM3) slow wave activity (SWA) is associated, in normal elderly, with high cerebrospinal fluid (CSF) Abeta, while active disruption of slow wave sleep (SWS) results in increases in CSF Abeta peptides within-subjects. Unlike Abeta, associations between poor SWS and tau have not been observed suggesting that disruption in other sleep oscillations could be linked to tau pathology. In a cross-sectional study with one-night in-lab nocturnal polysomnography (NPSG) and morning-to early afternoon CSF collection that was conducted on 50 community-dwelling, cognitively normal healthy subjects, with normal or mild obstructive sleep apnea (OSA) defined as an apnea-hypopnea index with 4% desaturation (AHI4%) <15, we found that spindles during NREM stage 2 (NREM2) sleep were negatively correlated with CSF T-tau levels and to a lesser degree to CSF P-tau. Spindle-duration count and fast spindle density were also negatively correlated with T-tau levels. Sleep duration and other measures of sleep quality were not correlated with spindle characteristics and did not modify the associations when included in the models. While reductions in NREM sleep oscillations, including SWS and sleep spindles, or the more recently reported reductions in REM sleep percentage from the Sleep Heart Health Study, may reflect a preclinical AD state, it remains unclear just how these attenuated oscillations are mechanistically linked to cellular processes regulating Abeta and tau. Candidate mechanisms would include patterned activity-driven synthesis or degradation of such molecules or the coupling of such oscillations to neuroimmune function. Longitudinal and interventional studies to assess changes in sleep oscillations as well as AD biomarkers are needed

OBJECTIVE:F-fluorodeoxyglucose [FDG] PET and structural MRI) in midlife. METHODS:Seventy 30- to 60-year-old cognitively normal participants with clinical, neuropsychological, and dietary examinations and imaging biomarkers at least 2 years apart were examined. These included 34 participants with higher (MeDi+) and 36 with lower (MeDi-) MeDi adherence. Statistical parametric mapping and volumes of interest were used to compare AD biomarkers between groups at cross section and longitudinally. RESULTS:< 0.001). No effects were observed on MRI. Higher MeDi adherence was estimated to provide 1.5 to 3.5 years of protection against AD. CONCLUSION/CONCLUSIONS:Lower MeDi adherence was associated with progressive AD biomarker abnormalities in middle-aged adults. These data support further investigation of dietary interventions for protection against brain aging and AD.

Alzheimer's disease (AD) is known to be associated with loss of cholinergic neurons in the nucleus basalis of Meynert, located in the posterior basal forebrain. Structural changes of septal nuclei, located in the anterior basal forebrain, have not been well studied in AD. Using a validated algorithm, we manually traced septal nuclei on high-resolution coronal magnetic resonance imaging (MRI) in 40 subjects with mild cognitive impairment (MCI) or AD, 89 healthy controls, and 18 subjects who were cognitively normal at the time of MRI but went on to develop AD an average of 2.8 years later. We found that cognitively normal subjects destined to develop AD in the future had enlarged septal nuclei as compared to both healthy controls and patients with current MCI or AD. To our knowledge, this is the first time a brain structure has been found to be enlarged in association with risk of AD. Further research is needed to determine if septal enlargement reflects neuroplastic compensation, amyloid deposition, inflammation, or another process and to determine whether it can serve as an early MRI biomarker of AD.

RATIONALE: Recent evidence suggests that Obstructive Sleep Apnea (OSA) may be a risk factor for developing Mild Cognitive Impairment and Alzheimer's disease. However, how sleep apnea affects longitudinal risk for Alzheimer's disease is less well understood. OBJECTIVE: To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly. METHODS: Data was derived from a 2-year prospective longitudinal study that sampled community-dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 to 90, were non-depressed and had a consensus clinical diagnosis of cognitively normal. CSF Amyloid beta was measured using ELISA. Subjects received Pittsburgh compound B Positron Emission Tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device. MEASUREMENTS AND MAIN RESULTS: We found that severity of OSA indices (lnAHIall [F1,88=4.26, p<.05] and lnAHI4% [F1,87=4.36, p<.05]) were associated with annual rate of change of CSF Abeta42 using linear regression after adjusting for age, sex, BMI and ApoE4 status. LnAHIall and lnAHI4 were not associated with increases in ADPiB-mask most likely due to the small sample size although there was a trend for lnAHIall (F1,28=2.96, p=.09 and F1,28=2.32, n.s. respectively). CONCLUSION: In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2 year follow-up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build-up in cognitively normal elderly.