Maritza Dowling

Reliability and Precision of Pseudo-continuous Arterial Spin Labeling Perfusion MRI on 3.0 T and Comparison with 15O-water PET in Elderly Subjects at Risk for Alzheimer’s Disease

Arterial spin labeling (ASL) offers MRI measurement of cerebral blood flow (CBF) in vivo, and may offer clinical diagnostic utility in populations such as those with early Alzheimers disease (AD). In the current study, we investigated the reliability and precision of a pseudo‐continuous ASL (pcASL) sequence that was performed two or three times within one hour on eight young normal control subjects, and 14 elderly subjects including 11 with normal cognition, one with AD and two with Mild Cognitive Impairment (MCI). Six of these elderly subjects including one AD, two MCIs and three controls also received 15O‐water positron emission tomography (PET) scans 2 h before their pcASL MR scan. The instrumental reliability of pcASL was evaluated with the intraclass correlation coefficient (ICC). The ICCs were greater than 0.90 in pcASL global perfusion measurements for both the young and the elderly groups. The cross‐modality perfusion imaging comparison yielded very good global and regional agreement in global gray matter and the posterior cingulate cortex. Significant negative correlation was found between age and the gray/white matter perfusion ratio (r = –0.62, p < 0.002). The AD and MCI patients showed the lowest gray/white matter perfusion ratio among all the subjects. The data suggest that pcASL provides a reliable whole brain CBF measurement in young and elderly adults whose results converge with those obtained with the traditional 15O‐water PET perfusion imaging method. pcASL perfusion MRI offers an alternative method for non‐invasive in vivo examination of early pathophysiological changes in AD. Copyright

Short-term Hormone Therapy with Transdermal Estradiol Improves Cognition for Postmenopausal Women with Alzheimer’s Disease: Results of a Randomized Controlled Trial

We aimed to conduct a placebo-controlled, double-blind, parallel-group design intervention study to evaluate the therapeutic efficacy of hormone therapy (HT) in postmenopausal women with mild to moderate Alzheimers disease (AD). The trial was designed to evaluate the dose-dependent effects of transdermal 17-β estradiol, unopposed and opposed with medroxyprogesterone (MPA, Provera©), for 12 months in 43 postmenopausal women with AD. Participants were assessed using cognitive measures at baseline, months 1, 3, 6, and 12 of treatment and eight weeks post treatment (month 15). The dropout rate was 49% across 12 months. As a result of the Womens Health Initiative (WHI) and anticipated increased attrition, the protocol was modified to examine data only at time points where attrition was less than 30%. The results of sensitivity analyses indicated robust and reliable data collected in the first three months of the trial. Data collected in the first three months of the trial for forty-three participants were analyzed. HT had favorable cognitive effects across multiple cognitive domains, including visual memory (p-values < 0.030) and semantic memory (p-values < 0.037) in postmenopausal women with AD. Moreover, treatment-related changes in plasma estradiol were positively correlated with improvements in visual memory. Short-term HT that includes the use of estradiol has favorable effects on cognition in women with AD.

Cognitive activities during adulthood are more important than education in building reserve.

Cognitive reserve is thought to reflect life experiences. Which experiences contribute to reserve and their relative importance is not understood. Subjects were 652 autopsied cases from the Rush Memory and Aging Project and the Religious Orders Study. Reserve was defined as the residual variance of the regressions of cognitive factors on brain pathology and was captured in a latent variable that was regressed on potential determinants of reserve. Neuropathology variables included Alzheimers disease markers, Lewy bodies, infarcts, microinfarcts, and brain weight. Cognition was measured with six cognitive domain scores. Determinants of reserve were socioeconomic status (SES), education, leisure cognitive activities at age 40 (CA40) and at study enrollment (CAbaseline) in late life. The four exogenous predictors of reserve were weakly to moderately inter-correlated. In a multivariate model, all except SES had statistically significant effects on Reserve, the strongest of which were CA40 (β = .31) and CAbaseline (β = .28). The Education effect was negative in the full model (β = -.25). Results suggest that leisure cognitive activities throughout adulthood are more important than education in determining reserve. Discrepancies between cognitive activity and education may be informative in estimating late life reserve.

The Effects of Ramipril in Individuals at Risk for Alzheimer’s Disease: Results of a Pilot Clinical Trial

Research shows that certain antihypertensives taken during midlife confer Alzheimers disease (AD) related benefits in later life. We conducted a clinical trial to evaluate the extent to which the angiotensin converting enzyme inhibitor (ACE-I), ramipril, affects AD biomarkers including cerebrospinal fluid (CSF) amyloid-β (Aβ) levels and ACE activity, arterial function, and cognition in participants with a parental history of AD. This four month randomized, double-blind, placebo-controlled, pilot clinical trial evaluated the effects of ramipril, a blood-brain-barrier crossing ACE-I, in cognitively healthy individuals with mild, or Stage I hypertension. Fourteen participants were stratified by gender and apolipoprotein E ε4 (APOE ε4) status and randomized to receive 5 mg of ramipril or matching placebo daily. Participants were assessed at baseline and month 4 on measures of CSF Aβ(1-42) and ACE activity, arterial function, and cognition. Participants were middle-aged (mean 54 y) and highly educated (mean 15.4 y), and included 50% men and 50% APOE ε4 carriers. While results did not show a treatment effect on CSF Aβ(1-42) (p = 0.836), data revealed that ramipril can inhibit CSF ACE activity (p = 0.009) and improve blood pressure, however, there were no differences between groups in arterial function or cognition. In this study, ramipril therapy inhibited CSF ACE activity and improved blood pressure, but did not influence CSF Aβ1-42. While larger trials are needed to confirm our CSF Aβ results, it is possible that prior research reporting benefits of ACE-I during midlife may be attributed to alternative mechanisms including improvements in cerebral blood flow or the prevention of angiotensin II-mediated inhibition of acetylcholine.

Occupational Complexity and Cognitive Reserve in a Middle-Aged Cohort at Risk for Alzheimer's Disease

Higher occupational attainment has previously been associated with increased Alzheimers disease (AD) neuropathology when individuals are matched for cognitive function, indicating occupation could provide cognitive reserve. We examined whether occupational complexity (OCC) associates with decreased hippocampal volume and increased whole-brain atrophy given comparable cognitive function in middle-aged adults at risk for AD. Participants (n = 323) underwent structural MRI, cognitive evaluation, and work history assessment. Three complexity ratings (work with data, people, and things) were obtained, averaged across up to 3 reported jobs, weighted by years per job, and summed to create a composite OCC rating. Greater OCC was associated with decreased hippocampal volume and increased whole-brain atrophy when matched for cognitive function; results remained substantively unchanged after adjusting for several demographic, AD risk, vascular, mental health, and socioeconomic characteristics. These findings suggest that, in people at risk for AD, OCC may confer resilience to the adverse effects of neuropathology on cognition.

Cardiorespiratory fitness attenuates the influence of amyloid on cognition

The aim of this study was to examine cross-sectionally whether higher cardiorespiratory fitness (CRF) might favorably modify amyloid-β (Aβ)-related decrements in cognition in a cohort of late-middle-aged adults at risk for Alzheimers disease (AD). Sixty-nine enrollees in the Wisconsin Registry for Alzheimers Prevention participated in this study. They completed a comprehensive neuropsychological exam, underwent 11C Pittsburgh Compound B (PiB)-PET imaging, and performed a graded treadmill exercise test to volitional exhaustion. Peak oxygen consumption (VO2peak) during the exercise test was used as the index of CRF. Forty-five participants also underwent lumbar puncture for collection of cerebrospinal fluid (CSF) samples, from which Aβ42 was immunoassayed. Covariate-adjusted regression analyses were used to test whether the association between Aβ and cognition was modified by CRF. There were significant VO2peak*PiB-PET interactions for Immediate Memory (p=.041) and Verbal Learning & Memory (p=.025). There were also significant VO2peak*CSF Aβ42 interactions for Immediate Memory (p<.001) and Verbal Learning & Memory (p<.001). Specifically, in the context of high Aβ burden, that is, increased PiB-PET binding or reduced CSF Aβ42, individuals with higher CRF exhibited significantly better cognition compared with individuals with lower CRF. In a late-middle-aged, at-risk cohort, higher CRF is associated with a diminution of Aβ-related effects on cognition. These findings suggest that exercise might play an important role in the prevention of AD.

Relationships between cardiorespiratory fitness, hippocampal volume, and episodic memory in a population at risk for Alzheimer's disease

Cardiorespiratory fitness (CRF) has been shown to be related to brain health in older adults. In individuals at risk for developing Alzheimers disease (AD), CRF may be a modifiable risk factor that could attenuate anticipated declines in brain volume and episodic memory. The objective of this study was to determine the association between CRF and both hippocampal volume and episodic memory in a cohort of cognitively healthy older adults with familial and/or genetic risk for Alzheimers disease (AD).

Meeting physical activity recommendations may be protective against temporal lobe atrophy in older adults at risk for Alzheimer's disease

Physical activity (PA) is associated with brain health in older adults. However, it is unknown whether the current physical activity recommendations (PAR) impart substantive benefit. The objective of this study was to compare temporal lobe volumes between older adults who met PAR and those who did not.

IMPACT OF SIMVASTATIN ON CEREBRAL BLOOD FLOW, PULSATILITY INDEX, AND ALZHEIMER’S DISEASE BIOMARKERS: A CLINICAL TRIAL

allele status, treatment group, and baseline LDL cholesterol and systolic BP, change in AIx was not associated with changes in PI (p values >0.74). Conclusions:AIx measured using radial arterial tonometry and cerebral PI measured by 4D Flow MRI were not significantly correlated at baseline, nor were changes in these measures after 18 months of simvastatin or placebo. These findings suggest that, in this population at risk for AD, radial artery tonometry and central measures of arterial stiffness may not be linked linearly. Further research is needed to elucidate how cerebral autoregulation and systemic vascular disease may contribute to central arterial dysregulation in the context of AD.

AN UPDATE ON MENOPAUSAL HORMONE THERAPY TRIALS

(w72-75y) is a critical transition period for identifying initiating mechanisms of AD and therapeutic targets to prevent, delay and reverse AD prodromal endophenotype. Methods: Transcriptomic, metabolomic, electrophysiological, FDG-PET and 7T-MRI analyses were conducted in female rodent models of human endocrine and chronological aging. Bioinformatic pathway analyses were followed by hierarchical clustering to identify activated gene networks. Women and men, 4060 years-of-age, underwent volumetric MRI, 18F-fluoro-2-deoxyglucose (FDG)–PET, and PIB–PET brain imaging. Cytochrome c oxidase activity (COX) was determined in platelet-derived mitochondria. Results:Two distinct aging programs emerged: chronological and endocrine. Early endocrine-aging transition was characterized by decline in bioenergetic gene expression which was confirmed by deficits in FDG-PET, mitochondrial function, and rise inflammatory signaling. Bioinformatic analysis predicted insulin/insulin-like growth factor 1 and AMPK/PGC1a signaling pathways as upstream regulators. Later endocrine-aging transition was accompanied by rise in genes required for fatty acid metabolism, inflammation, and mitochondrial function. An increase in fatty acids and fatty acid metabolism was coincident with rise in brain ketone bodies linking bioenergetic deficits early in aging with later age development of white matter degeneration. Bioinformatic pathway analyses indicated association of bioenergetic pathway decline with rise in genes involved in AD. Mechanistic outcomes were paralleled in human brain imaging analyses. Compared to age matched women and men, perimenopausal and menopausal women exhibited increased indicators of AD endophenotype, including hypometabolism, increased Ab deposition, reduced platelet mitochondrial COX activity and reduced gray and white matter volumes in AD-vulnerable regions. AD biomarker abnormalities were greatest in menopausal women, intermediate in perimenopausal women, and lowest in control age-matchedwomen andmen.Ab deposition was exacerbated in APOE4-positive menopausal women. Conclusions:Worldwide >850 million women are 40–60 years of age. Endocrine, chronologic and bioenergetic aging transitions are critical periods during which vulnerability for later life risk of AD can emerge. Research supported by: NIA P01AG026572 and Alzheimer’s Association SAGA-17-419459.