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Menopause impacts human brain structure, connectivity, energy metabolism, and amyloid-beta deposition

Mosconi, Lisa; Berti, Valentina; Dyke, Jonathan; Schelbaum, Eva; Jett, Steven; Loughlin, Lacey; Jang, Grace; Rahman, Aneela; Hristov, Hollie; Pahlajani, Silky; Andrews, Randolph; Matthews, Dawn; Etingin, Orli; Ganzer, Christine; de Leon, Mony; Isaacson, Richard; Brinton, Roberta Diaz
All women undergo the menopause transition (MT), a neuro-endocrinological process that impacts aging trajectories of multiple organ systems including brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. Yet, little is known of how this process impacts the human brain. This multi-modality neuroimaging study indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-menopause, peri-menopause, and post-menopause). These effects involved brain regions subserving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer's disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile during midlife endocrine aging of the female brain.
PMID: 34108509
ISSN: 2045-2322
CID: 4900082

Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients

Vidoni, Eric D; Choi, In-Young; Lee, Phil; Reed, Gregory; Zhang, Na; Pleen, Joseph; Mahnken, Jonathan D; Clutton, Jonathan; Becker, Annette; Sherry, Erica; Bothwell, Rebecca; Anderson, Heidi; Harris, Robert A; Brooks, William; Wilkins, Heather M; Mosconi, Lisa; Burns, Jeffrey M; Swerdlow, Russell H
INTRODUCTION/BACKGROUND:Brain bioenergetics are defective in Alzheimer's disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement data are lacking. METHODS:We orally administered 500 or 1000 mg OAA, twice daily for 1 month, to AD participants (n = 15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, we performed fluorodeoxyglucose positron emission tomography (FDG PET) and magnetic resonance spectroscopy before and after the intervention. We also assessed pharmacokinetics and cognitive performance. RESULTS:Both doses were safe and tolerated. Compared to the lower dose, the higher dose benefited FDG PET glucose uptake across multiple brain regions (P < .05), and the higher dose increased parietal and frontoparietal glutathione (P < .05). We did not demonstrate consistent blood level changes and cognitive scores did not improve. CONCLUSIONS:1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.
PMID: 32715609
ISSN: 1552-5279
CID: 4540092

Sex-driven modifiers of Alzheimer risk: A multimodality brain imaging study

Rahman, Aneela; Schelbaum, Eva; Hoffman, Katherine; Diaz, Ivan; Hristov, Hollie; Andrews, Randolph; Jett, Steven; Jackson, Hande; Lee, Andrea; Sarva, Harini; Pahlajani, Silky; Matthews, Dawn; Dyke, Jonathan; de Leon, Mony J; Isaacson, Richard S; Brinton, Roberta D; Mosconi, Lisa
OBJECTIVE:F-fluorodeoxyglucose [FDG] PET and structural MRI). METHODS:status, family history), medical (e.g., depression, diabetes mellitus, hyperlipidemia), hormonal (e.g., thyroid disease, menopause), and lifestyle AD risk factors (e.g., smoking, diet, exercise, intellectual activity) were assessed. Statistical parametric mapping and least absolute shrinkage and selection operator regressions were used to compare AD biomarkers between men and women and to identify the risk factors associated with sex-related differences. RESULTS:< 0.05, family-wise error corrected for multiple comparisons). The male group did not show biomarker abnormalities compared to the female group. Results were independent of age and remained significant with the use of age-matched groups. Second to female sex, menopausal status was the predictor most consistently and strongly associated with the observed brain biomarker differences, followed by hormone therapy, hysterectomy status, and thyroid disease. CONCLUSION/CONCLUSIONS:Hormonal risk factors, in particular menopause, predict AD endophenotype in middle-aged women. These findings suggest that the window of opportunity for AD preventive interventions in women is early in the endocrine aging process.
PMID: 32580974
ISSN: 1526-632x
CID: 4493352

Individualized clinical management of patients at risk for Alzheimer's dementia

Isaacson, Richard S; Hristov, Hollie; Saif, Nabeel; Hackett, Katherine; Hendrix, Suzanne; Melendez, Juan; Safdieh, Joseph; Fink, Matthew; Thambisetty, Madhav; Sadek, George; Bellara, Sonia; Lee, Paige; Berkowitz, Cara; Rahman, Aneela; Meléndez-Cabrero, Josefina; Caesar, Emily; Cohen, Randy; Lu, Pei-Lin; Dickson, Samuel P; Hwang, Mu Ji; Scheyer, Olivia; Mureb, Monica; Schelke, Matthew W; Niotis, Kellyann; Greer, Christine E; Attia, Peter; Mosconi, Lisa; Krikorian, Robert
INTRODUCTION/BACKGROUND:Multidomain intervention for Alzheimer's disease (AD) risk reduction is an emerging therapeutic paradigm. METHODS:Patients were prescribed individually tailored interventions (education/pharmacologic/nonpharmacologic) and rated on compliance. Normal cognition/subjective cognitive decline/preclinical AD was classified as Prevention. Mild cognitive impairment due to AD/mild-AD was classified as Early Treatment. Change from baseline to 18 months on the modified Alzheimer's Prevention Cognitive Composite (primary outcome) was compared against matched historical control cohorts. Cognitive aging composite (CogAging), AD/cardiovascular risk scales, and serum biomarkers were secondary outcomes. RESULTS:One hundred seventy-four were assigned interventions (age 25-86). Higher-compliance Prevention improved more than both historical cohorts (P = .0012, P < .0001). Lower-compliance Prevention also improved more than both historical cohorts (P = .0088, P < .0055). Higher-compliance Early Treatment improved more than lower compliance (P = .0007). Higher-compliance Early Treatment improved more than historical cohorts (P < .0001, P = .0428). Lower-compliance Early Treatment did not differ (P = .9820, P = .1115). Similar effects occurred for CogAging. AD/cardiovascular risk scales and serum biomarkers improved. DISCUSSION/CONCLUSIONS:Individualized multidomain interventions may improve cognition and reduce AD/cardiovascular risk scores in patients at-risk for AD dementia.
PMID: 31677936
ISSN: 1552-5279
CID: 4171902

Sleep oscillation-specific associations with Alzheimer's disease CSF biomarkers: novel roles for sleep spindles and tau

Kam, Korey; Parekh, Ankit; Sharma, Ram A; Andrade, Andreia; Lewin, Monica; Castillo, Bresne; Bubu, Omonigho M; Chua, Nicholas J; Miller, Margo D; Mullins, Anna E; Glodzik, Lidia; Mosconi, Lisa; Gosselin, Nadia; Prathamesh, Kulkarni; Chen, Zhe; Blennow, Kaj; Zetterberg, Henrik; Bagchi, Nisha; Cavedoni, Bianca; Rapoport, David M; Ayappa, Indu; de Leon, Mony J; Petkova, Eva; Varga, Andrew W; Osorio, Ricardo S
BACKGROUND:, P-tau, and T-tau with sleep spindle density and other biophysical properties of sleep spindles in a sample of cognitively normal elderly individuals. METHODS:, P-tau and T-tau. Seven days of actigraphy were collected to assess habitual total sleep time. RESULTS:, P-tau and T-tau. From the three, CSF T-tau was the most significantly associated with spindle density, after adjusting for age, sex and ApoE4. 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 between sleep spindle characteristics and the CSF biomarkers of AD. CONCLUSIONS:Reduced spindles during N2 sleep may represent an early dysfunction related to tau, possibly reflecting axonal damage or altered neuronal tau secretion, rendering it a potentially novel biomarker for early neuronal dysfunction. Given their putative role in memory consolidation and neuroplasticity, sleep spindles may represent a mechanism by which tau impairs memory consolidation, as well as a possible target for therapeutic interventions in cognitive decline.
PMID: 30791922
ISSN: 1750-1326
CID: 3686652

Sex and Gender Driven Modifiers of Alzheimer's: The Role for Estrogenic Control Across Age, Race, Medical, and Lifestyle Risks

Rahman, Aneela; Jackson, Hande; Hristov, Hollie; Isaacson, Richard S; Saif, Nabeel; Shetty, Teena; Etingin, Orli; Henchcliffe, Claire; Brinton, Roberta Diaz; Mosconi, Lisa
Research indicates that after advanced age, the major risk factor for late-onset Alzheimer's disease (AD) is female sex. Out of every three AD patients, two are females with postmenopausal women contributing to over 60% of all those affected. Sex- and gender-related differences in AD have been widely researched and several emerging lines of evidence point to different vulnerabilities that contribute to dementia risk. Among those being considered, it is becoming widely accepted that gonadal steroids contribute to the gender disparity in AD, as evidenced by the "estrogen hypothesis." This posits that sex hormones, 17β-estradiol in particular, exert a neuroprotective effect by shielding females' brains from disease development. This theory is further supported by recent findings that the onset of menopause is associated with the emergence of AD-related brain changes in women in contrast to men of the same age. In this review, we discuss genetic, medical, societal, and lifestyle risk factors known to increase AD risk differently between the genders, with a focus on the role of hormonal changes, particularly declines in 17β-estradiol during the menopause transition (MT) as key underlying mechanisms.
PMCID:6872493
PMID: 31803046
ISSN: 1663-4365
CID: 4218752

The clinical practice of risk reduction for Alzheimer's disease: A precision medicine approach

Isaacson, Richard S; Ganzer, Christine A; Hristov, Hollie; Hackett, Katherine; Caesar, Emily; Cohen, Randy; Kachko, Robert; Meléndez-Cabrero, Josefina; Rahman, Aneela; Scheyer, Olivia; Hwang, Mu Ji; Berkowitz, Cara; Hendrix, Suzanne; Mureb, Monica; Schelke, Matthew W; Mosconi, Lisa; Seifan, Alon; Krikorian, Robert
Like virtually all age-related chronic diseases, late-onset Alzheimer's disease (AD) develops over an extended preclinical period and is associated with modifiable lifestyle and environmental factors. We hypothesize that multimodal interventions that address many risk factors simultaneously and are individually tailored to patients may help reduce AD risk. We describe a novel clinical methodology used to evaluate and treat patients at two Alzheimer's Prevention Clinics. The framework applies evidence-based principles of clinical precision medicine to tailor individualized recommendations, follow patients longitudinally to continually refine the interventions, and evaluate N-of-1 effectiveness (trial registered at ClinicalTrials.gov NCT03687710). Prior preliminary results suggest that the clinical practice of AD risk reduction is feasible, with measurable improvements in cognition and biomarkers of AD risk. We propose using these early findings as a foundation to evaluate the comparative effectiveness of personalized risk management within an international network of clinician researchers in a cohort study possibly leading to a randomized controlled trial.
PMID: 30446421
ISSN: 1552-5279
CID: 3479132

Associations of lifestyle and vascular risk factors with Alzheimer's brain biomarker changes during middle age: a 3-year longitudinal study in the broader New York City area

Walters, Michelle J; Sterling, Joanna; Quinn, Crystal; Ganzer, Christine; Osorio, Ricardo S; Andrews, Randolph D; Matthews, Dawn C; Vallabhajosula, Shankar; de Leon, Mony J; Isaacson, Richard S; Mosconi, Lisa
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.
PMID: 30478117
ISSN: 2044-6055
CID: 3500262

How would we combat menopause as an Alzheimer's risk factor?

Mosconi, Lisa; Brinton, Roberta Diaz
PMID: 30091648
ISSN: 1744-8360
CID: 3226642

Precision Medicine for Alzheimer's Disease Prevention

Berkowitz, Cara L; Mosconi, Lisa; Scheyer, Olivia; Rahman, Aneela; Hristov, Hollie; Isaacson, Richard S
Precision medicine is an approach to medical treatment and prevention that takes into account individual variability in genes, environment, and lifestyle and allows for personalization that is based on factors that may affect the response to treatment. Several genetic and epigenetic risk factors have been shown to increase susceptibility to late-onset Alzheimer's disease (AD). As such, it may be beneficial to integrate genetic risk factors into the AD prevention approach, which in the past has primarily been focused on universal risk-reduction strategies for the general population rather than individualized interventions in a targeted fashion. This review discusses examples of a "one-size-fits-all" versus clinical precision medicine AD prevention strategy, in which the precision medicine approach considers two genes that can be commercially sequenced for polymorphisms associated with AD, apolipoprotein E (APOE), and methylenetetrahydrofolate reductase (MTHFR). Comparing these two distinct approaches provides support for a clinical precision medicine prevention strategy, which may ultimately lead to more favorable patient outcomes as the interventions are targeted to address individualized risks.
PMID: 30011822
ISSN: 2227-9032
CID: 3200532