Estrogen-Only Hormone Therapy and Dementia Wood Alexander, Madeline; Einstein, Gillian; Rabin, Jennifer S
JAMA : the journal of the American Medical Association,
05/2024, Letnik:
331, Številka:
18
Journal Article
Objectives
Amyloid‐beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and ...interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated.
Methods
One hundred thirty‐seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aβ (11C‐Pittsburgh compound B) and tau (18F‐flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aβ PET measures were assessed in regions of interest (ROIs) as well as vertex‐wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites.
Results
Higher levels of Aβ and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aβ was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aβ. A significant interaction between tau and Aβ was observed in both ROI and map‐level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies.
Interpretation
Our results are consistent with the supposition that both Aβ and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1–3 ANN NEUROL 2019;85:181–193.
Humans have the capacity to form new memories of events that are, at times, highly similar to events experienced in the past, as well as the capacity to integrate and associate new information within ...existing knowledge structures. The former process relies on mnemonic discrimination and is believed to depend on hippocampal pattern separation, whereas the latter is believed to depend on generalization signals and conceptual categorization supported by the neocortex. Here, we examine whether and how the ventromedial prefrontal cortex (vMPFC) supports discrimination and generalization on a widely used task that was primarily designed to tax hippocampal processes. Ten individuals with lesions to the vMPFC and 46 neurotypical control participants were administered an adapted version of the mnemonic similarity task Stark, S. M., Yassa, M. A., Lacy, J. W., & Stark, C. E. L. A task to assess behavioral pattern separation (BPS) in humans: Data from healthy aging and mild cognitive impairment. Neuropsychologia, 51, 2442-2449, 2013, which assesses the ability to distinguish previously learned images of everyday objects (targets) from unstudied, highly similar images (lures) and dissimilar images (foils). Relative to controls, vMPFC-lesioned individuals showed intact discrimination of lures from targets but a propensity to mistake studied targets and similar lures for dissimilar foils. This pattern was accompanied by inflated confidence despite low accuracy when responding to similar lures. These findings demonstrate a more general role of the vMPFC in memory retrieval, rather than a specific role in supporting pattern separation.
Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with ...men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals.
To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET).
This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women 61%) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women 51%) who underwent florbetapir and flortaucipir F 18 PET.
A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined.
The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers 31%; 89 individuals 30% with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β male = -0.11 0.05; 95% CI, -0.21 to -0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β male, APOE ε4+ = -0.15 0.09; 95% CI, -0.32 to 0.01; P = .07).
Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.
We investigated the effect of baseline Aβ, sex, and APOE on longitudinal tau accumulation in cerebrospinal fluid (CSF) in clinically normal older adults. Two hundred thirty-nine participants (aged ...56–89 years, clinical dementia rating = 0) underwent serial CSF collection for Aβ1–42, total-tau (t-tau) and phospho-tau181P (p-tau). We used preprocessed data from fully automated Roche Elecsys immunoassays. A series of linear regressions were used to examine cross-sectional effects of Aβ1–42, sex, and APOEε4 on baseline CSF tau and linear mixed models for longitudinal changes in CSF tau. Cross-sectionally, CSF t-tau and p-tau were associated with abnormal Aβ1–42 and APOEε4 but not with sex. Longitudinally, low baseline CSF Aβ1–42 levels, but not APOEε4 or sex, predicted faster p-tau accumulation. The relationship between baseline CSF Aβ1–42 and tau accumulation was strongest in APOEε4 carriers, and particularly female carriers, relative to other groups. The current findings support an association between baseline CSF Aβ1–42 and changes in CSF tau. Elevated risk in females, apparent only in carriers, reinforces findings of sex-related vulnerability in those with genetic predisposition for Alzheimer's disease.
•No sex, sex-APOE, or sex-Aβ1–42 effects on baseline CSF tau in healthy older adults.•Accelerated CSF t-tau and p-tau change in older adults with lower CSF Aβ1–42.•Female APOEɛ4 carriers with low Aβ1–42 show trends of greater CSF tau change.
Identifying asymptomatic individuals at high risk of impending cognitive decline because of Alzheimer disease is crucial for successful prevention of dementia. Vascular risk and β-amyloid (Aβ) ...pathology commonly co-occur in older adults and are significant causes of cognitive impairment.
To determine whether vascular risk and Aβ burden act additively or synergistically to promote cognitive decline in clinically normal older adults; and, secondarily, to evaluate the unique influence of vascular risk on prospective cognitive decline beyond that of commonly used imaging biomarkers, including Aβ burden, hippocampal volume, fludeoxyglucose F18-labeled (FDG) positron emission tomography (PET), and white matter hyperintensities, a marker of cerebrovascular disease.
In this longitudinal observational study, we examined clinically normal older adults from the Harvard Aging Brain Study. Participants were required to have baseline imaging data (FDG-PET, Aβ-PET, and magnetic resonance imaging), baseline medical data to quantify vascular risk, and at least 1 follow-up neuropsychological visit. Data collection began in 2010 and is ongoing. Data analysis was performed on data collected between 2010 and 2017.
Vascular risk was quantified using the Framingham Heart Study general cardiovascular disease (FHS-CVD) risk score. We measured Aβ burden with Pittsburgh Compound-B PET. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite. Models were corrected for baseline age, sex, years of education, and apolipoprotein E ε4 status.
Of the 223 participants, 130 (58.3%) were women. The mean (SD) age was 73.7 (6.0) years, and the mean (SD) follow-up time was 3.7 (1.2) years. Faster cognitive decline was associated with both a higher FHS-CVD risk score (β = -0.064; 95% CI, -0.094 to -0.033; P < .001) and higher Aβ burden (β = -0.058; 95% CI, -0.079 to -0.037; P < .001). The interaction of the FHS-CVD risk score and Aβ burden with time was significant (β = -0.040, 95% CI, -0.062 to -0.018; P < .001), suggesting a synergistic effect. The FHS-CVD risk score remained robustly associated with prospective cognitive decline (β = -0.055; 95% CI, -0.086 to -0.024; P < .001), even after adjustment for Aβ burden, hippocampal volume, FDG-PET uptake, and white matter hyperintensities.
In this study, vascular risk was associated with prospective cognitive decline in clinically normal older adults, both alone and synergistically with Aβ burden. Vascular risk may complement imaging biomarkers in assessing risk of prospective cognitive decline in preclinical Alzheimer disease.
•We analyzed data of depressed patients receiving transcranial magnetic stimulation.•Nearly half of these patients had depression with a seasonal pattern.•Patients with seasonal pattern improved ...similar to those without seasonal pattern.
Individuals with major depressive disorder (MDD) may exhibit a seasonal pattern. The impact of a seasonal pattern in depressive symptoms on rTMS outcomes is unexplored. A retrospective analysis was performed on patients with MDD receiving open-label high frequency rTMS to the left dorsolateral prefrontal cortex. Having a seasonal pattern was defined as scoring ≥ 12 on the Personal Inventory for Depression and Seasonal Affective Disorder (PIDS). Primary outcomes included improvement in the Hamilton Depression Rating Scale (HAMD) and remission. Secondary analyses included the use of the self-rated Quick Inventory of Depressive Symptomatology (QIDS) to assess for changes in atypical neurovegetative symptoms. Multiple linear regression, multiple logistic regression, and linear mixed effects analyses were performed. 46 % (58/127) of the sample had a seasonal pattern. Seasonal pattern did not significantly influence improvement in HAMD (PIDS < 12, 7.8, SD 5.9; PIDS ≥ 12, 10.4, SD 4.9 or remission (PIDS < 12, 30 %; PIDS ≥ 12, 34 %). There were equivalent degrees of improvement in atypical neurovegetative symptoms over time as assessed using the QIDS. Depression with seasonal pattern was found to respond to rTMS treatment similarly to depression without seasonal pattern, suggesting that this may be a viable treatment for this group.
Background and Objectives
Cannabis is a widely used substance that may impair select cognitive domains, including attention and memory. Problematic cannabis use is a common clinical problem among ...patients with major depressive disorder (MDD). Few studies have investigated the effects of cannabis abstinence on cognition in MDD. Thus, our study aimed to determine whether a 28‐day period of cannabis abstinence is associated with improvements in cognition in patients with MDD and comorbid cannabis use disorder (CUD).
Methods
We evaluated the effects of 28 days of cannabis abstinence on cognition in MDD patients with comorbid CUD facilitated by contingency management, motivational interviewing, psychoeducation, and coping‐skills training (N = 11). Primary outcomes included Baseline to Day 28 changes in verbal memory and learning, while secondary outcomes included Baseline to Day 28 changes in working memory, visuospatial working memory (VSWM), visual search speed, mental flexibility, response inhibition, attention, manual dexterity, and fine motor movement.
Results
Eight participants (72.7%) met the pre‐specified criteria for cannabis abstinence and three participants significantly reduced their cannabis use (≥90%). Visual search speed, selective attention, and VSWM improved over the study period. These improvements were not associated with changes in cannabis metabolite levels from baseline to endpoint.
Discussion and Conclusions
Our findings suggest that 28 days of cannabis abstinence may improve select cognitive domains in patients with MDD and comorbid CUD.
Scientific Significance
This is the first study to longitudinally examine the effects of cannabis on cognition in MDD. Clinical trial: Effects of Cannabis Abstinence on Symptoms and Cognition in Depression (NCT03624933; https://www.clinicaltrials.gov).
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