Angiotensin converting enzyme inhibitors and Alzheimer disease in the presence of the apolipoprotein E4 allele.

OBJECTIVE: The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. METHODS: This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. RESULTS: A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08-140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education. CONCLUSION: The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers.

Cognition Mediates the Association Between Cerebrospinal Fluid Biomarkers of Amyloid and P-Tau and Neuropsychiatric Symptoms.

Background: Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer's disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. Objective: We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aß1-42, p-tau181), cognitive function, and NPS. Methods: Primary models included 781 participants from the National Alzheimer's Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR®) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOEɛ4. Results: The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau181/Aß1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau181/Aß1-42 ratio and CDR global impairment. With dementia excluded, p-tau181/Aß1-42 ratio was no longer associated with the NPI-Q. Conclusions: NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia.

Identification of an APOE ε4-specific blood-based molecular pathway for Alzheimer's disease risk.

INTRODUCTION: The precise apolipoprotein E (APOE) ε4-specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear. METHODS: Plasma protein modules/cascades were analyzed using weighted gene co-expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), and brain glucose metabolism, stratified by APOE genotype. RESULTS: The Green Module was associated with AD diagnosis in APOE ε4 homozygotes. Three proteins from this module, C-reactive protein (CRP), complement C3, and complement factor H (CFH), had dose-dependent associations with CSF p-tau and cognitive impairment only in APOE ε4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE ε4 homozygotes. A Framingham Heart Study validation study supported the findings for AD. DISCUSSION: The study identifies the APOE ε4-specific CRP-C3-CFH inflammation pathway for AD, suggesting potential drug targets for the disease.Highlights: Identification of an APOE ε4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD.CRP, C3, and CFH had dose-dependent associations with CSF p-Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE ε4 homozygotes.Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE ε4 carriers.

Palpable multifocal and multicentric invasive lobular breast carcinoma in a young female.

Breast cancer is the most common carcinoma plaguing women in the United States. Invasive lobular carcinoma is the second most prevalent type of breast carcinoma with an incidence rate of 5% and 15% with high propensity for multifocal manifestation of disease. Multifocal disease is defined by two or more malignant foci within a single quadrant. Invasive lobular carcinoma is strongly associated with early menarche, late menopause, late age at first birth, and is typically seen in women ages 50 and older. Invasive lobular carcinoma can be difficult to detect clinically because lesions typically fail to form palpable masses, and it can be challenging to diagnose mammographically due to subtle imaging features of the lesions. Here we present a rare case of a palpable, unilateral, multifocal and multicentric lobular breast carcinoma in a young, previously healthy 41-year-old woman with no family history of breast cancer.

Clinical implications of chemotherapeutic agent organ toxicity on perioperative care.

Cancer is the second most common cause of death in the United States and is a challenging disease to treat. The treatment options for various cancers include but are not limited to surgery, radiation, and chemotherapy. The mechanism behind chemotherapy is intended to promote cellular damage to cells that are proliferating uncontrollably. Unfortunately for the recipients, most chemotherapeutic agents cannot differentiate between malignant cells and healthy cells and tissues. Thus, chemotherapy-induced toxicities are often observed in once-healthy organs. These effects can be acute and self-limiting or chronic, appearing long after chemotherapy is completed. Cancer survivors can then present for non-cancer related surgeries later in life, due to this toxicity. Furthermore, the administration of chemotherapeutic agents can profoundly impact the anesthetic management of patients who are undergoing surgery. This review discusses how chemotherapy-induced organ toxicity can occur in multiple organ systems and what drugs should be avoided if prior toxicity exists in these organ systems.

A longitudinal examination of plasma neurofilament light and total tau for the clinical detection and monitoring of Alzheimer's disease.

We examined baseline and longitudinal associations between plasma neurofilament light (NfL) and total tau (t-tau), and the clinical presentation of Alzheimer's disease (AD). A total of 579 participants (238, normal cognition [NC]; 185, mild cognitive impairment [MCI]; 156, AD dementia) had baseline blood draws; 82% had follow-up evaluations. Plasma samples were analyzed for NfL and t-tau using Simoa technology. Baseline plasma NfL was higher in AD dementia than MCI (standardized mean difference = 0.55, 95% CI: 0.37-0.73) and NC (standardized mean difference = 0.68, 95% CI: 0.49-0.88), corresponded to Clinical Dementia Rating scores (OR = 1.94, 95% CI: 1.35-2.79]), and correlated with all neuropsychological tests (r's = 0.13-0.42). Longitudinally, NfL did not predict diagnostic conversion but predicted decline on 3/10 neuropsychological tests. Baseline plasma t-tau was higher in AD dementia than NC with a small effect (standardized mean difference = 0.33, 95% CI: 0.10-0.57) but not MCI. t-tau did not statistically significant predict any longitudinal outcomes. Plasma NfL may be useful for the detection of AD dementia and monitoring of disease progression. In contrast, there was minimal evidence in support of plasma t-tau.

The homocysteine hypothesis of depression.

High levels of homocysteine are associated with cerebrovascular disease, monoamine neurotransmitters, and depression of mood. A plausible hypothesis for these associations is that high homocysteine levels cause cerebral vascular disease and neurotransmitter deficiency, which cause depression of mood. The homocysteine depression hypothesis, if true, would mandate inclusions of imaging studies for cerebrovascular disease and measures of homocysteine, folate, and B12 and B6 vitamins in the clinical evaluation of older depressed patients. Longitudinal studies and clinical trials should be designed to challenge the hypothesis.

A SUMO-ubiquitin relay recruits proteasomes to chromosome axes to regulate meiotic recombination.

Meiosis produces haploid gametes through a succession of chromosomal events, including pairing, synapsis, and recombination. Mechanisms that orchestrate these events remain poorly understood. We found that the SUMO (small ubiquitin-like modifier)-modification and ubiquitin-proteasome systems regulate the major events of meiotic prophase in mouse. Interdependent localization of SUMO, ubiquitin, and proteasomes along chromosome axes was mediated largely by RNF212 and HEI10, two E3 ligases that are also essential for crossover recombination. RNF212-dependent SUMO conjugation effected a checkpointlike process that stalls recombination by rendering the turnover of a subset of recombination factors dependent on HEI10-mediated ubiquitylation. We propose that SUMO conjugation establishes a precondition for designating crossover sites via selective protein stabilization. Thus, meiotic chromosome axes are hubs for regulated proteolysis via SUMO-dependent control of the ubiquitin-proteasome system.