Abstract Background Hypertension and diabetes have each been associated with an increased risk of progression to Alzheimer’s disease (AD) dementia. Here, we investigated their combined impact on progression from cognitively normal to clinically‐diagnosed AD. Method Cognitively normal individuals from the National Alzheimer’s Coordinating Center were identified as having neither hypertension nor diabetes (HTN‐/DM‐), hypertension without diabetes (HTN+/DM‐), or hypertension with diabetes (HTN+/DM+). The presence of HTN and DM were based on their diagnosis from recent medical history or medication use. This study investigated whether HTN+/DM‐ or HTN+/DM+ were predictors of progression to clinically‐diagnosed AD compared to HTN‐/DM‐. In a subgroup analysis with post‐mortem data, we investigated whether HTN+/DM‐, and HTN+/DM+ were predictors of progression to clinically diagnosed AD due to underlying AD‐ and/or vascular neuropathology. Result This study included N = 11074 cognitively normal individuals (mean age: 71.7 (9.0), MMSE: 28.9 (1.4), male: N = 3818 (34%)). Approximately 7% (N = 830) progressed to clinically‐diagnosed AD, and the average duration of follow‐up was 5.2 (3.6) years. Forty‐two percent (N = 4608) were HTN‐/DM‐, 45% (N = 5034) were HTN+/DM‐, and 13% (N = 1432) were HTN+/DM+. Both HTN+/DM‐ (hazard ratio (HR): 1.24 (1.17‐1.32), p<.001), and HTN+/DM+ (HR: 1.31 (1.19‐1.44), p<.001) were significant predictors of progression to clinically‐diagnosed AD. Subgroup analyses with post‐mortem data (N = 919) demonstrated that compared to HTN‐/DM‐, those with HTN+/DM‐ had a higher risk of progressing to clinically‐diagnosed AD with underlying cerebrovascular disease (CVD) neuropathology (HR: 1.54 (1.17‐2.03), p = .002), whereas those with HTN+/DB+ had a higher risk of progression to clinically‐diagnosed AD with underlying AD (HR: 2.10 (1.16‐3.79), p = .01) and cerebral amyloid angiopathy (CAA) neuropathology (HR: 1.52 (1.09‐2.12), p = .01). Conclusion These findings demonstrate that underlying CVD neuropathology contributes to the risk of clinically‐diagnosed AD in individuals with HTN+/DM‐, while both AD and CAA neuropathology contributes to the risk of clinically‐diagnosed AD in individuals with HTN+/DM+. This suggests that individuals with HTN+/DM‐ and HTN+/DM+ vary phenotypically and may warrant the need for different treatment strategies to reduce the future risk of AD.
Elevated vascular risk and beta-amyloid (Aβ) burden have been synergistically associated with cognitive decline in preclinical Alzheimer's disease (AD), although the underlying mechanisms remain unclear. We examined whether accelerated longitudinal tau accumulation mediates the vascular risk-Aβ interaction on cognitive decline.We included 175 cognitively unimpaired older adults (age 70.5 ± 8.0 years). Baseline vascular risk was quantified using the office-based Framingham Heart Study general cardiovascular disease risk score (FHS-CVD). Baseline Aβ burden was measured with Pittsburgh Compound-B positron emission tomography (PET). Tau burden was measured longitudinally (3.6 ± 1.5 years) with Flortaucipir PET, focusing on inferior temporal cortex (ITC). Cognition was assessed longitudinally (7.0 ± 2.0 years) using the Preclinical Alzheimer's Cognitive Composite. Linear mixed effects models examined the interactive effects of baseline vascular risk and Aβ on longitudinal ITC tau. Additionally, moderated mediation was used to determine whether tau accumulation mediated the FHS-CVD*Aβ effect on cognitive decline.We observed a significant interaction between elevated baseline FHS-CVD and Aβ on greater ITC tau accumulation (p = 0.004), even in individuals with Aβ burden below the conventional threshold for amyloid positivity. Examining individual vascular risk factors, we found elevated systolic blood pressure and body mass index showed independent interactions with Aβ on longitudinal tau (both p < 0.0001). ITC tau accumulation mediated 33% of the interactive association of FHS-CVD and Aβ on cognitive decline.Vascular risks interact with subthreshold levels of Aβ to promote cognitive decline, partially by accelerating early neocortical tau accumulation. Our findings support vascular risk reduction, especially treating hypertension and obesity, to attenuate Aβ-related tau pathology and reduce late-life cognitive decline. ANN NEUROL 2022;92:745-755.
In the absence of disease-modifying therapies for Alzheimer disease, there is a critical need to identify modifiable risk factors that may delay the progression of Alzheimer disease.To examine whether physical activity moderates the association of β-amyloid (Aβ) burden with longitudinal cognitive decline and neurodegeneration in clinically normal individuals and to examine whether these associations are independent of vascular risk.This longitudinal observational study included clinically normal participants from the Harvard Aging Brain Study. Participants were required to have baseline Aβ positron emission tomography data, baseline medical data to quantify vascular risk, and longitudinal neuropsychological and structural magnetic resonance imaging data. Data were collected from April 2010 to June 2018. Data were analyzed from August to December 2018.Baseline physical activity was quantified with a pedometer (mean steps per day). Baseline Aβ burden was measured with carbon 11-labeled Pittsburgh Compound B positron emission tomography. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite (PACC; median [interquartile range] follow-up, 6.0 [4.3-6.3] years). Neurodegeneration was assessed with longitudinal structural magnetic resonance imaging (2 to 5 scans per participant; median [interquartile range] follow-up, 4.5 [3.0-5.0] years), with a focus on total gray matter volume and regional cortical thickness. Physical activity and Aβ burden were examined as interactive predictors of PACC decline and volume loss in separate linear mixed models, adjusting for age, sex, education, apolipoprotein E ε4 status, and, where appropriate, intracranial volume. Secondary models adjusted for vascular risk and its interaction with Aβ burden.Of the 182 included participants, 103 (56.6%) were female, and the mean (SD) age was 73.4 (6.2) years. In models examining PACC decline and volume loss, there was a significant interaction of physical activity with Aβ burden, such that greater physical activity was associated with slower Aβ-related cognitive decline (β, 0.03; 95% CI, 0.02-0.05; P < .001) and volume loss (β, 482.07; 95% CI, 189.40-774.74; P = .002). Adjusting for vascular risk did not alter these associations. In these models, lower vascular risk was independently associated with slower Aβ-related PACC decline (β, -0.04; 95% CI, -0.06 to -0.02; P < .001) and volume loss (β, -483.41; 95% CI, -855.63 to -111.20; P = .01).Greater physical activity and lower vascular risk independently attenuated the negative association of Aβ burden with cognitive decline and neurodegeneration in asymptomatic individuals. These findings suggest that engaging in physical activity and lowering vascular risk may have additive protective effects on delaying the progression of Alzheimer disease.
Recently, the amnesic case D.A. was shown to circumvent his relational memory impairments, as observed in the transverse patterning (TP) task, using a self-generated unitization strategy, and such performance benefits were maintained over extended delays (Ryan et al., 2013). "Unitization" encourages fusing of distinct items, through an action, into a single unit from which the relations among the items may then be derived. Here, we provide the first documentation of the developmental amnesic case, N.C., who presents with relatively circumscribed lesions to the extended hippocampal system, and with impaired episodic memory. Despite impairments on standard versions of TP, N.C. benefited from unitization, showed evidence of transfer to novel stimuli, and maintained his performance over extended delays. These findings suggest that self-generation is not a requirement for the successful implementation of unitization, and further provides the first evidence of rapid transfer and long-lasting success of a learning strategy in a human amnesic case.
Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant depression (TRD). Although adverse effects have been reported in early-phase and a few randomized clinical trials, little is known about its overall safety profile, which has been assumed to be similar to that of DBS for movement disorders. The objective of this study was to pool existing safety data on DBS for TRD. Following PRISMA guidelines, PubMed was searched for English articles describing adverse outcomes after DBS for TRD. Studies were included if they reported at least 5 patients with a minimal follow-up of 6 months. After abstract (n = 607) and full-article review (n = 127), 28 articles reporting on 353 patients met criteria for final inclusion. Follow-up of the studies retrieved ranged from 12 to 96 months. Hemorrhages occurred in 0.8% of patients and infections in 10.2%. The rate of completed suicide was 2.5%. Development or worsening of depressive symptoms, anxiety, and mania occurred in 18.4%, 9.1%, and 5.1%, respectively. There were some differences between targets, but between-study heterogeneity precluded statistical comparisons. In conclusion, DBS for TRD is associated with surgical and psychiatric adverse events. Hemorrhage and infection occur at rates within an accepted range for other DBS applications. The risk of suicide after DBS for TRD is 2.5% but may not represent a significant deviation from the natural history of TRD. Finally, risks of worsening depression, anxiety, and the incidence of mania should be acknowledged when considering DBS for TRD.
Background Neurological symptoms associated with coronavirus disease 2019 (COVID‐19), such as fatigue and smell/taste changes, persist beyond infection. However, little is known of brain physiology in the post‐COVID‐19 timeframe. Purpose To determine whether adults who experienced flu‐like symptoms due to COVID‐19 would exhibit cerebral blood flow (CBF) alterations in the weeks/months beyond infection, relative to controls who experienced flu‐like symptoms but tested negative for COVID‐19. Study Type Prospective observational. Population A total of 39 adults who previously self‐isolated at home due to COVID‐19 (41.9 ± 12.6 years of age, 59% female, 116.5 ± 62.2 days since positive diagnosis) and 11 controls who experienced flu‐like symptoms but had a negative COVID‐19 diagnosis (41.5 ± 13.4 years of age, 55% female, 112.1 ± 59.5 since negative diagnosis). Field Strength and Sequences A 3.0 T; T1 ‐weighted magnetization‐prepared rapid gradient and echo‐planar turbo gradient‐spin echo arterial spin labeling sequences. Assessment Arterial spin labeling was used to estimate CBF. A self‐reported questionnaire assessed symptoms, including ongoing fatigue. CBF was compared between COVID‐19 and control groups and between those with ( n = 11) and without self‐reported ongoing fatigue ( n = 28) within the COVID‐19 group. Statistical Tests Between‐group and within‐group comparisons of CBF were performed in a voxel‐wise manner, controlling for age and sex, at a family‐wise error rate of 0.05. Results Relative to controls, the COVID‐19 group exhibited significantly decreased CBF in subcortical regions including the thalamus, orbitofrontal cortex, and basal ganglia (maximum cluster size = 6012 voxels and maximum t ‐statistic = 5.21). Within the COVID‐19 group, significant CBF differences in occipital and parietal regions were observed between those with and without self‐reported on‐going fatigue. Data Conclusion These cross‐sectional data revealed regional CBF decreases in the COVID‐19 group, suggesting the relevance of brain physiology in the post‐COVID‐19 timeframe. This research may help elucidate the heterogeneous symptoms of the post‐COVID‐19 condition. Evidence Level 2. Technical Efficacy Stage 3.
Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Standard treatment for operable patients with single peripheral lung metastases is metastasectomy. We report mature CyberKnife outcomes for high-risk surgical patients with biopsy proven single peripheral lung metastases. Twenty-four patients (median age 73 years) with a mean maximum tumor diameter of 2.5 cm (range, 0.8-4.5 cm) were treated over a 6-year period extending from September 2004 to September 2010 and followed for a minimum of 1 year or until death. A mean dose of 52 Gy (range, 45-60 Gy) was delivered to the prescription isodose line in three fractions over a 3-11 day period (mean, 7 days). At a median follow-up of 20 months, the 2-year Kaplan-Meier local control and overall survival rates were 87 and 50%, respectively. CyberKnife with fiducial tracking is an effective treatment for high-risk surgical patients with single small peripheral lung metastases. Trials comparing CyberKnife with metastasectomy for operable patients are necessary to confirm equivalence.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
