Metabolic and Environmental Biomarkers in Mild Cognitive Impairment and Dementia: An Exploratory Study.

Objective: To determine the frequency with which suspected pathogenic factors, including metals and metabolites that might contribute to Alzheimer's disease (AD), may be found in patients with cognitive impairment through commonly available blood tests. Methods: A variety of serum studies, including metals, ammonia, homocysteine, vitamin B12, folate, thyroid tests, metabolic products, and inflammatory markers, were measured in two cohorts: one meeting mild cognitive impairment (MCI) criteria and the other meeting mild-to-moderate dementia (DE) criteria. Medications these patients received were reviewed. Results: Metal abnormalities were detected in over half the subjects, including evidence of mercury, lead, and arsenic elevation as well as instances of excessive essential metals, iron (Fe), and copper. Some metal aberration was detected in 64% of the DE group and 66% of the MCI group. Females were more likely to have elevated copper, consistent with hormonal effects on copper excretion. Homocysteinemia was the most common abnormality, detected in 71% with DE and 67% with MCI, while methylmalonic acid was not elevated. Slight hyperammonemia was moderately common (38%) suggesting a hepatic factor in this subset. Findings of moderate insulin resistance were present in nearly half (44% DE, 52% MCI). Sixty of 65 (92%) had at least one abnormal biomarker and 60% had two or more. The most common drug taken by the total cohort was proton pump inhibitors at 22% DE and 38% MCI. Conclusions: This study suggests that both toxic metals and excessive vital metals such as copper and iron, as well as common metabolic and hepatic factors are detectable at both stages of MCI and DE. There appears to be a multiplicity of provocative factors leading to DE. Individualized interventions based on these parameters may be a means to reduce cognitive decline leading to DE. A more comprehensive prospective study of these environmental and metabolic factors with corrective early interventions appears warranted.

Association of ß-Amyloid Burden With Sleep Dysfunction and Cognitive Impairment in Elderly Individuals With Cognitive Disorders.

Importance: Evidence shows that sleep dysfunction and ß-amyloid (Aß) deposition work synergistically to impair brain function in individuals with normal cognition, increasing the risk of developing dementia later in life. However, whether Aß continues to play an integral role in sleep dysfunction after the onset of cognitive decline in individuals with dementia is unclear. Objective: To determine whether Aß deposition in the brain is associated with subjective measures of sleep quality and cognition in elderly individuals with cognitive disorders. Design, Setting, and Participants: A nested survey study was conducted at the Cognitive Disorders and Comprehensive Alzheimer Disease Center of Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. Participants included patients aged 65 years and older with cognitive disorders verified by neuropsychological testing. Eligible participants were identified from a referral center-based sample of patients who underwent fluorine 18-labeled florbetaben positron emission tomography imaging at Thomas Jefferson University Hospital as part of the multicenter Imaging Dementia-Evidence for Amyloid Scanning study. Data collection and analysis occurred between November 2018 and March 2019. Main Outcomes and Measures: Sleep quality was measured via responses to sleep questionnaires, Aß deposition was measured via fluorine 18-labeled florbetaben positron emission tomography, and cognition was measured via Mini-Mental State Examination (MMSE) performance. Results: Of the 67 eligible participants, 52 (77.6%) gave informed consent to participate in the study. Of the 52 enrolled participants (mean [SD] age, 76.6 [7.4] years), 27 (51.9%) were women. Daytime sleepiness was associated with Aß deposition in the brainstem (B = 0.0063; 95% CI, 0.001 to 0.012; P = .02), but not MMSE performance (B = -0.01; 95% CI, -0.39 to 0.37; P = .96). The number of nocturnal awakenings was associated with Aß deposition in the precuneus (B = 0.11; 95% CI, 0.06 to 0.17; P < .001) and poor MMSE performance (B = -2.13; 95% CI, -3.13 to -1.13; P < .001). Mediation analysis demonstrated an indirect association between Aß deposition and poor MMSE performance that relied on nocturnal awakenings as an intermediary (B = -3.99; 95% CI, -7.88 to -0.83; P = .01). Conclusions and Relevance: Nighttime sleep disruption may mediate the association between Aß and cognitive impairment, suggesting that there is an underlying sleep-dependent mechanism that links Aß burden in the brain to cognitive decline. Further elucidation of this mechanism may improve understanding of disease processes associated with Aß accumulation.

Cognition and Cerebral Infarction in Older Adults After Surgical Aortic Valve Replacement.

BACKGROUND: Aortic valve replacement (AVR) for calcific aortic stenosis is associated with high rates of perioperative stroke and silent cerebral infarcts on diffusion-weighted magnetic resonance imaging (MRI), but cognitive outcomes in elderly AVR patients compared with individuals with cardiac disease who do not undergo surgery are uncertain. METHODS: One hundred ninety AVR patients (mean age 76 ± 6 years) and 198 non-surgical participants with cardiovascular disease (mean age 74 ± 6 years) completed comprehensive cognitive testing at baseline (preoperatively) and 4 to 6 weeks and 1 year postoperatively. Surgical participants also completed perioperative stroke evaluations, including postoperative brain MRI. Mixed model analyses and reliable change scores examined cognitive outcomes. Stroke outcomes were evaluated in participants with and without postoperative cognitive dysfunction. RESULTS: From reliable change scores, only 12.4% of the surgical group demonstrated postoperative cognitive dysfunction at 4 to 6 weeks and 7.5% at 1 year. Although the surgical group had statistically significantly lower scores in working memory/inhibition 4 to 6 weeks after surgery, the groups did not differ at 1 year. In surgical participants, postoperative cognitive dysfunction was associated with a greater number (p < 0.01) and larger total volume (p < 0.01) of acute cerebral infarcts on MRI. CONCLUSIONS: In high-risk, aged participants undergoing surgical AVR for aortic stenosis, postoperative cognitive dysfunction was surprisingly limited and was resolved by 1 year in most. Postoperative cognitive dysfunction at 4 to 6 weeks was associated with more and larger acute cerebral infarcts.

The importance of multiple assessments of object knowledge in semantic dementia: the case of the familiar objects task.

Semantic dementia (SD) is characterized by a dramatic loss of conceptual knowledge about the meaning of words and the identity of objects. Previous research has suggested that SD patients' knowledge is differentially influenced by the disease and may decline at different degrees depending on a patient's everyday familiarity with certain items. However, no study has examined (a) semantic knowledge deterioration and (b) the potential significance of autobiographical experience for the maintenance of object concepts in the same cohort of SD patients by using comprehensive assessments of different aspects of object knowledge across an experience-based, distributed semantic memory network. Here, we tested four SD patients and three Alzheimer's disease (AD) control patients using a range of tasks - including naming, gesture generation, and autobiographical knowledge - with personally familiar objects or perceptually similar or different object analogs. Our results showed dissociations between performance on naming relative to other assessments of object knowledge between SD and AD patients, though we did not observe a reliable familiar objects advantage. We discuss different factors that may account for these findings, as well as their implications for research on SD.