Knopman, David S.

Prominent behavioral changes and language dysfunction are features of frontotemporal lobar degeneration (FTLD) but can also occur in AD. Recently, application of TAR DNA‐binding protein 43 (TDP‐43) antibody has been shown to be useful for demonstrating the pathologic lesions of FTLD‐U and FTLD‐MND. Since these cases might represent combined disorders (FTD and AD), we studied the utility of TDP‐43 staining to demonstrate inclusion bodies in brains of patients with clinical features of frontal or temporal lobe dysfunction but with autopsy features of AD. METHODS: Eight patients from 1998 to 2005 were identified, including 1 with combined pathologic features of FTLD‐U (previously identified with anti‐ubiquitin staining) and mild AD (Braak stage IV). Sections of hippocampus and frontal and temporal lobes were stained with anti‐TDP‐43 antibody (Proteintech Group). RESULTS: Of the 8 patients, 1 had advanced AD (Braak stage VI) and scattered TDP‐43 positive cytoplasmic inclusions in hippocampal dentate granular cells and frontal and temporal neocortical neurons. The previously identified patient with combined FTLD‐U and mild AD also had TDP‐43 positive cytoplasmic and nuclear inclusions. CONCLUSION: TDP‐43 aids in the identification of case with dual pathologies, particularly in advanced AD where inclusion may be masked by overwhelming AD pathology.

AbstractAmong individuals with dementia with Lewy bodies, pathologic correlates of clinical course include the presence and extent of coexisting Alzheimer’s pathology and the presence of transitional or diffuse Lewy body disease. The objectives of this study are to determine (i) whether 18F-fluorodeoxyglucose PET signature patterns of dementia with Lewy bodies are associated with the extent of coexisting Alzheimer’s pathology and the presence of transitional or diffuse Lewy body disease and (ii) whether these 18F-fluorodeoxyglucose pattern(s) are associated with clinical course in dementia with Lewy bodies. Two groups of participants were included: a pathology-confirmed subset with Lewy body disease (n = 34) and a clinically diagnosed group of dementia with Lewy bodies (n = 87). A subset of the clinically diagnosed group was followed longitudinally (n = 51). We evaluated whether 18F-fluorodeoxyglucose PET features of dementia with Lewy bodies (higher cingulate island sign ratio and greater occipital hypometabolism) varied by Lewy body disease subtype (transitional versus diffuse) and Braak neurofibrillary tangle stage. We investigated whether the PET features were associated with the clinical trajectories by performing regression models predicting Clinical Dementia Rating Scale Sum of Boxes. Among autopsied participants, there was no difference in cingulate island sign or occipital hypometabolism by Lewy body disease type, but those with a lower Braak tangle stage had a higher cingulate island sign ratio compared to those with a higher Braak tangle stage. Among the clinically diagnosed dementia with Lewy bodies participants, a higher cingulate island ratio was associated with better cognitive scores at baseline and longitudinally. A higher 18F-fluorodeoxyglucose PET cingulate island sign ratio was associated with lower Braak tangle stage at autopsy, predicted a better clinical trajectory in dementia with Lewy body patients and may allow for improved prognostication of the clinical course in this disease.

Background: The effective self-management of heart failure (HF) is highly dependent on cognitive function. Dementia frequently coexists with HF, but its exact prevalence and impact on health care utilization and death is not well understood. Methods: Residents from 7 southeast Minnesota counties with a first-ever code for HF (ICD-9 428 and ICD-10 I50) between 1/1/2012 and 12/31/2017 were identified. Dementia before and after the HF diagnosis was ascertained with codes recommended by the US Department of Health and Human Services. Patients were followed through 12/31/2018 for death and hospitalizations. Cox and Andersen-Gill models were used to examine associations between dementia (prior and post HF) and death and hospitalizations, respectively. Dementia after HF was analyzed as a time-dependent variable. Results: Among 6,312 patients with HF (mean age 75 years, 49% female), 636 (10%) had a prior diagnosis of dementia. After a mean (SD) follow-up of 3.1 (1.8) years, 601 (9.5%) patients were diagnosed with dementia post HF. The median time from HF to dementia was 1.3 years, with 43% of dementia cases occurring within 1 year and 64% within 2 years post HF. During follow-up, 2,678 deaths and 15,095 hospitalizations occurred. After adjustment, patients with dementia before HF had nearly a 2-times increased risk of death and 10% increased risk of hospitalization compared to those that did not have dementia (Table). Dementia after HF was associated with a 78% increased risk of death and 63% increased risk of hospitalization compared to those that did not have dementia. Conclusions: Approximately 10% of patients had dementia prior to HF and 10% develop dementia shortly after HF diagnosis. Patients with HF and dementia have an increased risk of death and hospitalization compared to dementia-free counterparts. These data underscore the importance of recognizing the presence and impact of dementia on outcomes in HF to optimize care delivery.

Introduction: Stiffening of the aorta is associated with greater pulse pressure and transmission of pulsatile energy into the cerebral circulation, which can increase susceptibility to microvascular damage in the brain. We tested the hypothesis that higher aortic stiffness measured in late-life is associated with a greater prevalence odds of dementia measured ~5 years later. Methods: Dementia-free ARIC-NCS participants (n=4753; mean age: 75 years; 42% male; 21% black) with measures of aortic stiffness at the visit 5 (2011-2013) examination were included. Aortic stiffness was measured by carotid-femoral pulse wave velocity (cfPWV) using the VP-1000 Plus device (Omron Co., Japan) and modeled as continuous (per standard deviation (SD)), categorical into distribution-based quartiles, and as elevated vs. non-elevated cfPWV according to the upper 25 th percentile (13.34 m/s). Cognitive status (normal/mild cognitive impairment (MCI)/dementia) was ascertained at the visit 5 and 6 (2016-2017) examinations with expert review by an adjudication committee of in-person cognitive testing. A multivariable logistic regression model estimated the adjusted association of cfPWV with 5-year odds of dementia. Results: Among dementia-free participants, a 1 SD higher cfPWV was associated with a greater odds of dementia (Odds Ratio (OR): 1.19 (95% Confidence Interval (CI): 1.03, 1.39). Elevated cfPWV (upper 25 th percentile) was also associated with a greater odds of dementia (OR: 1.54, 95% CI: 1.08, 2.19) in this sample. This association was stronger among participants who were cognitively normal at visit 5 (n=3758, Table): the multivariable-adjusted OR of dementia = 2.16 (95% CI: 1.35, 3.47) for elevated vs. non-elevated cfPWV. The risk of dementia among those with baseline MCI (n=955) was not associated with cfPWV levels. Results were robust to adjustment for vascular risk factors. Conclusions: Among older adults, especially when MCI is not present, greater central aortic stiffness is associated with dementia risk.

Introduction: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) among older adults are associated with mortality, and reportedly with lower cognitive performance, biomarkers of neurodegeneration, and dementia. We tested the associations of liver enzymes with cognition in ARIC-NCS. Methods: We studied 3191 participants (mean age 79 years, 59% female, 23% black) free of chronic liver disease and cirrhosis, and with AST:ALT ratio ≤2 at visit in 2016-2017. Serum ALT and AST were examined continuously and by quintiles, with the 3 rd quintile as the distribution-based modal reference range. Cognitive status (normal, mild cognitive impairment [MCI], dementia) was ascertained by an expert adjudication panel. A composite global cognition score was estimated from memory, executive function, and language tests. We used demographic and ApoE4 adjusted multinomial logistic and linear regressions. Results: Participants were classified as cognitively unimpaired (2375), MCI (602) or dementia (214). Lower levels of ALT and AST, and a higher AST:ALT ratio were associated with higher prevalence of dementia and lower global cognition scores ( Figure ). The prevalence odds ratio of dementia and MCI for the 1 st quintile, vs 3 rd quintile of ALT, were 1.73 (95% CI:1.06-2.81) and 1.27 (0.92-1.76), respectively. The corresponding estimates for AST were 1.71 (1.03-2.84) and 1.17 (0.87-1.59). Global cognition scores were lower in the 1 st vs 3 rd quintiles of ALT and AST by 0.13 (0.06-0.21) and 0.08 (0-0.15) standard deviation units, respectively. Additional adjustment for alcohol intake did not change the results. Conclusions: Liver hypometabolism is linked to reduced brain glucose metabolism, impaired production of neurotransmitters and synaptic maintenance, systemic insulin resistance and inflammation, while hepatic metabolite profiles are altered in dementia. Prospective assessments are warranted to characterize the role of hepatic metabolic dysfunction in cognitive impairment among older adults.

Background: Atrial fibrillation (AF) is a risk factor for cognitive decline, perhaps due to silent cerebral infarction, but it is unknown if it also acts on Alzheimer’s Disease (AD)-specific mechanisms, such as deposition of β-amyloid (Aβ). Left atrial changes in structure or function, or atrial cardiopathy, can lead to AF but may cause infarcts independently, and thus might also impact cognition. We hypothesize that Aβ is associated with AF and atrial cardiopathy, independent of AF, when defined similarly to an ongoing clinical trial (ARCADIA). Methods: 321 participants without dementia from the Atherosclerosis Risk in Communities study underwent florbetapir (FBP) PET, electrocardiogram and 2D echocardiography. Atrial cardiopathy was defined as ≥1 of: 1) left atrial volume index (LAVI) >34 ml/m2; 2) P-wave terminal force >5000 uV x ms and 3) serum NT proBNP>250 pg/mL. Cross-sectional associations between global cortical Aβ (>1.2 standardized uptake value ratio (SUVR)) and adjudicated history of atrial fibrillation and atrial cardiopathy, each, were evaluated using multivariable logistic regression. Results: Participants, with mean age 76 y, were 56% female and 42% black. Odds of elevated FBP SUVR was increased for those with atrial cardiopathy (Model 3) and nearly doubled among those with enlarged LAVI that remained significant after sequential adjustment, including AF (Table). There was no significant association between either P-wave terminal force or NT proBNP and elevated FBP SUVR (Table), nor between elevated SUVR and AF. Conclusions: In this cross-sectional analysis of a cohort of healthy, nondemented community-dwelling older individuals, we report a significant association between atrial cardiopathy as well as LAVI and elevated amyloid, by PET, without a similar association in individuals with AF. Potential limitations include reverse causation and survival bias. Ongoing work will help determine if changes in cardiac structure and function precede, or occur simultaneously with amyloid deposition.

Background: Cerebrovascular disease is often the consequence of cardiac disease. Our aim was to examine associations of biomarkers of cardiovascular disease, high sensitivity troponin T (hs-cTnT), NT-proBNP, and galectin-3, with cerebrovascular signs: lacunar infarcts, lobar and subcortical microhemorrhages, cortical infarcts, and white matter hyperintensity (WMH) volume. We also examined total cortical and Alzheimer’s Disease (AD) signature region volumes. Methods: We conducted a cross-sectional analysis of 1748 ARIC participants from the 2011-2013 exam who had biomarker measurements, completed a brain MRI, and did not have a clinical history of stroke. We used linear regression to model brain volumes, modeled as Z scores, and logistic regression for all other outcomes; biomarkers were log transformed. We repeated analyses excluding persons with coronary heart disease, atrial fibrillation, and heart failure. Results: The mean age of participants was 76, 62% were female, and 21% were Black. All biomarkers were associated with total cortical volume. Each standard deviation increase in log hs-cTnT was associated with lower total cortical volume (adjusted beta = -0.08, 95% CI: -0.12, -0.05); results for the other biomarkers were similar (Figure). All biomarkers were associated with lobar microhemorrhages. Hs-cTnT and NT-proBNP were associated with WMH volume, but galectin-3 was not. No biomarker was associated with subcortical microhemorrhages or cortical infarcts. Results were similar in persons without coronary heart disease, atrial fibrillation, or heart failure (conditions associated with cerebral thromboembolism). Conclusions: In persons free of clinical cardiovascular disease, biomarkers of cardiac stretch, strain, and fibrosis were associated cerebral small vessel disease and reduced cortical volume, but not in a specific pattern suggestive of AD pathogenesis. This suggests subclinical vascular insults affect brain structure through mixed pathogenic processes.