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Alzheimer’s disease neuropathologic change (ADNC) is defined by progressive accumulation of β-amyloid plaques and hyperphosphorylated tau (pTau) neurofibrillary tangles across diverse regions of brain. Non-demented individuals who reach advanced age without significant ADNC are considered to be resistant to AD, while those burdened with ADNC are considered to be resilient. Understanding mechanisms underlying ADNC resistance and resilience may provide important clues to treating and/or preventing AD associated dementia. ADNC criteria for resistance and resilience are not well-defined, so we developed stringent pathologic cutoffs for non-demented subjects to eliminate cases of borderline pathology. We identified 14 resistant (85+ years old, non-demented, Braak stage ≤ III, CERAD absent) and 7 resilient (non-demented, Braak stage VI, CERAD frequent) individuals out of 684 autopsies from the Adult Changes in Thought study, a long-standing community-based cohort. We matched each resistant or resilient subject to a subject with dementia and severe ADNC (Braak stage VI, CERAD frequent) by age, sex, year of death, and post-mortem interval. We expanded the neuropathologic evaluation to include quantitative approaches to assess neuropathology and found that resilient participants had lower neocortical pTau burden despite fulfilling criteria for Braak stage VI. Moreover, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) was robustly associated with clinical dementia and was more prevalent in cases with high pTau burden, supporting the notion that resilience to ADNC may depend, in part, on resistance to pTDP-43 pathology. To probe for interactions between tau and TDP-43, we developed a C. elegans model of combined human (h) Tau and TDP-43 proteotoxicity, which exhibited a severe degenerative phenotype most compatible with a synergistic, rather than simply additive, interaction between hTau and hTDP-43 neurodegeneration. Pathways that underlie this synergy may present novel therapeutic targets for the prevention and treatment of AD.

The AT(N) research framework categorizes eight biomarker profiles using amyloid (A), tauopathy (T), and neurodegeneration (N), regardless of dementia status. We evaluated associations with dementia risk in a community-based cohort by approximating AT(N) profiles using autopsy-based neuropathology correlates, and considered cost implications for clinical trials for secondary prevention of dementia based on AT(N) profiles. We used Consortium to Establish a Registry for Alzheimer's Disease (moderate/frequent) to approximate A+, Braak stage (IV-VI) for T+, and temporal pole lateral ventricular dilation for (N)+. Outcomes included dementia prevalence at death and incidence in the last 5 years of life. A+T+(N)+ was the most common profile (31%). Dementia prevalence ranged from 14% (A-T-[N]-) to 79% (A+T+[N]+). Between 8% (A+T-[N]-) and 68% (A+T+[N]-) of decedents developed incident dementia in the last 5 years of life. Clinical trials would incur substantial expense to characterize AT(N). Many people with biomarker-defined preclinical Alzheimer's disease will never develop clinical dementia during life, highlighting resilience to clinical expression of AD neuropathologic changes and the need for improved tools for prediction beyond current AT(N) biomarkers.

Background: A recent Alzheimer's disease research diagnosis framework groups amyloid (A), tauopathy (T), and neurodegeneration (N) biomarkers into eight AT(N) profiles. We determined prevalence at death of each profile in the Adult Changes in Thought (ACT) community-based cohort. Within each profile, we determined dementia prevalence at death and incident dementia among those dementia free 5-7 years antemortem. Methods: Setting: prospective study of individuals ≥65 years; 25-30% consented to autopsy. Cognition was prospectively evaluated every 2 years and dementia determined using research criteria. At autopsy, A used CERAD levels (none/sparse vs. moderate/frequent), T used Braak staging (0-III vs. IV-VI), and N used absence vs. presence of lateral ventricular dilation at the temporal tip. We compared prevalent and incident dementia for each AT(N) profile. We used inverse-probability weighting to address potential selection bias, and considered the relevance of seven additional autopsy findings in predicting dementia status. Findings: Of 5,236 ACT participants, 2,870 died, and 603 had known dementia status and autopsy. The two most common profiles were A+T+(N)+ (31%) and A-T-(N)+ (22%). Dementia prevalence ranged from 14% (A-T-(N)-) to 79% (A+T+(N)+). Dementia incidence ranged from 8% (A+T-(N)-) to 67% (A+T+(N)+) and 68% (A+T+(N)-). Each additional neuropathological finding was associated with 7% (prevalence) to 9% (incidence) higher dementia risk independent of A,T and (N) (prevalence RR 1·07 (95% CI: 1·05-1·10); incidence RR 1·09 (95% CI: 1·05-1·14)). Interpretation: Dementia rates varied across AT(N) categories. Costs of determining AT(N) status may be considerable. That >30% of dementia-free people with the highest risk AT(N) categories did not develop incident dementia before death suggests restraint in population-based settings for treatments with more than trivial toxicity. Funding Statement: National Institute on Aging (US National Institutes of Health). (AG006781) Declaration of Interests: PKC reports grants from the US National Institutes of Health (NIH) and prior funding from the Alzheimer’s Association. Ethics Approval Statement: Study procedures were approved by KPW and UW institutional review boards. Participants provided written informed consent.

Background It is unclear whether traditional and genetic risk factors in middle age predict the onset of gout in older age. Methods We studied the incidence of gout in older adults using the Atherosclerosis Risk in Communities study, a prospective U.S. population-based cohort of middle-aged adults enrolled between 1987 and 1989 with ongoing follow-up. A genetic urate score was formed from common urate-associated single nucleotide polymorphisms for eight genes. The adjusted hazard ratio and 95% confidence interval of incident gout by traditional and genetic risk factors in middle age were estimated using a Cox proportional hazards model. Results The cumulative incidence from middle age to age 65 was 8.6% in men and 2.5% in women; by age 75 the cumulative incidence was 11.8% and 5.0%. In middle age, increased adiposity, beer intake, protein intake, smoking status, hypertension, diuretic use, and kidney function (but not sex) were associated with an increased gout risk in older age. In addition, a 100 µmol/L increase in genetic urate score was associated with a 3.29-fold (95% confidence interval: 1.63-6.63) increased gout risk in older age. Conclusions These findings suggest that traditional and genetic risk factors in middle age may be useful for identifying those at risk of gout in older age.

Objective Gout prevalence is high in older adults and those affected are at risk of physical disability, yet it is unclear whether they have worse physical function. Methods We studied gout, hyperuricemia, and physical function in 5,819 older adults (age ≥65 years) attending the 2011–2013 Atherosclerosis Risk in Communities Study visit, a prospective US population-based cohort. Differences in lower extremity function (Short Physical Performance Battery [SPPB] and 4-meter walking speed) and upper extremity function (grip strength) by gout status and by hyperuricemia prevalence were estimated in adjusted ordinal logistic regression (SPPB) and linear regression (walking speed and grip strength) models. Lower scores or times signify worse function. The prevalence of poor physical performance (first quartile) by gout and hyperuricemia was estimated using adjusted modified Poisson regression. Results Ten percent of participants reported a history of gout and 21% had hyperuricemia. There was no difference in grip strength by history of gout (P = 0.77). Participants with gout performed worse on the SPPB test; they had 0.77 times (95% confidence interval [95% CI] 0.65, 0.90, P = 0.001) the prevalence odds of a 1-unit increase in SPPB score and were 1.18 times (95% CI 1.07, 1.32, P = 0.002) more likely to have poor SPPB performance. Participants with a history of gout had slower walking speed (mean difference −0.03; 95% CI −0.05, −0.01, P < 0.001) and were 1.19 times (95% CI 1.06, 1.34, P = 0.003) more likely to have poor walking speed. Similarly, SPPB score and walking speed, but not grip strength, were worse in participants with hyperuricemia. Conclusion Older adults with gout and hyperuricemia are more likely to have worse lower extremity, but not upper extremity, function.

Integrated behavioral health and primary care is emerging as a superior means by which to address the needs of the whole person, but we know neither the extent nor the distribution of integration. Using the Centers for Medicare and Medicaid Services' National Plan and Provider Enumeration System (NPPES) Downloadable File, this study reports where colocation exists for (a) primary care providers and any behavioral health provider and (b) primary care providers and psychologists specifically. The NPPES database offers new insights into where opportunities are limited for integration due to workforce shortages or nonproximity of providers and where possibilities exist for colocation, a prerequisite for integration.

Gout prevalence is high in older adults and those affected are at risk of physical disability, yet it is unclear whether they have worse physical function.We studied gout, hyperuricemia, and physical function in 5,819 older adults (age ≥65 years) attending the 2011-2013 Atherosclerosis Risk in Communities Study visit, a prospective US population-based cohort. Differences in lower extremity function (Short Physical Performance Battery [SPPB] and 4-meter walking speed) and upper extremity function (grip strength) by gout status and by hyperuricemia prevalence were estimated in adjusted ordinal logistic regression (SPPB) and linear regression (walking speed and grip strength) models. Lower scores or times signify worse function. The prevalence of poor physical performance (first quartile) by gout and hyperuricemia was estimated using adjusted modified Poisson regression.Ten percent of participants reported a history of gout and 21% had hyperuricemia. There was no difference in grip strength by history of gout (P = 0.77). Participants with gout performed worse on the SPPB test; they had 0.77 times (95% confidence interval [95% CI] 0.65, 0.90, P = 0.001) the prevalence odds of a 1-unit increase in SPPB score and were 1.18 times (95% CI 1.07, 1.32, P = 0.002) more likely to have poor SPPB performance. Participants with a history of gout had slower walking speed (mean difference -0.03; 95% CI -0.05, -0.01, P0.001) and were 1.19 times (95% CI 1.06, 1.34, P = 0.003) more likely to have poor walking speed. Similarly, SPPB score and walking speed, but not grip strength, were worse in participants with hyperuricemia.Older adults with gout and hyperuricemia are more likely to have worse lower extremity, but not upper extremity, function.

Background: Federally Qualified Health Centers are expanding to increase access for millions of more Americans with a goal of doubling capacity to serve 40 million people. Health centers provide a lot of behavioral health services but many have difficulty accessing mental health and substance use professionals for their patients. To meet the needs of the underserved and newly insured it is important to better estimate how many behavioral health professionals are needed. Methods: Using health center staffing data and behavioral health service patterns from the 2010 Uniform Data System and the 2010 National Survey on Drug Use and Health, we estimated the number of patients likely to need behavioral health care by insurance type, the number of visits likely needed by health center patients annually, and the number of full time equivalent providers needed to serve them. Results: More than 2.5 million patients, 12 or older, with mild or moderate mental illness, and more than 357,000 with substance abuse disorders, may have gone without needed behavioral health services in 2010. This level of need would have required more than 11,600 full time providers. This translates to approximately 0.9 licensed mental health provider FTE, 0.1 FTE psychiatrist, 0.4 FTE other mental health staff, and 0.3 FTE substance abuse provider per 2,500 patients. These estimates suggest that 90% of current centers could not access mental health services or provide substance abuse services to fully meet patients’ needs in 2010. If needs are similar after health center expansion, more than 27,000 full time behavioral health providers will be needed to serve 40 million medical patients, and grantees will need to increase behavioral health staff more than four-fold. Conclusions: More behavioral health is seen in primary care than in any other setting, and health center clients have greater behavioral health needs than typical primary care patients. Most health centers needed additional behavioral health services in 2010, and this need will be magnified to serve 40 million patients. Further testing of these workforce models are needed, but the degree of current underservice suggests that we cannot wait to move on closing the gap.