LPS-induced whole-blood cytokine production and depressive symptoms in dementia spousal caregivers: The moderating effect of childhood trauma.

Dementia spousal caregivers are at risk for adverse mental and physical health outcomes. Caregiver burden, anticipatory grief, and proinflammatory cytokine production may contribute to depressive symptoms among caregivers. People who report childhood trauma are more likely to have exaggerated stress responses that may also contribute to depressive symptoms in adulthood. This study aimed to test whether the relationship between whole-blood cytokine production and depressive symptoms is strongest in caregivers who report high levels of childhood trauma. METHODS: A sample of 103 dementia spousal caregivers provided self-report data on demographics, health information, caregiver burden, anticipatory grief, and depressive symptoms. We also determined lipopolysaccharide-induced whole-blood cytokine production as the primary measure of immune cell reactivity. We measured interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) and converted z-scores of each cytokine into a composite panel. We regressed depressive symptoms on proinflammatory cytokine production, caregiver burden, and anticipatory grief, adjusting for demographic and health-related covariates. RESULTS: Whole-blood cytokine production and childhood trauma were associated with depressive symptoms. Childhood trauma moderated the relationship between whole-blood cytokine production and depressive symptoms. Whole-blood cytokine production was only associated with depressive symptoms at mean and high levels of childhood trauma, but not at low levels of childhood trauma. The main effects of burden and anticipatory grief on depressive symptoms were strongest for caregivers reporting high levels of childhood trauma. DISCUSSION: Childhood trauma has lasting impacts on psychosocial experiences later in life and has effects that may confer susceptibility to inflammation-related depression. Our findings contribute to ongoing efforts to identify risk factors for adverse mental health in dementia spousal caregivers.

Angiotensin-II stimulating vs. inhibiting antihypertensive drugs and the risk of Alzheimer's disease or related dementia in a large cohort of older patients with colorectal cancer.

Background: Several previous studies showed that patients who received angiotensin II-stimulating antihypertensive medications had a lower incident dementia rate than those angiotensin II-inhibiting antihypertensive users, but no study has been conducted in long-term cancer survivors. Objectives: To determine the risk of Alzheimer's disease (AD) and related dementia (ADRD) associated with the types of antihypertensive medications in a large cohort of survivors with colorectal cancer in 2007-2015 with follow-up from 2007 to 2016. Methods: We identified 58,699 men and women with colorectal cancer aged 65 or older from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database in 17 SEER areas in 2007-2015 with follow-up to 2016, who were free of any diagnosed ADRD at the baseline (within 12 months prior to and 12 months after the date of diagnosis for colorectal cancer). All patients who were defined as having hypertension by ICD diagnosis code or received antihypertensive drugs during this baseline 2-year period were classified into 6 groups based on whether they received angiotensin-II stimulating or inhibiting antihypertensive drugs. Results: Crude cumulative incidence rates of AD and ADRD were similar between those who received angiotensin II-stimulating antihypertensive medications (4.3% and 21.7%) and those receiving angiotensin II-inhibiting antihypertensive medications (4.2% and 23.5%). As compared to patients who received angiotensin II-stimulating antihypertensive drugs, those who received angiotensin II-inhibiting antihypertensives were significantly more likely to develop AD (adjusted hazard ratio: 1.15, 95% CI: 1.01-1.32), vascular dementias (1.27, 1.06-1.53), and total ADRD (1.21, 1.14-1.28) after adjusting for potential confounders. These results remained similar after adjusting for medication adherence and considering death as a competing risk. Conclusions: The risk of AD and ADRD in patients with hypertension who received angiotensin II-inhibiting antihypertensive medications was higher than in those receiving angiotensin II-stimulating antihypertensive drugs in patients with colorectal cancer.

Associations Between Vascular Diseases and Alzheimer's Disease or Related Dementias in a Large Cohort of Men and Women with Colorectal Cancer.

BACKGROUND: Long term risk of Alzheimer's disease (AD) and related dementias (ADRD) associated with vascular diseases in people with colorectal cancer is unknown. OBJECTIVE: To determine the risk of ADRD in association with cardiovascular diseases (CVD), stroke, hypertension, and diabetes in a cohort of patients with colorectal cancer. METHODS: This retrospective cohort study consisted of 210,809 patients diagnosed with colorectal cancer at age≥65 years in 1991-2015 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database with follow-up from 1991-2016, who were free of any ADRD at the baseline (<12 months prior to or < 30 days after the date of cancer diagnosis). RESULTS: The crude 26-year cumulative incidence of total ADRD in men and women with colorectal cancer was higher in those with versus without CVD (31.92% versus 28.12%), with versus without stroke (39.82% versus 26.39%), with versus without hypertension (31.88% versus 24.88%), and with versus without diabetes (32.01% versus 27.66%). After adjusting for socio-demographic and tumor factors, the risk of developing ADRD was significantly higher in patients with CVD (adjusted hazard ratio: 1.17, 95% confidence intervals: 1.14-1.20), stroke (1.65, 1.62-1.68), hypertension (1.07, 1.05-1.09), and diabetes (1.26, 1.24-1.29) versus persons without. For those with 1, 2, 3 and 4 vascular diseases present versus absent, the risk of AD increased from 1.12 (1.07-1.16) to 1.31 (1.25-1.36), 1.66 (1.57-1.75), and 2.03 (1.82-2.27). CONCLUSION: In older patients with colorectal cancer, a significant dose-response relationship was observed between an increasing number of these vascular diseases and the risk of all types of dementia.

Risk of Developing Alzheimer's Disease and Related Dementias in Association with Cardiovascular Disease, Stroke, Hypertension, and Diabetes in a Large Cohort of Women with Breast Cancer and with up to 26 Years of Follow-Up.

BACKGROUND: No study on the long-term incidence of Alzheimer's disease (AD) and related dementias (ADRD) has been reported in women with breast cancer by vascular diseases. OBJECTIVE: To determine the risk of ADRD in association with cardiovascular diseases (CVD), stroke, hypertension, and diabetes in women with breast cancer. METHODS: Study identified 246,686 women diagnosed with breast cancer at age≥65 years in 1991-2015 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Women were free of ADRD at the time of cancer diagnosis and followed from 1991 to 2016. RESULTS: Cumulative incidence of AD over 26 years of follow-up varied from 10.7% to 13.6% by CVD, stroke, hypertension, and diabetes. Cumulative incidence of ADRD was higher in those with CVD (40.75%) versus no-CVD (31.32%), stroke (40.24%) versus no-stroke (31.34%), hypertension (33.06%) versus no-hypertension (30.47%), and diabetes (33.38%) versus no-diabetes (31.77%). After adjusting for confounders, those with CVD (hazard ratio:1.30, 95% CI: 1.27-1.33), stroke (1.50,1.47-1.54), hypertension (1.08,1.06-1.09), and diabetes (1.26,1.24-1.29) had significantly higher risks of developing ADRD. Women aged 80-84, and≥85 had 5- and 7-fold higher risks of AD than those aged 65-69. As compared to white women, black women had a significantly higher risk of AD (1.21, 1.16-1.27), whereas Asians/Pacific-Islanders had a significantly lower risk of AD (0.77, 0.71-0.83). CONCLUSION: In women with breast cancer, CVD, stroke, hypertension, and diabetes were associated with a significantly higher risk of developing any ADRD combined. The risk of ADRD was higher in black women and lower in Asian/Pacific-Islanders than white women.

Individualized Out-of-Pocket Price Estimators for "Shoppable" Surgical Procedures: A Nationwide Cross-Sectional Study of US Hospitals.

To estimate the nationwide prevalence of individualized out-of-pocket (OOP) price estimators at US hospitals, characterize patterns of inclusion of 14 specified "shoppable" surgical procedures, and determine hospital-level characteristics associated with estimators that include surgical procedures. Background: Price transparency for shoppable surgical services is a key requirement of several recent federal policies, yet the extent to which hospitals provide online OOP price estimators remains unknown. Methods: We reviewed a stratified random sample of 485 U.S. hospitals for the presence of a tool to allow patients to estimate individualized OOP expenses for healthcare services. We compared characteristics of hospitals that did and did not offer online price estimators and performed multivariable modeling to identify facility-level predictors of hospitals offering price estimator with and without surgical procedures. Results: Nearly two-thirds (66.0%) of hospitals in the final sample (95% confidence interval 61.6%-70.1%) offered an online tool for estimating OOP healthcare expenses. Approximately 58.5% of hospitals included at least one shoppable surgical procedure while around 6.6% of hospitals included all 14 surgical procedures. The most common price reported was laparoscopic cholecystectomy (55.1%), and the least common was recurrent cataract removal (20.0%). Inclusion of surgical procedures varied by total annual surgical volume and health system membership. Only 26.9% of estimators explicitly included professional fees. Conclusions: Our findings highlight an ongoing progress in price transparency, as well as key areas for improvement in future policies to help patients make more financially informed decisions about their surgical care.

Peripheral Delivery of Neural Precursor Cells Ameliorates Parkinson's Disease-Associated Pathology.

: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of motor control due to a wide loss of dopaminergic neurons along the nigro-striatal pathway. Some of the mechanisms that contribute to this cell death are inflammation, oxidative stress, and misfolded alpha-synuclein-induced toxicity. Current treatments are effective at managing the early motor symptoms of the disease, but they become ineffective over time and lead to adverse effects. Previous research using intracerebral stem cell therapy for treatment of PD has provided promising results; however, this method is very invasive and is often associated with unacceptable side effects. In this study, we used an MPTP-injected mouse model of PD and intravenously administered neural precursors (NPs) obtained from mouse embryonic and mesenchymal stem cells. Clinical signs and neuropathology were assessed. Female mice treated with NPs had improved motor function and reduction in the neuroinflammatory response. In terms of safety, there were no tumorigenic formations or any detectable adverse effect after treatment. Our results suggest that peripheral administration of stem cell-derived NPs may be a promising and safe therapy for the recovery of impaired motor function and amelioration of brain pathology in PD.

Diffusion Tensor Imaging of the Superior Thalamic Radiation and Cerebrospinal Fluid Distribution in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND AND PURPOSE: Ventricular enlargement in elderly raises a challenging differential diagnosis to physicians. While Alzheimer's disease is the most common form of dementia, idiopathic normal pressure hydrocephalus (iNPH) constitutes a potentially reversible syndrome. iNPH has a unique pathophysiology pertaining to cerebrospinal fluid (CSF) dynamics and periventricular white matter. We aimed to determine the effects of iNPH on periventricular white matter bundles and to further characterize its ventricular and sulcal CSF distribution by using diffusion tensor tractography (DTT) and CSF volumetrics on high resolution T1-weighted magnetic resonance imaging data. METHODS: Deterministic DTT and validated volumetric parcellation were performed on 20 healthy elderly, 13 Alzheimer's disease (AD), and 9 iNPH patients. The superior thalamic radiation, corticospinal tract, and dentatorubrothalamic tract were traced and quantified using DTI studio software. Cloud-based volumetric parcellation was also performed on 138 healthy subjects across the lifespan, 13 AD, and 9 iNPH-patients. Ventricular and sulcal CSF volumes in the three groups were compared. RESULTS: Combining increased mean diffusivity of the superior thalamic radiation with ventricular volume resulted in clear separation of iNPH from the AD and age-matched healthy subject groups. Additionally, ventricular to sulcal CSF ratio, utilizing fully automated methods, was significantly greater in the iNPH patients compared to AD and healthy age-matched controls. CONCLUSIONS: Combined microstructural (DTT) and macrostructural (ventricular volume) changes is a promising radiological approach in studying ventriculomegaly. Automated estimation of the disproportionate ventricular and sulcal CSF ratio in patients presenting with ventriculomegaly may be important as radiologic markers in differentiating iNPH from other causes of ventriculomegaly.

Auto-antibodies against P/Q- and N-type voltage-dependent calcium channels mimicking frontotemporal dementia.

The behavioral variant of frontotemporal dementia is usually a sporadic and progressive neurodegenerative disorder. Here, we report the subacute onset of a frontotemporal dementia phenotype with a treatable etiology. The patient has a history of rheumatoid arthritis, episcleritis, and thyroid eye disease on immunosuppressive therapy. He experienced a rapid personality change, including inappropriate behavior, which suggested frontotemporal dementia. Results of imaging and neuropsychological testing also suggested frontotemporal dementia. Because of his autoimmune diseases and unusually short onset of symptoms, serum paraneoplastic panel and cerebrospinal fluid were analyzed and revealed elevated P/Q- and N-type calcium channel antibodies. Treatment with therapeutic plasma exchange resulted in a rapid improvement of his behavior and cognition. This case suggests that there may be some treatable causes of frontotemporal dementia symptomatology, that is, paraneoplastic antibodies. In the context of atypical features of frontotemporal dementia, practitioners should maintain a high index of suspicion.

Medical-encounter mental health diagnoses, non-fatal injury and polypharmacy indicators of risk for accident death in the US Army enlisted soldiers, 2004-2009.

Accidents are a leading cause of deaths in U.S. active duty personnel. Understanding accident deaths during wartime could facilitate future operational planning and inform risk prevention efforts. This study expands prior research, identifying health risk factors associated with U.S. Army accident deaths during the Afghanistan and Iraq war. Military records for 2004-2009 enlisted, active duty, Regular Army soldiers were analyzed using logistic regression modeling to identify mental health, injury, and polypharmacy (multiple narcotic and/or psychotropic medications) predictors of accident deaths for current, previously, and never deployed groups. Deployed soldiers with anxiety diagnoses showed higher risk for accident deaths. Over half had anxiety diagnoses prior to being deployed, suggesting anticipatory anxiety or symptom recurrence may contribute to high risk. For previously deployed soldiers, traumatic brain injury (TBI) indicated higher risk. Two-thirds of these soldiers had first TBI medical-encounter while non-deployed, but mild, combat-related TBIs may have been undetected during deployments. Post-Traumatic Stress Disorder (PTSD) predicted higher risk for never deployed soldiers, as did polypharmacy which may relate to reasons for deployment ineligibility. Health risk predictors for Army accident deaths are identified and potential practice and policy implications discussed. Further research could test for replicability and expand models to include unobserved factors or modifiable mechanisms related to high risk. PTSD predicted high risk among those never deployed, suggesting importance of identification, treatment, and prevention of non-combat traumatic events. Finally, risk predictors overlapped with those identified for suicides, suggesting effective intervention might reduce both types of deaths.

Two different 18F-FDG brain PET metabolic patterns in autoimmune limbic encephalitis.

PURPOSE: Autoimmune limbic encephalitis (ALE) is a severe, but treatable, neuropsychiatric disorder that is difficult to diagnose clinically. With the goal of improving diagnosis of this disorder, we retrospectively evaluated the cerebral FDG PET pattern in a group of patients with ALE. MATERIALS AND METHODS: Nine adult patients with subacute cognitive decline were eventually diagnosed with ALE based on clinical presentation, cerebrospinal fluid inflammatory markers, and response to immunosuppressive therapy. All patients received FDG PET brain scanning during their diagnostic evaluation, which were retrospectively reviewed for this study. RESULTS: Our patients' scans fell into 2 readily separable patterns. Five younger patients had a mixed metabolic pattern most easily recognized by pronounced occipital hypometabolism, accentuated by hypermetabolism in the temporal and orbitofrontal cortex. Other, milder findings were also present. Once this unusual pattern was established as corresponding to ALE, it helped lead to the correct clinical diagnosis in the last 2 patients. Four older patients had scans that closely resembled diffuse neurodegenerative disease. CONCLUSIONS: We found 2 different PET scan patterns in patients with ALE. One is an easily recognizable mixture of hyper- and hypometabolism that has also been described in a few recent case reports and is potentially specific for ALE. The other is indistinguishable from neurodegenerative disease. We propose that awareness of these patterns may contribute to the diagnosis of this elusive, but treatable, neurologic disorder.

Medical and environmental risk factors associated with frontotemporal dementia: a case-control study in a veteran population.

BACKGROUND: Compared with other major dementias, very little is known about the medical and environmental risk factors associated with frontotemporal dementia (FTD). In this study, we evaluated medical and environmental disorders associated with FTD in a veteran population. METHODS: The medical records of 845 consecutive veterans who were evaluated for cognitive and/or behavioral complaints at a cognitive disorders clinic in an academic medical center between March 1, 2003, and June 30, 2008, were reviewed and 554 patients received a diagnosis of dementia. Medical disorders and environmental risk factors in 63 patients with behavioral variant of FTD were compared with 491 patients with non-FTD dementias. RESULTS: The prevalence of traumatic brain injury (TBI) was significantly greater in patients with FTD versus those with non-FTD dementias (12.7% vs 3.5%; P < .05). The FTD group also had a lower prevalence of heart disease (19.0% vs 36.7%; P < .05) and cerebrovascular diseases (12.7% vs 26.1%; P < .05), although the prevalence of vascular risk factors was comparable between FTD and non-FTD dementia groups: hypertension (65.1% vs 68.2%), diabetes (31.7% vs 26.9%), hyperlipidemia (42.9% vs 48.9%), and tobacco use (7.9% vs 8.8%; P > .05 for all). In multivariate analysis, the risk for FTD was increased in patients with TBI (OR, 4.4; 95% CI, 1.6-11.8). The risk for FTD was marginally decreased in patients with heart disease (OR, 0.4; 95% CI, 0.3-0.96). CONCLUSIONS: In a clinical sample of veterans, risk of FTD was increased in patients with TBI and marginally decreased in patients with heart disease. Prospective studies are needed to confirm these associations temporally and to identify their underlying mechanisms.

A decrease in body mass index is associated with faster progression of motor symptoms and shorter survival in ALS.

Our objective was to test the hypothesis that changes in body mass index (BMI) are associated with changes in the clinical course of ALS. We examined the relationships between BMI at first clinical visit and changes in BMI up to a two-year follow-up, and multiple clinical variables related to ALS: age of onset, rate of progression of motor symptoms, and survival. Baseline BMI was classified according to the World Health Organization (WHO) criteria. Changes in BMI were classified as a loss of >1 unit, no change, or a gain of >1 unit. Our results showed that baseline BMI was not associated with age of onset, rate of progression or survival. In contrast, a loss of BMI >1 over two years was associated with significantly shorter survival and a faster rate of progression. In a multiple regression model, these results were independent of gender, site of onset, history of diabetes mellitus and apolipoprotein (ApoE) genotype. In summary, a change in BMI after ALS diagnosis was significantly associated with rate of progression and survival. This raises the possibility that early changes in BMI may identify patients likely to have a more malignant course of the disease. However, further research is needed to clarify the relationship between BMI and ALS.