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Cerebrovascular reactivity to hypercapnia declines with age and low reactivity may be a biomarker of cognitive decline. Central elastic arteries that perfuse the brain stiffen with age, increasing their transmission of pulsatile mechanical forces into the cerebral microvasculature and impairing cerebral microvessel function. Habitual physical activity, however, has been shown to reduce central arterial stiffness and is associated with better cognitive function. Therefore, the purpose of this study was to evaluate cerebrovascular reactivity in young and older healthy adults who habitually exercise. We hypothesized that older adults who habitually exercised would have similar cerebrovascular reactivity when compared with young adults. However, because the underlying mechanisms of cerebral blood flow regulation may differ with age, we also evaluated blood pressure and central hemodynamic measures. We recruited 25 young (YA: age = 27 ± 1 y) and 20 older (OA: age = 59 ± 1 y) habitual exercisers. Middle cerebral artery velocity (MCAv) was recorded using transcranial Doppler ultrasound. In order to assess cerebrovascular reactivity, mean arterial pressure (MAP), end‐tidal carbon dioxide (ETCO 2 ), and MCAv were continuously recorded at rest and during stepwise elevations of inhaled CO 2 . Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. Reactivity was calculated as the linear relationship between the change in ETCO 2 and the change in each variable of interest (MCAv, CVCi and MAP). Central arterial stiffness (carotid‐femoral pulse wave velocity, PWV) and central hemodynamics (augmentation index, AIx) were assessed by applanation tonometry. Older adults had higher MAP (YA: 85 ± 2 mmHg; OA: 90 ± 3 mmHg; p<0.05) and AIx (YA: 0 ± 3 %; OA: 20 ± 2 %; p<0.05) at rest compared with young adults. PWV was not statistically different between groups (YA: 4.9 ± 0.3 cm/s; OA: 5.7 ± 0.5 cm/s; p=0.18). MCAv and CVCi reactivity to hypercapnia were similar between young and older adults (MCAv reactivity, YA: 2.0 ± 0.2 cm/s/mmHg; OA: 2.2 ± 0.1 cm/s/mmHg; p=0.46, CVCi reactivity, YA: 0.018 ± 0.002 cm/s/mmHg 2 ; OA: 0.016 ± 0.001 cm/s/mmHg 2 ; p=0.42); however, older adults demonstrated higher MAP reactivity to hypercapnia (YA: 0.3 ± 0.1 a.u.; OA: 0.8 ± 0.1 a.u.; p<0.05). PWV and AIx were not associated with MCAv, CVCi, or MAP reactivity to hypercapnia (p>0.05). Our results suggest that habitual exercise preserves cerebrovascular reactivity; however, MAP reactivity is augmented with aging allowing older adults to sufficiently increase cerebral blood flow during hypercapnia. Support or Funding Information Supported by National Institute of Health grant HL118154 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Mono‐and polyunsaturated fats in nuts, such as pistachios (PI), may improve lipoprotein and glycemic status. Overweight persons trend for dyslipidemia and high diabetes risk. The lower limits of PI consumption required for health benefits are unknown. This study determined if PI at bedtime promotes beneficial changes in metabolic status in overweight persons. Overweight subjects (n=22; 55 ± 2 yrs; 90 ± 3.6 kg; BMI 31 ± 1) were randomized to 35.4 g PI self‐administered at bedtime or control (CO; no PI) for 6 weeks. There was no difference in physical activity level between subjects receiving PI and CO. Body weight was not different in PI and CO at wk 0, 1, 2, 4, and 6. HDL cholesterol at wk 0 and 6 in PI was 49.2 ± 3.5 to 50.3 ± 3.0, and CO was 60.8 ± 3.8 and 58.0 ± 2.7 mg/dL, at wk 6 PI had improved slightly relative to CO (P= 0.12). Plasma glucose at wk 0 and 6 in PI was 104.6 ± 2.8 and 99.6 ± 2.6 mg/dL, and CO was 102.0 ± 2.8 and 101.1 ± 2.6 mg/dL, at wk 6 PI had improved slightly relative to CO (P= 0.16). Plasma insulin at wk 0 and 6 in PI was 8.5 ± 1.0 and 8.4 ± 0.9, and CO was 7.2 ± 0.7 to 8.8 ± 0.7 μU/mL, at wk 6 PI had improved slightly relative to CO (P = 0.21). Beneficial changes in HDL, glucose, and insulin probably requires slightly more than 35.4 g/d PI for 6 wks. To increase the probability of metabolic health benefits, nutritionists may wish to encourage levels of daily PI consumption higher than those administered in this study.

Abstract Background and study aim Delayed bleeding is a common adverse event following endoscopic mucosal resection (EMR) of large colorectal polyps. Prophylactic clip closure of the mucosal defect after EMR of nonpedunculated polyps larger than 20 mm reduces the incidence of severe delayed bleeding, especially in proximal polyps. This study aimed to evaluate factors associated with complete prophylactic clip closure of the mucosal defect after EMR of large polyps. Methods This is a post hoc analysis of the CLIP study (NCT01936948). All patients randomized to the clip group were included. Main outcome was complete clip closure of the mucosal resection defect. The defect was considered completely closed when no remaining mucosal defect was visible and clips were less than 1 cm apart. Factors associated with complete closure were evaluated in multivariable analysis. Results In total, 458 patients (age 65, 58 % men) with 494 large polyps were included. Complete clip closure of the resection defect was achieved for 338 polyps (68.4 %); closure was not complete for 156 (31.6 %). Factors associated with complete closure in adjusted analysis were smaller polyp size (odds ratio 1.06 for every millimeter decrease [95 % confidence interval 1.02–1.08]), good access (OR 3.58 [1.94–9.59]), complete submucosal lifting (OR 2.28 [1.36–3.90]), en bloc resection (OR 5.75 [1.48–22.39]), and serrated histology (OR 2.74 [1.35–5.56]). Conclusions Complete clip closure was not achieved for almost one in three resected large nonpedunculated polyps. While stable access and en bloc resection facilitate clip closure, most factors associated with clip closure are not modifiable. This highlights the need for alternative closure options and measures to prevent bleeding.

AbstractBackgroundFamilial frontotemporal dementia (f‐FTLD) is typically caused by mutations in one of three genes: microtubule‐associated protein tau (MAPT), progranulin (GRN), and a repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene. Accurate characterization of the natural history of each mutation is important for clinical prognostication and clinical trial design, and it could shed light on disease biology. Such models have not been thoroughly developed using participants that represent all disease stages, with longitudinal data. We characterized the trajectory of atrophy in each gene by using longitudinal voxel‐wise analyses of gray matter volume, and we assessed whether functional independence declined in tandem.MethodF‐FTLD participants (n=100) with a known mutation (MAPT+ (n=28), GRN+ (n=33), C9orf72+ (n=39)) were grouped according to disease stage (CDR®+NACC FTLD module). We included participants with at least two structural MRIs at a given disease stage: presymptomatic (CDR®+NACC‐FTLD=0, n=57), mild/questionable (CDR®+NACC‐FTLD=0.5, n=15), and symptomatic (CDR®+NACC‐FTLD ≥1, n=28). We fitted longitudinal linear mixed effects models to extract mean atrophy rates in each lobe compared to longitudinal imaging from family members without mutations (n=60). All results presented below were significant at p<.001.ResultUsing the left frontal lobe as an exemplar, in the presymptomatic stage, MAPT mutation carriers showed the greatest rate of atrophy compared to controls (88 mm3/year more volume loss than controls), followed by GRN+ (65 mm3/year) and then C9orf72+ (49 mm3/year). In the mild/questionable stage, MAPT+ showed a greater divergence from controls (374 mm3/year) than did GRN+ (107 mm3/year) or C9orf72+ (223 mm3/year). In the symptomatic stage, MAPT+ again lost volume at the fastest rate (2,099 mm3/year), followed by GRN+ (1,360 mm3/year). C9orf72 expansion carriers showed a much slower rate of volume loss (115 mm3/year). Similar patterns were observed for other brain regions. In contrast to the imaging results, C9orf72+ exhibited similar rates of functional decline compared to GRN+ and MAPT+ at all levels of disease severity.ConclusionThe primary f‐FTLD genes show divergent atrophy trajectories as a function of disease stage, with C9orf72 expansion carriers exhibiting a slow degeneration throughout the disease course, possibly due to unique pathophysiological mechanisms.

AbstractBackgroundPlasma NfL is a sensitive marker of axonal injury that is elevated in symptomatic FTLD and asymptomatic carriers of FTLD‐associated genetic mutations at short‐term risk of phenoconversion to mild behavioral or cognitive impairment or dementia. In carriers of FTLD‐associated genetic mutations, NfL is associated with clinical measures of disease severity.MethodPlasma NfL was measured using single molecule array technology in baseline blood samples from 290 participants in the ARTFL/LEFFTDS consortia. Participants included 181 asymptomatic mutation carriers (C9orf72, GRN, and MAPT); 45 with mild impairment (MBI/MCI), and 64 with dementia. 103 family members without FTLD‐associated mutations served as asymptomatic controls. Social cognition scales were obtained through clinical evaluation at baseline, year 1, and year 2. Stepwise linear regressions assessed NfL relationships with baseline social cognition measures. Linear mixed models were used to test the ability of baseline NfL to predict longitudinal changes. Analyses corrected for age, sex, and genotype.ResultAt baseline, plasma NfL correlated with all measures of social cognition, regardless of genotype. Associations were strongest for the Revised Self‐monitoring Scale (RSMS;β = ‐.50, p < .001), total score of the Social Norms questionnaire (β= .48, p < .001), and caregiver burden (Zarit burden;β = .55, p < .001). Regardless of disease severity, baseline NfL related to worse RSMS scores over time (‐3.7 points at year 2/ LogNfL unit increase, 95% CI ‐1.7 to ‐5.7, p < .001). In MBI/MCI, higher baseline NfL was associated with worse longitudinal scores on the Social Norms questionnaire (‐5.9 points at year 2/LogNfL unit increase, 95% CI ‐1.1 to ‐10.7, p = .016). No associations were seen in asymptomatic non‐carriers.ConclusionIn this familial FTLD cohort, plasma NfL is correlated with clinical measures of social cognition and caregiver burden. Higher baseline plasma NfL concentrations are associated with worsening self‐monitoring and social norms scores over time. These associations suggest that NfL is correlated with clinically meaningful measures that may be relevant to therapeutic development.

AbstractBackgroundThe LEFFTDS Consortium involves investigators at 8 centers in North America evaluating individuals in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72) genes using a standardized battery of measures. Participants are evaluated annually. We sought to determine possible correlations between FTLD disease progression and neuropsychiatric features.MethodThe Neuropsychiatric Inventory Questionnaire (NPI‐Q) scale is an informant‐based instrument that measures the presence and severity of 12 neuropsychiatric features in patients with dementia. The NPI‐Q was completed at each LEFFTDS visit. The individual NPI questions and total score were analyzed in those with CDR® Dementia Staging Instrument PLUS National Alzheimer Coordinating Center Frontotemporal Lobar Degeneration (CDR®+ NACC FTLD) ratings of 0 (i.e., clinically normal), 0.5 (i.e., questionably/minimally abnormal), 1, 2, and 3.ResultThe 472 participants enrolled to date with a baseline (Visit 1) assessment have the following characteristics: 261 (55.5%) female, mean age 48 (range 18‐80) years, mean education 16 (range 11‐22) years, and 275 participants with a CDR®+NACC FTLD=0 (58%) and known genetic status. Participants with a CDR®+NACC FTLD=0 plus a genetic mutation were compared to those without a mutation and found to have increased severity of apathy (mean score of 0.116 versus 0.035, p=0.0302). Regardless of the specific mutation, those with a CDR®+NACC FTLD=0.5 were reported to have increased severity of apathy, disinhibition, and irritability. For most domains, mean NPI‐Q severity scores increase between groups up to CDR®+NACC FTLD=2. Depression increases in severity up to CDR®+NACC FTLD=1, whereas apathy severity continues to increase with increasing disease severity through CDR®+NACC FTLD=3. Twenty participants converted from CDR®+NACC FTLD 0 to >0 between their baseline and most recent visit; apathy severity almost tripled in these participants. For those that converted, disinhibition, irritability, and NPI total score were different between baseline and most recent visit (Wilcoxon signed rank test, p<0.05).ConclusionKey neuropsychiatric features measured by the NPI‐Q demonstrate differences in apathy severity between clinically normal mutation vs non‐mutation carriers. Key domains differ at different levels of FTLD severity and show dynamic changes with increasing level of FTLD severity. Supported by AG063911, AG045390, NS092089, AG016976.

AbstractBackgroundIt is important to determine the natural history of sporadic and familial frontotemporal lobar degeneration (FTLD) and generate clinical, neuropsychological, neuroimaging and biofluid data for planning disease‐modifying trials.MethodAs part of the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD; U19 AG063911) protocol, investigators at 19 centers in North America will enroll 2100 participants with FTLD over the next 5 years beginning in early 2020.ResultAs of 1/20/20, the ARTFL/LEFFTDS (A/L) Consortium had enrolled 1832 participants, including 850 in kindreds with familial FTLD (239 associated with mutations in MAPT, 192 in GRN, 370 in C9orf72, 4 with mutations in both GRN and C9orf72, and 45 with a mutation in a different gene or no mutation in any known FTLD‐associated gene). Over 500 participants have undergone 2 or more annual visits to date. MRI has been performed in 1105. Biofluid samples have also been collected, with blood (DNA, plasma, serum, mRNA, PBMC) in 1413 and CSF in 303. Over 60 manuscripts using A/L data or samples have been published to date. Five clinical trials involving A/L and ALLFTD participants are in progress or planned. The longitudinal arm in ALLFTD will enroll 500 of existing A/L and 600 future participants for annual assessments with similar methodology to A/L. An additional 1000 FTLD patients will undergo focused one‐time clinical evaluations and biofluid collection.ConclusionThe data/samples from already‐enrolled and planned participants in ALLFTD and findings published to date underscore the utility of evaluating FTLD subjects. The absence of identifiable mutations in some with familial FTLD suggests that other genes are yet to be discovered. ALLFTD data will inform clinical trial design, and many participants will be eligible for future trials. The key data and samples in ALLFTD are available to interested investigators worldwide. Supported by: AG063911, AG045390, NS092089, AG016976, AG21886.

AbstractObjectiveMAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.MethodsWe studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel‐based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.ResultsSymptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.InterpretationA subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.