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OBJECTIVE To determine acute effects of intranasal insulin on regional cerebral perfusion and cognition in older adults with type 2 diabetes mellitus (DM). RESEARCH DESIGN AND METHODS This was a proof-of-concept, randomized, double-blind, placebo-controlled intervention evaluating the effects of a single 40-IU dose of insulin or saline on vasoreactivity and cognition in 15 DM and 14 control subjects. Measurements included regional perfusion, vasodilatation to hypercapnia with 3-Tesla MRI, and neuropsychological evaluation. RESULTS Intranasal insulin administration was well tolerated and did not affect systemic glucose levels. No serious adverse events were reported. Across all subjects, intranasal insulin improved visuospatial memory (P ≤ 0.05). In the DM group, an increase of perfusion after insulin administration was greater in the insular cortex compared with the control group (P = 0.0003). Cognitive performance after insulin administration was related to regional vasoreactivity. Improvements of visuospatial memory after insulin administration in the DM group (R2adjusted = 0.44, P = 0.0098) and in the verbal fluency test in the control group (R2adjusted = 0.64, P = 0.0087) were correlated with vasodilatation in the middle cerebral artery territory. CONCLUSIONS Intranasal insulin administration appears safe, does not affect systemic glucose control, and may provide acute improvements of cognitive function in patients with type 2 DM, potentially through vasoreactivity mechanisms. Intranasal insulin-induced changes in cognitive function may be related to vasodilatation in the anterior brain regions, such as insular cortex that regulates attention-related task performance. Larger studies are warranted to identify long-term effects and predictors of positive cognitive response to intranasal insulin therapy.

Background and Purpose— Orthostatic intolerance and falls differ between sexes and change with age. However, it remains unclear what role cerebral autoregulation may play in this response. This study was designed to determine whether cerebral autoregulation, assessed using transcranial Doppler ultrasound, is more effective in elderly females than in males. Methods— We used transcranial Doppler ultrasound to evaluate cerebral autoregulation in 544 (236 male) subjects older than age 70 years recruited as part of the MOBILIZE Boston study. The MOBILIZE Boston study is a prospective cohort study of a unique set of risk factors for falls in seniors in the Boston area. We assessed CO 2 reactivity and transfer function gain, phase, and coherence during 5 minutes of quiet sitting and autoregulatory index during sit-to-stand tests. Results— Male subjects had significantly lower CO 2 reactivity (males, 1.10±0.03; females, 1.32±0.43 (cm/s)/%CO 2 ; P P P =0.002), and lower phase (males, 42.7±23.6; females, 49.4±24.9; P =0.002) in the autoregulatory band, implying less effective cerebral autoregulation. However, reduced autoregulation in males was not below the normal range, indicating autoregulation was intact but less effective. Conclusions— Female subjects were better able to maintain cerebral flow velocities during postural changes and demonstrated better cerebral autoregulation. The mechanisms of sex-based differences in autoregulation remain unclear but may partially explain the higher rates of orthostatic hypotension-related hospitalizations in elderly men.

OBJECTIVES: To examine the relationship between gait speed and falls risk. DESIGN: Longitudinal analysis of the association between gait speed and subsequent falls and analysis of gait speed decline as a predictor of future falls. SETTING: Population-based cohort study. PARTICIPANTS: Seven hundred sixty-three community-dwelling older adults underwent baseline assessments and were followed for falls; 600 completed an 18-month follow-up assessment to determine change in gait speed and were followed for subsequent falls. MEASUREMENTS: Gait speed was measured during a 4-m walk, falls data were collected from monthly post-card calendars, and covariates were collected from in-home and clinic visits. RESULTS: There was a U-shaped relationship between gait speed and falls, with participants with faster (\u22651.3 m/s, incident rate ratio (IRR)=2.12, 95% confidence interval (CI)=1.48\u20133.04) and slower (

Background and Purpose— Our objective was to investigate the associations between polymorphisms in representative genes of the renin angiotensin system with measures of cerebral blood flow regulation in older adults. Methods— Participants in this analysis were white subjects (n=335) in the MOBILIZE Boston study (Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly of Boston), an observational study of community-dwelling elders who underwent transcranial Doppler while sitting and standing and during hypercapnea and hypocapnea. Autoregulation phenotype was the change in cerebrovascular resistance from sit to stand. Vasoreactivity phenotype was the slope of the change in cerebrovascular conductance versus change in end-tidal CO 2 . A total of 33 tagged single nucleotide polymorphisms were selected in the angiotensinogen gene, the angiotensin converting enzyme gene, and the angiotensin receptor gene. Regression analyses adjusted for age, gender, body mass index, mean arterial blood pressure, stroke, and use of antihypertensives were conducted for each single nucleotide polymorphism and outcome. Bonferroni corrections were used to adjust P values for multiple testing. Results— In the angiotensinogen gene, only the rs699 single nucleotide polymorphism was associated with vasoreactivity after Bonferroni correction ( P =0.00028). Homozygous carriers of the CC genotype of this single nucleotide polymorphism had lower vasoreactivity compared with the CT or TT genotypes. There were no significant associations with autoregulation measures. None of the single nucleotide polymorphisms in the other genes were associated with our phenotypes. Conclusion— This analysis suggests that the angiotensinogen gene may be involved in vasoreactivity independent of blood pressure. Larger studies are needed to confirm the role of this gene in cerebrovascular health and aging.

Background Hallux valgus (HV), a common structural foot deformity, can cause foot pain and lead to limited mobility. The purpose of this study was to evaluate differences in plantar pressure and force during gait by HV status in a large population-based cohort of men and women. Methods A trained examiner performed a validated physical examination on participants’ feet and recorded the presence of hallux valgus and other specific foot disorders. Each foot was classified into one of four mutually exclusive groups based on the foot examination. Foot groups were: (i) HV only, (ii) HV and at least one additional foot disorder (FD), (iii) no HV but at least one other FD, and (iv) neither HV nor FD (referent). Biomechanical data for both feet were collected using Tekscan Matscan. Foot posture during quiet standing, using modified arch index (MAI), and foot function during gait, using center of pressure excursion index (CPEI), were calculated per foot. Further, walking scans were masked into eight sub-regions using Novel Automask, and peak pressure and maximum force exerted in each region were calculated. Results There were 3205 participants, contributing 6393 feet with complete foot exam data and valid biomechanical measurements. Participants with HV had lower hallucal loading and higher forces at lesser toes as well as higher MAI and lower CPEI values compared to the referent. Participants with HV and other FDs were also noted to have aberrant rearfoot forces and pressures. Conclusions These results suggest that HV alters foot loading patterns and pressure profiles. Future work should investigate how these changes affect the risk of other foot and lower extremity ailments.

Neurovascular coupling may be involved in compensatory mechanisms responsible for preservation of gait speed in elderly people with cerebrovascular disease. Our study examines the association between neurovascular coupling in the middle cerebral artery and gait speed in elderly individuals with impaired cerebral vasoreactivity.Twenty-two fast and 20 slow walkers in the lowest quartile of cerebral vasoreactivity were recruited from the MOBILIZE Boston Study. Neurovascular coupling was assessed in bilateral middle cerebral arteries by measuring cerebral blood flow during the N-Back task. Cerebral white matter hyperintensities were measured for each group using magnetic resonance imaging.Neurovascular coupling was attenuated in slow compared to fast walkers (2.8%; 95% confidence interval [CI], -0.9 to 6.6 vs 8.2%; 95% CI, 4.7-11.8; p = 0.02). The odds ratio of being a slow walker was 6.4 (95% CI, 1.7-24.9; p = 0.007) if there was a high burden of white matter hyperintensity; however, this risk increased to 14.5 (95% CI, 2.3-91.1; p = 0.004) if neurovascular coupling was also attenuated.Our results suggest that intact neurovascular coupling may help preserve mobility in elderly people with cerebral microvascular disease.

It is known that impaired balance is associated with falls in older adults; however, there is no accepted gold standard on how balance should be measured. Few studies have examined measures of postural sway and clinical balance concurrently in large samples of community-dwelling older adults. We examined the associations among 4 types of measures of laboratory- and clinic-based balance in a large population-based cohort of older adults.We evaluated balance measures in the Maintenance of Balance, Independent Living, Intellect and Zest in the Elderly Boston Study (276 men and 489 women ages 64-97 years). The measures included laboratory-based anteroposterior (AP) path length and mean sway speed, mediolateral (ML) mean sway and root mean square, and area of ellipse postural sway; the Short Physical Performance Battery (SPPB); the Berg Balance Scale; and the one-leg stand test. Spearman's rank correlation coefficients were assessed among the balance measures.The area of ellipse sway was highly correlated with the ML sway measures (r =0.91, P0.0001) and sway speed was highly correlated with AP sway (r = 0.97, P0.0001). The Berg Balance Scale was highly correlated with the SPPB (r = 0.74, P0.001) and the one-leg stand test (r = 0.82, P0.001). Correlations between the laboratory- and clinic-based balance measures were low but statistically significant (-0.29 ≤ r ≤ -0.16, P0.0001).Clinic-based balance measures, and laboratory-based measures comparing area of ellipse with ML sways or sway speed with AP sway, are highly correlated. There is less correlation between the clinic- and laboratory-based measures. Since both laboratory- and clinic-based measures inform balance in older adults, but are not highly correlated with each other, future work should investigate the differences.

Objective: To determine whether alterations in cerebral blood flow regulation are associated with slow gait speed and falls in community-dwelling elderly individuals. Methods: The study sample consisted of 419 individuals from the MOBILIZE Boston Study (MBS) who had transcranial Doppler ultrasound measures of cerebral blood flow velocity. The MBS is a prospective cohort study of a unique set of risk factors for falls in seniors in the Boston area. We measured beat-to-beat blood flow velocity in the middle cerebral artery in response to 1) changes in end-tidal CO 2 (cerebral vasoreactivity) and 2) blood pressure changes during a sit-to-stand protocol (cerebral autoregulation). Gait speed was measured during a 4-meter walk. Falls were tracked by monthly calendars, and demographic and clinical characteristics were assessed at baseline. Results: A multivariate linear regression analysis showed that cerebral vasoreactivity was cross-sectionally related to gait speed ( p = 0.039). Individuals in the lowest quintile of vasoreactivity had lower gait speeds as compared to those in the highest quintile ( p = 0.047). In a negative binomial regression analysis adjusted for relevant covariates, the relationship between cerebral vasoreactivity and fall rate did not reach significance. However, when comparing individuals in the lowest to highest quintile of cerebral vasoreactivity, those in the lowest quintile had a higher fall rate ( p = 0.029). Conclusions: Impaired cerebral blood flow regulation, as measured by cerebral vasoreactivity to CO 2 , is associated with slow gait speed and may lead to the development of falls in elderly people.

The purpose of this study was to investigate the effect of subsensory vibratory noise applied to the soles of the feet on gait variability in a population of elderly recurrent fallers compared to non-fallers and young controls. Eighteen elderly recurrent fallers and 18 elderly non-fallers were recruited from the MOBILIZE Boston Study (MBS), a population-based cohort study investigating novel risk factors for falls. Twelve young participants were included as controls. Participants performed three 6-minute walking trials while wearing a pair of insoles containing vibrating actuators. During each trial, the noise stimulus was applied for 3 of the 6 minutes, and differences in stride-, stance-, and swing-time variability were analyzed between noise and no-noise conditions. The use of vibrating insoles significantly reduced stride-, stance-, and swing-time variability measures for elderly recurrent fallers. Elderly non-fallers also demonstrated significant reductions in stride and stance time variability. Although young participants showed decreases in all variability measures, the results did not achieve statistical significance. Gait variability reductions with noise were similar between the elderly recurrent fallers and elderly non-fallers. This study supports the hypothesis that subsensory vibratory noise applied to the soles of the feet can reduce gait variability in elderly participants. Future studies are needed to determine if this intervention reduces falls risk.