The effect of a change in antihypertensive treatment on orthostatic hypotension in older adults: A systematic review and meta-analysis.

BACKGROUND: Orthostatic hypotension (OH) is common in older adults with hypertension. Antihypertensive treatment (AHT) prevents cardio- and cerebrovascular events. However, physicians are concerned to cause OH, making them hesitant to initiate or augment AHT in older adults with hypertension. METHODS: We systematically researched electronic databases for trials with older participants (≥65 years) with hypertension and OH assessment after initiating, discontinuing, or augmenting AHT. Study quality was assessed using the ROBINS-I tool. Meta-analyses on OH prevalence and postural blood pressure (BP) drop were performed. RESULTS: Twenty-five studies (26,695 participants) met inclusion criteria, of which fifteen could be included in the meta-analyses. OH prevalence decreased after AHT initiation or augmentation (risk ratio 0.39 (95 % CI = 0.21-0.72; I2 = 47 %; p < 0.01), n = 6 studies), but also after AHT discontinuation (risk ratio 0.39 (95 % CI = 0.28-0.55; I2 = 0 %; p < 0.01), n = 2 studies). Postural BP drop did not change after initiation or augmentation of AHT (mean difference 1.07 (95 % CI = -0.49-2.64; I2 = 92 %; p = 0.18), n = 11 studies). The main reason for ten studies not to be included in the meta-analyses was absence of baseline OH data. Most of these studies reported OH incidences between 0 and 2 %. Studies were heterogeneous in OH assessment methods (postural change, timing of BP measurements, and OH definition). Risk of bias was moderate to serious in twenty studies. CONCLUSION: Results suggest that AHT initiation or augmentation decreases OH prevalence, implying that the risk of inducing OH may be overestimated in current AHT decision-making in older adults. However, the overall low level of evidence and the finding that AHT discontinuation reduces OH prevalence limit firm conclusions at present and highlight an important research gap. Future AHT trials in older adults should measure OH in a standardized protocol, adhering to consensus guidelines to overcome these limitations.

A multidomain lifestyle intervention to maintain optimal cognitive functioning in Dutch older adults-study design and baseline characteristics of the FINGER-NL randomized controlled trial.

BACKGROUND: Evidence on the effectiveness of multidomain lifestyle interventions to prevent cognitive decline in older people without dementia is mixed. Embedded in the World-Wide FINGERS initiative, FINGER-NL aims to investigate the effectiveness of a 2-year multidomain lifestyle intervention on cognitive functioning in older Dutch at risk individuals. METHODS: Multi-center, randomized, controlled, multidomain lifestyle intervention trial with a duration of 24 months. 1210 adults between 60-79 years old with presence of ≥ 2 modifiable risk factors and ≥ 1 non-modifiable risk factor for cognitive decline were recruited between January 2022 and May 2023 via the Dutch Brain Research Registry and across five study sites in the Netherlands. Participants were randomized to either a high-intensity or a low-intensity intervention group. The multidomain intervention comprises a combination of 7 lifestyle components (physical activity, cognitive training, cardiovascular risk factor management, nutritional counseling, sleep counseling, stress management, and social activities) and 1 nutritional product (Souvenaid®) that could help maintain cognitive functioning. The high-intensity intervention group receives a personalized, supervised and hybrid intervention consisting of group meetings (on-site and online) and individual sessions guided by a trained lifestyle coach, and access to a digital intervention platform that provides custom-made training materials and selected lifestyle apps. The low-intensity intervention group receives bi-monthly online lifestyle-related health advice via the digital intervention platform. Primary outcome is 2-year change on a cognitive composite score covering processing speed, executive function, and memory. RESULTS: Within 17 months, participant recruitment has been successfully completed (N = 1210; mean age: 67.7 years (SD: 4.6); 64% female). Modifiable risk factors commonly present at baseline were physical inactivity (89%), low mental/cognitive activity (50%), low social engagement (39%), hypertension (39%) and high alcohol consumption (39%). The mean body mass index of participants was 28.3 (SD: 4.2) and the total serum cholesterol was 5.4 mmol/L (SD: 1.2). CONCLUSIONS: Baseline lifestyle and clinical measurements showed successful recruitment of participants with sufficient potential for prevention. Results of FINGER-NL will provide further insight into the efficacy of a multidomain lifestyle intervention to prevent cognitive decline in older adults. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT05256199)/2022-01-11.

Antihypertensives in dementia: Good or bad for the brain?

We discuss the current evidence for both benefit and harm of antihypertensive treatment in people with dementia. We conclude that there is a lack of evidence to support the claim that there is an increased risk of cerebral hypoperfusion with antihypertensive treatment in dementia, and that there is growing evidence which refutes this claim.

Capturing postural blood pressure dynamics with near-infrared spectroscopy-measured cerebral oxygenation.

Orthostatic hypotension (OH) is highly prevalent in older adults and associated with dizziness, falls, lower physical and cognitive function, cardiovascular disease, and mortality. OH is currently diagnosed in a clinical setting with single-time point cuff measurements. Continuous blood pressure (BP) devices can measure OH dynamics but cannot be used for daily life monitoring. Near-infrared spectroscopy (NIRS) has potential diagnostic value in measuring cerebral oxygenation continuously over a longer time period, but this needs further validation. This study aimed to compare NIRS-measured (cerebral) oxygenation with continuous BP and transcranial Doppler-measured cerebral blood velocity (CBv) during postural changes. This cross-sectional study included 41 participants between 20 and 88 years old. BP, CBv, and cerebral (long channels) and superficial (short channels) oxygenated hemoglobin (O2Hb) were measured continuously during various postural changes. Pearson correlations between BP, CBv, and O2Hb were calculated over curves and specific characteristics (maximum drop amplitude and recovery). BP and O2Hb only showed good curve-based correlations (0.58-0.75) in the initial 30 s after standing up. Early (30-40 s) and 1-min BP recovery associated significantly with O2Hb, but no consistent associations were found for maximum drop amplitude and late (60-175 s) recovery values. Associations between CBv and O2Hb were poor, but stronger for long-channel than short-channel measurements. BP associated well with NIRS-measured O2Hb in the first 30 s after postural change. Stronger associations for CBv with long-channel O2Hb suggest that long-channel NIRS specifically reflects cerebral blood flow during postural transitions, necessary to better understand the consequences of OH such as intolerance symptoms.

Day-To-Day Home Blood Pressure Variability and All-Cause Mortality in a Memory Clinic Population.

BACKGROUND: High day-to-day blood pressure variability (BPV) has been associated with an increased risk for cognitive decline and mortality in the general population. Whether BPV is associated with increased all-cause mortality in older people with cognitive impairment is unknown. OBJECTIVE: To investigate the association between day-to-day home BPV and all-cause mortality in older patients attending a memory clinic. METHODS: We included 279 patients attending a memory clinic, who measured home blood pressure (BP) for 7 consecutive days in the morning and evening. Within-subject BPV was defined as the variation independent of the mean (VIM). Time-to-death was verified through the Dutch population registry. Cox proportional hazard regression was used. Separate analyses were performed for morning-to-morning and evening-to-evening BPV. RESULTS: Mean age was 73±9 years, dementia and mild cognitive impairment were diagnosed in 35% and 34% respectively, and mean home BP was 139/79 mmHg. After a mean follow-up of 3.2 years, 52 patients had died. Neither day-to-day systolic nor diastolic VIM were associated with mortality (adjusted hazard ratio [HR] systolic VIM: 0.99, 95% -CI 0.92-1.06, p = 0.770, HR diastolic VIM: 1.04, 95% -CI 0.93-1.17, p = 0.517). When morning and evening measurements were analyzed separately, systolic morning-to-morning VIM was associated with mortality (adjusted HR: 1.09, 95% -CI 1.01-1.18, p = 0.033). CONCLUSION: In this study, day-to-day BPV was not associated with all-cause mortality in patients attending a memory clinic. However, morning-to-morning BPV was. Due to the short assessment window, there is still a lack of clarity; hence future research is warranted to clarify the role of all BPV components in aging.

Effect of Antihypertensive Treatment on Cerebral Blood Flow in Older Adults: a Systematic Review and Meta-Analysis.

BACKGROUND: In older age, the benefits of antihypertensive treatment (AHT) become less evident, with greater associated risk. Of particular concern is compromising cerebral blood flow (CBF), especially in those with cognitive impairment. METHODS: We created a synthesis of the published evidence by searching multiple electronic databases from 1970 to May 2021. Included studies had participants with mean age ≥50 years, hypertension or cognitive impairment, and assessed CBF before and after initiating AHT. Two authors independently determined eligibility and extracted data. Study quality was assessed using The Risk of Bias in Nonrandomized Studies of Interventions tool. We summarized study characteristics (qualitative synthesis) and performed random-effects meta-analyses (quantitative synthesis). RESULTS: Thirty-two studies (total n=1306) were included, of which 23 were eligible for meta-analysis. In line with the qualitative synthesis, the meta-analysis indicated no effect of AHT initiation on CBF (standardized mean difference, 0.08 [95% CI, -0.07 to 0.22]; P=0.31, I2=42%). This was consistent across subgroups of acute versus chronic AHT, drug class, study design, and CBF measurement. Subgroups by age demonstrated an increase in CBF after AHT in those aged >70 years (standardized mean difference, 4.15 [95% CI, 0.16-8.15]; P=0.04, I2=42%), but not in those aged 50 to 65 and 65 to 70 years (standardized mean difference, 0.18 [95% CI,-2.02 to 2.38]; P=0.87, I2=49%; standardized mean difference, 1.22 [95% CI, -0.45 to 2.88]; P=0.15, I2=68%). Overall, risk of bias was moderate-to-high and quality of evidence (Grading of Recommendations Assessment, Development and Evaluation) was very low, reflecting the observational nature of the data. CONCLUSIONS: Accepting the observed limitations, current evidence does not suggest a harmful effect of AHT on CBF. Concerns over CBF should not preclude treatment of hypertension.

Longitudinal changes in the control mechanisms for blood pressure and cerebral blood flow in Alzheimer's disease: Secondary results of a randomized controlled trial.

Objective: Dynamic cerebral autoregulation (dCA) and baroreflex sensitivity (BRS) are key mechanisms involved in the homeostasis of blood pressure (BP) and cerebral blood flow. We assessed changes in these mechanisms in Alzheimer's disease (AD) during a 1.5 year follow-up. Methods: In this secondary analysis of a randomized controlled trial we measured beat-to-beat BP, heart rate, and cerebral blood flow velocity at baseline, 0.5 and 1.5 years, during: rest (spontaneous oscillations), repeated sit-stand maneuvers (induced oscillations), an orthostatic challenge, and hypo- and hypercapnia. dCA was estimated using transfer function analysis and the autoregulatory index on spontaneous and induced oscillations. BRS was estimated by calculating the heart rate response to BP changes during induced oscillations. Linear mixed models were used to assess changes over time. Results: 56 patients were included (mean age:73 ± 6 years, 57% female). BRS did not change over time. dCA parameters showed small changes after 0.5 years, suggestive of a reduction in efficiency (e.g. higher gain [linear mixed effect model: B = 0.09, SE = 0.03, P = 0.008] and lower phase [B = -9.7, SE= 3.2, P = 0.004] in the very low frequency domain, and lower autoregulatory index during induced oscillations [B = -0.69, SE = 0.26, P = 0.010]). These changes did not show further progression after 1.5 years of follow-up. Discussion: In this sample of patients with dementia due to AD we found no evidence that dCA or BRS become impaired during AD progression. This paves the way for further studies that investigate the safety and benefits of antihypertensive treatment in patients with AD.

Association Between Blood Pressure Variability With Dementia and Cognitive Impairment: A Systematic Review and Meta-Analysis.

[Figure: see text].

Orthostatic Blood Pressure Recovery Is Associated With the Rate of Cognitive Decline and Mortality in Clinical Alzheimer's Disease.

BACKGROUND: Impaired recovery of blood pressure (BP) after standing has been shown to be related to cognitive function and mortality in people without dementia, but its role in people with Alzheimer's disease (AD) is unknown. The aim of this study was to investigate the association of the orthostatic BP response with cognitive decline and mortality in AD. METHODS: In this post hoc analysis of a randomized controlled trial (Nilvad), we measured the beat-to-beat response of BP upon active standing in mild-to-moderate AD. This included the initial drop (nadir within 40 seconds) and recovery after 1 minute, both expressed relative to resting values. We examined the relationship between a small or large initial drop (median split) and unimpaired (≥100%) or impaired recovery (<100%) with 1.5-year change in Alzheimer's Disease Assessment-cognitive subscale (ADAS-cog) scores and all-cause mortality. RESULTS: We included 55 participants (age 73.1 ± 6.2 years). Impaired BP recovery was associated with higher increases in ADAS-cog scores (systolic: ß [95% confidence interval] = 5.6 [0.4-10.8], p = .035; diastolic: 7.6 [2.3-13.0], p = .006). During a median follow-up time of 49 months, 20 participants died. Impaired BP recovery was associated with increased mortality (systolic: HR [95% confidence interval] = 2.9 [1.1-7.8], p = .039; diastolic: HR [95% confidence interval] = 5.5 [1.9-16.1], p = .002). The initial BP drop was not associated with any outcome. Results were adjusted for age, sex, and intervention group. CONCLUSIONS: Failure to fully recover BP after 1 minute of standing is associated with cognitive decline and mortality in AD. As such, BP recovery can be regarded as an easily obtained marker of progression rate of AD.

Objectively-Measured Activity Patterns are Associated with Home Blood Pressure in Memory Clinic Patients.

BACKGROUND: Physicians are cautious to prescribe antihypertensive drugs in frail older adults because of the potential adverse effects, especially in those with cognitive complaints. Lifestyle aspects might provide safe targets to lower blood pressure in older adults. OBJECTIVE: Our goal was to evaluate the associations between activity patterns and blood pressure in memory clinic patients. METHODS: We used an observational cross-sectional study to measure activity patterns with the ActivPAL accelerometer, and simultaneous home blood pressure levels in memory clinic patients (age range 51-87 years old). Office blood pressure was assessed during routine clinical practice. RESULTS: 41 patients (mean age of 74.3 (7.7) years of age, 46% female) were included. Sedentary parameters were associated with higher mean home blood pressure, with the strongest correlation between more prolonged sitting bouts and higher SBP (r = 0.58, p < .0001). Physical activity parameters were negatively associated with mean home blood pressure. Adjusted regression estimates remained significant, showing, e.g., a 4.5 (95% CI = 1.6;7.4) mmHg increase in SBP for every hour of sitting per day and a -1.0 (95% CI = -1.8;-0.2) mmHg decrease in DBP for every additional 1000 steps per day. No strong correlations were found between any of the activity pattern variables and office blood pressure. CONCLUSION: Associations between activity pattern variables and blood pressure were only found with home blood pressure measurements, not with office measurements. Longitudinal evaluations of these associations are now needed to explore if reducing prolonged sedentary bouts and increasing step count indeed serve as safe targets to lower blood pressure.

Day-to-Day Home Blood Pressure Variability is Associated with Cerebral Small Vessel Disease Burden in a Memory Clinic Population.

BACKGROUND: High visit-to-visit blood pressure variability (BPV) has been associated with cognitive decline and cerebral small vessel disease (cSVD), in particular cerebrovascular lesions. Whether day-to-day BPV also relates to cSVD has not been investigated. OBJECTIVE: To investigate the cross-sectional association between day-to-day BPV and total cSVD MRI burden in older memory clinic patients. METHODS: We included outpatients referred to our memory clinic, who underwent cerebral MRI as part of their diagnostic assessment. We determined the validated total cSVD score (ranging from 0-4) by combining four markers of cSVD that were visually rated. Home blood pressure (BP) measurements were performed for one week, twice a day, according to international guidelines. BPV was defined as the within-subject coefficient of variation (CV; standard deviation/mean BP*100). We used multivariable ordinal logistic regression analyses adjusted for age, sex, smoking, diabetes, antihypertensive medication, history of cardiovascular disease, and mean BP. RESULTS: For 82 patients (aged 71.2±7.9 years), mean home BP was 140/79±15/9 mmHg. Dementia and mild cognitive impairment were diagnosed in 46% and 34%, respectively. 78% had one or more markers of cSVD. Systolic CV was associated with cSVD burden (adjusted odds ratio per point increase in CV = 1.29, 95% confidence interval = 1.04-1.60, p = 0.022). There were no differences in diastolic CV and mean BP between the cSVD groups. When we differentiated between morning and evening BP, only evening BPV remained significantly associated with total cSVD burden. CONCLUSION: Day-to-day systolic BPV is associated with cSVD burden in memory clinic patients. Future research should indicate whether lowering BPV should be included in BP management in older people with memory complaints.

Diagnostic accuracy of office blood pressure compared to home blood pressure in patients with mild cognitive impairment and dementia.

BACKGROUND: Hypertension and cognitive impairment often coexist in older people. Office blood pressure measurement is a poor indicator for diagnosing hypertension in the general population. However, its diagnostic accuracy has not been substantially studied in patients with cognitive impairment. AIM: The aim of this study was to determine the proportion of misdiagnosis of hypertension in patients with mild cognitive impairment and dementia compared to no cognitive impairment, by comparing office blood pressure measurement with home blood pressure measurement. METHODS: A cross-sectional study including consecutive patients visiting a memory clinic between 2014 and 2017. Home blood pressure was measured for one week according to the European guidelines. Office blood pressure was assessed during routine clinical practice. Using guideline definitions for normal blood pressure and hypertension, we investigated the proportion of disagreement between office blood pressure measurement and home blood pressure measurement. Univariable and multivariable logistic regression compared disagreement in diagnosis between patients with dementia, mild cognitive impairment and no cognitive impairment. RESULTS: Of 213 patients (aged 73.4±9.0 years, 42% women) 82 had dementia, 65 had mild cognitive impairment and 66 had no cognitive impairment. Mean office blood pressure was 156/84±23/11 mmHg and mean home blood pressure was 139/79±16/10 mmHg. In 31% of patients, there was disagreement in hypertension diagnosis. This proportion was higher for mild cognitive impairment (38.5%) and dementia (35.4%) compared to no cognitive impairment (18.2%), with adjusted odds ratios of 3.7 (95% confidence interval 1.5-9.0), P=0.005 for mild cognitive impairment and 3.4 (1.3-8.6), P=0.011 for dementia. CONCLUSIONS: In memory clinic patients with dementia and mild cognitive impairment, the diagnostic accuracy of office blood pressure measurement is lower compared to patients without cognitive impairment. To avoid the risk of making improper treatment decisions in this vulnerable group, a diagnosis of hypertension should be based on home blood pressure measurement, not office blood pressure measurement.

Blood Pressure Variability and Progression of Clinical Alzheimer Disease.

Blood pressure variability (BPV) has been shown to have predictive value over blood pressure (BP) levels alone in stroke patients. We assessed whether BPV predicts cognitive and functional decline in Alzheimer disease, using data from a randomized trial (NILVAD [A European Multicentre Double-blind Placebo-controlled Phase III Trial of Nilvadipine in Mild to Moderate Alzheimer's Disease]). Patients with mild-to-moderate Alzheimer disease were included if they had ≥3 office BP measurements available to determine visit-to-visit BPV. Day-to-day BPV was assessed using home BP measurements in a subsample. The variation independent of mean was used to calculate BPV. Outcomes were change in Alzheimer's Disease Assessment Scale-cognitive subscale-12 and Disability Assessment for Dementia after 1 and 1.5 years. A total of 460 patients aged 72.1 (SD=8.1) years, with mean BP of 134.0/75.1 (10.9/6.3) mm Hg were included. After 1 year, patients in the highest quartile of BPV had deteriorated more on Alzheimer's Disease Assessment Scale-cognitive subscale compared with patients in the lowest quartile (systolic: ß, 2.24 [95% CI, 0.11-4.38], P=0.040; diastolic: ß, 2.54 [95% CI, 0.33-4.75] P=0.024). This association was still present after 1.5 years (systolic: ß, 2.86 [95% CI, 0.35-5.36], P=0.026; diastolic: ß, 3.30 [95% CI, 0.67-5.93], P=0.014). There was no effect of visit-to-visit BPV on Disability Assessment for Dementia. Day-to-day BPV was available for 46 patients. Significant associations were observed between day-to-day BPV and deterioration on Alzheimer's Disease Assessment Scale-cognitive subscale (systolic: P=0.036) and Disability Assessment for Dementia (systolic: P=0.020; diastolic: P=0.007) after 1 year, but not after 1.5 years. All associations were adjusted for potential confounders, including intervention group. In conclusion, this post hoc analysis indicates that higher visit-to-visit and day-to-day BPV might be associated with progression of Alzheimer disease. Targeting BPV may be a future target to slow decline in patients with Alzheimer disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02017340.

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension.

Background Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. Methods and Results Four hundred seventy-seven patients with mild-to-moderate Alzheimer disease were randomized to the calcium-channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop ≥20/≥10 mm Hg after 1 minute of standing) and OH-related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow-up visits. Mean age of the study population was 72.2±8.2 years and mean Mini-Mental State Examination score was 20.4±3.8. Baseline blood pressure was 137.8±14.0/77.0±8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by -7.8/-3.9 mm Hg for nilvadipine and by -0.4/-0.8 mm Hg for placebo ( P<0.001). Across the 78-week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI]=1.1 [0.8-1.5], P=0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7±13.8% versus 7.3±11.6%). OH-related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. Conclusions This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild-to-moderate Alzheimer disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02017340.

Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease.

Cerebrovascular changes, including reduced cerebral blood flow (CBF), occur early in the development of Alzheimer disease and may accelerate disease progression. This randomized, double-blind, placebo-controlled study investigated how 6 months of treatment with the calcium antagonist nilvadipine would affect CBF in patients with mild-to-moderate Alzheimer disease. CBF was measured with magnetic resonance arterial spin labeling in whole-brain gray matter and in a priori defined regions of interest including the hippocampus. Fifty-eight patients were randomly assigned (29 in each group), of whom 22 in both groups had no magnetic resonance exclusion criteria and were medication compliant over 6 months. Mean age was 72.8±6.2 years, mean mini-mental state examination was 20.4±3.4. Nilvadipine treatment lowered systolic blood pressure (Δ=-11.5 [95% CI, -19.7 to -3.2] mm Hg; P<0.01), while whole-brain gray-matter CBF remained stable (Δ=5.4 [95% CI, -6.4 to 17.2] mL/100 g per minute; P=0.36). CBF in the hippocampus increased (left: Δ=24.4 [95% CI, 4.3-44.5] mL/100 g per minute; P=0.02; right: Δ=20.1 [95% CI, -0.6 to 40.8] mL/100 g per minute; P=0.06). There was no significant change in CBF in the posterior cingulate cortex (Δ=5.2 [95% CI, -16.5 to 27.0] mL/100 g per minute; P=0.63) or other regions of interest. In conclusion, nilvadipine reduced blood pressure and increased CBF in the hippocampus, whereas other regions showed stable or small nonsignificant increases in CBF. These findings not only indicate preserved cerebral autoregulation in Alzheimer disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02017340.

Dynamic Regulation of Cerebral Blood Flow in Patients With Alzheimer Disease.

Cerebral autoregulation and baroreflex sensitivity are key mechanisms that maintain cerebral blood flow. This study assessed whether these control mechanisms are affected in patients with dementia and mild cognitive impairment due to Alzheimer disease, as this would increase the risks of antihypertensive treatment. We studied 53 patients with dementia (73.1 years [95% confidence interval (CI), 71.4-74.8]), 37 patients with mild cognitive impairment (69.2 years [95% CI, 66.4-72.0]), and 47 controls (69.4 years [95% CI, 68.3-70.5]). Beat-to-beat blood pressure (photoplethysmography), heart rate, and cerebral blood flow velocity (transcranial Doppler) were measured during 5-minute rest (sitting) and 5 minutes of orthostatic challenges, using repeated sit-to-stand maneuvers. Cerebral autoregulation was assessed using transfer function analysis and the autoregulatory index. Baroreflex sensitivity was estimated with transfer function analysis and by calculating the heart rate response to blood pressure changes during the orthostatic challenges. Dementia patients had the lowest cerebral blood flow velocity (P=0.004). During rest, neither transfer function analysis nor the autoregulatory index indicated impairments in cerebral autoregulation. During the orthostatic challenges, higher autoregulatory index (P=0.011) and lower transfer function gain (P=0.017), indicating better cerebral autoregulation, were found in dementia (4.56 arb. unit [95% CI, 4.14-4.97]; 0.59 cm/s per mm Hg [95% CI, 0.51-0.66]) and mild cognitive impairment (4.59 arb. unit [95% CI, 4.04-5.13]; 0.51 cm/s per mm Hg [95% CI, 0.44-0.59]) compared with controls (3.71 arb. unit [95% CI, 3.35-4.07]; 0.67 cm/s per mm Hg [95% CI, 0.59-0.74]). Baroreflex sensitivity measures did not differ between groups. In conclusion, the key mechanisms to control blood pressure and cerebral blood flow are not reduced in 2 stages of Alzheimer disease compared with controls, both in rest and during orthostatic changes that reflect daily life challenges.

Dose-Dependent Effects of Oral Tyrosine Administration on Plasma Tyrosine Levels and Cognition in Aging.

The effects of tyrosine on plasma response and cognition in aging are unknown. We assessed the dose-dependent response to tyrosine administration in older adults in both plasma tyrosine concentrations and working memory performance. In this double blind randomized cross-over trial 17 older adults (aged 60-75 years) received a single administration of 100, 150, or 200 mg/kg body weight of tyrosine. For comparison, 17 young adults (aged 18-35 years) received a dose of 150 mg/kg body weight of tyrosine. Tyrosine plasma concentrations were determined before and 90, 120, 150, 180, 210, and 240 min after tyrosine intake. Working memory was assessed using the N-back task at 90 min after tyrosine administration. Older adults showed a dose-dependent increase in plasma tyrosine concentrations (p < 0.001), and the plasma response was higher than for young adults with the same dose (p < 0.001). Load-dependent working memory performance decreased with higher doses of tyrosine (p = 0.048), especially in older adults with greater dose-dependent plasma tyrosine responses (p = 0.035). Our results show an age-related increase in plasma tyrosine response, which was associated with a dose-dependent decline in cognitive functioning in older adults.