Associations between CSF cortisol and CSF norepinephrine in cognitively normal controls and patients with amnestic MCI and AD dementia.

OBJECTIVE: This study evaluated the effects of Alzheimer disease (AD) on the relationship between the brain noradrenergic system and hypothalamic pituitary adrenocortical axis (HPA). Specifically, relationships between cerebrospinal fluid (CSF) norepinephrine (NE) and CSF cortisol were examined in cognitively normal participants and participants with AD dementia and amnestic mild cognitive impairment (aMCI). We hypothesized that there would a positive association between these 2 measures in cognitively normal controls and that this association would be altered in AD. METHODS: Four hundred twenty-one CSF samples were assayed for NE and cortisol in controls (n = 305), participants with aMCI (n = 22), and AD dementia (n = 94). Linear regression was used to examine the association between CSF cortisol and NE, adjusting for age, sex, education, and body mass index. RESULTS: Contrary to our hypothesis, CSF cortisol and NE levels were not significantly associated in controls. However, higher cortisol levels were associated with higher NE levels in AD and aMCI participants. Regression coefficients ± standard errors for the change in cortisol per 100-pg/mL increase in NE are as follows: controls 0.0 ± 0.2, P = 1.0; MCI, 1.4 ± 0.7, P = .14; and AD 1.1 ± 0.4, P = .032. Analysis with MCI and AD participants combined strengthened statistical significance (1.2 ± 0.3, P = .007). CONCLUSIONS: Enhanced responsiveness of the HPA axis to noradrenergic stimulatory regulation in AD and disruption of the blood brain barrier may contribute to these findings. Because brainstem noradrenergic stimulatory regulation of the HPA axis is substantially increased by both acute and chronic stress, these findings are also consistent with AD participants experiencing higher levels of acute and chronic stress.

Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression.

OBJECTIVES: Agitation/aggression in Alzheimer disease (AD) is a major cause of patient distress, caregiver burden, and institutionalization. Enhanced behavioral responsiveness to central nervous system norepinephrine (NE) release may contribute to the pathophysiology of agitation/aggression in AD. Prazosin, a nonsedating generic medication used for hypertension and benign prostatic hypertrophy, antagonizes NE effects at brain postsynaptic alpha-1 adrenoreceptors. This pilot study examined the efficacy and tolerability of prazosin for behavioral symptoms in patients with agitation/aggression in AD. DESIGN: Double-blind, placebo controlled, parallel group study. SETTING: A university AD center and a nursing home in Seattle, WA. PARTICIPANTS: Twenty-two nursing home and community-dwelling participants with agitation/aggression and probable or possible AD (mean age: 80.6 +/- 11.2). INTERVENTION: Randomization to placebo (N = 11) or prazosin (N = 11). Medication was initiated at 1 mg/day and increased up to 6 mg/day using a flexible dosing algorithm. MEASUREMENTS: The Brief Psychiatric Rating Scale (BPRS) and Neuropsychiatric Inventory (NPI) at Weeks 1, 2, 4, 6, and 8. The Clinical Global Impression of Change (CGIC) at Week 8. RESULTS: Participants taking prazosin (mean dose: 5.7 +/- 0.9 mg/day) had greater improvements than those taking placebo (mean dose: 5.6 +/- 1.2 mg/day) on the NPI (mean change: -19 +/- 21 versus -2 +/- 15, chi = 6.32, df = 1, p = 0.012) and BPRS (mean change: -9 +/- 9 versus -3 +/- 5, chi = 4.42, df = 1, p = 0.036) based on linear mixed effects models and the CGIC (mean: 2.6 +/- 1.0 versus 4.5 +/- 1.6, z = 2.57, p = 0.011 [Mann-Whitney test]). Adverse effects and blood pressure changes were similar between prazosin and placebo groups. CONCLUSION: Prazosin was well tolerated and improved behavioral symptoms in patients with agitation/aggression in AD.

Cognitive impairment in older adults without dementia: clinical and pathologic outcomes in a community-based sample.

This study examines clinical and neuropathologic characteristics of 37 participants in a community-based dementia series who had cognitive complaints at enrollment but did not meet dementia criteria. Participants had neuropsychological testing, were followed until death, and underwent autopsy. Twenty-four participants progressed to dementia, and their baseline characteristics were analyzed. Of the 24, 13 met criteria for neuropathologic Alzheimer disease (AD). The 13 participants who progressed to neuropathologic AD (mean intake age 78.5 +/- 7.7, mean enrollment 6.4 +/- 2.1 years) performed worse than the 11 who progressed to neuropathologic non-AD dementias (mean intake age 79.0 +/- 6.0, mean enrollment 6.0 +/- 3.2 years) on baseline Wechsler Memory Scale (WMS) delayed logical memory (3.4 +/- 2.9 vs 6.3 +/- 3.9, P = .05) and delayed visual reproduction (1.4 +/- 2.1 vs 3.1 +/- 2.7, P = .02). These observations are consistent with the view that nondemented patients with underlying AD may be more likely to present with memory than nonmemory cognitive impairment.

Common psychiatric problems in cognitively impaired older patients: causes and management.

Although dementias are defined by their cognitive and functional deficits, psychiatric problems are common, contribute to patient distress and caregiver burden, and precipitate institutionalization. Successful treatment involves understanding that physiologic, psychological, and environmental factors can contribute to the development of these symptoms. By carefully assessing each of these factors, clinicians can individualize treatment and flexibly use nonpharmacologic and pharmacologic approaches tailored to patients and the context of care. Although there exist limitations to many treatment options, clinicians can still adapt current knowledge to develop a multifaceted treatment approach that improves the quality of life for patients and their caregivers.

Cerebrospinal fluid norepinephrine and cognition in subjects across the adult age span.

Adequate central nervous system noradrenergic activity enhances cognition, but excessive noradrenergic activity may have adverse effects on cognition. Previous studies have also demonstrated that noradrenergic activity is higher in older than younger adults. We aimed to determine relationships between cerebrospinal fluid (CSF) norepinephrine (NE) concentration and cognitive performance by using data from a CSF bank that includes samples from 258 cognitively normal participants aged 21-100 years. After adjusting for age, gender, education, and ethnicity, higher CSF NE levels (units of 100 pg/mL) are associated with poorer performance on tests of attention, processing speed, and executive function (Trail Making A: regression coefficient 1.5, standard error [SE] 0.77, p = 0.046; Trail Making B: regression coefficient 5.0, SE 2.2, p = 0.024; Stroop Word-Color Interference task: regression coefficient 6.1, SE 2.0, p = 0.003). Findings are consistent with the earlier literature relating excess noradrenergic activity with cognitive impairment.

Temporal relationship between depression and dementia: findings from a large community-based 15-year follow-up study.

CONTEXT: Late-life depression is associated with increased risk of dementia, but the temporal relationship between depression and development of dementia remains unclear. OBJECTIVES: To examine the association between risk of dementia and baseline depressive symptoms; history of depression, particularly early-life (<50 years) vs late-life depression (≥50 years); and individual domains of the Center for Epidemiologic Studies Depression Scale. DESIGN: A large cohort with initially nondemented participants was followed up biennially for up to 15 years. Baseline depressive symptoms were assessed using the 11-item version of the Center for Epidemiologic Studies Depression Scale; presence of significant depressive symptoms was defined as a score of 11 or greater. Self-reported history of depression was collected at the baseline interview. Cox proportional hazards regression was used to assess the association between depression and dementia risk. SETTING: Population-based cohort drawn from members of the Group Health Cooperative in Seattle, Washington. PARTICIPANTS: A cohort of 3410 participants without dementia aged at least 65 years. RESULTS: During a mean of 7.1 years of follow-up, 658 participants (19.3%) developed dementia. At baseline, 9.4% of participants had presence of significant depressive symptoms, and 21.2% reported a history of depression. The adjusted hazard ratio for dementia associated with baseline depressive symptoms was 1.71 (95% confidence interval, 1.37-2.13), after adjusting for age at entry, sex, educational level, and wave of enrollment. Compared with participants without depression history, those with late-life depression were at increased dementia risk (adjusted hazard ratio, 1.46; 95% confidence interval, 1.16-1.84), but early-life depression had no association with dementia risk (1.10 [0.83-1.47]). Depressed mood (adjusted hazard ratio, 1.48; 95% confidence interval, 1.25-1.76) and perceived performance difficulty (1.39 [1.15-1.67]) were independently associated with dementia. CONCLUSION: This study confirmed that late-life depression is associated with increased risk of dementia and supplied evidence that late-life depression may be an early manifestation of dementia rather than increasing risk for dementia.

Blood pressure and brain injury in older adults: findings from a community-based autopsy study.

OBJECTIVES: To examine correlations between blood pressure (BP) and dementia-related pathological brain changes in a community-based autopsy sample. DESIGN: Prospective cohort study. SETTING: A large health maintenance organization in Seattle, Washington. PARTICIPANTS: A cohort of 250 participants aged 65 and older and cognitively normal at time of enrollment in the Adult Changes in Thought (ACT) Study and who underwent autopsy. MEASUREMENTS: BP and history of antihypertensive treatment were taken at enrollment. A linear regression model was used to examine the relationship between BP (systolic (SBP) and diastolic (DBP)) at enrollment and pathological changes in the cerebrum (cystic macroscopic infarcts, microinfarcts, neuritic plaques, neurofibrillary tangles, and cortical Lewy bodies). RESULTS: The presence of more than 2 microinfarcts, but not any other pathological change, was independently associated with SBP in younger participants (65-80, n=137) but not in older participants (>80, n=91). The relative risk (RR) for more than two microinfarcts with each 10-mmHg increase in SBP was 1.15 (95% confidence interval (CI)=1.00-1.33) in the younger participants, adjusted for age at entry, sex, and time to death. This RR was particularly strong in younger participants not taking antihypertensive medications (RR=1.48, 95% CI=1.21, 1.81); significant associations were not observed in participants treated for hypertension. Findings for DBP were negative. CONCLUSION: The association between high SBP and cerebrovascular damage in untreated older adults (65-80) suggests that adequate hypertension treatment may reduce dementia risk by minimizing microvascular injury to cerebrum.