Small Vessel Cerebrovascular Pathology Identified by Magnetic Resonance Imaging Is Prevalent in Alzheimer's Disease and Mild Cognitive Impairment: A Potential Target for Intervention.

BACKGROUND: There is evidence that Alzheimer's disease (AD) has significant cerebrovascular etiopathogenesis. Understanding potentially modifiable risk factors for vascular disease can help design long-term intervention strategies for controlling or preventing cognitive dysfunction attributable to cerebrovascular disease. OBJECTIVE: To evaluate the presence and severity of markers of cerebrovascular pathology, its relationship to diagnostic categories of dementia, including AD, and association with the metabolic biomarker homocysteine. METHODS: In a cross-sectional observational study, 340 community-dwelling elders received a clinical evaluation including brain MRI and neuropsychological tests. Dementia and mild cognitive impairment (MCI) were diagnosed by consensus committee. Fasting total plasma homocysteine was measured. Statistical analyses were adjusted for demographics and cerebrovascular risk factors. RESULTS: Nearly 25% of those diagnosed with AD had small vessel infarcts (SVI). Periventricular white matter hyperintensity (pvWMHI) was prevalent in participants with AD (61%) or MCI (amnesic 61% and non-amnesic 54%, respectively). Participants with SVI and/or pvWMHI also had greater brain atrophy. Homocysteine concentrations were higher in individuals with cerebrovascular findings than in those without. In individuals with cerebrovascular disease, homocysteine was inversely related to executive function (p = 0.022) and directly related to degree of brain atrophy (p = 0.009). CONCLUSIONS: We demonstrated a significant prevalence of small vessel markers of cerebrovascular pathology in individuals diagnosed with AD, with a significant concurrence between cerebrovascular disease and brain and ventricular atrophy. While current research on AD has focused on amyloid-ßpeptide deposition, tau-pathology, and microglial activation and inflammation, greater attention to the cerebrovascular contribution to this neurodegenerative disease presents an additional target for therapeutic prevention and intervention.

Validity of estimated dietary eicosapentaenoic acid and docosahexaenoic acid intakes determined by interviewer-administered food frequency questionnaire among older adults with mild-to-moderate cognitive impairment or dementia.

Epidemiologic research is increasingly being focused on elderly persons, many of whom exhibit mild-to-moderate cognitive impairment. This presents a challenge for collection and interpretation of self-reported dietary data. There are few reports on the impact of cognitive function and dementia on the validity of self-reported dietary intakes. Using plasma phospholipid fatty acid profiles as a biomarker of intake, the authors assessed the validity of an interviewer-administered food frequency questionnaire (FFQ) to estimate intakes of 2 marine-based omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), among 273 community-dwelling adults aged > or =60 years participating in the Nutrition, Aging, and Memory in Elders Study (Boston, Massachusetts, 2002-2008). Age- and energy-adjusted Pearson correlation coefficients for correlations between dietary intakes and plasma phospholipids were consistent across categories of high and low cognitive function (r = 0.48), based on Mini-Mental State Examination score, and were similar across clinically diagnosed categories of normal functioning (r = 0.49), mild cognitive impairment (r = 0.45), and dementia (r = 0.52). The FFQ ranked 78% of subjects to within 1 quartile of their plasma phospholipid EPA + DHA quartile. This frequency was consistently high across all cognitive categories. With interviewer administration, this FFQ seems to be a valid method of assessing dietary EPA + DHA intake in older adults with mild-to-moderate cognitive impairment.

Vitamin D is associated with cognitive function in elders receiving home health services.

BACKGROUND: The objective of this study was to examine the association between 25-hydroxyvitamin D, 25(OH)D, and cognitive function. METHODS: A cross-sectional investigation of 25(OH)D and cognition was completed in 377 black and 703 non-black (mainly Caucasian) elders (65-99 years) participating in the nutrition and memory in elders study. Participants underwent a comprehensive neuropsychological battery, and 25(OH)D concentrations were obtained. RESULTS: More than 65% of elders had suboptimal 25(OH)D concentrations (< or =20 ng/mL or < or =50 nmol/L). Approximately 18% were deficient in 25(OH)D (<10 ng/mL or <25 nmol/L). After adjusting for age, sex, race, body mass index, education, center, kidney function, seasonality, physical activity, and alcohol use, 25(OH)D was associated with better performance on trails A (beta = -0.49, p < .03), trails B (beta = -0.73, p < .02), digit symbol (beta = 0.19, p < .001), matrix reasoning (beta = 0.04, p < .02), and block design (beta = 0.07, p < .04) tests. Associations remained after adjustment for homocysteine, apoE4 allele, plasma B vitamins, and multivitamin use (y/n). 25(OH)D concentrations >20 ng/mL were associated with better performance on tests of executive function, including trails A (80.5 vs 95, p < .05), trails B (205s vs 226s, p < .05), matrix reasoning (7.8 vs 7.0, p = .03), and digit symbol (31.5 vs 37, p < .01). There were no associations between 25(OH)D and memory tests. Factor analysis yielded factors for memory, executive function, and attention/processing speed. After adjustment, 25(OH)D was associated with the executive function (beta = 0.01, p < 0.01) and attention/processing speed factors (beta = 0.01, p = .03), but not the memory factor (beta = -0.001, p = 0.65). CONCLUSIONS: 25(OH)D was positively associated with cognitive performance, particularly with measures of executive function in this elderly population.

Albuminuria, cognitive functioning, and white matter hyperintensities in homebound elders.

BACKGROUND: Albuminuria, a kidney marker of microvascular disease, may herald microvascular disease elsewhere, including in the brain. STUDY DESIGN: Cross sectional. SETTING & PARTICIPANTS: Boston, MA, elders receiving home health services to maintain independent living who consented to brain magnetic resonance imaging. PREDICTOR: Urine albumin-creatinine ratio (ACR). OUTCOME: Performance on a cognitive battery assessing executive function and memory by using principal components analysis and white matter hyperintensity volume on brain imaging, evaluated in logistic and linear regression models. RESULTS: In 335 participants, mean age was 73.4 +/- 8.1 years and 123 participants had microalbuminuria or macroalbuminuria. Each doubling of ACR was associated with worse executive function (beta = -0.05; P = 0.005 in univariate and beta = -0.07; P = 0.004 in multivariable analyses controlling for age, sex, race, education, diabetes, cardiovascular disease, hypertension, medications, and estimated glomerular filtration rate [eGFR]), but not with worse memory or working memory. Individuals with microalbuminuria or macroalbuminuria were more likely to be in the lower versus the highest tertile of executive functioning (odds ratio, 1.18; 95% confidence interval, 1.06 to 1.32; odds ratio, 1.19; 95% confidence interval, 1.05 to 1.35 per doubling of ACR in univariate and multivariable analyses, respectively). Albuminuria was associated with qualitative white matter hyperintensity grade (odds ratio, 1.13; 95% confidence interval, 1.02 to 1.25; odds ratio, 1.15; 95% confidence interval, 1.02 to 1.29 per doubling of ACR) in univariate and multivariable analyses and with quantitative white matter hyperintensity volume (beta = 0.11; P = 0.007; beta = 0.10; P = 0.01) in univariate and multivariable analyses of log-transformed data. Results were similar when excluding individuals with macroalbuminuria. LIMITATIONS: Single measurement of ACR, indirect creatinine calibration, and reliance on participant recall for elements of medical history. CONCLUSIONS: Albuminuria is associated with worse cognitive performance, particularly in executive functioning, as well as increased white matter hyperintensity volume. Albuminuria likely identifies greater brain microvascular disease burden.

Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis.

Clinical and epidemiological studies have found that type 2 diabetes, and hyperinsulinaemia, increased the risk of developing Alzheimer's disease (AD) in the elderly. The link between hyperinsulinaemia and AD may be insulin-degrading enzyme (IDE). This enzyme degrades both insulin and amylin, peptides related to the pathology of type 2 diabetes, along with amyloid-beta peptide (Abeta), a short peptide found in excess in the AD brain. We review the current evidence, which suggests that hyperinsulinaemia may elevate Abeta through insulin's competition with Abeta for IDE. Genetic studies have also shown that IDE gene variations are associated with the clinical symptoms of AD as well as the risk of type 2 diabetes. The deficiency of IDE can be caused by genetic variation or by the diversion of IDE from the metabolism of Abeta to the metabolism of insulin. It is intriguing to notice that both hyperinsulinaemia and IDE gene variations are related to the risk of AD when the Apolipoprotein E4 (ApoE4) allele, the major risk factor of late-onset AD, is not present. Further studies of the role of IDE in the pathogenesis of AD, which may uncover potential treatment target, are much needed.

Homocysteine and B vitamins relate to brain volume and white-matter changes in geriatric patients with psychiatric disorders.

OBJECTIVE: There is a growing literature on the relationship between low serum B-vitamins, elevated homocysteine, and cognitive impairment; however, few studies have examined radiological markers of associated neuropathology in geropsychiatry inpatients. The authors examined the relationship of homocysteine, folate, and vitamin B12 with magnetic resonance imaging (MRI) markers of neuropathology. METHODS: In this archival study, authors reviewed the MRIs and medical records of 34 inpatients in a geriatric psychiatry unit. Patients were selected if folate, B12, and/or homocysteine levels had been assessed and if the appropriate clinical MRIs were performed (19 men; mean age, 75 years). Patients with schizophrenia or current substance dependence were excluded. The relationships between MRI volume measures, white-matter hyperintensity (WMH) grade, and serum concentrations of folate, B12, and homocysteine were analyzed, using age-adjusted Pearson correlations. RESULTS: Homocysteine was related to WMH grade, but not brain-volume measures. Folate was associated with hippocampus and amygdala, and negatively associated with WMH. B12 level was not statistically associated with any brain measure. CONCLUSIONS: Elevated homocysteine and low folate were associated with radiological markers of neuropathology. Since no patient had clinically deficient folate, it may be important to rethink what defines functionally significant micronutrient deficiency and explore what this means in different age- and health-status groups. Larger samples will be needed to assess interactions between homocysteine, micronutrients, and other neuropathology risk factors.

Decreased levels of plasma vitamin C and increased concentrations of inflammatory and oxidative stress markers after stroke.

BACKGROUND AND PURPOSE: Inflammatory response is a critical component of the complex pathophysiological response to stroke. Vitamin C has been shown to have important roles in cell performance and vascular function. In this study, we compared the nutritional status and levels of inflammatory markers between stroke cases and controls and assessed which antioxidant was associated with levels of inflammatory markers and oxidative stress among cases and controls. METHODS: We evaluated the nutritional status and measured plasma levels of vitamins C and E, uric acid, serum levels of C-reactive protein (CRP), the cytokines tumor necrosis factor-alpha and interleukin-1beta, intercellular adhesion molecule-1 (ICAM-1) and chemokine monocyte chemoattractant protein-1 (MCP-1), prostaglandins PGE2 and PGI2, and 8-isoprostanes (8-epiPGF2alpha) for 15 patients with ischemic stroke within 2 to 5 days after stroke onset and for 24 control subjects. RESULTS: Stroke patients had significantly lower plasma levels of vitamin C than did controls. Among stroke patients, CRP was significantly elevated, as were the ICAM-1, MCP-1, and 8-epiPGF2alpha, but the prostaglandins PGE2 and PGI2 were significantly reduced. Interestingly, vitamin C concentration was significantly inversely correlated with the levels of CRP and 8-epiPGF2alpha among stroke patients, and 8-epiPGF2alpha was significantly associated with the levels of CRP. Uric acid was also elevated among stroke patients. CONCLUSIONS: Lower vitamin C concentration, higher serum levels of inflammatory (CRP, ICAM-1, MCP-1) and oxidative stress (8-epiPGF2alpha) markers, and lower PGI2 and PGE2 concentrations among stroke patients indicate the presence of an inflammatory response associated with stroke.

Psychiatric perspectives on headache and facial pain.

For a subset of headache patients, an understanding of psychological antecedents and interpersonal difficulties is an important part of the headache evaluation. This subset includes patients with chronic headache, frequent headache, treatment-refractory headache, analgesic misuse problems, and serious compliance issues. Inadequate coping with stress is central to the persistence of headache in many such patients. Other patients present to the headache specialist but actually suffer from a serious comorbid psychiatric disorder, such as major depression, panic disorder, substance abuse, or personality disorder. For successful treatment of headache, it is important that these related problems be detected and either treated (as outlined here) or referred to a specialist for treatment.

Results of a high-resolution genome screen of 437 Alzheimer's disease families.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.

The Dementia Signs and Symptoms Scale: A New Scale for Comprehensive Assessment of Psychopathology in Alzheimer's Disease.

The Dementia Signs and Symptoms (DSS) Scale documents non-cognitive signs and symptoms (e.g., delusions, hallucinations, anxiety, depression, mania, and behavioral disturbances) in dementia. Patients, informants, and a clinical examiner rated signs and symptoms over the preceding month. Fifty-six Alzheimer's disease patients were administered the DSS, the BEHAVE-AD, the Cornell Scale for Depression in Dementia, the Young Mania Rating Scales, the Hamilton Depression Scale, the Hamilton Anxiety Scale, and the Psychogeriatric Dependency Rating Scale. DSS subscale scores correlated with corresponding scale scores, confirming construct validity. The DSS subscales were internally consistent (Cronbach's alpha, 0.3 7-0.75) and interrater reliability was high (ICC, 0.92-0.99).