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.

The relationship between plasma amyloid-ß peptides and the medial temporal lobe in the homebound elderly.

BACKGROUND: The ratio of high amyloid-ß peptide40 (Aß40) and low Aß42 in plasma predicts the risk of Alzheimer's disease (AD) and is associated with episodic recall in depression. We thus examined the relationship between plasma Aß levels and brain volumes. METHODS: Homebound elders (N = 352) who had undergone brain MRI were used. Plasma Aß1-40 and Aß1-42 were measured by ELISA. Volumes of medial temporal regions, including the amygdala and hippocampus, were manually measured. RESULTS: Amygdala volume was associated with log(10) of plasma Aß1-42 (ß = +0.19, SE = 0.07, p = 0.005) after adjusting for AD, infarcts, white matter hyperintensities and demographics. In the absence of dementia, decreasing quartiles of plasma Aß1-42 (Mean + SD ml: Q4 = 4.1 ± 0.8; Q3 = 3.9 ± 0.7; Q2 = 3.6 ± 0.8 and Q1 = 3.7 ± 0.8, p = 0.01) and increasing quartiles of plasma Aß1-40/1-42 ratio were associated with smaller amygdala volume. Those depressed subjects with a high plasma Aß1-40/1-42 ratio had smaller amygdala (Mean + SD ml: 3.3 ± 0.8 vs. 3.6 ± 0.8, p = 0.04) and total brain volume (Mean + SD liter: 0.95 ± 0.07 vs. 1.04 ± 0.12, p = 0.005), and had a higher rate of MCI (67 vs. 36%, p = 0.02) than those with a low plasma Aß1-40/1-42 ratio. CONCLUSIONS: The combination of low plasma Aß1-42 concentration and atrophy of the medial temporal lobe structures, which regulates mood and cognition, may represent a biomarker for a prodromal stage of AD.

Depression and glycemic intake in the homebound elderly.

BACKGROUND: Depression is associated with an increase in the incidence of type 2 diabetes, but the mechanism is unclear. We aimed to study the relationship between depression and glycemic intake in the elderly, and examine whether antidepressant use modified this relationship. DESIGN, SETTING AND PARTICIPANTS: We evaluated 976 homebound elders in a cross-sectional study. Depression was defined by having a Center for Epidemiological Studies Depression (CES-D) score ≥16. Antidepressant use was documented. Glycemic index (GI), Glycemic load (GL), and fasting blood insulin levels were measured. RESULTS: Depressed elders had slightly higher GI (Mean±SD: 55.8±3.8 vs. 55.1±3.7, P=0.003) and higher insulin levels (Median: 84.0 vs. 74.4pmol/ml, P=0.05) than non-depressed elders. Depressed elders receiving antidepressants, primarily selective serotonin reuptake inhibitors (SSRI), had lower GI (Mean±SD: 55.1±4.7 vs. 56.2±3.4, P=0.002) and GL (Median: 170.3 vs. 6826.3, P=0.03) than those not taking antidepressants. After adjusting for potential confounding variables, GI remained positively associated with depression (ß=+0.65, SE=0.28, P=0.02); the logarithm of GL was positively associated with depression (ß=+0.33, SE=0.17, P=0.05) and negatively associated with antidepressant use (ß=-0.54, SE=0.18, P=0.003). CONCLUSIONS: Prospective studies are needed to examine whether high glycemic intake is a mediating factor between late life depression and the risk of type 2 diabetes.

Functional expressions of the aging brain.

In the conventional view, aging of the brain is associated with atrophy vascular abnormalities and loss of volume in hippocampus and amygdala. Cognitively, aging is associated with slowing of processing and memory loss. However, many studies of aging do not examine the cases to exclude demented people. The nutrition and memory in the homebound elderly study (NAME) excluded cases clinically diagnosed as having dementia. Cortical atrophy based on MRI ratings was significantly correlated with vascular disease, white matter hyperintensities, processing speed, and memory but not hippocampus and amygdala volume. Renal function and homocysteine were also associated with cortical atrophy but not with the cognitive variables. In conclusion, brain atrophy of aging in the absence of dementia is related to vascular disease but not hippocampal atrophy. Studies of nutritional interventions should consider using MRI atrophy rather than cognition as outcome.

Plasma Amyloid-ß Peptides and Homocysteine in Depression in the Homebound Elderly.

OBJECTIVES: Both plasma amyloid-ß peptide 40 (Aß40) and homocysteine (tHcy) are linked to vascular disease, which is related to depression in the elderly. We sought to study whether the relationship between tHcy and plasma Aß40 differs in those with and without depression. STUDY DESIGN AND METHODS: In a cross-sectional study of 1058 homebound elders, vascular depression was defined as a score ≥ 16 on the Center for Epidemiological Studies Depression scale (CES-D) along with self-reported cardiovascular disease (CVD). Plasma Aß40 and Aß42, and serum tHcy and creatinine were measured. RESULTS: Elders with high tHcy had higher concentrations of plasma Aß40 (median: 147.5 vs. 123.1 pg/ml, P < 0.0001) and Aß42 (median: 20.2 vs. 16.6 pg/ml, P < 0.0001) than those with low tHcy. In elders with depression, the relationship between logarithm of plasma Aß40 (LogAß40), but not LogAß42, and tHcy was significant (ß = +0.010, SE = 0.004, P = 0.007); in contrast, this relationship was not observed in those without depression. Subjects with vascular depression had the highest concentration of tHcy (mean ± SD: 12.8 ± 4.6 vs. 11.7 ± 4.5 vs. 11.9 + 5.5, P = 0.008) compared to those without CVD and those without depression. Depressed subjects without CVD had the lowest concentration of plasma Aß42 (median: 15.5 vs. 19.1 vs. 18.7, P = 0.01) compared to those with CVD and those without depression. CONCLUSIONS: Vascular depression, which is associated with tHcy and Aß40 in blood, appears to be different from depression that is associated with low plasma Aß42. This suggests that reducing tHcy and Aß40 may be an adjunct treatment for vascular depression.

Diffusion tensor imaging, white matter lesions, the corpus callosum, and gait in the elderly.

BACKGROUND AND PURPOSE: Gait impairment is common in the elderly, especially those with stroke and white matter hyperintensities on conventional brain MRI. Diffusion tensor imaging (DTI) is more sensitive to white matter damage than conventional MRI. The relationship between DTI measures and gait has not been previously evaluated. Our purpose was to investigate the relationship between the integrity of white matter in the corpus callosum as determined by DTI and quantitative measures of gait in the elderly. METHODS: One hundred seventy-three participants of a community-dwelling elderly cohort had neurological and neuropsychological examinations and brain MRI. Gait function was measured by Tinetti gait (0 to 12), balance (0 to 16) and total (0 to 28) scores. DTI assessed fractional anisotropy in the genu and splenium of the corpus callosum. Conventional MRI was used to evaluate for brain infarcts and white matter hyperintensity volume. RESULTS: Participants with abnormal gait had low fractional anisotropy in the genu of the corpus callosum but not the splenium. Multiple regressions analyses showed an independent association between these genu abnormalities and all 3 Tinetti scores (P<0.001). This association remained significant after adding MRI infarcts and white matter hyperintensity volume to the analysis. CONCLUSIONS: The independent association between quantitative measures of gait function and DTI findings shows that white matter integrity in the genu of corpus callosum is an important marker of gait in the elderly. DTI analyses of white matter tracts in the brain and spinal cord may improve knowledge about the pathophysiology of gait impairment and help target clinical interventions.

Depression and plasma amyloid beta peptides in the elderly with and without the apolipoprotein E4 allele.

Depression associated with low plasma amyloid-beta peptide 42 (Abeta42) leading to a high ratio of Abeta40/Abeta42, a biomarker of Alzheimer disease (AD), may represent a unique depression subtype. The relationship between low plasma Abeta42 in depression and the major risk factor of AD, apolipoprotein E4 (ApoE4), is unknown. With the goal of clarifying this relationship, we analyzed 1060 homebound elders with ApoE characterization and depression status in a cross-sectional study. Plasma Abeta40 and Abeta42 were measured, and cognition were evaluated. In the absence of the ApoE4 allele, depressed subjects had lower plasma Abeta42 [median (Q1, Q3): 17.1 (11.6, 27.8) vs. 20.2 (12.9, 32.9) pg/mL, P=0.006], a higher Abeta40/Abeta42 ratio [median (Q1, Q3): 7.1 (4.6, 11.3) vs. 6.9 (3.4, 9.7), P=0.03], and lower cognitive function (mean+/-SD of Mini-Mental State Examination: 24.5+/-3.1 vs. 25.5+/-3.3, P<0.0001) than those without depression. In contrast, these relationships were not observed in the presence of ApoE4. Instead, regardless the depression status ApoE4 carriers had lower plasma Abeta42 and a higher Abeta40/Abeta42 ratio than non-ApoE4 carriers. Using multivariate logistic regression, it was found that depression was not associated with ApoE4 allele, but with the interaction between plasma Abeta42 and ApoE4 (odds ratio=3.94, 95% confidence interval=1.50, 10.33, P=0.005), denoting low plasma Abeta42 in the absence of ApoE4. Both ApoE4 carriers and non-ApoE4 carriers with depression had lower Abeta42 and a higher Abeta40/Abeta42 ratio in plasma compared with non-ApoE4 carriers without depression in the homebound elderly. As a combination of low plasma Abeta42 and high plasma Abeta40 has been shown to increase the risk of AD in 2 large cohort studies, amyloid-associated depression shown in this study may suggest a risk factor of AD in the absence of ApoE4.

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.

Amyloid-associated depression: a prodromal depression of Alzheimer disease?

CONTEXT: A high ratio of plasma amyloid-beta peptide 40 (Abeta(40)) to Abeta(42), determined by both high Abeta(40) and low Abeta(42) levels, increases the risk of Alzheimer disease. In a previous study, we reported that depression is also associated with low plasma Abeta(42) levels in the elderly population. OBJECTIVE: To characterize plasma Abeta(40):Abeta(42) ratio and cognitive function in elderly individuals with and without depression. DESIGN: Cross-sectional study. SETTING: Homecare agencies. PARTICIPANTS: A total of 995 homebound elderly individuals of whom 348 were defined as depressed by a Center for Epidemiological Studies Depression score of 16 or greater. MAIN OUTCOME MEASURES: Cognitive domains of memory, language, executive, and visuospatial functions according to levels of plasma Abeta(40) and Abeta(42) peptides. RESULTS: Subjects with depression had lower plasma Abeta(42) levels (median, 14.1 vs 19.2 pg/mL; P = .006) and a higher plasma Abeta(40):Abeta(42) ratio (median, 8.9 vs 6.4; P < .001) than did those without depression in the absence of cardiovascular disease and antidepressant use. The interaction between depression and plasma Abeta(40):Abeta(42) ratio was associated with lower memory score (beta = -1.9, SE = 0.7, P = .006) after adjusting for potentially confounders. Relative to those without depression, "amyloid-associated depression," defined by presence of depression and a high plasma Abeta(40):Abeta(42) ratio, was associated with greater impairment in memory, visuospatial ability, and executive function; in contrast, nonamyloid depression was not associated with memory impairment but with other cognitive disabilities. CONCLUSION: Amyloid-associated depression may define a subtype of depression representing a prodromal manifestation of Alzheimer disease.

Depression, antidepressants, and plasma amyloid beta (Beta) peptides in those elderly who do not have cardiovascular disease.

BACKGROUND: Low plasma amyloid-beta peptide 42 (Abeta42) is associated with depressive symptoms independently of cardiovascular disease (CVD) in the elderly. It is critical to investigate whether antidepressants modify this relationship. METHODS: We evaluated 324 elders without CVD in a cross-sectional study. Depression was evaluated with the Center for Epidemiological Studies Depression (CES-D) scale. Antidepressants were documented. Plasma Abeta40 and Abeta42 were measured. RESULTS: In the absence of CVD, those with depression had lower plasma Abeta42 (median: 13.7 vs. 18.8 pg/mL, p = .003) than those without. Depressed subjects on antidepressant treatment had a lower concentration of plasma Abeta40 (median: 97.8 vs. 133.5 pg/mL, p = .008), but not Abeta42, than those without the treatment. Multivariate logistic regression showed that antidepressant use did not influence the relationship between depression and low plasma Abeta42 (odds ratio = .55; 95% CI = .33, .90; p = .02) after adjusting for confounders, but its use interacted with plasma Abeta40 in the model. CONCLUSIONS: Lower concentration of plasma Abeta42 is associated with depression in the absence of CVD that is not related to the antidepressant use by those subjects. Prospective studies are needed to determine whether depression associated with low plasma Abeta42 predicts the onset of Alzheimer's disease.

The homocysteine hypothesis of depression.

High levels of homocysteine are associated with cerebrovascular disease, monoamine neurotransmitters, and depression of mood. A plausible hypothesis for these associations is that high homocysteine levels cause cerebral vascular disease and neurotransmitter deficiency, which cause depression of mood. The homocysteine depression hypothesis, if true, would mandate inclusions of imaging studies for cerebrovascular disease and measures of homocysteine, folate, and B12 and B6 vitamins in the clinical evaluation of older depressed patients. Longitudinal studies and clinical trials should be designed to challenge the hypothesis.

Improving dementia assessment by reducing sample heterogeneity.

Outcome assessment for clinical dementia trials could be enhanced by using the Mini-mental State Examination (MMSE) and the Hopkins Verbal Learning Test (HVLT), in addition to imaging and genetic screening. The statistical power of trials could be increased if heterogeneity of the sample were reduced by the administration of a risk factor inventory which could be used for subject selection or selection of drug responders.

Depression is associated with low plasma Abeta42 independently of cardiovascular disease in the homebound elderly.

BACKGROUND: Depression often precedes the onset of Alzheimer's disease (AD) before the appearance of cognitive symptoms. Plasma Amyloid-beta peptide 42 (Abeta42) declines before and soon after the onset of AD, yet the relationship between plasma Abeta42 and depression is unclear. METHODS: We used 515 homebound elders aged 60 and older in a population-based, cross-sectional study to investigate associations between plasma Abeta levels and depression with and without cardiovascular co-morbidities. Depression was evaluated by using the Center for Epidemiological Studies Depression (CES-D) scale. Plasma Abeta40 and Abeta42 were measured. RESULTS: The elderly with depression had lower plasma Abeta42 (median: 15.3 vs. 18.9, p = 0.008) than those without depression. The CES-D score was inversely associated with plasma Abeta42 (p = 0.001) in subjects with no cardiovascular disease (CVD); however, in the presence of CVD, this association did not exist. Low plasma Abeta42 (OR = 0.41, p = 0.007) and the presence of CVD (OR = 1.84, p = 0.005) were independently associated with depression after adjusting for the confounders of age, stroke and apolipoprotein E4. CONCLUSIONS: Depressive symptoms are associated with low plasma Abeta42 independently of CVD. Prospective studies are needed to determine whether depression associated with low plasma Abeta42 is a separate depression subtype that could predict the onset of AD.

The Nutrition, Aging, and Memory in Elders (NAME) study: design and methods for a study of micronutrients and cognitive function in a homebound elderly population.

BACKGROUND: Micronutrient status can affect cognitive function in the elderly; however, there is much to learn about the precise effects. Understanding mediating factors by which micronutrient status affects cognitive function would contribute to elders' quality of life and their ability to remain in the home. OBJECTIVES: The Nutrition, Aging, and Memory in Elders (NAME) Study is designed to advance the current level of knowledge by investigating potential mediating factors by which micronutrient status contributes to cognitive impairment and central nervous system abnormalities in the elderly. NAME targets homebound elders because they are understudied and particularly at risk for poor nutritional status. METHODS: Subjects are community-based elders aged 60 and older, recruited through area Aging Services Access Points. The NAME core data include demographics; neuropsychological testing and activities of daily living measures; food frequency, health and behavioral questionnaires; anthropometrics; gene status; plasma micronutrients, homocysteine, and other blood determinants. A neurological examination, psychiatric examination, and brain MRI and volumetric measurements are obtained from a sub-sample. RESULTS: Preliminary data from first 300 subjects are reported. These data show that the NAME protocol is feasible and that the enrolled subjects are racially diverse, at-risk, and had similar basic demographics to the population from which they were drawn. CONCLUSION: The goal of the NAME study is to evaluate novel relationships between nutritional factors and cognitive impairment. These data may provide important information on potential new therapeutic strategies and supplementation standards for the elderly to maintain cognitive function and potentially reduce the public health costs of dementia.

Executive dysfunction in homebound older people with diabetes mellitus.

OBJECTIVES: To describe patterns of cognitive deficits and activities of daily living (ADLs) in older people with diabetes mellitus. DESIGN: Cross-sectional, population-based study. SETTING: Three homecare agency areas in Boston, Massachusetts. PARTICIPANTS: Two hundred ninety-one homebound people aged 60 and older; 40% with diabetes mellitus. MEASUREMENTS: Demographic data; evidence of diabetes mellitus and other diseases; Mini-Mental State Examination and tests of memory and executive function; ADLs. RESULTS: Executive and visuospatial functions were more impaired in individuals with diabetes mellitus than in those without, as assessed using Block Design (mean score+/-standard deviation 17.1+/-8.6 vs 20.5+/-9.6, P=.003) and Trails B (median seconds to accomplish the task: 255 vs 201, P=.03). For memory, word retention score was lower in those with diabetes mellitus than without (39.1+/-28.9 vs 48.0+/-29.7, P=.01), but the other memory tests did not show a difference between these two subgroups. More individuals with diabetes mellitus suffered from depressive symptoms than those without (55% vs 42%, P=.03). The ADL scores of those with diabetes mellitus were higher than those without. CONCLUSION: The pattern of cognitive deficits in people with diabetes mellitus suggests frontal-subcortical dysfunction, as seen in microvascular disease of the brain. The impairment in ADLs may be associated with this executive dysfunction, which cerebral microvascular disease in diabetes mellitus may cause.

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.