Alzheimer Disease: Mielke MM

Lyketsos CG, Szekely CA, Mielke MM, Rosenberg PB, Zandi PP. · Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland, U.S.A. · Int Psychogeriatr. · Pubmed #18498669 No free full text.

Abstract: This synthetic review presents an approach to the use of biomarkers for the development of new treatments for Alzheimer's disease (AD). After reviewing the process of translation as applied to AD, the paper provides a general update on what is known about the biology of the disease, and highlights currently available treatments. This is followed by a discussion of future drug development for AD emphasizing the roles that biomarkers are likely to play in this process: (1) define patients who are going to progress rapidly for the purpose of trial enrichment; (2) differentiate disease and therapeutically relevant AD subtypes; (3) assess the potential activity of specific therapies in vivo or ex vivo; and (4) measure the underlying disease state, so as to (a) detect disease and assess drug response in asymptomatic patients, (b) serve as a secondary outcome measure in clinical trials of symptomatic patients, and (c) decide if further development of a treatment should be stopped if not likely to be effective. Several examples are used to illustrate each biomarker utility in the AD context.

Mielke MM, Lyketsos CG. · Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry, and the Alzheimer's Disease Research Center, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA. · Int Rev Psychiatry. · Pubmed #16777671 No free full text.

Abstract: Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder characterized pathologically by amyloid-beta plaques, neurofibrillary tangles and neuronal loss. Its fundamental cause(s) and the pathological cascades leading to clinical symptoms remain unknown. Lipids and lipid peroxidation products have important roles in the homeostasis of the central nervous system. As well, lipid transport genes and vascular changes associated with peripheral dyslipidemia have been associated with an increased risk of AD. The present review discusses ways in which lipids may be involved in the pathogenesis of AD-associated neurodegeneration through their roles as neuronal structural components, cell modulators, or second messengers. Given the many possibilities through which lipids may be directly involved in or contribute to the pathogenesis of AD, the use of lipids as biomarkers for disease progression is discussed, as are other avenues for future research.

Mielke MM, Zandi PP. · Center on Aging and Health and the Alzheimer Disease Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Dement Geriatr Cogn Disord. · Pubmed #16508297 No free full text.

Abstract: Multiple studies have implicated vascular-related conditions as risk factors for dementia. Clarification of these factors in dementia is important because most are modifiable, and may serve as the basis for preventive strategies. Several hematologic factors are associated with vascular diseases, but their relation to dementia is unclear. This review examines biological and epidemiological evidence concerning the role of these hematologic factors in dementia, and dementia subtypes. Reviewed factors include homocysteine, cholesterol, fatty acids, antioxidants, and C-reactive protein. The vast majority of studies reviewed are cross-sectional. Longitudinal studies with serial hematologic measures are needed to clarify the relationship between these factors and dementia over the lifespan. A necessary step is to examine multiple hematologic factors simultaneously, rather than in isolation, to determine how these factors are interrelated.

Rosenberg PB, Mielke MM, Tschanz J, Cook L, Corcoran C, Hayden KM, Norton M, Rabins PV, Green RC, Welsh-Bohmer KA, Breitner JC, Munger R, Lyketsos CG. · Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA. · Am J Geriatr Psychiatry. · Pubmed #18978249 links to  free full text

Abstract: BACKGROUND: Evidence suggests that cardiovascular medications, including statins and antihypertensive medications, may delay cognitive decline in patients with Alzheimer dementia (AD). We examined the association of cardiovascular medication use and rate of functional decline in a population-based cohort of individuals with incident AD. METHODS: In the Dementia Progression Study of the Cache County Study on Memory, Health, and Aging, 216 individuals with incident AD were identified and followed longitudinally with in-home visits for a mean of 3.0 years and 2.1 follow-up visits. The Clinical Dementia Rating (CDR) was completed at each follow-up. Medication use was inventoried during in-home visits. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) as the outcome and cardiovascular medication use as the major predictors. RESULTS: CDR-Sum increased an average of 1.69 points annually, indicating a steady decline in functioning. After adjustment for demographic variables and the baseline presence of cardiovascular conditions, use of statins (p = 0.03) and beta-blockers (p = 0.04) was associated with a slower annual rate of increase in CDR-Sum (slower rate of functional decline) of 0.75 and 0.68 points respectively, while diuretic use was associated with a faster rate of increase in CDR-Sum (p = 0.01; 0.96 points annually). Use of calcium-channel blockers, angiotensin-converting enzyme inhibitors, digoxin, or nitrates did not affect the rate of functional decline. CONCLUSIONS: In this population-based study of individuals with incident AD, use of statins and beta-blockers was associated with delay of functional decline. Further studies are needed to confirm these results and to determine whether treatment with these medications may help delay AD progression.

Mielke MM, Rosenberg PB, Tschanz J, Cook L, Corcoran C, Hayden KM, Norton M, Rabins PV, Green RC, Welsh-Bohmer KA, Breitner JC, Munger R, Lyketsos CG. · Johns Hopkins University School of Medicine, Department of Psychiatry, Division of Geriatric Psychiatry and Behavioral Sciences, 550 N. Broadway, Suite 308, Baltimore, MD 21205, USA. · Neurology. · Pubmed #17984453 No free full text.

Abstract: BACKGROUND: While there is considerable epidemiologic evidence that cardiovascular risk factors increase risk of incident Alzheimer disease (AD), few studies have examined their effect on progression after an established AD diagnosis. OBJECTIVE: To examine the effect of vascular factors, and potential age modification, on rate of progression in a longitudinal study of incident dementia. METHODS: A total of 135 individuals with incident AD, identified in a population-based sample of elderly persons in Cache County, UT, were followed with in-home visits for a mean of 3.0 years (range: 0.8 to 9.5) and 2.1 follow-up visits (range: 1 to 5). The Clinical Dementia Rating (CDR) Scale and Mini-Mental State Examination (MMSE) were administered at each visit. Baseline vascular factors were determined by interview and physical examination. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) or MMSE as the outcome, and vascular index or individual vascular factors as independent variables. RESULTS: Atrial fibrillation, systolic hypertension, and angina were associated with more rapid decline on both the CDR-Sum and MMSE, while history of coronary artery bypass graft surgery, diabetes, and antihypertensive medications were associated with a slower rate of decline. There was an age interaction such that systolic hypertension, angina, and myocardial infarction were associated with greater decline with increasing baseline age. CONCLUSION: Atrial fibrillation, hypertension, and angina were associated with a greater rate of decline and may represent modifiable risk factors for secondary prevention in Alzheimer disease. The attenuated decline for diabetes and coronary artery bypass graft surgery may be due to selective survival. Some of these effects appear to vary with age.

Morgan MD, Mielke MM, O'Brien R, Troncoso JC, Zonderman AB, Lyketsos CG. · Johns Hopkins University, Baltimore, MD 21224, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17804951 links to  free full text

Abstract: The prevalence of major depression is increased in Alzheimer disease (AD), but currently the basis of this association remains unclear. The present study examined rates of depression in 4 groups of participants with postmortem examination from the Baltimore Longitudinal Study of Aging: (1) cognitively normal controls with no Alzheimer pathology, (2) cognitively normal individuals with Alzheimer pathology, (3) individuals with mild cognitive impairment plus Alzheimer pathology, (4) individuals with clinical diagnoses of dementia plus Alzheimer pathology. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Individuals with Alzheimer pathology but no cognitive decline before death had significantly lower rates of depression than cognitively normal controls with no Alzheimer pathology and individuals with Alzheimer pathology plus clinical diagnoses of dementia. These findings suggest that depression is a risk factor for AD in the presence of AD pathology, but depression is not a risk factor for AD pathology.

Kozauer NA, Mielke MM, Chan GK, Rebok GW, Lyketsos CG. · Division of Geriatric and Neuropsychiatry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. · Int Psychogeriatr. · Pubmed #17711604 No free full text.

Abstract: OBJECTIVE: The relationship of apolipoprotein E (APOE) genotype to lifetime cognitive decline was examined over 22 years in a large community-based population study. METHOD: The sample for the present study was derived from follow-up of a probability sample of the adult household residents of East Baltimore. From the Baltimore cohort of the Epidemiologic Catchment Area Study, genotype data were collected on 818 participants at the study's fourth wave between 2003 and 2004. Participants were administered the Mini-mental State Examination (MMSE) at all four study waves. Three tests of verbal learning - immediate recall, delayed recall, and word recognition - were completed at waves 3 and 4. The 659 participants for whom genetic data were available had also completed cognitive testing at all time points. Test scores and changes in these scores were examined by APOE genotype group (x/x or 4/x) in younger and older subcohorts defined by age at wave 4 (< or > or = age 65). RESULTS: Cross-sectional wave 4 scores on all four cognitive tasks were lower in APOEepsilon4 carriers when compared to non-carriers. In longitudinal univariate models epsilon4 carriers in the younger cohort demonstrated a greater annual rate of decline on a delayed recall task and MMSE. After adjusting for covariates only the decline in the delayed recall task was significant. CONCLUSION: We report an association between APOE genotype and decline in delayed recall and possibly MMSE over this extended time period limited to younger individuals. The lack of an association between APOE and decline in older individuals is likely to be the result of survival bias. Although a clear association exists between APOE genotype and cognitive decline or dementia in late life, these findings suggest that over the lifespan the relationship between APOE and cognitive decline is more complicated.

Mielke MM, Zandi PP, Blennow K, Gustafson D, Sjögren M, Rosengren L, Skoog I. · Center on Aging and Health, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16493233 No free full text.

Abstract: Low serum potassium increases risk of hypertension and stroke, and cardiovascular factors increase the risk of Alzheimer disease (AD). We examined the association between serum potassium and the biologic marker cerebrospinal fluid amyloid-beta (Abeta42), which is decreased in Alzheimer disease patients. Psychiatric examinations, laboratory and other tests were conducted on a population-based sample of 1080 women aged 46 to 60 in 1968, with follow-ups in 1974, 1980, and 1992. In 1992, cerebrospinal fluid Abeta42 levels were obtained from 81 women. Increasing serum potassium in 1968 was associated with increasing cerebrospinal fluid Abeta42 (beta = 153.9, P = 0.041) in 1992 using age-adjusted linear regression. Compared with the lowest tertile of potassium, the middle (beta = 95.3, P = 0.138) and highest tertiles (beta = 193.5, P = 0.004) had incrementally increased cerebrospinal fluid Abeta42 levels. Associations remained after controlling for blood pressure and other factors, and were similar among the 17 women in 1974 with available serum potassium. Potassium in 1980 and 1992 was not associated with cerebrospinal fluid Abeta42. Findings suggest low serum potassium in mid life, but not late life, is associated with low cerebrospinal fluid Abeta42 levels in late life. It is possible potassium co-varies with another variable that is associated with cerebrospinal fluid Abeta42. Nonetheless, serum potassium is a modifiable risk factor and further examination of the potassium-dementia relationship is warranted.

Rosenberg PB, Mielke MM, Lyketsos CG. · Department of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, 550 N. Broadway #308, Baltimore, MD 21205, USA. · Am J Geriatr Psychiatry. · Pubmed #16166413 No free full text.

Abstract: OBJECTIVE: Caregiver input is important in the assessment of depression in Alzheimer disease (AD), but depression and subjective burden can bias this input. METHODS: In a 12-week, controlled, clinical trial of sertraline in depressed AD patients, authors correlated caregiver mood and subjective burden on several patient mood measures, incorporating varied degrees of caregiver input. RESULTS: Caregiver variables accounted for up to 33% of the variance in patient mood ratings. Caregiver depression and burden decreased regardless of treatment assignment. CONCLUSION: Caregiver depression and burden affect their rating of AD patients' mood, but the majority of variance is due to patient characteristics.

Mielke MM, Zandi PP, Sjögren M, Gustafson D, Ostling S, Steen B, Skoog I. · Center on Aging and Health, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. · Neurology. · Pubmed #15911792 No free full text.

Abstract: OBJECTIVE: To examine the longitudinal association between plasma total cholesterol and triglyceride levels and incident dementia. METHODS: Neuropsychiatric, anthropometric, laboratory, and other assessments were conducted for 392 participants of a 1901 to 1902 birth cohort first examined at age 70. Follow-up examinations were at ages 75, 79, 81, 83, 85, and 88. Information on those lost to follow-up was collected from case records, hospital linkage system, and death certificates. Cox proportional hazards regression examined lipid levels at ages 70, 75, and 79 and incident dementia between ages 70 and 88. RESULTS: Increasing cholesterol levels (per mmol/L) at ages 70 (hazard ratio [HR] 0.77, 95% CI: 0.61 to 0.96, p = 0.02), 75 (HR 0.70, CI: 0.52 to 0.93, p = 0.01), and 79 (HR 0.73, CI: 0.55 to 0.98, p = 0.04) were associated with a reduced risk of dementia between ages 79 and 88. Examination of cholesterol levels in quartiles showed that the risk reduction was apparent only among the highest quartile at ages 70 (8.03 to 11.44 mmol/L [311 to 442 mg/dL]; HR 0.31, CI: 0.11 to 0.85, p = 0.03), 75 (7.03 to 9.29 mmol/L [272 to 359 mg/dL]; HR 0.20, CI: 0.05 to 0.75, p = 0.02), and 79 (6.82 to 9.10 mmol/L [264 to 352 mg/dL]; HR 0.45, CI: 0.17 to 1.23, p = 0.12). Triglyceride levels were not associated with dementia. CONCLUSIONS: High cholesterol in late life was associated with decreased dementia risk, which is in contrast to previous studies suggesting high cholesterol in mid-life is a risk factor for later dementia. The conflicting results may be explained by the timing of the cholesterol measurements in relationship to age and the clinical onset of dementia.