Dorothea Strozyk

CSF Aβ 42 levels correlate with amyloid-neuropathology in a population-based autopsy study

Objective: To investigate the relationship of amyloid neuropathology to postmortem CSF Aβ 42 levels in an autopsy sample of Japanese American men from the population-based Honolulu–Asia Aging Study. Methods: In 1991, participants were assessed and diagnosed with dementia (including subtype) based on published criteria. At death CSF was obtained from the ventricles. Neuritic plaques (NP) and diffuse plaques in areas of the neocortex and hippocampus were examined using Bielschowsky silver stains. Cerebral amyloid angiopathy (CAA) was measured by immunostaining for β4 amyloid in cerebral vessels in the neocortex. Neuropathologically confirmed AD was diagnosed using Consortium to Establish a Registry for Alzheimer’s Disease criteria. In 155 autopsy samples, log transformed linear regression models were used to examine the association of NP and CAA to Aβ 42 levels, controlling for clinical dementia severity, time between diagnosis and death, age at death, brain weight, hours between death and collection of CSF, education, and APOE genotype. Results: Higher numbers of NP in the neocortex (p trend = 0.001) and in the hippocampus (p trend = 0.03) were strongly associated with lower levels of Aβ 42. Individuals with CAA had lower Aβ 42 levels (β coefficient = −0.48; 95% CI −0.9, −0.1). Compared to participants with a diagnosis of clinical dementia, those with pathologically confirmed AD had lower Aβ 42 levels (β coefficient = −0.74; 95% CI −1.4, −0.1). Conclusion: The current study suggests that lower Aβ 42 levels reflect neuropathologic processes implicated in amyloid-related pathologies, such as NP and CAA.

Elevated cortical zinc in Alzheimer disease.

Objective: To determine whether changes in brain biometals in Alzheimer disease (AD) and in normal brain tissue are tandemly associated with amyloid β-peptide (Aβ) burden and dementia severity. Methods: The authors measured zinc, copper, iron, manganese, and aluminum and Aβ levels in postmortem neocortical tissue from patients with AD (n = 10), normal age-matched control subjects (n = 14), patients with schizophrenia (n = 26), and patients with schizophrenia with amyloid (n = 8). Severity of cognitive impairment was assessed with the Clinical Dementia Rating Scale (CDR). Results: There was a significant, more than twofold, increase of tissue zinc in the AD-affected cortex compared with the other groups. Zinc levels increased with tissue amyloid levels. Zinc levels were significantly elevated in the most severely demented cases (CDR 4 to 5) and in cases that had an amyloid burden greater than 8 plaques/mm2. Levels of other metals did not differ between groups. Conclusions: Brain zinc accumulation is a prominent feature of advanced Alzheimer disease (AD) and is biochemically linked to brain amyloid β-peptide accumulation and dementia severity in AD.

Zinc and Copper Modulate Alzheimer Aβ Levels in Human Cerebrospinal Fluid

Abnormal interaction of β-amyloid 42 (Aβ42) with copper, zinc and iron induce peptide aggregation and oxidation in Alzheimers disease (AD). However, in health, Aβ degradation is mediated by extracellular metalloproteinases, neprilysin, insulin degrading enzyme (IDE) and matrix metalloproteinases. We investigated the relationship between levels of Aβ and biological metals in CSF. We assayed CSF copper, zinc, other metals and Aβ42 in ventricular autopsy samples of Japanese American men (N= 131) from the population-based Honolulu–Asia Aging Study. There was a significant inverse correlation of CSF Aβ42 with copper, zinc, iron, manganese and chromium. The association was particularly strong in the subgroup with high levels of both zinc and copper. Selenium and aluminum levels were not associated to CSF Aβ42. In vitro, the degradation of synthetic Aβ substrate added to CSF was markedly accelerated by low levels (2 μM) of exogenous zinc and copper. While excessive interaction with copper and zinc may induce neocortical Aβ precipitation in AD, soluble Aβ degradation is normally promoted by physiological copper and zinc concentrations.

Serum estradiol and risk of stroke in elderly men

Objective: To determine if levels of serum estradiol and testosterone can predict stroke in a population-based sample of elderly men. Methods: Serum 17β estradiol and testosterone were measured in 2,197 men aged 71 to 93 years who participated in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent stroke, coronary heart disease, and cancer. Participants were followed to the end of 1998 for thromboembolic and hemorrhagic events. Results: During the course of follow-up, 124 men developed a stroke (9.1/1,000 person-years). After age adjustment, men in the top quintile of serum estradiol (≥125 pmol/L [34.1 pg/mL]) experienced a twofold excess risk of stroke vs men whose estradiol levels were lower (14.8 vs 7.3/1,000 person-years, p < 0.001). Among the lower quintiles, there were little differences in the risk of stroke. Findings were also significant and comparable for bioavailable estradiol and for thromboembolic and hemorrhagic events. After additional adjustment for hypertension, diabetes, adiposity, cholesterol concentrations, atrial fibrillation, and other characteristics, men in the top quintile of serum estradiol continued to have a higher risk of stroke vs those whose estradiol levels were lower (relative hazards = 2.2; 95% CI = 1.5 to 3.4, p < 0.001). Testosterone was not related to the risk of stroke. Conclusions: High levels of serum estradiol may be associated with an elevated risk of stroke in elderly men.

Contribution of vascular pathology to the clinical expression of dementia

Vascular lesions in the brain are common with advancing age; however, the independent and cumulative contributions of postmortem vascular lesions to antemortem cognitive status are not well established. We examined association of six vascular lesions (large infarcts, lacunar infarcts, leukoencephalopathy, microinfarcts, cribriform changes, and cerebral amyloid angiopathy) with antemortem diagnoses of dementia, Alzheimers disease (AD), and vascular dementia (VaD) in 190 older adults from an autopsy series. We also developed a summary score based on three macroscopic vascular lesions: large infarcts (0, 1, and >or=2), lacunar infarcts (0, 1, and >or=2), and leukoencephalopathy (none, mild, and moderate-to-severe). Sixty-eight percent of cases had vascular lesions. Only leukoencephalopathy was associated with dementia (odds ratio (OR) 3.5, 95% CI 1.0-12.4), and only large infarcts were associated with VaD (OR 4.3, 95% CI 1.2-15.4). The vascular score was associated with dementia (OR 1.6, 95% CI 1.2-2.3), AD (OR 1.5, 95% CI 1.0-2.1) and VaD (OR 2.0, 95% CI 1.4-3.0). Leukoencephalopathy, large infarcts, and higher vascular burden is associated with the clinical expression of dementia and subtypes.

Radioiodinated clioquinol as a biomarker for β-amyloid: Zn2+ complexes in Alzheimer's disease

Neocortical β‐amyloid (Aβ) aggregates in Alzheimers disease (AD) are enriched in transition metals that mediate assembly. Clioquinol (CQ) targets metal interaction with Aβ and inhibits amyloid pathology in transgenic mice. Here, we investigated the binding properties of radioiodinated CQ ([125I]CQ) to different in vitro and in vivo Alzheimer models. We observed saturable binding of [125I]CQ to synthetic Aβ precipitated by Zn2+ (Kd = 0.45 and 1.40 nm for Aβ1‐42 and Aβ1‐40, respectively), which was fully displaced by free Zn2+, Cu2+, the chelator DTPA (diethylene triamine pentaacetic acid) and partially by Congo red. Sucrose density gradient of post‐mortem AD brain indicated that [125I]CQ concentrated in a fraction enriched for both Aβ and Zn, which was modulated by exogenous addition of Zn2+ or DTPA. APP transgenic (Tg2576) mice injected with [125I]CQ exhibited higher brain retention of tracer compared to non‐Tg mice. Autoradiography of brain sections of these animals confirmed selective [125I]CQ enrichment in the neocortex. Histologically, both thioflavine‐S (ThS)‐positive and negative structures were labeled by [125I]CQ. A pilot SPECT study of [123I]CQ showed limited uptake of the tracer into the brain, which did however, appear to be more rapid in AD patients compared to age‐matched controls. These data support metallated Aβ species as the neuropharmacological target of CQ and indicate that this drug class may have potential as in vivo imaging agents for Alzheimer neuropathology.

Endogenous sex hormones, cognitive decline, and future dementia in old men

To estimate the association of endogenous levels of bioavailable testosterone and estradiol with risk for cognitive decline and dementia in old men.

Brain lesions on MRI and endogenous sex hormones in elderly men.

We investigated the association between MRI detected brain lesions and levels of endogenous sex hormones in Japanese-American men aged 74-95 years. Logistic regression was used to estimate the association (OR (95% CI)) of MRI outcome with tertiles of bioavailable testosterone, 17beta estradiol and sex hormone binding globulin (SHBG). There was a significantly increased risk for cerebral atrophy in the highest tertile of testosterone (3.1 (1.2-7.8)) compared to the lowest. We also found that men with the highest estradiol had a higher risk of lacunes (1.92 (1.1-3.2)). These relationships did not change with adjustment for the other sex hormones, cardiovascular risk factors, or other brain lesions. In contrast, men with the highest SHBG had a lower risk both of cerebral atrophy and lacunes, after adjusting for sex hormones and cardiovascular risk factors. There were no associations between sex hormones and hippocampal atrophy, white matter lesions, and large infarcts. Because the levels of hormone were measured close in time to the acquisition of the MRI, these associations may reflect neurodegeneration in brain regions regulating hormone levels.

Sex hormones and neuropathology in elderly men: the HAAS.

Experimental studies suggest 17-beta estradiol (E2) and testosterone (T) may have neuroprotective properties that are associated with Alzheimers and vascular pathology. However, there are limited studies correlating steroid hormones with autopsy findings in humans. In this community-based autopsy study of elderly men (n=232) participating in the Honolulu Asia Aging Study, we found a significant decrease of neurofibrillary tangles in the highest tertile of free serum estradiol [IRR=0.43 (0.3-0.7)] after controlling for age at blood draw, interval from blood draw until death, ApoE allele, and socio-demographic health factors. Higher Free-T levels were associated with a two-fold increased risk for micro infarcts [IRR=2.2; 95% CI (1.2-4.1)]. There was no association between sex hormones and amyloid plaques or cerebral amyloid angiopathy. This community-based autopsy study suggests that peripheral levels of sex hormones are associated with neurofibrillary tangles and micro-infarcts, but not with other neuropathologic markers of brain disease in elderly men.

Vascular and Alzheimer's Disease pathologies in relation to cognitive decline: Data from the Einstein Aging Study Autopsy series

P2-127 THE IMPACT OF DEPRESSION ON COGNITION VARIES BYAPOE4 STATUS Andrew Dentino, James Hall, Robert Barber, Rachelle Doody, Donald Royall, Sidney O’Bryant, Texas Tech University Health Sciences Center (TTUHSC)/Texas Alzheimer’s Research and Care Consortium (TARCC), Lubbock, Texas, United States; University of North Texas Health Sciences Center (UNTHSC)/Texas Alzheimer’s Research and Care Consortium (TARCC), Fort Worth, Texas, United States; Baylor College of Medicine (BCOM)/Texas Alzheimer’s Research and Care Consortium (TARCC), Houston, Texas, United States; University of Texas Health Science Center at San Antonio (UTHSCSA)/Texas Alzheimer’s Research and Care Consortium (TARCC), San Antonio, Texas, United States.