Christopher Fowler

Changes in plasma amyloid beta in a longitudinal study of aging and Alzheimer's disease

A practical biomarker is required to facilitate the preclinical diagnosis of Alzheimers disease (AD).

Homocysteine, Vitamin B12, and Folic Acid Levels in Alzheimer's Disease, Mild Cognitive Impairment, and Healthy Elderly: Baseline Characteristics in Subjects of the Australian Imaging Biomarker Lifestyle Study.

There is some debate regarding the differing levels of plasma homocysteine, vitamin B12 and serum folate between healthy controls (HC), mild cognitive impairment (MCI), and Alzheimers disease (AD). As part of the Australian Imaging Biomarker Lifestyle (AIBL) study of aging cohort, consisting of 1,112 participants (768 HC, 133 MCI patients, and 211 AD patients), plasma homocysteine, vitamin B12, and serum and red cell folate were measured at baseline to investigate their levels, their inter-associations, and their relationships with cognition. The results of this cross-sectional study showed that homocysteine levels were increased in female AD patients compared to female HC subjects (+16%, p-value < 0.001), but not in males. Red cell folate, but not serum folate, was decreased in AD patients compared to HC (-10%, p-value = 0.004). Composite z-scores of short- and long-term episodic memory, total episodic memory, and global cognition all showed significant negative correlations with homocysteine, in all clinical categories. Increasing red cell folate had a U-shaped association with homocysteine, so that high red cell folate levels were associated with worse long-term episodic memory, total episodic memory, and global cognition. These findings underscore the association of plasma homocysteine with cognitive deterioration, although not unique to AD, and identified an unexpected abnormality of red cell folate.

An anemia of Alzheimer's disease

Lower hemoglobin is associated with cognitive impairment and Alzheimers disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that individuals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-ɛ4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline.

Decreased Plasma Iron in Alzheimer’s Disease Is Due to Transferrin Desaturation

Plasma iron levels are decreased in Alzheimers disease (AD) and associated with an idiopathic anemia. We examined iron-binding plasma proteins from AD patients and healthy controls from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing using size exclusion chromatography-inductively coupled plasma-mass spectrometry. Peak area corresponding to transferrin (Tf) saturation was directly compared to routine pathological testing. We found a significant decrease in transferrin-associated iron in AD that was missed by routine pathological tests of transferrin saturation, and that was able to discriminate between AD and controls. The AD cases showed no significant difference in transferrin concentration, only a decrease in total transferrin-bound iron. These findings support that a previously identified decrease in plasma iron levels in AD patients within the AIBL study is attributable to decreased loading of iron into transferrin, and that this subtle but discriminatory change is not observed through routine pathological testing.

Longitudinal Analysis of Serum Copper and Ceruloplasmin in Alzheimer's Disease

BACKGROUND Several studies have reported that peripheral levels of copper and ceruloplasmin (CP) can differentiate patients with Alzheimers disease (AD) from non-AD cases. The aim of this study was to determine the diagnostic value of serum copper, CP, and non-CP copper levels in a large cohort of AD subjects. METHODS Serum copper and CP concentrations were measured at baseline and at 18-months in participants from the Australian Imaging Biomarkers and Lifestyle Study of Ageing. Cross-sectional and longitudinal analyses were conducted using both univariate and multivariate testing adjusting for age, gender, total protein, and ApoE ε4 genotype status. RESULTS There was no significant difference in levels of serum copper or CP between the AD and healthy control groups, however, we identified a near-significant decrease in non-CP copper in the mild cognitive impairment and AD groups at baseline (p = 0.02) that was significant at 18-months (p = 0.003). CONCLUSION Our results suggest that there may be decreased non-CP copper levels in mild cognitive impairment and AD, which is consistent with diminished copper-dependent biochemical activities described in AD.

Decreased Copper in Alzheimer's Disease Brain Is Predominantly in the Soluble Extractable Fraction

Alzheimers disease (AD) is the leading cause of dementia and represents a significant burden on the global economy and society. The role of transition metals, in particular copper (Cu), in AD has become of significant interest due to the dyshomeostasis of these essential elements, which can impart profound effects on cell viability and neuronal function. We tested the hypothesis that there is a systemic perturbation in Cu compartmentalization in AD, within the brain as well as in the periphery, specifically within erythrocytes. Our results showed that the previously reported decrease in Cu within the human frontal cortex was confined to the soluble (P < 0.05) and total homogenate (P < 0.05) fractions. No differences were observed in Cu concentration in erythrocytes. Our data indicate that there is a brain specific alteration in Cu levels in AD localized to the soluble extracted material, which is not reflected in erythrocytes. Further studies using metalloproteomics approaches will be able to elucidate the metabolic mechanism(s) that results in the decreased brain Cu levels during the progression of AD.

The relationship between sleep quality and brain amyloid burden

STUDY OBJECTIVES To evaluate the association between self-reported sleep quality and levels of brain β-amyloid (Aβ) burden, and to determine the effect of the apolipoprotein E (APOE) ε4 allele on any associations found. METHODS This study is a cross-sectional analysis of 184 cognitively healthy men and women aged over 60 y. We measured sleep quality factors: specifically, sleep duration, latency (time taken to fall asleep), disturbances, efficiency, daytime dysfunction, and overall sleep quality, using the Pittsburgh Sleep Quality Index. All participants underwent Aβ positron emission tomography imaging for the quantification of brain Aβ burden and were APOE genotyped. Linear regression analyses were used to evaluate the relationship between sleep quality factors and brain Aβ burden, adjusting for age, body mass index, cardiovascular disease, and symptoms of depression, with APOE ε4 carriage entered as a moderator. RESULTS Of the sleep factors, longer sleep latency was associated with higher levels of brain Aβ (B = 0.003 [standard error = 0.001], P = 0.02). APOE ε4 allele (carrier/noncarrier) did not moderate the relationship between sleep latency and brain Aβ burden. CONCLUSIONS Our findings suggest a relationship between brain Aβ burden and sleep latency, independent of APOE ε4 genotype.

Decreased serum zinc is an effect of ageing and not Alzheimer's disease

We examined the distribution of zinc in the periphery (erythrocytes and serum) in a large, well-characterised cohort, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, in order to determine if there is systemic perturbation in zinc homeostasis in Alzheimers disease (AD). We observed an age dependent decrease in serum zinc of approximately 0.4% per year. When correcting for the age dependent decline in serum zinc no significant difference between healthy controls (HC), mildly cognitively impaired (MCI) or AD subjects was observed.

Aβ-related memory decline in APOE ε4 noncarriers: Implications for Alzheimer disease

Objective:As the absence of A&bgr;-related memory decline in APOE &egr;4 noncarriers may be due to the relative brevity of previous studies, we aimed to characterize A&bgr;-related cognitive decline over 72 months in APOE &egr;4 carriers and noncarriers who were cognitively normal (CN). Methods:CN older adults (n = 423) underwent A&bgr; imaging and APOE genotyping. Participants completed comprehensive neuropsychological testing at baseline 18-, 36-, 54-, and 72-month assessments. Results:Relative to A&bgr;− CN &egr;4 noncarriers, both A&bgr;+ CN &egr;4 carriers and noncarriers showed significantly increased decline in measures of memory, language, and executive function as well as higher rates of progression to a clinical classification of mild cognitive impairment. Memory decline was greater in A&bgr;+ CN &egr;4 carriers than in A&bgr;+ CN &egr;4 noncarriers. No cognitive decline was evident in A&bgr;− CN &egr;4 carriers. Conclusions:In CN older adults, A&bgr;+ is associated with memory decline in &egr;4 noncarriers; however, the rate of this decline is much slower than that observed in &egr;4 carriers. These data indicate that the processes by which &egr;4 carriage increases the rate of A&bgr;-related cognitive decline occur in the preclinical stage of Alzheimer disease.Objective: As the absence of Aβ-related memory decline in APOE ε4 noncarriers may be due to the relative brevity of previous studies, we aimed to characterize Aβ-related cognitive decline over 72 months in APOE ε4 carriers and noncarriers who were cognitively normal (CN). Methods: CN older adults (n = 423) underwent Aβ imaging and APOE genotyping. Participants completed comprehensive neuropsychological testing at baseline 18-, 36-, 54-, and 72-month assessments. Results: Relative to Aβ− CN ε4 noncarriers, both Aβ+ CN ε4 carriers and noncarriers showed significantly increased decline in measures of memory, language, and executive function as well as higher rates of progression to a clinical classification of mild cognitive impairment. Memory decline was greater in Aβ+ CN ε4 carriers than in Aβ+ CN ε4 noncarriers. No cognitive decline was evident in Aβ− CN ε4 carriers. Conclusions: In CN older adults, Aβ+ is associated with memory decline in ε4 noncarriers; however, the rate of this decline is much slower than that observed in ε4 carriers. These data indicate that the processes by which ε4 carriage increases the rate of Aβ-related cognitive decline occur in the preclinical stage of Alzheimer disease.

Regulation of the slow afterhyperpolarization in enteric neurons by protein kinase A

The slow after-hyperpolarization (sAHP) following the action potential is an important determinant of the firing patterns of enteric neurons. The channel responsible for the sAHP thus serves as a critical control point at which neurotransmitters and inflammatory mediators modulate gut motility. Many of these receptor-evoked pathways are known to inhibit the sAHP and, thus, excite enteric neurons. They act through protein kinase A (PKA) which is a strong inhibitor of the sAHP current while protein phosphatases enhance the current. Increasing evidence suggests that the sAHP is mediated by the opening of intermediate-conductance Ca-activated potassium (IK) channels. This neuronal IK channel, previously known to be expressed in a variety of non-excitable cells, is strongly influenced by protein kinases. Investigation of the molecular basis for the modulation of IK channels by protein phosphorylation indicates that there are multiple mechanisms of channel control. Inhibition of channel activity by PKA involves phosphorylation sites located within the calmodulin-binding domain of the channel. The localization of these sites within the region involved in Ca2+ activation suggests that PKA-mediated phosphorylation of the channel opposes the conformational changes caused by binding of Ca/calmodulin, which would otherwise lead to opening of the channel. We suggest that the channel exists as a macromolecular complex involving calmodulin, protein kinases, protein phosphatase and possibly other proteins. The regulation of the channel through kinases and phophatases results in exquisite control of neuronal firing and subsequent modulation of enteric reflexes.