David K. Johnson

Longitudinal Study of the Transition From Healthy Aging to Alzheimer Disease

BACKGROUND Detection of the earliest cognitive changes signifying Alzheimer disease is difficult. OBJECTIVE To model the cognitive decline in preclinical Alzheimer disease. DESIGN Longitudinal archival study comparing individuals who became demented during follow-up and people who remained nondemented on each of 4 cognitive factors: global, verbal memory, visuospatial, and working memory. SETTING Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri. PARTICIPANTS One hundred thirty-four individuals who became demented during follow-up and 310 who remained nondemented. MAIN OUTCOME MEASURES Inflection point in longitudinal cognitive performance. RESULTS The best-fitting model for each of the 4 factors in the stable group was linear, with a very slight downward trend on all but the Visuospatial factor. In contrast, a piecewise model with accelerated slope after a sharp inflection point provided the best fit for the group that progressed. The optimal inflection point for all 4 factors was prior to diagnosis of dementia: Global, 2 years; Verbal and Working Memory, 1 year; and Visuospatial, 3 years. These results were also obtained when data were limited to the subset (n = 44) with autopsy-confirmed Alzheimer disease. CONCLUSIONS There is a sharp inflection point followed by accelerating decline in multiple domains of cognition, not just memory, in the preclinical period in Alzheimer disease when there is insufficient cognitive decline to warrant clinical diagnosis using conventional criteria. Early change was seen in tests of visuospatial ability, most of which were speeded. Research into early detection of cognitive disorders using only episodic memory tasks may not be sensitive to all of the early manifestations of disease.

Cytotoxic chelators and chelates 1. Inhibition of DNA synthesis in cultured rodent and human cells by aroylhydrazones and by a copper(II) complex of salicylaldehyde benzoyl hydrazone

Abstract Aroylhydrazones of pyridoxal and of salicylaldehyde, a series of tridentate chelating agents, are potent inhibitors of DNA synthesis and cell growth in a number of human and rodent cell lines grown in culture. A copper(II) complex of the most potent of the chelators, salicylaldehyde benzoyl hydrazone (SBH), exhibits significantly greater inhibitory activity than does SBH itself. Although the bioactive forms and mechanism of action of these agents are uncertain, their cytotoxic activity can equal or exceed that of many chelators and chelates previously known to possess such properties, including compounds used clinically. SBH and its copper complex are relatively non-toxic to mice and show some measure of selectivity in their effects on different cell types. It is possible that aroylhydrozones of this type and/or their metal complexes could prove to be useful therapeutic agents.

Reduced Lean Mass in Early Alzheimer Disease and Its Association With Brain Atrophy

OBJECTIVE To examine body composition in individuals with early AD and without dementia and its relation to cognition and brain volume. DESIGN Cross-sectional case-control study. PARTICIPANTS Individuals without dementia (Clinical Dementia Rating, 0; n = 70) and with early-stage AD (Clinical Dementia Rating, 0.5 or 1; n = 70) in the Alzheimer and Memory Program at the University of Kansas School of Medicine. MAIN OUTCOME MEASURES Participants were evaluated with brain magnetic resonance imaging (MRI), neuropsychological testing, and dual-energy x-ray absorptiometry to determine whole-body fat and lean masses. Body mass index was calculated as weight in kilograms divided by height in meters squared. RESULTS Lean mass was reduced in persons with early AD compared with controls without dementia (F = 7.73; P = .006) after controlling for sex. Whole-brain volume (beta = .20; P < .001), white matter volume (beta = .19; P < .001), and global cognitive performance (beta = .12; P = .007) were associated with lean mass (dependent variable) when controlling for age and sex. The total body fat and percentage of body fat values were not different across groups or related to cognition and brain volume. CONCLUSION Loss of lean mass is accelerated in AD and is associated with brain atrophy and cognitive performance, perhaps as a direct or indirect consequence of AD pathophysiology or through shared mechanisms common to both AD and sarcopenia.

Druggable Protein Interaction Sites Are More Predisposed to Surface Pocket Formation than the Rest of the Protein Surface

Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests that many protein interaction surfaces may not be intrinsically “druggable” by small molecules, and elevates in importance the few successful examples as model systems for improving our fundamental understanding of druggability. Here we describe an approach for exploring protein fluctuations enriched in conformations containing surface pockets suitable for small molecule binding. Starting from a set of seven unbound protein structures, we find that the presence of low-energy pocket-containing conformations is indeed a signature of druggable protein interaction sites and that analogous surface pockets are not formed elsewhere on the protein. We further find that ensembles of conformations generated with this biased approach structurally resemble known inhibitor-bound structures more closely than equivalent ensembles of unbiased conformations. Collectively these results suggest that “druggability” is a property encoded on a protein surface through its propensity to form pockets, and inspire a model in which the crude features of the predisposed pocket(s) restrict the range of complementary ligands; additional smaller conformational changes then respond to details of a particular ligand. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention.

Hepatocyte iron kinetics in the rat explored with an iron chelator

Summary. The hepatocyte metabolism of 59Fe‐labelled ferritin, haemoglobin‐haptoglobin and transferrin has been examined in rats. All three forms of 59Fe became transiently available to desferrioxamine (DF) at the time they would otherwise have entered storage or alternative pathways of iron metabolism. However, differences in both the patterns of spontaneous 59Fe reutilization by normal and iron deficient rats and the partition of chelate iron excretion between bile and urine, suggested that iron in transit within hepatocytes did not behave as a single common pool. Ferritin 59Fe, entering a pool of non‐radioactive iron the size of which is determined by liver iron stores, was chelated predominantly into the bile. Transferrin 59Fe was distinguished by a greater reflux to the erythron in iron deficient rats, and by excretion of a larger proportion of 59Fe chelated by DF in the urine. Haemoglobin‐haptoglobin 59Fe followed a metabolic pathway which was relatively independent of both the iron stores and DF. If the heterogeneous behaviour of rat hepatocyte transit iron has a parallel in man, alterations in the size of similar chelatable iron pools could explain the dependence of DF‐induced urine and faecal iron excretion on both liver iron stores and the level of erythropoiesis.

Body mass index and cognitive decline in mild cognitive impairment

ObjectiveTo examine the relationship between body mass index (BMI) and cognitive decline in subjects diagnosed with mild cognitive impairment (MCI). MethodsNeuropsychologic and clinical evaluations were conducted at baseline, 6-months, and 1-year on 286 MCI subjects enrolled in the Alzheimers Disease Neuroimaging Initiative. A global cognitive composite score was derived (mean Z-score) from performance on 9 neuropsychologic subtests. Height and weight were assessed at baseline and used to calculate BMI. Generalized estimating equations (linear and logistic) assessed the relationships of baseline BMI with cognitive outcomes, clinician judgment of “clinically significant decline” over 1-year, and diagnostic progression from MCI to Alzheimer disease. ResultsLower baseline BMI was associated with significant declines in cognitive performance in individuals with MCI over 1 year (Mini-Mental State Examination, Alzheimer Disease Assessment Scale-Cognitive subscale, and a global cognitive composite; all P<0.05). We observed a significant protective effect of baseline BMI in reducing the risk of a clinically significant decline in Alzheimer Disease Assessment Scale-Cognitive subscale and mini-mental state examination (P<0.05). No association was found between BMI and changes in the clinical dementia rating sum of boxes or conversion to Alzheimer disease. ConclusionsLower baseline BMI is associated with more rapid cognitive decline in MCI. This relationship suggests either body composition may influence the rate of cognitive decline in MCI or factors related to MCI influence body composition.

Dose-Response of Aerobic Exercise on Cognition: A Community-Based, Pilot Randomized Controlled Trial

Epidemiological studies suggest a dose-response relationship exists between physical activity and cognitive outcomes. However, no direct data from randomized trials exists to support these indirect observations. The purpose of this study was to explore the possible relationship of aerobic exercise dose on cognition. Underactive or sedentary participants without cognitive impairment were randomized to one of four groups: no-change control, 75, 150, and 225 minutes per week of moderate-intensity semi-supervised aerobic exercise for 26-weeks in a community setting. Cognitive outcomes were latent residual scores derived from a battery of 16 cognitive tests: Verbal Memory, Visuospatial Processing, Simple Attention, Set Maintenance and Shifting, and Reasoning. Other outcome measures were cardiorespiratory fitness (peak oxygen consumption) and measures of function functional health. In intent-to-treat (ITT) analyses (n = 101), cardiorespiratory fitness increased and perceived disability decreased in a dose-dependent manner across the 4 groups. No other exercise-related effects were observed in ITT analyses. Analyses restricted to individuals who exercised per-protocol (n = 77) demonstrated that Simple Attention improved equivalently across all exercise groups compared to controls and a dose-response relationship was present for Visuospatial Processing. A clear dose-response relationship exists between exercise and cardiorespiratory fitness. Cognitive benefits were apparent at low doses with possible increased benefits in visuospatial function at higher doses but only in those who adhered to the exercise protocol. An individual’s cardiorespiratory fitness response was a better predictor of cognitive gains than exercise dose (i.e., duration) and thus maximizing an individual’s cardiorespiratory fitness may be an important therapeutic target for achieving cognitive benefits. Trial Registration ClinicalTrials.gov NCT01129115

Metabolic Syndrome and Cognitive Decline in Early Alzheimer’s Disease and Healthy Older Adults

Metabolic syndrome (MetS) is a cluster of risk factors (i.e., abdominal obesity, hypertension, dyslipidemia, glucose and insulin dysregulation) that is associated with cardiovascular disease, diabetes, and dementia. Recent studies addressing the association of MetS with cognitive performance and risk for dementia report mixed results. An important step in clarifying these conflicting results is determining whether cognition is influenced by the effects of individual MetS components versus the additive effects of multiple components. We assessed the effect of MetS on cognitive performance and decline over two years in 75 cases of early Alzheimers disease (AD) and 73 healthy older adult controls in the Brain Aging Project. Using factor analytic techniques, we compared the effect of a combined MetS factor to the effect of individual MetS components on change in attention, verbal memory, and mental status. In healthy controls, a combined MetS factor did not significantly predict cognitive performance, though higher insulin predicted poorer cognitive performance outcomes. In the AD group, higher scores on a combined MetS factor predicted better cognitive outcomes. Our findings suggest that MetS does not have the same association with cognitive decline in healthy older adults and those with early AD. We suggest that individual MetS components should not be evaluated in isolation and that careful methodological approaches are needed to understand the timing and non-linear relationships among these components over time.

Structural studies of Fe(III) and Cu(II) complexes of salycylaldehyde benzoyl hydrazone, a synthetic chelating agent exhibiting diverse biological properties

Salicylaldehyde benzoyl hydrazone (SBH) is a Schiff base that can function as a tridentate chelating agent [l-3]. Some thirty years ago, it was shown that this compound has modest bacteriostatic properties when tested in vitro against microorganisms such as Mycobacten’um tuberculosis, Mycobacterium smegmatis, Candida albicans and Aspergillus niger, although these effects were not sufficiently marked to encourage further study at that time [4, 51. Recently, however, interest in the biological properties of SBH has been renewed with the recognrtion that aroylhydrazones of this type are able to induce iron excretion in mammals and thus are potentially of use in the treatment of iron overload on man [6, 71. SBH itself can mobilize iron from iron-loaded reticulocytes in vitro [8] and produces high levels of iron excretion when administered to rats [9] . preliminary studies have also shown that SBH is an unusually potent inhibitor of DNA synthesis in a variety of cultured human and rodent cells and that the complex [CuCl(SBH)]*H,O produces significant inhibition of tumor growth when given to mice bearing a transplanted fibrosarcoma [lo-121. The common mechanism underlying these various biological effects of SBH appears to be an ability to penetrate cell membranes and disrupt the intracellular metabolism of essential metal ions. The exact nature of such disruptions, and the extent to which they may be exploited for therapeutic purposes, require much additional study, including detailed elucidation of the chemical properties of complexes formed between SBH and physiologically-important transition metals. This paper reports single crystal X-ray diffraction studies of two such complexes, [FeCla(SBH)(CHsOH)] and [CuCl(SBH)]~H,O. TABLE I. Selected Bond Distances, in A.

Neuropsychiatric profiles in dementia.

We compared patterns of neuropsychiatric symptoms across 4 dementia types [Alzheimer disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB), and Parkinson disease dementia], and 2 mixed groups (AD/VAD and AD/DLB) in sample of 2,963 individuals from the National Alzheimers Coordinating Center Uniform Data Set between September 2005 and June 2008. We used confirmatory factor analysis to compare neuropsychiatric symptom severity ratings made by collateral sources on the Neuropsychiatric Inventory Questionnaire for people with Clinical Dementia Rating scores of 1 or higher. A 3-factor model of psychiatric symptoms (mood, psychotic, and frontal) was shared across all dementia types. Between-group comparisons revealed unique neuropsychiatric profiles by dementia type. The AD group had moderate levels of mood, psychotic, and frontal symptoms whereas VAD exhibited the highest levels and Parkinson disease dementia had the lowest levels. DLB and the mixed dementias had more complex symptom profiles. Depressed mood was the dominant symptom in people with mild diagnoses. Differing psychiatric symptom profiles provide useful information regarding the noncognitive symptoms of dementia.