Adhesion of Escherichia coli under flow conditions reveals potential novel effects of FimH mutations.

FimH-mediated adhesion of Escherichia coli to bladder epithelium is a prerequisite for urinary tract infections. FimH is also essential for blood-borne bacterial dissemination, but the mechanisms are poorly understood. The purpose of this study was to assess the influence of different FimH mutations on bacterial adhesion using a novel adhesion assay, which models the physiological flow conditions bacteria are exposed to. We introduced 12 different point mutations in the mannose binding pocket of FimH in an E. coli strain expressing type 1 fimbriae only (MSC95-FimH). We compared the bacterial adhesion of each mutant across several commonly used adhesion assays, including agglutination of yeast, adhesion to mono- and tri-mannosylated substrates, and static adhesion to bladder epithelial and endothelial cells. We performed a comparison of these assays to a novel method that we developed to study bacterial adhesion to mammalian cells under flow conditions. We showed that E. coli MSC95-FimH adheres more efficiently to microvascular endothelium than to bladder epithelium, and that only endothelium supports adhesion at physiological shear stress. The results confirmed that mannose binding pocket mutations abrogated adhesion. We demonstrated that FimH residues E50 and T53 are crucial for adhesion under flow conditions. The coating of endothelial cells on biochips and modelling of physiological flow conditions enabled us to identify FimH residues crucial for adhesion. These results provide novel insights into screening methods to determine the effect of FimH mutants and potentially FimH antagonists.

A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy.

BACKGROUND: Iron deficiency anaemia is the most common deficiency disorder in the world, affecting more than one billion people, with pregnant women at particular risk. OBJECTIVES AND DESIGN: We conducted a single site, prospective, nonblinded randomized-controlled trial to compare the efficacy, safety, tolerability and compliance of standard oral daily iron versus intravenous iron. SUBJECTS: We prospectively screened 2654 pregnant women between March 2007 and January 2009 with a full blood count and iron studies, of which 461 (18%) had moderate IDA. Two hundred women matched for haemoglobin concentration and serum ferritin level were recruited. INTERVENTIONS: Patients were randomized to daily oral ferrous sulphate 250 mg (elemental iron 80 mg) with or without a single intravenous iron polymaltose infusion. RESULTS: Prior to delivery, the intravenous plus oral iron arm was superior to the oral iron only arm as measured by the increase in haemoglobin level (mean of 19.5 g/L vs. 12 g/L; P < 0.001); the increase in mean serum ferritin level (222 microg/L vs. 18 ug/L; P < 0.001); and the percentage of mothers with ferritin levels below 30 microg/L (4.5% vs. 79%; P < 0.001). A single dose of intravenous iron polymaltose was well tolerated without significant side effects. CONCLUSIONS: Our data indicate that intravenous iron polymaltose is safe and leads to improved efficacy and iron stores compared to oral iron alone in pregnancy-related IDA.

Isolation and chemical characterization of Alzheimer's disease paired helical filament cytoskeletons: differentiation from amyloid plaque core protein.

The paired helical filaments (PHFs) of Alzheimer's disease were purified by a strategy in which the neurons and amyloid plaque cores of protein (APCP) were initially isolated. This was achieved by several steps of isocratic sucrose centrifugations of increasing molarity and a discontinuous isotonic Percoll density gradient. After collagenase elimination of contaminating blood vessels, lysis of neurons was produced by SDS treatment. The released PHF cytoskeletons were separated from contaminating APCP and lipofuscin by sucrose density gradient. A final step consisted in the chemical purification of highly enriched PHFs and APCP components via a formic acid to guanidine hydrochloride transition. PHFs and APCPs were fractionated by size exclusion HPLC and further characterized and quantitated by automatic amino acid analysis. We also present some of the morphological and immunochemical characteristics of PHF polypeptides and APCP. Our studies indicate that apart from differences in localization and morphology, PHF and APCP significantly differ in (a) chemical structure (peptide and amino acid composition); (b) epitope specificity (antiubiquitin, antitau, antineurofilament); (c) physicochemical properties (structural conformation in guanidine hydrochloride); and (d) thioflavine T fluorescence emission. These parameters strongly suggest important differences in the composition and, probably, in the etiopathology of PHF and APCP of Alzheimer's disease.

Translational research in medical informatics or from theory to practice. A call for an applied informatics journal.

OBJECTIVE: To bridge the divide between health informatics 'bench research' and the application of informatics in clinical and health care settings. METHOD: Identifying weak points in translational activities, i.e. in the process from health informatics research outcomes to IT system design and information management in clinical practice. RESULTS AND CONCLUSIONS: The creation of a new peer-reviewed journal, designed to cultivate broad readership across health care, is suggested in order to communicate on informatics topics of translational interest and on the application of informatics principals. Such an applied informatics journal may appeal to practicing physicians, healthcare administrators and CIOs as well as medical informaticians. In a globalizing world with eHealth initiatives spanning across borders, such a journal should be an international effort. Close ties to the International Medical Informatics Association (IMIA) and to the journal Methods of Information in Medicine are suggested.

Failure to provide clinicians useful IT systems: opportunities to leapfrog current technologies.

OBJECTIVE: To discuss why clinical information systems are failing. METHOD: Subjectively analyzing the development of clinical IT systems during the last decades. RESULTS AND CONCLUSIONS: The challenge is to anticipate what information clinicians need and then deliver it in a way that is tailored for their unique views. Clinicians need workstations that offer the highest level possible of user-determined flexibility and customization. We envision and outline a so-called point of care work station, automatically scaling to the display, hardware capacity, operating system, applications (local or distributed) the user needs and across diverse health IT systems.

The effect of 4-week chilli supplementation on metabolic and arterial function in humans.

OBJECTIVE: To investigate the effects of regular chilli ingestion on some indicators of metabolic and vascular function. DESIGN: A randomized cross-over dietary intervention study. SETTING: Launceston, Australia. SUBJECTS: Healthy free-living individuals. INTERVENTION: Thirty-six participants (22 women and 14 men), aged 46+/-12 (mean+/-s.d.) years; BMI 26.4+/-4.8 kg/m(2), consumed 30 g/day of a chilli blend (55% cayenne chilli) with their normal diet (chilli diet), and a bland diet (chilli-free) for 4 weeks each. Metabolic and vascular parameters, including plasma glucose, serum lipids and lipoproteins, insulin, basal metabolic rate, blood pressure, heart rate, augmentation index (AIx; an indicator of arterial stiffness), and subendocardial-viability ratio (SEVR; a measure of myocardial perfusion), were measured at the end of each diet. In a sub-study, during week 3 of each dietary period, the vascular responses of 15 subjects to glyceryl-trinitrate (GTN) and salbutamol were also studied. RESULTS: For the whole group, there were no significant differences between any of the measured parameters when compared at the end of the two dietary periods. When analysed separately, men had a lower resting heart rate (P=0.02) and higher SEVR (P=0.05) at the end of the chilli diet than the bland diet. In the sub-study, baseline AIx on the chilli diet was lower (P<0.001) than on the bland diet, but there was no difference in the effects of GTN and salbutamol between the two diets. CONCLUSION: Four weeks of regular chilli consumption has no obvious beneficial or harmful effects on metabolic parameters but may reduce resting heart rate and increase effective myocardial perfusion pressure time in men.

The effect of an ultra-endurance running race on mucosal and humoral immune function.

AIM: There are reports of the effect of endurance exercise on mucosal immune function and of the effect of short duration exercise on humoral immune function. However, little is known of the effect of endurance exercise on humoral immune function and the related risk of infection. This study examined the effects of an ultra-endurance running race on salivary immunoglobulin-A (s-IgA), serum IgA, leukocyte subset concentrations and the incidence of upper respiratory tract infections (URTI). METHODS: Thirteen male and 4 female competitors provided saliva samples and blood before and at several times after the running race. Self-reported symptoms of URTI were also recorded for 2 weeks before and 2 weeks after the race. RESULTS: Salivary IgA secretion rate (P=0.005) and ratio to osmolality (P=0.006) were lower immediately postrace and decreased further for at least 2 more h. s-IgA secretion rate had not returned to normal the next morning (P=0.009). Serum IgA concentration was lower post- than prerace (P=0.003) and was even lower the next morning (P<0.001). Leukocyte concentration was elevated postrace (P<0.001), mainly because of an increase in neutrophils (P<0.001) and both remained high the morning after the race (P<0.001). Lymphocyte concentration decreased postrace (P<0.001) and was still depressed the next morning (P=0.032). The incidence of symptoms of URTI was the same in the two 2-week periods before and after the race. CONCLUSION: These findings support the hypotheses that an ultra-endurance run may adversely affect mucosal immunity and cause significant changes in the concentration of leukocyte subsets.

Baseline serum lipids and renal function in chronic kidney disease patients entering the LORD trial.

OBJECTIVE: Previous studies investigating associations between serum lipids and renal disease have generally not taken into account dietary intake or physical activity both known to influence circulating lipids. Furthermore, inclusion of patients on HMG-CoA reductase inhibitors may also have influenced findings due to the pleiotropic effect of this medication. Therefore, the aim of this study is to determine the relationships between serum lipids and renal function in a group of patients not taking lipid-lowering medication and taking into account dietary intake and physical activity. METHODS: Data from 100 patients enrolled in the Lipid Lowering and Onset of Renal Disease (LORD) trial were used in this study. Patients were included with serum creatinine > 120 micromol/l, and excluded if they were taking lipid-lowering medication. Unadjusted and adjusted relationships were determined between fasting serum lipid concentrations (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol/HDL ratio) and measures of renal function (estimated glomerular filtration rate (eGFR), creatinine clearance and serum creatinine) and urinary protein excretion. RESULTS: Significant (p < 0.05) negative unadjusted relationships were found between lipids (total cholesterol, LDL and HDL cholesterol) and serum creatinine. In support of these findings, logarithmically-transformed lipids (total cholesterol, LDL and HDL cholesterol) were significantly associated with eGFR and creatinine clearance although the effects were of a smaller magnitude. Adjustment for dietary saturated fat intake and physical activity did not substantially change these effects. CONCLUSION: These data do not support the premise that lipids are associated with renal dysfunction in patients with normocholesterolemia.

Dietary supplementation with chickpeas for at least 5 weeks results in small but significant reductions in serum total and low-density lipoprotein cholesterols in adult women and men.

AIM: To compare the effects of a chickpea-supplemented diet and those of a wheat-supplemented diet on human serum lipids and lipoproteins. METHODS: Forty-seven free-living adults participated in a randomized crossover weight maintenance dietary intervention involving two dietary periods, chickpea-supplemented and wheat-supplemented diets, each of at least 5 weeks duration. RESULTS: The serum total cholesterol and low-density lipoprotein cholesterol levels were significantly lower (both p < 0.01) by 3.9 and 4.6%, respectively, after the chickpea-supplemented diet as compared with the wheat-supplemented diet. Protein (0.9% of energy, p = 0.01) and monounsaturated fat (3.3% of total fat, p < 0.001) intakes were slightly but significantly lower and the carbohydrate intake significantly higher (1.7% of energy, p < 0.001) on the chickpea-supplemented diet as compared with the wheat-supplemented diet. Multivariate analyses suggested that the differences in serum lipids were mainly due to small differences in polyunsaturated fatty acid and dietary fibre contents between the two intervention diets. CONCLUSIONS: Inclusion of chickpeas in an intervention diet results in lower serum total and low-density lipoprotein cholesterol levels as compared with a wheat-supplemented diet.

Senile plaques in Alzheimer's diseased brains: possible association of beta-amyloid with herpes simplex virus type 1 (HSV-1) L-particles.

The characteristic insoluble, senile (neuritic) plaques found extracellularly in brains of patients with Alzheimer's disease (AD) contain the fibrillar form of beta-amyloid (Abeta42). A substantial proportion of autopsied elderly brains have demonstrated DNA evidence of herpes simplex virus type 1 (HSV-1) infiltration. HSV-1-infected cells produce significant quantities of non-infectious, non-DNA-containing light particles (L-particles) comprised of viral envelope and tegument proteins. HSV-induced L-particles can be exocytosed out of their host cells. This report advances the hypothesis that (1) Abeta binds to L-particles; (2) Abeta permeabilizes L-particles, destroying the integrity of the envelope and allowing the contained tegument proteins to spill into the extracellular space; and (3) these events are followed by a conformational shift of Abeta into its fibrillar form, physically trapping the L-particle-derived substances and resulting in the plaques characteristic of AD. These hypotheses are supported by reports of biomolecular changes and pathophysiologies which have been simultaneously observed in both AD- and HSV-infected brains.

Reflections on the Yearbook from the 1990's to the Present.

The authors highlight IMIA's progress over the past twenty years as a key bridging organization that translates health informatics theory into practice. In contrast, they describe that electronic health record (EHR) systems built in the 20th Century are not meeting the needs of clinical users. Moreover, these EHRs are not architected to keep pace with the rapid changes in the evolving health ecosystem. They conclude that 21st Century health IT systems need to be architected into an ecosystem-wide suite of interacting complex adaptive systems that support individuals, clinicians, managers and policy-makers with the high value/high usability computing paradigm that dominates the Internet today.

Lupin kernel fibre-enriched foods beneficially modify serum lipids in men.

OBJECTIVE: To examine the effect of a diet containing a novel legume food ingredient, Australian sweet lupin (Lupinus angustifolius) kernel fibre (LKFibre), compared to a control diet without the addition of LKFibre, on serum lipids in men. DESIGN: Randomized crossover dietary intervention study. SETTING: Melbourne, Australia--Free-living men. SUBJECTS: A total of 38 healthy males between the ages of 24 and 64 y completed the intervention. INTERVENTION: Subjects consumed an LKFibre and a control diet for 1 month each. Both diets had the same background menus with seven additional experimental foods that either contained LKFibre or did not. Depending on energy intake, the LKFibre diet was designed to contain an additional 17 to 30 g/day fibre beyond that of the control diet. RESULTS: Compared to the control diet, the LKFibre diet reduced total cholesterol (TC) (mean+/-s.e.m.; 4.5+/-1.7%; P=0.001), low-density lipoprotein cholesterol (LDL-C) (5.4+/-2.2%; P=0.001), TC: high-density lipoprotein cholesterol (HDL-C) (3.0+/-2.0%; P=0.006) and LDL-C:HDL-C (3.8+/-2.6%; P=0.003). No effects on HDL-C, triacylglycerols, glucose or insulin were observed. CONCLUSIONS: Addition of LKFibre to the diet provided favourable changes to some serum lipid measures in men, which, combined with its high palatability, suggest this novel ingredient may be useful in the dietary reduction of coronary heart disease risk.

Can a herpes simplex virus type 1 neuroinvasive score be correlated to other risk factors in Alzheimer's disease?

Herpes simplex virus type 1 (HSV-1) is latent in the nervous system of most humans. Ball [Can J Neurol Sci 9 (1982) 303] first suggested the hypothesis that HSV-1 could be involved in the pathogenesis of Alzheimer's Disease (AD) by noting that regions of the brain particularly and earliest affected in AD were the same as those most damaged during HSV encephalitis. Data from Itzhaki's research suggests that HSV-1 in the brain and the carriage of an apolipoprotein E allele 4 (ApoE e4) together confer risk for AD [J Pathol 97 (2002) 395], [Mol Chem Neuropathol 28 (1996) 135], [Alzheimer's Rep 1 (1998) 173], [Biochem Soc Trans 26 (1998) 273]. Of the two other studies based on Itzhaki's findings, one showed similar results [Lancet 349 (1997) 1102], and the other showed a similar trend [Lancet 351 (1998) 1330], [Lancet 352 (1998) 1312]. To further examine the role of HSV-1 in the etiology of AD, we have formulated a Neuroinvasive Score that quantifies the presence and viral load of HSV-1 in eight brain regions. These regions are: entorhinal cortex, hippocampus, pons, cerebellum, and neocortex (temporal, parietal, occipital, and frontal). We hypothesize that the Neuroinvasive Score that encompasses the presence, amount, and extent of HSV-1 spreading (neuroinvasiveness), will correlate with the genetic risk factor, ApoE e4, in the assessment of autopsy samples from AD patients. If the neuroinvasive score can be directly correlated to the different stages of AD (mild, moderate, severe), this will strengthen the hypothesis that HSV-1 is involved in AD and that ApoE e4 also confers risk for the development and progression of AD.

Metabolic effects of alterations in meal frequency in type 2 diabetes.

OBJECTIVE: The effects of altering meal frequency on measures of glucose and lipid metabolism in type 2 diabetes were examined by comparing isocaloric dietary regimens in which daily food intake was provided by three or nine meals each day. RESEARCH DESIGN AND METHODS: A total of 13 free-living men and women with type 2 diabetes or persistently impaired glucose tolerance participated in a randomized crossover study in which three- and nine-meal regimes were followed for 4-week periods. Fasting plasma lipid and lipoprotein, glucose and insulin concentrations were measured at weekly intervals and glucose, insulin, and triglyceride responses following a 75-g glucose load at weeks 2 and 4 of each diet period. Dietary intake was also recorded during these weeks. RESULTS: Nutrient intakes and all measures of carbohydrate and lipid metabolism were similar on the three- and nine-meal regimes. CONCLUSIONS: This longer-term study could not confirm the potential benefits of increased meal frequency suggested by comparable 4-week studies in type 2 diabetic individuals and acute experiments in individuals with diabetes. However, as there were no adverse effects of consuming nine meals per day, it would seem appropriate that meal frequency in those with type 2 diabetes should be left to personal choice, provided that energy balance is maintained.

Omega-3 dietary Fatty Acid status of healthy older adults in Tasmania, Australia: an observational study.

OBJECTIVES: To determine the dietary and supplement intake of omega-3 (n-3) polyunsaturated fatty acids (PUFA) of older Tasmanian adults; their plasma n-3 PUFA status and the relationship between n-3 PUFA intake and plasma status. DESIGN: Cross-sectional study. SETTING: Launceston and surrounding regions, Tasmania, Australia. PARTICIPANTS: Seventy-three community-dwelling older adults: 23 men aged 70 ± 6.1 years and 50 women aged 70 ± 6.7 years. MEASUREMENTS: A validated, semi-quantitative food frequency questionnaire estimated dietary PUFA intake. The plasma phospholipid fraction of venous blood samples was analysed for fatty acid content. Anthropometric data was recorded. RESULTS: Thirty-five participants (48%) regularly ingested a fish oil supplement. Their plasma n-3 PUFA profile contained significantly more eicosapentaenoic acid (EPA) (odds ratio 3.14; 95% CI 1.37% to 7.30%; p<0.05) and docosahexaenoic acid (DHA) (odds ratio 2.64; 95% CI 1.16% to 6.01%; p<0.05) than non-supplement users. Fish and meat were the main dietary sources of n-3 PUFAs. Participants most commonly consumed fish 3-4 times per week. Significant associations of dietary α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA) and DHA with plasma n-3 PUFAs were noted but not always between dietary and plasma counterparts. CONCLUSION: Without the use of fish oil supplements, most study participants were unable to meet the recommended daily intake of 0.5g EPA and DHA combined; however, the plasma n-3 PUFA profile of non-supplement-users was still robust compared to other Australian and overseas studies.

Topography of Pick inclusion bodies in hippocampi of demented patients. A quantitative study.

Topographic analysis was performed on the distribution of argyrophilic inclusions in hippocampal neurones of patients with Pick's dementia. A semiautomated scanning stage microscope linked potentiometrically to an XY pen recorder permitted the plotting of cytoarchitectonic "scattergrams" from the sequentially screened hippocampal formations. The density of Pick body-bearing nerve cells per cubic mm. of (pyramidal) cortex was quantified by measuring the area of each of six "zones" with a digitizer and programmable calculator. The ranking orders of relative severity showed that neurones in Rose's H1 field, the adjacent subiculum, and the entorhinal cortex are severely involved; that H2 and the presubiculum are less afflicted; and that the endplate is the least affected of all. The similarity of these predilections to those already demonstrated for Hirano bodies, granulovacuoles and neurofibrillary tangles in Alzheimer's disease suggests that a specific neurotransmitter defect may also underlie the dementia of Pick's disease.

Granulovacuolar degeneration in the ageing brain and in dementia.

Quantitative morphometry with a sampling stage light microscope was performed to determine the severity of granulovacuolar degeneration of hippocampal neurones in serially sectioned temporal lobe from mentally normal subjects of different ages and from demented patients. The degree of granulovacuolar change in control brains increased slightly with increasing age; the "granulovacuolar index" of cases with Alzheimer's disease exceeded by many times that of age-matched controls. This significant difference was demonstrable whether the granulovacuolar severity was expressed as number of affected cells per volume of cortex analysed, or as the percentage involvement of total neurones counted in the hippocampus. The posterior half of each dement's hippocampus was found to be more susceptible to this augmented granulovacuolar degeneration than the anterior half, a selectivity already observed for neurofibrillary tangel formation in the same material.

Serum leptin levels are associated with bone mass in nonobese women.

Both serum leptin and bone mineral density are positively correlated with body fat, generating the hypothesis that leptin may be a systemic and/or local regulator of bone mass. We investigated 214 healthy, nonobese Australian women aged 20-91 yr. Bone mineral content, projected bone area, and body fat mass were measured by dual energy x-ray absorptiometry and fasting serum leptin levels by RIA. Associations between bone mineral content (adjusted for age, body weight, body fat mass, and bone area) and the natural logarithm of serum leptin concentrations were analyzed by multiple regression techniques. There was a significant positive association at the lateral spine, two proximal femur sites (Ward's triangle and trochanter), and whole body (partial r(2) = 0.019 to 0.036; all P < 0.05). Similar trends were observed at the femoral neck and posterior-anterior-spine. With bone mineral density the dependent variable (adjusted for age, body weight, and body fat mass), the association with the natural logarithm of leptin remained significant at the lateral spine (partial r(2) = 0.030; P = 0.011), was of borderline significance at the proximal femur sites (partial r(2) = 0.012 to 0.017; P = 0.058 to 0.120), and was not significant at the other sites. Our results demonstrate an association between serum leptin levels and bone mass consistent with the hypothesis that circulating leptin may play a role in regulating bone mass.

Morphometric analyses of neuronal populations and dendritic extent in normal aging and dementia of Alzheimer type: a frank appraisal of the difficulties.

This comprehensive review provides an insightful and frank discussion of the methodological limitations in the literature dealing with analyses of neuronal numbers and the extent of the dendritic tree, both in animal models of physiological aging and human CNS tissue from aged control subjects as well as from patients with Alzheimer's disease. Of special interest are data from Flood and Coleman's own laboratory in which the unique behaviour of hippocampal nerve cells in autopsy studies suggests that hippocampal pyramidal neurones are a key to the neurobiology of dementia of the Alzheimer type. Such investigations could elucidate what happens to the dendritic apparatus of neurones which develop neurofibrillary change, and eventually help determine whether the paired helical filaments of neurofibrillary tangles are even more critical for the pathogenesis of senile dementia than the amyloid of neuritic plaques and of congophilic vessels.

Neuropathological criteria for the diagnosis of Alzheimer's disease: are we really ready yet?

The specific diagnosis of AD as a particular dementia from which a patient suffered assumes, debatably, a reasonably pure clinicopathological entity in which the same concatenation of lesions will not be encountered in others dying with a similar clinical disorder. Statistically complex computations such as multivariate analyses of morphometric data from our laboratory and similar attempts in Swedish and British series may not prove pragmatic for pathological confirmation. The Braaks' schema posits six stages in the evolution of AD. Unfortunately, application of this model to 50 British autopsies cannot reliably identify those cases clinically diagnosed as demented. Furthermore, lack of universal definition for each of the probable lesional subtypes augments the difficulty devising a quantitative consensus. Disease stage refers to a progressive increase in anatomical (geographic) extent of involvement, whereas, grade refers to a progressive increase in severity of affliction within any one site. There is only a tendency for stage and grade to progress in parallel. Nor is it obligatory that either always does progress. More energies should be concentrated upon determining which histopathological abnormality is most injurious to neuronal integrity. Dutch workers opine that in both normal aging and AD, claims of massive, neocortical nerve cell loss may have been based on inadequate morphometry and/or a loss of markers. Requiring urgent resolution is whether cellular changes seen in brains of aging normals represent merely the earliest phase of typical AD (and therefore a good model for Alzheimer pathogenesis), or rather reflect a totally different aging syndrome distinct from AD. We have proposed that abnormalities in the hippocampal formation (with or without neocortical neuronal lesions) may underlie a decline of all higher cognitive functions in senile dementia Alzheimer type. West and colleagues optical disector approach likewise shows that neurodegeneration associated within aging individuals' hippocampi is quantitatively and qualitatively distinct from the neuronal loss in AD. Clinical confreres' imprecision whether or when to term subtle cognitive loss "incipient AD" is understandably mirrored by residual neuropathological struggles to dichotomize such brains as "normative aging" distinct from "putative AD."