Alzheimer Disease: Rapoport SI

Rapoport SI. · Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Building 9, Room 1S128, 9 Memorial Drive, Bethesda, MD 20892, USA. · Prostaglandins Leukot Essent Fatty Acids. · Pubmed #18973997 No free full text.

Abstract: Metabolic cascades involving arachidonic acid (AA) and docosahexaenoic acid (DHA) within brain can be independently targeted by drugs, diet and pathological conditions. Thus, AA turnover and brain expression of AA-selective cytosolic phospholipase A(2) (cPLA(2)), but not DHA turnover or expression of DHA-selective Ca(2+)-independent iPLA(2), are reduced in rats given agents effective against bipolar disorder mania, whereas experimental excitotoxicity and neuroinflammation selectively increase brain AA metabolism. Furthermore, the brain AA and DHA cascades are altered reciprocally by dietary n-3 polyunsaturated fatty acid (PUFA) deprivation in rats. DHA loss from brain is slowed and iPLA(2) expression is decreased, whereas cPLA(2) and COX-2 are upregulated, as are brain concentrations of AA and its elongation product, docosapentaenoic acid (DPA). Positron emission tomography (PET) has shown that the normal human brain consumes 17.8 and 4.6 mg/day, respectively, of AA and DHA, and that brain AA consumption is increased in Alzheimer disease patients. In the future, PET could help to determine how human brain AA or DHA consumption is influenced by diet, aging or disease.

Rapoport SI. · Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Psychol Neuropsychiatr Vieil. · Pubmed #15929923 No free full text.

Abstract: In vivo imaging of regional brain glucose metabolism or blood flow (which is coupled to glucose metabolism) can elucidate regional brain synaptic activity, which is supported by mitochondrial oxidative phosphorylation. In Alzheimer disease, postmortem evidence indicates that synaptic loss correlates with dementia severity, and that oxidative phosphorylation in individual neurons declines in relation to the severity of synaptic dysfunction and the intracellular accumulation of neurofibrillary tangles. Brain imaging in asymptomatic and diagnosed Alzheimer disease patients confirms and extends this scenario. Resting state brain glucose metabolism falls with dementia severity, particularly in brain association areas. However, the brain can be almost normally activated in the early stages of disease, although not during moderate-severe dementia. Thus, in vivo imaging during graded parametric stimulation can be used to evaluate synaptic efficacy, and the ability of therapeutic intervention to ameliorate synaptic dysfunction, in pre-symptomatic and diagnosed Alzheimer disease patients.

Rapoport SI. · Brain Physiology and Metabolism Sections, Bldg. 10, Rm. 6N202, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Neurotox Res. · Pubmed #14715441 No free full text.

Abstract: In vivo, post-mortem and biopsy data suggest that coupled declines occur in brain synaptic activity and brain energy consumption during the evolution of Alzheimer disease. In the first stage of these declines, changes in synaptic structure and function reduce neuronal energy demand and lead to potentially reversible downregulation of oxidative phosphorylation (OXPHOS) within neuronal mitochondria. At this stage, measuring brain glucose metabolism or brain blood flow in patients, using positron emission tomography (PET), shows that the brain can be almost normally activated in response to stimulation. Thus, therapy at this stage should be designed to re-establish synaptic integrity or prevent its further deterioration. As disease progresses, neurofibrillary tangles with abnormally phosphorylated tau protein accumulate within neuronal cytoplasm, to the point that they co-opt the nonphosphorylated tau necessary for axonal transport of mitochondria between the cell nucleus and the synapse. In this second stage, severe energy depletion and other pathological processes associated with irreversibly downregulated OXPHOS lead to cell death, and the brain cannot normally respond to functional stimulation.

Rapoport SI. · Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Lancet Neurol. · Pubmed #12849509 No free full text.

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Rapoport SI. · Section on Brain Physiology and Metabolism, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · J Mol Neurosci. · Pubmed #11478380 No free full text.

Abstract: A method, model, and "operational equations" are described to quantify in vivo turnover rates and half-lives of fatty acids within brain phospholipids, as well as rates of incorporation of these fatty acids into brain from plasma. In awake rats, recycling of fatty acids within brain phospholipids, due to deesterification and reesterification, is very rapid, with half-lives in some cases of minutes to hours. Plasma fatty acids make only a small contribution (2-4%) to the net quantity of fatty acids that are reesterified. This explains why many weeks are necessary to recover normal brain n-3 polyunsaturated fatty acid concentrations following their prolonged dietary deprivation. Changes in recycling of specific fatty acids in response to centrally acting drugs can help to identify enzyme targets for drug action. For example, recycling of arachidonate is specifically reduced by 80% in rats treated chronically with lithium, a drug effective against bipolar disorder; the effect reflects downregulation of gene expression of an arachidonate-specific phospholipase A2. When combined with neuroimaging (quantitative autoradiography in rodents or positron-emission tomography [PET] in macaques or humans), intravenously injected radiolabeled fatty acids can be used to localize and quantify brain PLA2-mediated signal transduction, and to examine neuroplastic remodeling of brain lipid membranes.

Rapoport SI. · Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. · Ann N Y Acad Sci. · Pubmed #10672235 No free full text.

Abstract: In vivo brain imaging of patients with Alzheimer's disease (AD) using positron emission tomography (PET) demonstrates progressive reductions in resting-state brain glucose metabolism and blood flow in relation to dementia severity, more so in association than primary cortical regions. During cognitive or psychophysical stimulation, blood flow and metabolism in the affected regions can increase to the same extent in mildly demented AD patients as in age-matched controls, suggesting that energy delivery is not rate limiting. Activation declines with dementia severity, and is markedly reduced in severely demented patients. These results suggest that there is an initial "normal" functionally-responsive stage in AD, followed by a late less responsive stage. Studies of biopsied and postmortem brain indicate that the initial stage is accompanied by selective and potentially reversible down-regulation of the brain enzymes, including cytochrome oxidase, which mediate mitochondrial oxidative-phosphorylation.

Rapoport SI. · Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, Md. 20892, USA. · Eur Arch Psychiatry Clin Neurosci. · Pubmed #10654100 No free full text.

Abstract: In vivo brain imaging of patients with Alzheimer's disease (AD) using positron emission tomography (PET) demonstrates progressive reductions in resting-state brain glucose metabolism and blood flow (markers of synaptic activity) in relation to dementia severity, more so in association than primary cortical regions. During cognitive or psychophysical stimulation, however, blood flow and metabolism in the affected brain regions can increase to the same extent in mildly demented AD patients as in age-matched controls, despite reduced resting state values. The extent of activation declines with dementia severity and is markedly reduced in severely demented patients. Thus, there appears to be an initial functionally-responsive stage in AD, which direct brain analysis suggests is accompanied by reversible down-regulation because of reduced synaptic energy demand of enzymes mediating mitochondrial oxidative-phosphorylation. A later irreversible stage of AD is accompanied by marked synaptic loss, accumulation of intracellular neurofibrillary tangles, reduced general transcriptional capacity, and death of neurons.

Buerger K, Zinkowski R, Teipel SJ, Tapiola T, Arai H, Blennow K, Andreasen N, Hofmann-Kiefer K, DeBernardis J, Kerkman D, McCulloch C, Kohnken R, Padberg F, Pirttilä T, Schapiro MB, Rapoport SI, Möller HJ, Davies P, Hampel H. · Dementia Research Section and Memory Clinic, Alzheimer Memorial Center, Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstrasse 7, 80336 Munich, Germany. · Arch Neurol. · Pubmed #12164722 links to  free full text

Abstract: BACKGROUND: Phosphorylation of tau protein at threonine 231 (using full-length tau, 441 amino acids, for the numbering scheme) (p-tau(231)) occurs specifically in postmortem brain tissue of patients with Alzheimer disease (AD) and can be sensitively detected in cerebrospinal fluid (CSF). OBJECTIVES: To determine to what extent CSF levels of p-tau(231) distinguish patients with AD from control subjects and from patients with other dementias, and to investigate whether p-tau(231) levels are a better diagnostic marker than levels of total tau protein (t-tau) in CSF. DESIGN AND SETTING: Cross-sectional, multicenter, memory clinic-based studies. PARTICIPANTS: One hundred ninety-two patients with a clinical diagnosis of AD, frontotemporal dementia (FTD), vascular dementia, Lewy body dementia, or other neurological disorder and healthy controls. MAIN OUTCOME MEASURES: Levels of CSF tau proteins as measured with enzyme-linked immunosorbent assays. RESULTS: Mean CSF levels of p-tau(231) were significantly elevated in the AD group compared with all other groups. Levels of p-tau(231) did not correlate with dementia severity in AD, and discriminated with a sensitivity of 90.2% and a specificity of 80.0% between AD and all non-AD disorders. Moreover, p-tau(231) levels improved diagnostic accuracy compared with t-tau levels when patients with AD were compared with healthy controls (P =.03) and demented subjects (P<.001), particularly those with FTD (P<.001), but not those with vascular and Lewy body dementias. Sensitivity levels between AD and FTD were raised by p-tau(231) compared with t-tau levels from 57.7% to 90.2% at a specificity level of 92.3% for both markers. CONCLUSION: Increased levels of CSF p-tau(231) may be a useful, clinically applicable biological marker for the differential diagnosis of AD, particularly for distinguishing AD from FTD.

Hampel H, Teipel SJ, Bayer W, Alexander GE, Schwarz R, Schapiro MB, Rapoport SI, Möller HJ. · Dementia Research and Neuroimaging Section, Memory Clinic, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstr.7, 80336, Munich, Germany. · J Neurol Sci. · Pubmed #11809161 No free full text.

Abstract: OBJECTIVE: The specificity of magnetic resonance imaging (MRI)-based hippocampal measurements in detecting Alzheimer's disease (AD) pathology is reduced by an age-related reduction of the hippocampus volume. We propose an adjustment for this age effect to increase the diagnostic accuracy of hippocampal volumes in AD. METHOD: Using an orthogonal rotational transformation of the coordinate system, values of MRI-determined volumes of hippocampus-amygdala formation (HAF) were transformed according to the age effect in 27 AD patients and 28 age- and sex-matched healthy control subjects. RESULTS: The age transformation increased the diagnostic accuracy of HAF volumes in the study sample and in an independent sample from the literature. The age-transformed HAF volume predicted AD in a subject with mild cognitive impairment (MCI) with later biopsy-confirmed AD. CONCLUSION: Age transformation may provide an easily applicable method to increase the clinical diagnostic accuracy of hippocampal measurements by considering the effect of aging on hippocampus volume.

Grady CL, Furey ML, Pietrini P, Horwitz B, Rapoport SI. · Rotman Research Institute, Baycrest Centre for Geriatric Care, University of Toronto, Toronto, Ontario, Canada. · Brain. · Pubmed #11287374 links to  free full text

Abstract: To examine functional interactions between prefrontal and medial temporal brain areas during face memory, blood flow was measured in patients with Alzheimer's disease and healthy controls using PET. We hypothesized that controls would show correlated activity between frontal and posterior brain areas, including the medial temporal cortex, whereas patients would not, although frontal activity per se might be spared or even increased compared with controls. We used a delayed match to sample paradigm with delays from 1 to 16 s. There was no change in recognition accuracy with increasing delay in controls, whereas patients showed impaired recognition over all delays that worsened as delay increased. Controls showed increased activity in the bilateral prefrontal and parietal cortex with increasing delay, whereas the patients had increased activity in the right prefrontal, anterior cingulate and left amygdala. Increased activity in the right prefrontal cortex was associated with better memory performance in both groups and activity in the left amygdala was correlated with better performance in the patients. Based on these task and behavioural effects, we examined functional connectivity of the right prefrontal cortex and left amygdala in both groups by determining those areas whose activity was correlated with activity in these regions. In controls, activity in the right prefrontal cortex was positively correlated with blood flow in the left prefrontal cortex, bilateral extrastriate and parietal areas and the right hippocampus. In patients, activity in the right prefrontal cortex was correlated mainly with other prefrontal regions. Areas where activity was correlated with the left amygdala in patients included the bilateral posterior parahippocampal gyri, a number of left prefrontal regions, anterior and posterior cingulate, thalamus, and insula. Controls had a relatively restricted set of regions where activity correlated with the left amygdala, mainly temporal and occipital areas. These results support the idea of a functional disconnection between the prefrontal cortex and the hippocampus in Alzheimer's disease and suggest that memory breakdown in early Alzheimer's disease is related to a reduction in the integrated activity within a distributed network that includes these two areas. The unexpected finding of increased involvement of the amygdala suggests that the patients may have processed the emotional content of the faces to a greater degree than did the controls. Furthermore, the positive association between amygdala activity and memory performance in the patients suggests a possible compensatory role for an emotion-related network of regions.

Rapoport SI. · Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · J Nutr. · Pubmed #19022981 No free full text.

Abstract: Kinetic methods in unanesthetized rodents have shown that turnover rates of arachidonic acid (AA) and docosahexaenoic acid (DHA) in brain membrane phospholipids are rapid and energy consuming and that phospholipase A(2) (PLA(2)) and acyl-CoA synthetase enzymes that regulate turnover are specific for one or the other PUFA. Thus, AA turnover in brain phospholipids was reduced, and AA-selective cytosolic cPLA(2) or acyl-CoA synthetase, as well as cyclooxygenase (COX)-2, were downregulated in brains of rats given drugs effective against bipolar disorder, whereas DHA turnover and expression of DHA-selective calcium-independent iPLA(2) were unchanged. Additionally, the brain AA and DHA cascades can be altered reciprocally by dietary or genetic conditions. Thus, following 15 wk of dietary (n-3) PUFA deprivation, DHA loss from rat brain was slowed because of reduced iPLA(2) and COX-1 expression, whereas AA-selective cPLA(2), sPLA(2), and COX-2 were upregulated, as were AA and docosapentaenoic acid concentrations. Measured rates of AA and DHA incorporation into brain represent their respective rates of metabolic consumption, because these PUFA are not synthesized de novo or converted significantly from their precursors in brain. In healthy human volunteers, positron emission tomography (PET) was used to show that the brain consumes AA and DHA at respective rates of 17.8 and 4.6 mg/d, whereas in patients with Alzheimer disease, AA consumption is elevated. In the future, PET could be used to relate human brain rates of AA and DHA consumption to liver PUFA metabolism and dietary PUFA intake.

Esposito G, Giovacchini G, Liow JS, Bhattacharjee AK, Greenstein D, Schapiro M, Hallett M, Herscovitch P, Eckelman WC, Carson RE, Rapoport SI. · Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. · J Nucl Med. · Pubmed #18703605 No free full text.

Abstract: Incorporation coefficients (K*) of arachidonic acid (AA) in the brain are increased in a rat model of neuroinflammation, as are other markers of AA metabolism. Data also indicate that neuroinflammation contributes to Alzheimer's disease (AD). On the basis of these observations, K* for AA was hypothesized to be elevated in patients with AD. METHODS: A total of 8 patients with AD with an average (+/-SD) Mini-Mental State Examination score of 14.7+/-8.4 (mean age, 71.7+/-11.2 y) and 9 controls with a normal Mini-Mental State Examination score (mean age, 68.7+/-5.6 y) were studied. Each subject received a (15)O-water PET scan of regional cerebral blood flow, followed after 15 min by a 1-(11)C-AA scan of regional K* for AA. RESULTS: In the patients with AD, compared with control subjects, global gray matter K* for AA (corrected or uncorrected for the partial-volume error [PVE]) was significantly elevated, whereas only PVE-uncorrected global cerebral blood flow was reduced significantly (P<0.05). A false-discovery-rate procedure indicated that PVE-corrected K* for AA was increased in 78 of 90 identified hemispheric gray matter regions. PVE-corrected regional cerebral blood flow, although decreased in 12 regions at P<0.01 by an unpaired t test, did not survive the false-discovery-rate procedure. The surviving K* increments were widespread in the neocortex but were absent in caudate, pallidum, and thalamic regions. CONCLUSION: These preliminary results show that K* for AA is widely elevated in the AD brain, particularly in regions reported to have high densities of senile (neuritic) plaques with activated microglia. To the extent that the elevations represent upregulated AA metabolism associated with neuroinflammation, PET with 1-(11)C-AA could be used to examine neuroinflammation in patients with AD and other brain diseases.

Teipel SJ, Alexander GE, Schapiro MB, Möller HJ, Rapoport SI, Hampel H. · Alzheimer Memorial Center and Geriatric Psychiatry Branch, Dementia and Neuroimaging Section, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstrasse 7, 80336 Munich, Germany. · Brain. · Pubmed #14985261 links to  free full text

Abstract: Ageing in Down's syndrome is accompanied by amyloid and neurofibrillary pathology the distribution of which replicates pathological features of Alzheimer's disease. With advancing age, an increasing proportion of Down's syndrome subjects >40 years old develop progressive cognitive impairment, resembling the cognitive profile of Alzheimer's disease. Based on these findings, Down's syndrome has been proposed as a model to study the predementia stages of Alzheimer's disease. Using an interactive anatomical segmentation technique and volume-of-interest measurements of MRI, we showed recently that non-demented Down's syndrome adults had significantly reduced hippocampus, entorhinal cortex and corpus callosum sizes with increasing age. In this study, we applied the automated and objective technique of voxel-based morphometry, implemented in SPM99, to the analysis of structural MRI from 27 non-demented Down's syndrome adults (mean age 41.1 years, 15 female). Regional grey matter volume was decreased with advancing age in bilateral parietal cortex (mainly the precuneus and inferior parietal lobule), bilateral frontal cortex with left side predominance (mainly middle frontal gyrus), left occipital cortex (mainly lingual cortex), right precentral and left postcentral gyrus, left transverse temporal gyrus, and right parahippocampal gyrus. The reductions were unrelated to gender, intracranial volume or general cognitive function. Grey matter volume was relatively preserved in subcortical nuclei, periventricular regions, the basal surface of the brain (bilateral orbitofrontal and anterior temporal) and the anterior cingulate gyrus. Our findings suggest grey matter reductions in allocortex and association neocortex in the predementia stage of Down's syndrome. The most likely substrate of these changes is alterations or loss of allocortical and neocortical neurons due to Alzheimer's disease-type pathology.

Teipel SJ, Schapiro MB, Alexander GE, Krasuski JS, Horwitz B, Hoehne C, Möller HJ, Rapoport SI, Hampel H. · Alzheimer Memorial Center and Geriatric Psychiatry Branch, Ludwig-Macimilian University, Munich, Germany. · Am J Psychiatry. · Pubmed #14514503 links to  free full text

Abstract: OBJECTIVE: Aging in Down's syndrome is accompanied by amyloid and neurofibrillary pathology, the regional and laminar distribution of which resembles pathological changes seen in Alzheimer's disease. Previous studies using magnetic resonance imaging (MRI) demonstrated age-related atrophy of medial temporal lobe structures in nondemented older subjects with Down's syndrome, reflecting early allocortical pathology. Corpus callosum atrophy has been established as a marker of neocortical neuronal loss in Alzheimer's disease. This study investigated whether atrophy of the corpus callosum and hippocampus occurs in nondemented subjects with Down's syndrome and compared the degree of age-related atrophy between these structures. METHOD: Hippocampus and corpus callosum measures were obtained from volumetric T(1)-weighted MRI scans of 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women) and 31 healthy comparison subjects (mean age=41.8 years, 14 women). RESULTS: Down's syndrome subjects had smaller corpus callosum areas and hippocampal volumes relative to age-matched healthy comparison subjects, even after age and total intracranial volume were controlled. There was an age-related decrease of corpus callosum area (most prominent in posterior regions) and hippocampal volume in the Down's syndrome group. The degree of the age effect was comparable between the total corpus callosum and hippocampus, and corpus callosum size was correlated with cognitive performance in the Down's syndrome subjects. There was no correlation between age and corpus callosum or hippocampal size in the comparison group. CONCLUSIONS: Comparable decrease of corpus callosum and hippocampal size with age in nondemented subjects with Down's syndrome suggests that neocortical neuronal alterations accompany allocortical changes in the predementia phase of Down's syndrome.

Buerger K, Zinkowski R, Teipel SJ, Arai H, DeBernardis J, Kerkman D, McCulloch C, Padberg F, Faltraco F, Goernitz A, Tapiola T, Rapoport SI, Pirttilä T, Möller HJ, Hampel H. · Dementia Research Section and Memory Clinic, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. · Am J Psychiatry. · Pubmed #12562590 links to  free full text

Abstract: OBJECTIVE: Differentiation of geriatric major depression from Alzheimer's disease is hampered by overlapping symptoms. Increased CSF concentrations of tau protein phosphorylated at threonine 231 (p-tau(231)) have been suggested as a biomarker for Alzheimer's disease. The authors asked whether p-tau(231) levels improve the differential diagnosis between geriatric major depression and Alzheimer's disease. METHOD: Included were 34 depression subjects, 64 with probable Alzheimer's disease, 17 with possible Alzheimer's disease, and 21 healthy comparison subjects. P-tau(231) concentrations were measured with an enzyme-linked immunosorbent assay. RESULTS: P-tau(231) levels were significantly higher in Alzheimer's disease than in geriatric major depression patients and healthy comparison subjects. For differentiation of probable Alzheimer's disease from major depression, p-tau(231) correctly allocated 87% of subjects. When possible mild Alzheimer's disease was compared to major depression, p-tau(231) correctly allocated 78% of subjects. CONCLUSIONS: CSF p-tau(231) should be evaluated as a potential biological marker for differentiation of geriatric depression from Alzheimer's disease.

Teipel SJ, Bayer W, Alexander GE, Bokde AL, Zebuhr Y, Teichberg D, Müller-Spahn F, Schapiro MB, Möller HJ, Rapoport SI, Hampel H. · Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstr 7, 80336, Munich, Germany. · Neurobiol Aging. · Pubmed #12493554 No free full text.

Abstract: We used volumetric MRI and analysis of areas under receiver operating characteristic (ROC) curves to directly compare the extent of hippocampus-amygdala formation (HAF) and corpus callosum atrophy in patients with Alzheimer's disease (AD) in different clinical stages of dementia. Based on neuropathological studies, we hypothesized that HAF atrophy, representing allocortical neuronal degeneration, would precede atrophy of corpus callosum, representing loss of neocortical association neurons, in early AD. HAF and corpus callosum sizes were significantly reduced in 27 AD patients (37% and 16%, respectively) compared to 28 healthy controls. In mildly- and moderately-demented AD patients, the ROC derived index of atrophy was greater for HAF volume than for total corpus callosum area. The index of atrophy of posterior corpus callosum was not significantly different from HAF at mild, moderate or severe stages of dementia. In conclusion, these findings suggest a characteristic regional pattern of allocortical and neocortical neurodegeneraton in AD. Our data indicate that neuronal loss in parietotemporal cortex (represented by atrophy of corpus callosum splenium) may occur simultaneously with allocortical neurodegeneration in mild AD. Moreover, ROC analysis may provide a statistical framework to determine atrophy patterns of different brain structures in neurodegenerative diseases in vivo.

Hampel H, Teipel SJ, Alexander GE, Pogarell O, Rapoport SI, Möller HJ. · Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Dementia and Neuroimaging Section, Ludwig-Maximilian University, Munich, Federal Republic of Germany. · J Neural Transm. · Pubmed #12111472 No free full text.

Abstract: Neuropathological studies in Alzheimer's disease (AD) indicate specific loss of layer III and V large pyramidal neurons in association cortex. These neurons give rise to long cortico-cortical connections, projecting through the corpus callosum, in an anterior-posterior topology. Based on these findings we hypothesized that regional corpus callosum atrophy may be a potential in vivo marker for neocortical neuronal loss in AD. To evaluate this hypothesis, we developed a method to measure cross-sectional area of the corpus callosum and of five corpus callosum subregions on midsagittal magnetic resonance imaging scans (MRI). In a subsequent series of six experimental studies using MRI, (18)FDG-PET and EEG, we investigated the relation of white matter hyperintensities (WMH) to corpus callosum size and correlated regional pattern of corpus callosum atrophy with regional cortical metabolic decline as well as intracortical coherencies. Mean total corpus callosum area was reduced significantly in AD patients compared to healthy age-matched controls, with the greatest changes in the rostrum and the splenium and relative sparing of the truncus. The regional pattern of corpus callosum atrophy was independent of WMH load and correlated significantly with pattern of regional metabolic decline measured with (18)FDG-PET, the degree of cognitive impairment and regional decline of bilateral intracortical-coherency in EEG in AD patients. We further found that hippocampus atrophy, as a marker of early allocortical degeneration, was more pronounced than total corpus callosum atrophy in mild stages of AD. Regional corpus callosum atrophy in mild disease, however, suggested early neocortical degeneration in AD. In a longitudinal study, AD patients showed significantly greater rates of corpus callosum atrophy than controls. Rates of atrophy correlated with progression of clinical dementia severity in AD. Our results indicate that regional corpus callosum atrophy in AD patients represents the loss of callosal efferent neurons in corresponding regions of the neocortex. As these neurons are a subset of cortico-cortical projecting neurons, region-specific corpus callosum atrophy may serve as a marker of progressive neocortical disconnection in AD. In combination with measurement of hippocampal atrophy, assessment of corpus callosum atrophy over time in individual patients is useful to evaluate effects on brain structure of currently developed drugs, thought to slow or modify AD progression.

Alexander GE, Chen K, Pietrini P, Rapoport SI, Reiman EM. · Arizona Alzheimer's Research Center and Department of Psychiatry, Arizona State University, Tempe, 85287-1104, USA. · Am J Psychiatry. · Pubmed #11986126 links to  free full text

Abstract: OBJECTIVE: It is well established that regional cerebral metabolic rates for glucose assessed by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with Alzheimer's disease in the mental resting state (eyes and ears covered) provide a sensitive, in vivo metabolic index of Alzheimer's disease dementia. Few studies, however, have evaluated longitudinal declines in regional cerebral glucose metabolism in patients with dementia caused by Alzheimer's disease. In addition, the available studies have not used recently developed brain mapping algorithms to characterize the progression of Alzheimer's disease throughout the brain, and none considered the statistical power of regional cerebral glucose metabolism in testing the ability of treatments to attenuate the progression of dementia. METHOD: The authors used FDG PET and a brain mapping algorithm to investigate cross-sectional reductions in regional cerebral glucose metabolism, longitudinal decline in regional cerebral glucose metabolism after a 1-year follow-up, and the power of this method to evaluate treatments for Alzheimer's disease in patients with mild to moderate dementia. PET scans were initially acquired in 14 patients with Alzheimer's disease and 34 healthy comparison subjects of similar age and sex. Repeat scans were obtained in the patients 1 year later. Power analyses for voxels showing maximal decline over the 1-year period in regional cerebral glucose metabolism (mg/100 g per minute) were computed to estimate the sample sizes needed to detect a significant treatment response in a 1-year, double-blind, placebo-controlled treatment study. RESULTS: The patients with Alzheimer's disease had significantly lower glucose metabolism than healthy comparison subjects in parietal, temporal, occipital, frontal, and posterior cingulate cortices. One year later, the patients with Alzheimer's disease had significant declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. Using maximal glucose metabolism reductions in the left frontal cortex, we estimated that as few as 36 patients per group would be needed to detect a 33% treatment response with one-tailed significance of p</=0.005 and 80% power in a 1-year, double-blind, placebo-controlled treatment study. CONCLUSIONS: These findings indicate that brain metabolism as assessed by FDG PET during mental rest is a sensitive marker of disease progression in Alzheimer's disease over a 1-year period. These findings also support the feasibility of using FDG PET as an outcome measure to test the ability of treatments to attenuate the progression of Alzheimer's disease.

Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA, Murri L, Rapoport SI, Solaini G. · Scuola Superiore di Studi Universitari e di Perfezionamento S. Anna, Via G. Carducci 40, 56127 Pisa, Italy. · Neurobiol Aging. · Pubmed #11959398 No free full text.

Abstract: Evidence suggests that mitochondrial dysfunction is prominent in Alzheimer's disease (AD). A failure of one or more of the mitochondrial electron transport chain enzymes or of F(1)F(0)-ATPase (ATP synthase) could compromise brain energy stores, generate damaging reactive oxygen species (ROS), and lead to neuronal death. In the present study, cytochrome c oxidase (COX) and F(1)F(0)-ATPase activities of isolated mitochondria from platelets and postmortem motor cortex and hippocampus from AD patients and age-matched control subjects were assayed. Compared with controls, COX activity was decreased significantly in platelets (-30%, P < 0.01, n = 20) and hippocampus (-35 to -40%, P < 0.05, n = 6), but not in motor cortex from the AD patients. In contrast, in AD platelets and brain tissues, F(1)F(0)-ATP hydrolysis activity was not significantly changed. Moreover, the ATP synthesis rate was similar in mitochondria of platelets from AD patients and controls. These results demonstrate that COX but not F(1)F(0)-ATPase is a mitochondrial target in AD, in both a brain association area and in platelets. A reduced COX activity may make the tissue vulnerable to excitotoxicity or reduced oxygen availability.

Teipel SJ, Bayer W, Alexander GE, Zebuhr Y, Teichberg D, Kulic L, Schapiro MB, Möller HJ, Rapoport SI, Hampel H. · and Harald Hampel, MD, Dementia and Neuroimaging Section, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstr 7, 80336 Munich, Germany. · Arch Neurol. · Pubmed #11843695 links to  free full text

Abstract: BACKGROUND: Atrophy of the corpus callosum in the absence of primary white matter degeneration reflects loss of intracortical projecting neocortical pyramidal neurons in Alzheimer disease (AD). OBJECTIVES: To determine individual rates of atrophy progression of the corpus callosum in patients with AD and to correlate rates of atrophy progression with clinical disease severity and subcortical disease. METHODS: Magnetic resonance imaging-derived measurements of corpus callosum size were studied longitudinally in 21 patients clinically diagnosed as having AD (mean observation time, 17.0 +/- 8.5 months) and 10 age- and sex-matched healthy controls (mean observation time, 24.1 +/- 6.8 months). RESULTS: Corpus callosum size was significantly reduced in AD patients at baseline. Annual rates of atrophy of total corpus callosum, splenium, and rostrum were significantly larger in AD patients (-7.7%, -12.1%, and -7.3%, respectively) than in controls (-0.9%, -1.5%, and 0.6%, respectively). Rates of atrophy of the corpus callosum splenium were correlated with progression of dementia severity in AD patients (rho = 0.52, P<.02). The load of subcortical lesions at baseline (P<.05) predicted rate of anterior corpus callosum atrophy in healthy controls. Rates of atrophy of corpus callosum areas were independent of white matter hyperintensity load in patients with AD. CONCLUSIONS: Measurement of corpus callosum size allows in vivo mapping of neocortical neurodegeneration in AD over a wide range of clinical dementia severities and may be used as a surrogate marker for evaluation of drug efficacy.

Krasuski JS, Alexander GE, Horwitz B, Rapoport SI, Schapiro MB. · Laboratory of Neurosciences, National Institute on Aging, Bethesda, MD, USA. · Am J Psychiatry. · Pubmed #11772693 links to  free full text

Abstract: OBJECTIVE: In Down's syndrome (trisomy 21), a dementia syndrome occurs that is phenotypically similar to Alzheimer's disease; the initial phase is characterized by memory loss. The authors used an in vivo structural technique in the predementia stage of Alzheimer's disease in adults with Down's syndrome to investigate whether atrophy of medial temporal lobe structures occurs in these subjects and whether volumes of these structures correlate specifically with performance on memory tests. METHOD: The subjects were 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women and 17 men) and 33 healthy comparison subjects (mean age=41.3, 15 women and 18 men). By using T(1)-weighted magnetic resonance imaging slices taken perpendicular to the Sylvian fissure, volumes of the hippocampus, amygdala, anterior and posterior parahippocampal gyrus, and temporal pole CSF were measured in both hemispheres. These data were normalized to the total intracranial volume. RESULTS: For Down's syndrome, smaller volumes of the right and left amygdala, hippocampus, and posterior parahippocampal gyrus were significantly associated with greater age; this association was not seen in the anterior parahippocampal gyrus. The amygdala and hippocampus volumes were positively correlated with memory measures. For the comparison group, there was no relationship between volume and age in any region. CONCLUSIONS: In the predementia phase of Down's syndrome, significant volume changes in medial temporal lobe structures occur with age and are related to memory. These structures are affected early in Alzheimer's disease in Down's syndrome, and their evaluation may help identify people in the preclinical stages of Alzheimer's disease.

Silverman DH, Small GW, Chang CY, Lu CS, Kung De Aburto MA, Chen W, Czernin J, Rapoport SI, Pietrini P, Alexander GE, Schapiro MB, Jagust WJ, Hoffman JM, Welsh-Bohmer KA, Alavi A, Clark CM, Salmon E, de Leon MJ, Mielke R, Cummings JL, Kowell AP, Gambhir SS, Hoh CK, Phelps ME. · Ahmanson Biological Imaging Center, CHS AR-144, Department of Molecular and Medical Pharmacology, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095-6942, USA. · JAMA. · Pubmed #11694153 links to  free full text

Abstract: CONTEXT: Deficits in cerebral glucose utilization have been identified in patients with cognitive dysfunction attributed to various disease processes, but their prognostic and diagnostic value remains to be defined. OBJECTIVE: To assess the sensitivity and specificity with which cerebral metabolic patterns at a single point in time forecast subsequent documentation of progressive dementia. DESIGN, SETTING, AND PATIENTS: Positron emission tomography (PET) studies of [(18)F]fluorodeoxyglucose in 146 patients undergoing evaluation for dementia with at least 2 years' follow-up for disease progression at the University of California, Los Angeles, from 1991 to 2000, and PET studies in 138 patients undergoing evaluation for dementia at an international consortium of facilities, with histopathological diagnoses an average of 2.9 years later, conducted from 1984 to 2000. MAIN OUTCOME MEASURES: Regional distribution of [(18)F]fluorodeoxyglucose in each patient, classified by criteria established a priori as positive or negative for presence of a progressive neurodegenerative disease in general and of Alzheimer disease (AD) specifically, compared with results of longitudinal or neuropathologic analyses. RESULTS: Progressive dementia was detected by PET with a sensitivity of 93% (191/206) and a specificity of 76% (59/78). Among patients with neuropathologically based diagnoses, PET identified patients with AD and patients with any neurodegenerative disease with a sensitivity of 94% and specificities of 73% and 78%, respectively. The negative likelihood ratio of experiencing a progressive vs nonprogressive course over the several years following a single negative brain PET scan was 0.10 (95% confidence interval, 0.06-0.16), and the initial pattern of cerebral metabolism was significantly associated with the subsequent course of progression overall (P<.001). CONCLUSION: In patients presenting with cognitive symptoms of dementia, regional brain metabolism was a sensitive indicator of AD and of neurodegenerative disease in general. A negative PET scan indicated that pathologic progression of cognitive impairment during the mean 3-year follow-up was unlikely to occur.

Huang W, Alexander GE, Chang L, Shetty HU, Krasuski JS, Rapoport SI, Schapiro MB. · Department of Radiology, State University of New York at Stony Brook, USA. · Neurology. · Pubmed #11524470 No free full text.

Abstract: OBJECTIVE: (1)H-MRS studies have shown abnormalities in brain levels of myo-inositol (mI) and N-acetyl aspartate (NAA) in AD, but the relation of these abnormalities with dementia severity was not examined. The authors sought to determine whether altered brain levels of mI and other metabolites occur in mild AD and whether they change as dementia severity worsens. METHODS: The authors used (1)H-MRS with external standards to measure absolute brain concentrations of mI, NAA, total creatine (Cr), and choline (Cho)-containing compounds in 21 subjects with AD and 17 age- and sex-matched controls in occipital and left and right parietal regions. RESULTS: Concentrations of NAA were significantly decreased, whereas mI and Cr concentrations were significantly increased in all three brain regions in subjects with AD compared with controls. Higher concentrations of mI and Cr occurred even in mild AD. A discriminant analysis of the (1)H-MRS data combined with CSF volume measurements distinguished subjects with AD, ranging from mild to severe dementia, from controls with 100% correct classification. NAA concentration, though not other metabolites, was positively correlated with Mini-Mental State Examination score. CONCLUSION: The measurements with (1)H-MRS of absolute metabolite concentrations in the neocortex showed abnormal concentrations of brain metabolites in AD; these metabolite concentrations do not necessarily correlate with disease severity. Although changes in myo-inositol and creatine occur in the early stages of AD, abnormalities of N-acetyl aspartate do not occur in mild AD but progressively change with dementia severity. Further, subjects with mild AD can be differentiated from controls with (1)H-MRS.

Bosetti F, Solaini G, Tendi EA, Chikhale EG, Chandrasekaran K, Rapoport SI. · Section on Brain Physiology and Metabolism, National Institute on Aging, NIH, Bethesda, MD 20892, USA. · Neuroreport. · Pubmed #11277571 No free full text.

Abstract: Aluminum (Al) has been implicated in several neurological diseases including dialysis dementia and Alzheimer's disease (AD). One possible mechanism of Al neurotoxicity could involve alteration of mitochondrial gene expression. We exposed PC12 cells to 0.1-100 microM AlCl3 for 6h at pH 7.4. Internalized Al, measured by atomic absorption spectrometry, was linearly proportional to the extracellular Al concentration. Northern blot analyses showed that cytochrome c oxidase subunit III (COX III) mRNA was significantly reduced by 70% after addition of 1 microM AlCl3. Higher concentrations of AlCl3 did not show a significant further effect. These results suggest that Al neurotoxicity involves a specific impairment of cytochrome c oxidase.

Bokde AL, Pietrini P, Ibáñez V, Furey ML, Alexander GE, Graff-Radford NR, Rapoport SI, Schapiro MB, Horwitz B. · Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Arch Neurol. · Pubmed #11255453 links to  free full text

Abstract: BACKGROUND: Brain glucose metabolic rates measured by positron emission tomography can be more affected by partial volume effects in Alzheimer disease (AD) than in healthy aging because of disease-associated brain atrophy. OBJECTIVE: To determine whether the distinct distribution of cerebral metabolic lesions in patients with the visual variant of AD (AD + VS) represents a true index of neuronal/synaptic dysfunction or is the consequence of brain atrophy. SETTING: Government research hospital. DESIGN: Resting cerebral metabolic rate for glucose was measured with positron emission tomography in a cross-sectional study of AD and AD + VS groups and in healthy control subjects. Segmented magnetic resonance images were used to correct for brain atrophy. PATIENTS: Patients with AD + VS had prominent visual and visuospatial symptoms. There were 15 patients with AD, 10 with AD + VS, and 37 age-matched control subjects. MAIN OUTCOME MEASURE: Measurement of the rate of cerebral glucose metabolism. RESULTS: Before atrophy correction, the AD + VS group, compared with the control subjects, showed hypometabolism in primary and extrastriate visual areas and in parietal and superior temporal cortical areas. Compared with the AD group, the AD + VS group showed hypometabolism in visual association areas. After atrophy correction, hypometabolism remained significantly different between patients and controls and between the 2 AD groups. CONCLUSIONS: The reductions in cerebral hypometabolism represent a true loss of functional activity and are not simply an artifact caused by brain atrophy. The different patterns of hypometabolism indicate the differential development of the lesions between the AD and AD + VS groups.