Alzheimer Disease: Dekosky ST

Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. · INSERM U610, Hôpital de la Salpêtrière, Paris, France. · Lancet Neurol. · Pubmed #17616482 No free full text.

Abstract: The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.

Ikonomovic MD, Abrahamson EE, Isanski BA, Debnath ML, Mathis CA, Dekosky ST, Klunk WE. · Department of Neurology and Psychiatry, University of Pittsburgh, Pennsylvania 15213, USA. · Methods Enzymol. · Pubmed #17046656 No free full text.

Abstract: Postmortem pathological diagnosis and basic research investigations of neurodegenerative disorders rely on histochemical staining procedures developed specifically to visualize abnormal protein conformation. In Alzheimer's disease (AD), two major pathological hallmarks are required to confirm the clinical diagnosis. Both consist of abnormally aggregated proteins that share the structural and histological properties common to all amyloid deposits. Amyloid-beta peptide (Abeta) of extracellular senile plaques (SP) and hyperphosphorylated tau of intracellular neurofibrillary tangles (NFT) are assembled in the abnormal beta-pleated sheet (amyloid-like) structural conformation that can be visualized with histological staining procedures using Congo red or its derivatives. These histochemical dyes bind amyloid with high affinity and allow easy detection of amyloid structure in postmortem brain samples. This chapter focuses on the development and application of a histological protocol using the compound X-34, a highly fluorescent derivative of Congo red, for sensitive detection of pathological amyloid structures in histopathological investigations of postmortem brain tissue. This procedure provides a simple and effective method for detailed fluorescent visualization of the localization and distribution of the majority of currently known major histopathological structures in AD, including compact cored, neuritic, and diffuse-appearing SP, NFT, dystrophic neurites, neuropil threads, and cerebrovascular amyloidosis.

Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, Lopresti BJ, Koeppe RA, Meltzer CC, Constantine G, Davis JG, Mathis CA, Dekosky ST, Moore RY. · University of Pittsburgh, Liliane S Kaufmann Building, Suite 811, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #15716518 links to  free full text

Abstract: OBJECTIVES: To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer's disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy. METHODS: Cognitive and N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy. RESULTS: Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = -7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = -14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R(2) = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = -2.7; p<0.05). CONCLUSIONS: Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.

Ikonomovic MD, Wecker L, Abrahamson EE, Wuu J, Counts SE, Ginsberg SD, Mufson EJ, Dekosky ST. · Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. · Arch Neurol. · Pubmed #19433665 No free full text.

Abstract: OBJECTIVE: To examine alpha7 nicotinic acetylcholine receptor (nAChR) binding and beta-amyloid (Abeta) peptide load in superior frontal cortex (SFC) across clinical and neuropathological stages of Alzheimer disease (AD). DESIGN: Quantitative measures of alpha7 nAChR by [(3)H]methyllycaconitine binding and Abeta concentration by enzyme-linked immunosorbent assay in SFC were compared across subjects with antemortem clinical classification of no cognitive impairment, mild cognitive impairment, or mild to moderate AD, and with postmortem neuropathological diagnoses. SETTING: Academic medical center. Subjects Twenty-nine elderly retired clergy. MAIN OUTCOME MEASURES: Quantitative measures of alpha7 nAChR binding and Abeta peptide concentration in SFC. RESULTS: Higher concentrations of total Abeta peptide in SFC were associated with clinical diagnosis of mild to moderate AD (P = .02), lower Mini-Mental State Examination scores (P = .003), presence of cortical Abeta plaques (P = .02), and likelihood of AD diagnosis by the National Institute on Aging-Reagan criteria (P = .002). Increased alpha7 nAChR binding was associated with National Institute on Aging-Reagan diagnosis (P = .02) and, albeit weakly, the presence of cortical Abeta plaques (P = .08). There was no correlation between the 2 biochemical measures. CONCLUSIONS: These observations suggest that during the clinical progression from normal cognition to neurodegenerative disease state, total Abeta peptide concentration increases while alpha7 nAChRs remain relatively stable in SFC. Regardless of subjects' clinical status, however, elevated alpha7 nAChR binding is associated with increased Abeta plaque pathology, supporting the hypothesis that cellular expression of these receptors may be upregulated selectively in Abeta plaque-burdened brain areas.

Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, Klunk W, Dekosky ST. · Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #19204022 No free full text.

Abstract: BACKGROUND: Patients using cholinesterase inhibitors (ChEIs) have a delay in nursing home (NH) admission compared with those who were not using the medication. There are no long-term studies of the effects of memantine in combination with ChEIs use in Alzheimer disease (AD). This study was conducted to examine the effects of ChEIs and memantine on time to death and time to NH admission. METHODS: Time to NH admission and death was examined in 943 probable AD patients who had at least a 1-year follow-up evaluation. Of these patients, 140 (14.9%) used both ChEIs and memantine, 387 (45.0%) used only ChEIs, and 416 (40.1%) used neither. The mean (SD) follow-up time was 62.3 (35.8) months. The analysis was conducted with multivariable Cox proportional hazard models controlling for critical covariates (ie, age, education level, gender, severity of the dementia, hypertension, diabetes mellitus, heart disease, psychiatric symptoms and use of psychotropic medications). RESULTS: Compared with those who never used cognitive enhancers, patients who used ChEIs had a significant delay in NH admission (HR: 0.37, 95% CI 0.27 to 0.49); this effect was significantly augmented with the addition of memantine (HR: 0.29, 95% CI 0.11 to 0.72) (memantine+ChEI vs ChEI alone). ChEIs alone, or in combination with memantine had no significant association on time to death. CONCLUSIONS: This observational study revealed that the addition of the NMDA receptor antagonist memantine to the treatment of AD with ChEI significantly altered the treated history of AD by extending time to nursing home admission.

Weamer EA, Emanuel JE, Varon D, Miyahara S, Wilkosz PA, Lopez OL, Dekosky ST, Sweet RA. · Department of Psychiatry, University of Pittsburgh, Pittsburgh, USA. · Int Psychogeriatr. · Pubmed #18814807 links to  free full text

Abstract: BACKGROUND: Psychotic symptoms in Alzheimer disease (AD + P) identify a heritable phenotype associated with greater cognitive impairment. Knowing when the cognitive course of AD + P subjects diverges from that of subjects without psychosis would enhance understanding of how genetic variation results in AD + P and its associated cognitive burden. This study seeks to determine whether the degree of cognitive impairment and cognitive decline in early AD predicts subsequent AD + P onset. METHODS: 361 subjects with possible or probable AD or mild cognitive impairment (MCI) without psychosis were evaluated every 6 months until psychosis onset. RESULTS: Severity of cognitive dysfunction was a strong predictor of AD + P up to two years prior to psychosis onset. Cognition did not decline more rapidly prior to onset of AD + P. CONCLUSIONS: Individuals who will develop AD + P already demonstrate excess cognitive impairment during the mild stages of disease. Genetic variation and brain pathophysiology may lead to a cognitive risk phenotype which is present prior to dementia onset.

Ikonomovic MD, Abrahamson EE, Uz T, Manev H, Dekosky ST. · Department of Neurology, University of Pittsburgh School of Medicine, BSTWR S-521, Pittsburgh, PA 15261, USA. · J Histochem Cytochem. · Pubmed #18678882 No free full text.

Abstract: The proinflammatory enzyme 5-lipoxygenase (5-LOX) is upregulated in Alzheimer's disease (AD), but its localization and association with the hallmark lesions of the disease, beta-amyloid (Abeta) plaques and neurofibrillary tangles (NFTs), is unknown. This study examined the distribution and cellular localization of 5-LOX in the medial temporal lobe from AD and control subjects. The spatial relationship between 5-LOX immunoreactive structures and AD lesions was also examined. We report that, in AD subjects, 5-LOX immunoreactivity is elevated relative to controls, and its localization is dependent on the antibody-targeted portion of the 5-LOX amino acid sequence. Carboxy terminus-directed antibodies detected 5-LOX in glial cells and neurons, but less frequently in neurons with dystrophic (NFT) morphology. In contrast, immunoreactivity observed using 5-LOX amino terminus-directed antibodies was virtually absent in neurons and abundant in NFTs, neuritic plaques, and glia. Double-labeling studies showed a close association of 5-LOX-immunoreactive processes and glial cells with Abeta immunoreactive plaques and vasculature and also detected 5-LOX in tau immunoreactive and amyloid containing NFTs. Different immunolabeling patterns with antibodies against carboxy vs amino terminus of 5-LOX may be caused by post-translational modifications of 5-LOX protein in Abeta plaques and NFTs. The relationship between elevated intracellular 5-LOX and hallmark AD pathological lesions provides further evidence that neuroinflammatory pathways contribute to the pathogenesis of AD.

Lingler JH, Hirschman KB, Garand L, Dew MA, Becker JT, Schulz R, Dekosky ST. · Department of Health and Community Systems, University of Pittsburgh, Pittsburgh, PA, USA. · Am J Geriatr Psychiatry. · Pubmed #18669942 No free full text.

Abstract: OBJECTIVE: To examine the prevalence and sociodemographic correlates of written advance planning among patients with or at risk for dementia-imposed decisional incapacity. DESIGN: Retrospective, cross-sectional. SETTING: University-based memory disorders clinic. PARTICIPANTS: Persons with a consensus-based diagnosis of mild cognitive impairment (N = 112), probable or possible Alzheimer disease (AD; N = 549), and nondemented comparison subjects (N = 84). INTERVENTION: N/A. MEASUREMENTS: Semistructured interviews to assess durable power of attorney (DPOA) and living will (LW) status upon initial presentation for a dementia evaluation. RESULTS: Sixty-five percent of participants had a DPOA and 56% had a LW. Planning rates did not vary by diagnosis. European Americans (adjusted odds ratio = 4.75; 95% CI, 2.40-9.38), older adults (adjusted odds ratio = 1.05; 95% CI, 1.03-1.07) and college graduates (adjusted odds ratio = 2.06; 95% CI, 1.33-3.20) were most likely to have a DPOA. Findings were similar for LW rates. CONCLUSIONS: Although a majority of persons with and at risk for the sustained and progressive decisional incapacity of AD are formally planning for the future, a substantial minority are not.

Wolk DA, Signoff ED, Dekosky ST. · Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA 15213-2582, USA. · Neuropsychologia. · Pubmed #18328509 links to  free full text

Abstract: Despite memory failures being a central feature of amnestic mild cognitive impairment (a-MCI), there is limited research into the nature of the memory impairment associated with this condition. A further understanding could lead to refinement of criteria needed to qualify for this designation and aid in prediction of who will progress to development of clinical Alzheimer's disease. Dual process models posit that recognition memory is supported by the dissociable processes of recollection and familiarity. The present study sought to evaluate recognition memory in a-MCI in the framework of the dual process model. Patients with a-MCI and age- and education-matched controls were tested on three memory paradigms. Two paradigms were modifications of the process-dissociation procedure in which recollection required either memory of word-pair associations (associative) or the font color of words at study (featural). A final paradigm utilized the task-dissociation methodology comparing performance for item and visual spatial source memory. All three tasks revealed that familiarity was impaired to at least the same extent as recollection. As familiarity is thought to be spared in normal aging, its measurement may provide a relatively specific marker for the early pathological changes of Alzheimer's disease.

Johnson KA, Gregas M, Becker JA, Kinnecom C, Salat DH, Moran EK, Smith EE, Rosand J, Rentz DM, Klunk WE, Mathis CA, Price JC, Dekosky ST, Fischman AJ, Greenberg SM. · Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA. · Ann Neurol. · Pubmed #17683091 No free full text.

Abstract: OBJECTIVE: Cerebrovascular deposition of beta-amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the beta-amyloid-binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes. METHODS: We compared specific cortical PiB retention in 6 nondemented subjects diagnosed with probable CAA with 15 healthy control subjects and 9 patients with probable Alzheimer's disease (AD). RESULTS: All CAA and AD subjects were PiB-positive, both by distribution volume ratio measurements and by visual inspection of positron emission tomographic images. Global cortical PiB retention was significantly increased in CAA (distribution volume ratio 1.18 +/- 0.06) relative to healthy control subjects (1.04 +/- 0.10; p = 0.0009), but was lower in CAA than in AD subjects (1.41 +/- 0.17; p = 0.002). The occipital-to-global PiB ratio, however, was significantly greater in CAA than in AD subjects (0.99 +/- 0.07 vs 0.86 +/- 0.05; p = 0.003). INTERPRETATION: We conclude that PiB-positron emission tomography can detect cerebrovascular beta-amyloid and may serve as a method for identifying the extent of CAA in living subjects.

McIntyre JA, Chapman J, Shavit E, Hamilton RL, Dekosky ST. · HLA-Vascular Biology Laboratory, St Francis Hospital and Health Care Centers, Beech Grove, IN 46107, USA. · Autoimmunity. · Pubmed #17612901 No free full text.

Abstract: Oxidation of cerebrospinal fluid (CSF) causes differential unmasking of autoantibodies in control CSF vs. that obtained from postmortem CSF samples from autopsy confirmed Alzheimer's disease (AD) cases. This study demonstrates that normal CSF from both living patients and from non-demented autopsy cases contains redox-reactive autoantibodies with specificities that include antiphospholipid antibodies (aPL). In contrast, CSF from autopsy confirmed AD subjects contained little or no redox-reactive aPL autoantibodies. Tests using an in vitro rat synaptosome model showed that the oxidized CSF autoantibodies from a normal individual can cause ERK1/2 phosphorylation at a level consistent with reports of pathogenic changes found in brain tissues from AD patients. The decrease or absence of redox-reactive antibodies in CSF from Alzheimer's patients suggests that these antibodies may have been previously unmasked by the oxidative conditions that exist in the CNS in AD patients. These unmasked autoantibodies could then bind to neuronal tissues and possibly participate in the initial cascade leading to the dementia in Alzheimer's. To our knowledge, this is the first description of resident autoantibodies with the potential to cause brain cell damage documented in CSF without a breech in the blood-brain barrier. The untimely and inappropriate physiological unmasking of these redox-reactive autoantibodies in AD patients CSF may represent a valuable biomarker for diagnosis and progression of this and perhaps other neurodegenerative diseases which also have oxidative stress components. These novel autoantibody observations may stimulate thoughts about additional therapeutic approaches and warrant similar studies for other neurodegenerative diseases.

Lopez OL, Kuller LH, Becker JT, Dulberg C, Sweet RA, Gach HM, Dekosky ST. · Departments of Neurology and Psychiatry, University of Pittsburgh School of Medicine, 3501 Forbes Ave, Suite 830, Oxford Bldg, Pittsburgh, PA 15213-3323, USA. · Arch Neurol. · Pubmed #17353386 links to  free full text

Abstract: OBJECTIVES: To examine the incidence of dementia in subjects with mild cognitive impairment (MCI) in the Cardiovascular Health Study Cognition Study. DESIGN: Prospective epidemiological study. SETTING: The Cardiovascular Health Study Cognition Study of Pittsburgh, Pa, was conducted from 2002 through 2003 to determine the incidence of dementia in participants classified as having MCI in 1998 and 1999. Subjects There were 136 subjects with MCI. Mild cognitive impairment was subclassified as MCI amnestic type and MCI multiple cognitive deficits type (MCI-MCDT); subjects with MCI-MCDT were also grouped based on the presence of a memory impairment. Subjects with MCI were classified as possible when there were comorbidities that could explain the subjects' cognitive deficits and as probable when there were none. Main Outcome Measure Dementia. RESULTS: The incidence of all dementias in the subjects with MCI was 147 per 1000 person-years (mean follow-up overall, 4.3 years). Of the 136 subjects with MCI, 69 (51%) in 1998 through 1999 progressed to dementia (57 [83%] to Alzheimer disease [AD]), but 25 (18%) returned to normal. Of the 10 subjects with probable MCI amnestic type, 7 (70%) progressed to dementia (all of them to AD) and none returned to normal, whereas 7 (41%) of the 17 subjects with possible MCI amnestic type became demented (6 [86%] to AD) and 3 (18%) returned to normal. Of the 40 subjects with probable MCI-MCDT, 21 (52%) progressed to dementia (17 [81%] to AD) and 2 (5%) returned to normal. Of the 69 subjects with possible MCI-MCDT, 34 (49%) progressed to dementia (28 [82%] to AD) and 20 (29%) returned to normal. Among the subjects with probable MCI-MCDT, 15 (54%) of 28 with and 6 (50%) of 12 without memory deficits progressed to dementia. CONCLUSIONS: Subjects with MCI are at high risk for dementia. The probable MCI diagnosis identified individuals in the earliest stages of dementia, usually AD, whereas the possible MCI diagnosis identified a more heterogeneous group. However, this latter group had only a slightly lower rate of conversion to dementia than the group with probable MCI, suggesting that even with comorbid conditions, there is a high likelihood of the presence of a progressive dementing disorder.

Wilkosz PA, Miyahara S, Lopez OL, Dekosky ST, Sweet RA. · Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Am J Geriatr Psychiatry. · Pubmed #16582044 No free full text.

Abstract: BACKGROUND: Psychotic symptoms in Alzheimer disease (AD+P) identify a heritable phenotype associated with more rapid cognitive decline. The authors have proposed that AD+P is itself a composite of a misidentification and a paranoid subtype with increased cognitive impairment restricted to the misidentification type. Most prior studies of the clinical correlates of AD+P have been limited, however, by the inclusion of prevalent cases. METHODS: Subjects with possible or probable AD or mild cognitive impairment (MCI) without psychosis at study entry were assessed at the time of initial presentation and then annually. Psychotic symptoms were assessed using the CERAD Behavioral Rating Scale. Survival analyses used Cox proportional hazard models with time-dependent covariates to examine the predictors of psychosis onset. RESULTS: A total of 288 subjects completed at least one follow-up examination. Mean duration of follow-up was 22.1 months. The incidence of psychosis was 0.19 per person-year. Cognitive impairment was associated with onset of psychosis, largely as a result of its association with onset of the misidentification, but not the paranoid, subtype. Including psychotropic medication use in the model revealed an association of antidepressant use with the onset of psychosis. This latter association appeared to arise from an underlying association between depression and the risk of psychosis onset rather than from antidepressant treatment. CONCLUSION: These findings are consistent with the hypothesis that the misidentification and the paranoid subtypes each define a more biologically homogeneous group than AD+P as a whole. Further exploration of the relationship between depressive symptoms and psychosis in patients with AD is warranted.

Counts SE, Chen EY, Che S, Ikonomovic MD, Wuu J, Ginsberg SD, Dekosky ST, Mufson EJ. · Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Dement Geriatr Cogn Disord. · Pubmed #16410678 No free full text.

Abstract: Galanin (GAL)-containing fibers enlarge and hyperinnervate remaining cholinergic basal forebrain (CBF) neurons within the anterior nucleus basalis (NB) in late-stage Alzheimer's disease (AD). Whether GAL hypertrophy occurs in the CBF in the prodromal or early stages of AD remains unknown. The present study used GAL immunohistochemistry and an unbiased semiquantitative scoring method to evaluate GAL innervation in the anterior NB of subjects clinically diagnosed as having no cognitive impairment, mild cognitive impairment or early-stage (mild/moderate) AD. There was no difference in GAL fiber staining within the anterior NB across the three clinical groups examined. Furthermore, GAL fiber innervation was not correlated with the number of NB neurons expressing the nerve growth factor receptors p75(NTR) or TrkA or with cortical choline acetyltransferase activity in the same cases. Single-cell gene expression analysis demonstrated that cholinergic NB neurons express mRNA for the GAL receptors GALR1, GALR2 and GALR3, yet the levels of these mRNAs were unchanged across the three diagnostic groups. These observations indicate that GAL hypertrophy within the anterior NB subfield is a late-stage AD response, which may play a role in regulating the cholinergic tone of remaining basocortical projection neurons.

Bell-McGinty S, Lopez OL, Meltzer CC, Scanlon JM, Whyte EM, Dekosky ST, Becker JT. · Department of Psychiatry, University of Pittsburgh Medical Center, PA, USA. · Arch Neurol. · Pubmed #16157746 links to  free full text

Abstract: OBJECTIVE: To compare gray matter brain volumes in patients diagnosed with subtypes of mild cognitive impairment (MCI) (those with a focal amnestic disorder and those with more diffuse cognitive dysfunction) with those of elderly controls. DESIGN: Magnetic resonance imaging volumetric study of MCI subgroups (MCI-amnestic [MCI-A], and MCI-multiple cognitive domain [MCI-MCD]) using a whole brain voxel-based analysis. SETTING: Referral dementia clinic.Patients Thirty-seven patients with MCI (age range, 49-85 years; MCI-A, n = 9; MCI-MCD, n = 28) and 47 control subjects (age range, 55-81 years). MAIN OUTCOME MEASURES: Volumetric anatomical magnetic resonance imaging differences between MCI subgroups and normal controls, and between patients with MCI who progressed to dementia. Magnetic resonance imaging scans were analyzed using statistical software SPM99. RESULTS: Overall, the patients with MCI had significantly decreased volume in the hippocampus and middle temporal gyrus, bilaterally, compared with control subjects. Compared with patients with MCI-MCD, patients with MCI-A had significant volume loss of the left entorhinal cortex and inferior parietal lobe. Compared with patients with MCI-A, patients with MCI-MCD had significantly reduced volume of the right inferior frontal gyrus, right middle temporal gyrus, and bilateral superior temporal gyrus. Patients with MCI who progressed to Alzheimer disease during follow-up (mean interval 2 years, maximum 4.5 years), showed greater atrophy in the left entorhinal cortex, bilateral superior temporal gyri, and right inferior frontal gyrus compared with those who did not progress. CONCLUSIONS: These data provide evidence of distinct brain structural abnormalities in 2 groups of patients with MCI. While both have mesial temporal and cortical volume loss, those with a focal memory deficit have more involvement of the mesial temporal structures and less involvement of the neocortical heteromodal association areas than those patients with MCI with diffuse cognitive dysfunction. Thus, MCI may represent a more heterogeneous group than currently conceived, possibly reflecting 2 different etiological processes to dementia. These data also suggest that these structural abnormalities precede the development of Alzheimer disease.

Newman AB, Fitzpatrick AL, Lopez O, Jackson S, Lyketsos C, Jagust W, Ives D, Dekosky ST, Kuller LH. · Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. · J Am Geriatr Soc. · Pubmed #16108925 No free full text.

Abstract: OBJECTIVES: To determine whether coronary artery disease, peripheral arterial disease (PAD), or noninvasive markers of cardiovascular disease (CVD) predict the onset of dementia and Alzheimer's disease (AD). DESIGN: Longitudinal cohort study. SETTING: Four U.S. communities. PARTICIPANTS: Men and women (N=3,602) with a brain magnetic resonance imaging (MRI) scan but no dementia were followed for 5.4 years. Participants with stroke were excluded. MEASUREMENTS: Neurologists and psychiatrists classified incident cases of dementia and subtype using neuropsychological tests, examination, medical records and informant interviews. CVD was defined at the time of the MRI scan. Noninvasive tests of CVD were assessed within 1 year of the MRI. Apolipoprotein E allele status, age, race, sex, education, Mini-Mental State Examination score, and income were assessed as potential confounders. RESULTS: The incidence of dementia was higher in those with prevalent CVD, particularly in the subgroup with PAD. The rate of AD was 34.4 per 1,000 person-years for those with a history of CVD, versus 22.2 per 1,000 person-years without a history of CVD (adjusted hazard ratio (HR)=1.3, 95% confidence interval (CI)=1.0-1.7). Rates of AD were highest in those with PAD (57.4 vs 23.7 per 100 person-years, adjusted HR=2.4, 95% CI=1.4-4.2). Results were similar with further exclusion of those with vascular dementia from the AD group. A gradient of increasing risk was noted with the extent of vascular disease. CONCLUSION: Older adults with CVD other than stroke had a higher risk of dementia and AD than did those without CVD. The risk was highest in people with PAD, suggesting that extensive peripheral atherosclerosis is a risk factor for AD.

Mizukami K, Ishikawa M, Iwakiri M, Ikonomovic MD, Dekosky ST, Kamma H, Asada T. · Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki 305-8575, Japan. · Neurosci Lett. · Pubmed #15993539 No free full text.

Abstract: To elucidate the post-transcriptional regulation in the subjects with Alzheimer's disease (AD), we employed immunohistochemical techniques and examined the expression of the heterogeneous nuclear ribonucleoprotein (hnRNP) A2 and B1 in the hippocampus with neurofibrillary tangle (NFT) neuropathology. In the mildly affected subjects (Braak stages I and II), the most intense A2 immunoreactivity was observed in the CA3 to CA1 neurons. In the moderately (Braak stages III and IV) and severely affected subjects (Braak stages V and VI), the CA1 region demonstrated a decrease in the number of A2 immunoreactive neurons and in immunoreactivity in the remaining neurons, while within the CA4 to CA2 in the severely affected subjects, the majority of neurons showed increased A2 immunoreactivity. An intense B1 immunoreactivity was observed throughout the CA subfields. In the CA1 subfield of the moderately affected subjects and in the extensive hippocampal regions of the severely affected subjects, a decrease in B1 immunoreactivity was observed. Double-immunolabeling studies demonstrated that tangle-bearing neurons reduced A2 and B1 immunoreactivity. Our study suggests that hnRNP A2 and B1 display different responses in the AD hippocampus, and further suggests that the post-transcriptional regulation is disturbed in neurons of the AD hippocampus.

Eror EA, Lopez OL, Dekosky ST, Sweet RA. · Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. · Biol Psychiatry. · Pubmed #15978552 No free full text.

Abstract: BACKGROUND: Recent findings have demonstrated the familiality of psychotic symptoms occurring during Alzheimer disease (AD with psychosis, AD+P), particularly for subjects with multiple psychotic symptoms. We have proposed a model in which genes that confer a small risk for psychosis interact with neurodegenerative illness to yield manifest psychotic symptoms during AD. One prediction of this model would be that AD+P subjects would have evidence of increased degrees of subsyndromal psychosis before AD onset. METHODS: We used the psychosis (positive symptoms) and psychotic personality disorder sections (paranoid, schizoid, and schizotypal) of the Family Interview for Genetic Studies (FIGS) to interview the primary caregivers of AD subjects. Caregivers were specifically instructed to answer questions with regard to the subject's behavior before AD onset. Interviewers were blind to presence of psychosis during AD. Subjects were grouped by whether they had at least one or had multiple psychotic symptoms during AD. RESULTS: Scores on the FIGS subscales were generally low, reflecting a low frequency of endorsement of psychotic symptoms before AD. There was a trend for the schizotypal scores to be elevated in the AD+P group, which was highly significant in the AD+P group with multiple psychotic symptoms. There was no significant association of paranoid or schizoid scores with either group. CONCLUSIONS: Although limited by small sample size and retrospective design, these data are novel in that they indicate an association of subsyndromal psychotic symptoms before AD onset with psychosis in AD. Subsyndromal psychosis might be useful for classifying AD+P families for genetic mapping studies. Prospective confirmation is required.

Ozturk A, Desai PP, Minster RL, Dekosky ST, Kamboh MI. · Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA 15261, USA. · Neurobiol Aging. · Pubmed #15917099 No free full text.

Abstract: Linkage studies suggest the presence of putative risk and/or age-at-onset genes for Alzheimer's disease on Chromosome 10. Recently, a genomic converging approach using a combination of linkage, expression and association studies has reported significant associations of the glutathione S-transferase omega 1 and 2 (GSTO1 and GSTO2) genes and possibly the protease serine 11 (PRSS11) gene on chromosome 10 with age-at-onset, but not risk, for Alzheimer's disease (AD) and Parkinson disease. We investigated the association of the reported three polymorphisms in 990 sporadic late-onset AD cases (26% autopsy confirmed) and 735 controls. In our sample, we found no association either with age-at-onset in AD cases or with disease risk in the case-control cohort. However, haplotype analysis revealed a modest association of one haplotype with AD risk (p = 0.04). Additional markers in these genes need to be screened to explore their role in the etiology of AD.

Ishikawa M, Mizukami K, Iwakiri M, Kamma H, Ikonomovic MD, Dekosky ST, Asada T. · Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba city, Ibaraki 305-8575, Japan. · Neurosci Res. · Pubmed #15567486 No free full text.

Abstract: In order to examine the post-transcriptional regulations in Alzheimer's disease, we employed immunohistochemical techniques and examined the expression of heterogeneous nuclear ribonucleoprotein (hnRNP) B1 in the inferior temporal cortex of subjects with Alzheimer's disease. In the mild cases, intense B1 immunoreactivity was observed in neurons of layer V, and less intense immunoreactivity was observed in layers II and III. The overall distributions and intensities of B1 immunoreactivity were undistinguishable among mild, moderate, and severe cases. Double-immunolabeling with MC1 and B1 demonstrated that B1 immunoreactivity was preserved in the majority of neurofibrillary tangle (NFT)-bearing neurons. Our study suggests that hnRNP B1-associated post-transcriptional regulations are preserved in the inferior temporal cortex of Alzheimer's disease.