Alzheimer Disease: Lopez OL

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Becker JT, Tárraga Mestre L, Mestre LT, Ziolko S, Lopez OL. · No affiliation provided · Am J Psychiatry. · Pubmed #17541039 links to  free full text

This publication has no abstract.

Kuller LH, Lopez OL. · Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. · Alzheimers Dement. · Pubmed #18632006 No free full text.

Abstract: One of Dr Leon Thal's major contributions to Alzheimer's disease (AD) research was the network of clinical trials and his strong commitment to finding effective therapies for both the prevention and treatment of AD in the population. AD and dementia research has matured since the inception of the Alzheimer's Disease Center program from a primary social service problem to clinical-pathologic correlates and better definition of disease to evaluation of measures of cognition, in vivo images of the brain, and then to measures of beta amyloid and tau in vivo and relationship to clinical dementia. Unfortunately, we still do not know the etiology of AD or the relationship to other brain abnormalities such as vascular disease and Lewy bodies. We also do not have good preventive or treatment strategies. Both are badly needed. The critical question is whether this field is ready for a major change in focus from primarily a descriptive science to analytical, longitudinal studies testing new research hypotheses that will lead to better preventive and treatment approaches.

Thompson PM, Hayashi KM, Dutton RA, Chiang MC, Leow AD, Sowell ER, De Zubicaray G, Becker JT, Lopez OL, Aizenstein HJ, Toga AW. · Department of Neurology, Laboratory of Neuro Imaging, UCLA School of Medicine, 635 Charles E. Young Drive South, Suite 225E, Los Angeles, CA 90095-7332, USA. · Ann N Y Acad Sci. · Pubmed #17413023 No free full text.

Abstract: Population-based brain mapping provides great insight into the trajectory of aging and dementia, as well as brain changes that normally occur over the human life span. We describe three novel brain mapping techniques, cortical thickness mapping, tensor-based morphometry (TBM), and hippocampal surface modeling, which offer enormous power for measuring disease progression in drug trials, and shed light on the neuroscience of brain degeneration in Alzheimer's disease (AD) and mild cognitive impairment (MCI). We report the first time-lapse maps of cortical atrophy spreading dynamically in the living brain, based on averaging data from populations of subjects with Alzheimer's disease and normal subjects imaged longitudinally with MRI. These dynamic sequences show a rapidly advancing wave of cortical atrophy sweeping from limbic and temporal cortices into higher-order association and ultimately primary sensorimotor areas, in a pattern that correlates with cognitive decline. A complementary technique, TBM, reveals the 3D profile of atrophic rates, at each point in the brain. A third technique, hippocampal surface modeling, plots the profile of shape alterations across the hippocampal surface. The three techniques provide moderate to highly automated analyses of images, have been validated on hundreds of scans, and are sensitive to clinically relevant changes in individual patients and groups undergoing different drug treatments. We compare time-lapse maps of AD, MCI, and other dementias, correlate these changes with cognition, and relate them to similar time-lapse maps of childhood development, schizophrenia, and HIV-associated brain degeneration. Strengths and weaknesses of these different imaging measures for basic neuroscience and drug trials are discussed.

Perez-Madriñan G, Cook SE, Saxton JA, Miyahara S, Lopez OL, Kaufer DI, Aizenstein HJ, DeKosky ST, Sweet RA. · Dept. of Psychiatry, Univ. of Pittsburgh, PA, USA. · Am J Geriatr Psychiatry. · Pubmed #15353383 No free full text.

Abstract: OBJECTIVE: Psychotic symptoms occur in 30%-60% of individuals with Alzheimer disease (AD) with psychosis (AD+P). AD+P identifies a distinct AD phenotype, with increased severity of cognitive impairment and a more rapid cognitive decline. Using factor and cluster analysis, we previously proposed two subtypes of patients with AD+P, one characterized by misidentifications and hallucinations (Misidentification), the other by persecutory delusions (Paranoid). We hypothesized that these two groups differed in their patterns of cognitive impairment, compared with AD subjects without psychosis. METHODS: Subjects (N=119) with possible or probable AD were assessed with a comprehensive neuropsychological test battery at the time of initial presentation. Psychotic symptoms were ascertained with the CERAD Behavioral Rating Scale. Cognitive test scores were compared among groups by use of general linear-regression models, with age, education, and duration of illness entered as covariates. All results were corrected for multiple comparisons. RESULTS: The Misidentification group was significantly more impaired than the Non-Psychotic group on tests of verbal fluency and visuospatial function. The Paranoid group did not differ from the Non-Psychotic group on any test. CONCLUSIONS: These results support the identification of the Misidentification and Paranoid groups as distinct subgroups of AD+P. The ability to detect meaningful biologic associations of AD+P in future studies would be enhanced by separate analysis of the Misidentification and Paranoid phenotypes.

McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, Dickson D, Dubois B, Duda JE, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez OL, Carlos Machado J, O'Brien J, Playfer J, Reid W, Anonymous00116. · Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne, UK. · Lancet Neurol. · Pubmed #14693108 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

Lopez OL, Becker JT, Kaufer DI, Hamilton RL, Sweet RA, Klunk W, DeKosky ST. · Alzheimer's Disease Research Center, University of Pittsburgh, Pa, USA. · Arch Neurol. · Pubmed #11790229 links to  free full text

Abstract: OBJECTIVE: To evaluate the relative merits of recently developed criteria for dementia with Lewy bodies (DLBs) in a longitudinal study of dementia. DESIGN: The diagnosis of DLBs was used in combination with other clinical diagnosis. Patients were classified primarily based on the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) clinical criteria for probable or possible Alzheimer disease, or with other disease process that can cause dementia (eg, Parkinson disease), and secondarily according to the consensus guidelines for DLBs. This "double" clinical diagnosis was implemented to capture different pathological entities. The neuropathological diagnosis of Lewy bodies was made with monoclonal antibodies against alpha-synuclein. SETTING: Multidisciplinary research clinic. RESULTS: Prospective application of the consensus guidelines for DLBs from January 1, 1997, to September 29, 2000, identified 11 patients having the diagnosis of probable DLBs and 35 having possible DLBs. The diagnosis of probable or possible DLBs was associated with probable Alzheimer disease in 34 patients, with possible Alzheimer disease in 5 patients, with Parkinson disease in 2 patients, and with other disease processes in 2 patients. Three patients were diagnosed as having probable DLBs alone. An autopsy was performed in 26 of the cases who were clinically examined during the study period. Cortical Lewy bodies were identified in 13 cases; 4 had had premortem diagnosis of DLBs (sensitivity, 30.7%; specificity, 100%). CONCLUSIONS: The prospective validation of the clinical criteria for DLBs showed poor accuracy in this series. We believe that current criteria for DLBs are useful when DLBs occur in isolation, but have low sensitivity when Lewy bodies coexist with the pathological abnormalities of Alzheimer disease.

Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, Lopez OL, DeKosky ST. · Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania, USA. · J Neuropsychiatry Clin Neurosci. · Pubmed #11001602 links to  free full text

Abstract: The Neuropsychiatric Inventory (NPI) is a validated clinical instrument for evaluating psychopathology in dementia. The authors developed a brief questionnaire form of the NPI (NPI-Q), intended for use in routine clinical practice, and cross-validated it with the NPI in 60 Alzheimer's patients. Test-retest reliability of the NPI-Q was acceptable. The prevalence of analogous symptoms reported on the NPI and NPI-Q differed on average by 5%; moderate or severe symptom ratings differed by less than 2%. The NPI-Q provides a brief, reliable, informant-based assessment of neuropsychiatric symptoms and associated caregiver distress that may be suitable for use in general clinical practice.

Fitzpatrick AL, Kuller LH, Lopez OL, Diehr P, O'Meara ES, Longstreth WT, Luchsinger JA. · Department of Epidemiology, University of Washington, Collaborative Health Studies Coordinating Center, Seattle, 98115, USA. · Arch Neurol. · Pubmed #19273752 No free full text.

Abstract: BACKGROUND: While high adiposity in middle age appears to be related to greater dementia risk, studies exploring this association in the elderly are conflicting. OBJECTIVE: To evaluate associations between midlife and late-life obesity and risk of dementia. DESIGN: Prospective study with mean follow-up of 5.4 years (1992-1994 through 1999). SETTING: Community-dwelling sample in 4 US sites recruited from Medicare eligibility files. PARTICIPANTS: A total of 2798 adults without dementia (mean age, 74.7 years; 59.1% women) participating in the Cardiovascular Health Study who underwent magnetic resonance imaging were measured for height and weight at baseline at age 65 years or older (late life), and self-reported weight at age 50 years (midlife). Body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) was calculated at both times. MAIN OUTCOME MEASURES: Dementia, Alzheimer disease, and vascular dementia classified by a multidisciplinary committee using standardized criteria. RESULTS: Classification resulted in 480 persons with incident dementia, 245 with Alzheimer disease (no vascular dementia), and 213 with vascular dementia (with or without Alzheimer disease). In evaluations of midlife obesity, an increased risk of dementia was found for obese (BMI >30) vs normal-weight (BMI 20-25) persons, adjusted for demographics (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.03-1.87) and for cardiovascular risk factors (1.36; 0.94-1.95). The risk estimates were reversed in assessments of late-life BMI. Underweight persons (BMI <20) had an increased risk of dementia (1.62; 1.02-2.64), whereas being overweight (BMI >25-30) was not associated (0.92; 0.72-1.18) and being obese reduced the risk of dementia (0.63; 0.44-0.91) compared with those with normal BMI. CONCLUSION: These results help explain the "obesity paradox" as differences in dementia risk across time are consistent with physical changes in the trajectory toward disability.

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.

Dai W, Lopez OL, Carmichael OT, Becker JT, Kuller LH, Gach HM. · Department of Radiology, Harvard Medical School, Boston, Mass, USA. · Radiology. · Pubmed #19164119 links to  free full text

Abstract: PURPOSE: To examine regional cerebral blood flow (rCBF) in incident mild cognitive impairment (MCI) and Alzheimer disease (AD) by using continuous arterial spin-labeling (CASL) magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was approved by the local institutional review board and was compliant with HIPAA regulations. Informed consent was obtained. rCBF was measured in 38 control subjects, 29 MCI patients, and 37 AD patients who were participating in a longitudinal epidemiologic study. Multisection CASL MR imaging with alternating single and double adiabatic inversion pulses and ramp-sampled echo-planar imaging were performed to acquire 19 contiguous axial sections. Voxel-level rCBF was compared among groups by using an analysis of variance design; clusters of voxels with significant group differences were identified. Multiple regression models controlled for age, sex, and presence of hypertension and related the mean rCBF in those clusters to the presence of MCI and AD. RESULTS: MCI and AD patients had decreased rCBF in the posterior cingulate gyrus (P = .01) with extension to the medial precuneus compared with that in control subjects. MCI patients had increased rCBF in the left hippocampus (P < .001), right amygdala (P = .007), and rostral head of the right caudate nucleus and ventral putamen and globus pallidus (P = .003) compared with that in control subjects. AD patients had decreased rCBF relative to that in control subjects and MCI patients in the left inferior parietal (P = .005), left lateral frontal (P < .001), left superior temporal (P = .001), and left orbitofrontal (P = .003) cortices. AD patients had increased rCBF in the right anterior cingulate gyrus (P = .02) compared with that in control subjects. CONCLUSION: The transition from normal cognition to AD is associated with dynamic pathologic processes in the brain, and this is reflected by both decreases and increases in rCBF. Increases in rCBF suggest a cellular and vascular compensatory process associated with incipient AD. Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/2503080751/DC1.

Dai W, Carmichael OT, Lopez OL, Becker JT, Kuller LH, Gach HM. · Department of Computer Science, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · J Magn Reson Imaging. · Pubmed #19025942 No free full text.

Abstract: PURPOSE: To fully understand the effects of an image processing methodology on the comparisons of regional patterns of brain perfusion over time and between subject groups. MATERIALS AND METHODS: Two brain normalization methods were compared using images of elderly controls and subjects with MCI and AD: the normalization package of statistical parametric mapping (SPM2), and a fully deformable model (FDM). The performance of these two normalization methods was quantitatively evaluated based on two criteria: (a) the alignment accuracy of five brain structures to the colin27 reference volume, and (b) impact of spatial normalization methods on the sensitivity of perfusion magnetic resonance imaging (pMRI). RESULTS: The delineations of all five brain structures had significantly higher overlap with expert manual tracings using FDM compared to SPM (two-tailed, P < 0.025). When applied to the biostatistical analysis of CBF maps, a larger number of statistically significant voxels was identified from FDM compared with SPM2 regardless of the effects of the threshold and smoothing kernel. CONCLUSION: The greater degree of deformation freedom associated with FDM may yield more accurate region matching and higher statistical sensitivity in identifying regions of CBF differences between elderly groups with prevalent late-life neurodegenerative conditions.

Lopez OL, Mackell JA, Sun Y, Kassalow LM, Xu Y, McRae T, Li H. · Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. · J Natl Med Assoc. · Pubmed #19024233 links to  free full text

Abstract: BACKGROUND: Hispanics represent 10% of the U.S. population and are the fastest growing group. Studies show a higher prevalence and incidence of Alzheimer's disease (AD) in Hispanics than in the non-Hispanic white population, with an earlier age of onset. Among the currently estimated 200,000 Hispanics with AD, a significant number remain undiagnosed and untreated, and Hispanic participation in AD clinical trials has been historically low. This study evaluated the efficacy and safety of donepezil hydrochloride (donepezil) in Hispanics with mild-to-moderate AD. METHODS: In this multicenter, open-label, 12-week study conducted in the United States, subjects were Hispanic men or women aged > or =50 years with a diagnosis of mild-to-moderate AD (DSMV-IV and NINCDS/ADRDA criteria), with Mini-Mental State Examination (MMSE) scores of 10-26 (inclusive) at screening. Subjects were treated with donepezil 5 mg/day for 6 weeks followed by 10 mg/day for 6 weeks. Clinical evaluation was performed at baseline, week 6 and week 12. Cognitive improvement was measured using the MMSE, Fuld Object Memory Evaluation (FOME) and Symbol Digit Modality Test (SDMT). Behavioral symptoms and associated caregiver distress were assessed with the Neuropsychiatric Inventory (NPI). RESULTS: One-hundred-six patients with mild-to-moderate AD (mean age 68.6 years) were enrolled (intent to treat, n=97); most chose to have assessments conducted in Spanish. With 12 weeks of treatment, subjects showed statistically significant improvement from baseline on MMSE (P<0.0001), FOME retrieval (P=0.0042), FOME repeated retrieval (P=0.0020) and SDMT correct scores (P<0.0001). The NPI subdomain "apathy/indifference" showed statistically significant improvement (P=0.0010).The NPI Caregiver Distress scale (NPI-D) total score was statistically significantly improved (P=0.0500), suggesting a positive impact on relieving caregivers' burden associated with patient behavior. Most patients tolerated the treatment well, with only 2 discontinuing because of adverse events. The most common (>5%) adverse events were insomnia (9.5%), dizziness (7.6%), diarrhea (5.7%) and nausea (5.7%). CONCLUSION: The cognitive improvement and safety results from this study were consistent with those reported for donepezil in the general population. Increased awareness of AD in the Hispanic population will help more Hispanics with AD to benefit from early diagnosis and effective treatment.

DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, Lopez OL, Burke G, Carlson MC, Fried LP, Kuller LH, Robbins JA, Tracy RP, Woolard NF, Dunn L, Snitz BE, Nahin RL, Furberg CD, Anonymous00029. · University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · JAMA. · Pubmed #19017911 links to  free full text

Abstract: CONTEXT: Ginkgo biloba is widely used for its potential effects on memory and cognition. To date, adequately powered clinical trials testing the effect of G. biloba on dementia incidence are lacking. OBJECTIVE: To determine effectiveness of G. biloba vs placebo in reducing the incidence of all-cause dementia and Alzheimer disease (AD) in elderly individuals with normal cognition and those with mild cognitive impairment (MCI). DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled clinical trial conducted in 5 academic medical centers in the United States between 2000 and 2008 with a median follow-up of 6.1 years. Three thousand sixty-nine community volunteers aged 75 years or older with normal cognition (n = 2587) or MCI (n = 482) at study entry were assessed every 6 months for incident dementia. INTERVENTION: Twice-daily dose of 120-mg extract of G. biloba (n = 1545) or placebo (n = 1524). MAIN OUTCOME MEASURES: Incident dementia and AD determined by expert panel consensus. RESULTS: Five hundred twenty-three individuals developed dementia (246 receiving placebo and 277 receiving G. biloba) with 92% of the dementia cases classified as possible or probable AD, or AD with evidence of vascular disease of the brain. Rates of dropout and loss to follow-up were low (6.3%), and the adverse effect profiles were similar for both groups. The overall dementia rate was 3.3 per 100 person-years in participants assigned to G. biloba and 2.9 per 100 person-years in the placebo group. The hazard ratio (HR) for G. biloba compared with placebo for all-cause dementia was 1.12 (95% confidence interval [CI], 0.94-1.33; P = .21) and for AD, 1.16 (95% CI, 0.97-1.39; P = .11). G. biloba also had no effect on the rate of progression to dementia in participants with MCI (HR, 1.13; 95% CI, 0.85-1.50; P = .39). CONCLUSIONS: In this study, G. biloba at 120 mg twice a day was not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI. Trial Registration clinicaltrials.gov Identifier: NCT00010803.

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.

Hall AM, Moore RY, Lopez OL, Kuller L, Becker JT. · Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Alzheimers Dement. · Pubmed #18631978 links to  free full text

Abstract: BACKGROUND: Alzheimer's disease (AD) is the most common degenerative neurologic disorder. The onset of symptoms is insidious and follows a long period of progression of an asymptomatic pathology that proceeds in a precise anatomic and temporal sequence. Recent studies with quantitative magnetic resonance imaging techniques have shown the localization of the in vivo pathology of AD and its antecedent, mild cognitive impairment. The objective of the present study was to determine whether a sensitive and reliable marker for the presymptomatic phase of the disorder could be identified by longitudinal analysis of an initially asymptomatic, community-based population. METHODS: One hundred forty-eight healthy, cognitively normal participants in the Cardiovascular Health Study-Cognition Study had detailed clinical examinations and magnetic resonance imaging scans in 1998-1999 and 2002-2003. Modulated voxel-based morphometry was used to compare regional brain volumes in subjects who remained cognitively normal after 5 to 6 years of follow-up (n = 127) with those who developed probable AD during the same period (n = 21). RESULTS: Among normal subjects destined to develop AD, there was significant atrophy in the basal forebrain area as long as 4.5 years before the development of clinical symptoms. When the left hippocampus was also atrophic, the onset of dementia typically occurred earlier than in cases in which the atrophy was confined to basal forebrain. CONCLUSIONS: Atrophy in the basal forebrain precedes the development of AD in subjects with cognition judged to be normal by neuropsychological testing. The time required to develop dementia appears to be shortened if hippocampal atrophy is also present. These data indicate that atrophy restricted to medial basal forebrain is a biomarker that predicts development of probable AD in asymptomatic elderly subjects.

Lopez OL, Kuller LH, Mehta PD, Becker JT, Gach HM, Sweet RA, Chang YF, Tracy R, DeKosky ST. · Department of Psychiatry and Neurology, University of Pittsburgh, PA, USA. · Neurology. · Pubmed #18401021 links to  free full text

Abstract: OBJECTIVES: To examine the association between incident Alzheimer disease (AD), and plasma A beta 1-40 and A beta 1-42 levels in normal and mild cognitive impairment (MCI) subjects in a subgroup of participants of the Cardiovascular Health Study Cognition Study. METHODS: We determined the plasma A beta 1-40 and A beta 1-42 levels of 274 nondemented subjects (232 normals and 42 with MCI) in 1998-1999 and repeated the measurements in 2002-2003. The mean age of the subjects at baseline was 79.3 +/- 3.6 years. We examined the association between A beta levels and incident AD over the ensuing 4.5 years, controlling for age, cystatin C level (marker of glomerular function), apolipoprotein E-4 allele, Modified-Mini-Mental State Examination scores, and MRI-identified infarcts. RESULTS: In an unadjusted prospective model in normal subjects, both A beta 1-40 and A beta 1-42 levels in 1998-1999 were associated with incident AD (n = 55) in 2002-2003 (longitudinal analysis). In the fully adjusted multivariate model, neither A beta 1-42 nor A beta 1-40 nor their ratio was associated with incident AD. However, adjustment had a very small effect on point estimates for A beta 1-42, from an odds ratio (OR) of 1.61 (p = 0.007) in the unadjusted model to an OR of 1.46 (p = 0.08) in the fully adjusted model. In 2002-2003 (cross-sectional analysis), only the unadjusted models showed that both peptides were associated with AD. CONCLUSIONS: Plasma A beta levels are affected by age and by systemic and CNS vascular risk factors. After controlling for these conditions, A beta-40 and A beta 1-42 are weak predictors of conversion to Alzheimer disease (AD) in normal subjects and are only weakly associated with AD in cross-sectional analysis. Consequently, plasma levels of A beta do not seem to be useful biomarkers for AD.

Irie F, Fitzpatrick AL, Lopez OL, Kuller LH, Peila R, Newman AB, Launer LJ. · Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, 7201 Wisconsin Ave, Bethesda, MD, USA. · Arch Neurol. · Pubmed #18195144 links to  free full text

Abstract: BACKGROUND: Diabetes and the apolipoprotein E epsilon4 allele (APOE epsilon4) increase the risk for Alzheimer disease (AD). We hypothesize that APOE epsilon4 may modify the risk for AD in individuals with diabetes. OBJECTIVE: To examine the joint effect of type 2 diabetes and APOE epsilon4 on the risk of AD, AD with vascular dementia (mixed AD), and vascular dementia without AD. DESIGN: The Cardiovascular Health Study (CHS) Cognition Study (1992-2000) is a prospective study designed to identify all existing and new cases of dementia among study participants. Diagnoses were made according to international criteria for dementia and subtypes. There were 2547 dementia-free participants in the CHS Cognition Study cohort with complete information on APOE epsilon4 and type 2 diabetes status; among these, 411 new cases of dementia developed. Risk of dementia was estimated with a Cox proportional hazard model adjusted for age and other demographic and cardiovascular risk factors. RESULTS: Compared with those who had neither type 2 diabetes nor APOE epsilon4, those with both factors had a significantly higher risk of AD (hazard ratio, 4.58; 95% confidence interval, 2.18-9.65) and mixed AD (hazard ratio, 3.89; 95% confidence interval, 1.46-10.40). CONCLUSION: These data suggest that having both diabetes and APOE epsilon4 increases the risk of dementia, especially for AD and mixed AD.

Dai W, Lopez OL, Carmichael OT, Becker JT, Kuller LH, Gach HM. · Department of Computer Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Stroke. · Pubmed #18174483 links to  free full text

Abstract: BACKGROUND AND PURPOSE: The purpose of this study was to examine regional cerebral blood flow (rCBF) in normal cognitive-performing subjects with hypertension (HTN) using continuous arterial spin-labeled MRI. The most common explanation for the effect of blood pressure on cognition is that HTN increases the risk of cerebrovascular disease, and it may increase the risk for Alzheimer disease possibly through small vessel disease, ischemia, oxidative stress, and inflammation. However, few studies to date have examined the rCBF of cognitively normal subjects with HTN in population-based cohorts, and none have used continuous arterial spin-labeled MRI. This is a noninvasive technique that does not require either injections or ionizing radiation and can measure absolute rCBF rates over the entire brain. METHODS: rCBF was measured at 1.5 T using continuous arterial spin-labeled MRI in 41 cognitively normal subjects who were participating in the Cardiovascular Health Study Cognition Study. A deformable atrophy-corrected registration method was used to warp the rCBF maps to the standard colin27 brain space. Image and cluster-based statistical analyses were performed between subject groups. RESULTS: Cognitively normal subjects with HTN (n=19) had decreased rCBF in the putamen, globus pallidus, bilaterally, and in the left hippocampus compared with normotensives (n=22). In addition, decreased rCBF was observed in the right and left anterior cingulate gyrus with extension to the subcallosal region, left posterior cingulate gyrus and medial precuneus, left lateral inferior and superior frontal, and inferior parietal, left orbitofrontal, and left superior temporal cortices. CONCLUSIONS: rCBF is affected in normal subjects with HTN, not only in the subcortical regions, but also in limbic and paralimbic structures. We hypothesize that the HTN creates a vulnerability state for the development of neurodegenerative disorders, especially Alzheimer disease.

Wilkosz PA, Kodavali C, Weamer EA, Miyahara S, Lopez OL, Nimgaonkar VL, DeKosky ST, Sweet RA. · Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #17525976 No free full text.

Abstract: Psychotic symptoms in Alzheimer disease (AD + P) identify a heritable phenotype associated with a more severe course. We recently found an association of AD + P with depression symptom severity. Reports have shown an association of a serotonin-2A receptor (HTR2A) gene T102C polymorphism with AD + P and with depression during AD. We examined the interaction of this common genetic polymorphism with depression and increased psychosis risk. Subjects with possible or probable AD or mild cognitive impairment (MCI) without psychosis at study entry were genotyped for the HTR2A T102C polymorphism and reassessed every 6 months until psychosis onset. Psychotic and depressive symptoms were rated using the CERAD behavioral rating scale (CBRS). Cox proportional hazard models with time-dependent covariates were used to examine associations with psychosis onset. A total of 324 Caucasian subjects completed at least one follow-up exam. Depressive symptom severity was a strong predictor of psychosis onset. Neither psychosis onset nor depression severity was associated with the HTR2A genotype. Genotype interacted with depression severity to moderate the risk of AD + P onset. This did not result from an interaction of HTR2A genotype with antidepressant use. Psychosis onset in AD is strongly associated with severity of depressive symptoms, an association that may be modified by HTR2A genotype.

Rosano C, Aizenstein HJ, Wu M, Newman AB, Becker JT, Lopez OL, Kuller LH. · School of Public Health, Department of Epidemiology, University of Pittsburgh, Pennysylvania, USA. · J Neuroimaging. · Pubmed #17441836 No free full text.

Abstract: BACKGROUND AND PURPOSE: This study investigated the association of medial temporal lobe (MTL) atrophy and cerebrovascular disease (white matter hyperintensities [WMH], subclinical infarcts) with the risk of developing Alzheimer's disease (AD) among cognitively normal older adults. METHODS: Risk of developing AD was examined for 155 cognitively normal older adults (77.4 years, 60% women, 81% white). The MTL volumes and the presence of WMH and of subclinical infarcts were determined from brain magnetic resonance imaging (MRI) at the beginning of the study. Follow-up cognitive evaluations (average 4.3 years) identified those who developed AD. RESULTS: The presence of either MTL atrophy or subclinical infarcts was independently and significantly associated with a greater risk to develop AD (OR [95% CI]: 4.4 [1.5, 12.3] and 2.7 [1.0, 7.1], respectively). In addition, those participants with both MTL atrophy and at least one brain infarct had a 7-fold increase in the risk of developing AD (OR [95% CI]: 7.0 [1.5, 33.1]), compared to those who had neither of these conditions. CONCLUSIONS: In cognitively normal older adults, markers of neurodegeneration (as reflected by MTL atrophy) and of cerebrovascular disease (as reflected by infarcts on MRI) independently contribute to the risk to develop AD.

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.

Lopez OL, Becker JT, Sweet RA, Martin-Sanchez FJ, Hamilton RL. · Alzheimer's Disease Research Center, Department of Neurology, University of Pittsburgh School of Medicine, PA, USA. · Neurology. · Pubmed #16924019 No free full text.

Abstract: OBJECTIVE: To determine the relationship between major depression and the presence of Lewy bodies (LBs) in patients with Alzheimer disease (AD). METHODS: The authors examined the presence of major depression in 267 pathologically diagnosed AD cases with Mini-Mental State Examination (MMSE) scores >9. LBs were identified in 142 (53%) patients using alpha-synuclein immunohistochemistry. Subjects were classified according to the Consensus Guidelines for the Clinical and Pathologic Diagnosis of Dementia with LB: 1 to 2 (n = 21), 3 to 6 (n = 26), and 7 to 10 (n = 69). Twenty-six patients had LB only in the amygdala. All cases with LB scores 7 to 10 (or cortical) had amygdala LBs. The association between LBs and major depression was examined with logistic regression analyses, controlled for age at study entry, education level, MMSE scores, antidepressant use, follow-up time, and the presence of cerebrovascular disease. RESULTS: Major depression was present in 11 (9%) AD alone cases, and in 25 (18%) of the AD + LBs cases; amygdala: 8 (31%), scores 1 to 2: 1 (5%), scores 3 to 6: 3 (11.5%), and scores 7 to 10: 13 (14%). Major depression was associated with LBs, in general (relative risk [RR] = 3.06, 95% CI: 1.25 to 7.46), with amygdala only LBs (RR = 8.56 (95% CI: 1.83 to 40.3), and with LB scores 7 to 10 (RR = 3.83, 95% CI: 1.33 to 11.0). There was an association between all amygdala LBs cases (amygdala only LBs + LB scores 7 to 10) and major depression (RR = 4.77, 95% CI: 1.78 to 12.7), but no association was noted between LBs and depression in the absence of amygdala LBs (RR = 0.96, 95% CI: 0.46 to 1.06). CONCLUSION: Lewy bodies (LBs) in the amygdala and in cortical areas increase the risk for major depression in Alzheimer disease. What is common in these two groups is the presence of LBs in the amygdala. That is, all of the cases with cortical LBs also had LBs in the amygdala, making this region the critical area for the development of depression.

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.

Becker JT, Davis SW, Hayashi KM, Meltzer CC, Toga AW, Lopez OL, Thompson PM, Anonymous00178. · Alzheimer's Disease Research Center, University of Pittsburgh, PA 15213, USA. · Arch Neurol. · Pubmed #16401741 links to  free full text

Abstract: OBJECTIVE: To measure hippocampal volumes in patients diagnosed as having subtypes of mild cognitive impairment (MCI) relative to those of elderly control subjects and those of patients with Alzheimer disease (AD) using 3-dimensional mesh reconstructions. DESIGN: A magnetic resonance imaging volumetric study of MCI subgroups (MCI, amnesic subtype [MCI-A]; and MCI, multiple cognitive domain subtype) using 3-dimensional mesh reconstructions of the structure. SETTING: Referral dementia clinic. SUBJECTS: Twenty-six subjects with MCI (MCI-A, n = 6; and MCI, multiple cognitive domain subtype, n = 20), 20 subjects with AD, and 20 controls who were equivalent in age, education, and sex distributions. MAIN OUTCOME MEASURES: Three-dimensional parametric mesh models of the hippocampus and total hippocampal volumes. RESULTS: The hippocampi of the patients with AD were significantly atrophic relative to those of the healthy controls. The MCI, multiple cognitive domain subtype, group did not differ from the controls, yet was significantly different from the MCI-A and the AD groups. The MCI-A patients had significant hippocampal atrophy compared with the controls, and did not differ significantly from the patients with AD. CONCLUSION: These data add to the growing evidence that there are multiple forms of MCI, that they have distinct neuropathological correlates, and that MCI, multiple cognitive domain subtype, is not a more advanced form of the MCI-A subtype.