Biomedical subjects

Oscar L Lopez

Publications and source records attributed to Oscar L Lopez.

At least 19 recordsLinked to original sources

PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗

PubMed2006

3D pattern of brain atrophy in HIV/AIDS visualized using tensor-based morphometry.

UNLABELLED: 35% of HIV-infected patients have cognitive impairment, but the profile of HIV-induced brain damage is still not well understood. Here we used tensor-based morphometry (TBM) to visualize brain deficits and clinical/anatomical correlations in HIV/AIDS. To perform TBM, we developed a new MRI-based analysis technique that uses fluid image warping, and a new alpha-entropy-based information-theoretic measure of image correspondence, called the Jensen-Rényi divergence (JRD). METHODS: 3D T1-weighted brain MRIs of 26 AIDS patients (CDC stage C and/or 3 without HIV-associated dementia; 47.2+/-9.8 years; 25M/1F; CD4+ T-cell count: 299.5+/-175.7/microl; log10 plasma viral load: 2.57+/- 1.28 RNA copies/ml) and 14 HIV-seronegative controls (37.6+/-12.2 years; 8M/6F) were fluidly registered by applying forces throughout each deforming image to maximize the JRD between it and a target image (from a control subject). The 3D fluid registration was regularized using the linearized Cauchy-Navier operator. Fine-scale volumetric differences between diagnostic groups were mapped. Regions were identified where brain atrophy correlated with clinical measures. RESULTS: Severe atrophy ( approximately 15-20% deficit) was detected bilaterally in the primary and association sensorimotor areas. Atrophy of these regions, particularly in the white matter, correlated with cognitive impairment (P = 0.033) and CD4+ T-lymphocyte depletion (P = 0.005). CONCLUSION: TBM facilitates 3D visualization of AIDS neuropathology in living patients scanned with MRI. Severe atrophy in frontoparietal and striatal areas may underlie early cognitive dysfunction in AIDS patients, and may signal the imminent onset of AIDS dementia complex.

Acquired Immunodeficiency Syndrome↗

PubMed2006

The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia.

The epidemic of late life dementia, prominence of use of alternative medications and supplements, and initiation of efforts to determine how to prevent dementia have led to efforts to conduct studies aimed at prevention of dementia. The GEM (Ginkgo Evaluation of Memory) study was initially designed as a 5-year, randomized double-blind, placebo-controlled trial of Ginkgo biloba, administered in a dose of 120 mg twice per day as EGb761, in the prevention of dementia (and especially Alzheimer's disease) in normal elderly or those with mild cognitive impairment. The study anticipates 8.5 years of participant follow-up. Initial power calculations based on estimates of incidence rates of dementia in the target population (age 75+) led to a 3000-person study, which was successfully recruited at four clinical sites around the United States from September 2000 to June 2002. Primary outcome is incidence of all-cause dementia; secondary outcomes include rate of cognitive and functional decline, the incidence of cardiovascular and cerebrovascular events, and mortality. Following screening to exclude participants with incident dementia at baseline, an extensive neuropsychological assessment was performed and participants were randomly assigned to treatment groups. All participants are required to have a proxy who agreed to provide an independent assessment of the functional and cognitive abilities of the participant. Assessments are repeated every 6 months. Significant decline at any visit, defined by specific changes in cognitive screening scores, leads to a repeat detailed neuropsychological battery, neurological and medical evaluation and MRI scan of the brain. The final diagnosis of dementia is achieved by a consensus panel of experts. Side effects and adverse events are tracked by computer at the central data coordinating center and unblinded data are reviewed by an independent safety monitoring board. Studies such as these are necessary for this and a variety of other potential protective agents to evaluate their effectiveness in preventing or slowing the emergence of dementia in the elderly population.

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PubMed2006

Ventricular volume and dementia progression in the Cardiovascular Health Study.

Elevated cerebral ventricular volume may be associated with dementia risk and progression. A fully-automated technique that agreed highly with radiological readings was used to estimate lateral ventricle volume on MR scans done at baseline in 1997-99 of 377 subjects in the Cardiovascular Health Study (CHS) from the Pittsburgh Center. 327 subjects were normal or diagnosed with mild cognitive impairment (MCI) at baseline and were evaluated 4 years later. Baseline ventricular volume was analyzed in multivariate models with age, gender, education level, presence and incidence of cerebral infarcts, and dementia category (normal, MCI, or dementia) at baseline and follow-up as fixed effects. Ventricular volume at baseline was significantly higher among subjects normal at baseline and demented 4 years later. Age, gender, education level, and dementia progression were significant factors affecting ventricular volume. Ventricular volume was higher in dementia compared to MCI, higher in MCI compared to controls, and higher in Possible-Alzheimer's-disease (AD) dementia compared to Probable-AD. Larger ventricles in healthy subjects may indicate susceptibility to, or progression of, dementia-related pathology.

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PubMed2006

3D mapping of ventricular and corpus callosum abnormalities in HIV/AIDS.

OBJECTIVE: 40 million people worldwide are now infected with HIV/AIDS, an illness that often leads to rapidly progressing dementia and death. Even so, little is known about how AIDS affects the brain. Using computational anatomy techniques, we mapped how AIDS impacts the corpus callosum (CC) and ventricular system, two systems that show prominent changes on MRI. We (1) identified regions with greatest differences between AIDS patients and healthy controls and (2) correlated specific 3D patterns of structural differences with measures of immune system deterioration and cognitive decline. METHODS: 51 3D brain MRI scans from 30 non-demented AIDS patients (age: 43.4 years +/- 7.6 SD) and 21 HIV-seronegative controls (age: 39.5 years +/- 12.2) were aligned to ICBM standard space. 3D surface mesh reconstructions of the lateral ventricles and CC were spatially averaged and compared across diagnostic groups. Structural alterations were correlated with viral load, T cell counts, and cognitive impairment. RESULTS: Statistical maps revealed the 3D profile of ventricular expansion and callosal thinning in AIDS. Specific 3D ventricular changes were linked with immune system decline (CD4+ T cell counts; P < 0.001) and cognitive impairment (P < 0.009), but not viral load. Frontal horn maps distinguished AIDS patients from controls better than occipital and temporal horn measures. T cell decline linked with callosal thinning in anterior regions connecting frontal areas with greatest cortical atrophy. CONCLUSION: These maps (1) reveal how brain changes in HIV/AIDS relate to immune decline and impaired cognition, and, after further validation and testing, (2) may offer possible neuroimaging markers for anti-viral drug trials, which gauge how well treatments oppose disease progression in the brain.

AIDS Dementia Complex↗

PubMed2006

Three-dimensional patterns of hippocampal atrophy in mild cognitive impairment.

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.

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PubMed2006

Perspectives on depression, mild cognitive impairment, and cognitive decline.

CONTEXT: The public health implications of depression and cognitive impairment in late life are enormous. Cognitive impairment and late-life depression are associated with increased risk for subsequent dementia; however, investigations of these phenomena appear to be proceeding along separate tracks. OBJECTIVES AND DATA SOURCE: The National Institute of Mental Health organized the conference "Perspectives on Depression, Mild Cognitive Impairment, and Cognitive Decline" to consider how the varied perspectives might be better integrated to examine the associations among depression, mild cognitive impairment, and cognitive decline and to illuminate the common or distinct mechanisms involved in these associations. DATA SYNTHESIS: The following 2 broad questions were addressed: (1) What gaps in our knowledge have the greatest public health significance? (2) Can we more efficiently use our research dollars and participant resources to fill these gaps? Meeting participants included grantees from the National Institute of Mental Health and the National Institute on Aging and program staff from the National Institute of Mental Health, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke. CONCLUSIONS: One of the most important recommendations to emerge from the meeting discussions is for increased collaboration among clinical and epidemiological investigators whose work focuses in the area of depression with those working primarily in the area of memory disorders. Directions for future research were identified.

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PubMed2006

Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study.

CONTEXT: Depressive symptoms are common in patients with dementia and may be associated with increased risk of developing dementia. It has been hypothesized that depressive symptoms and dementia may be attributable to underlying vascular disease in some older persons. OBJECTIVES: To test the hypotheses (1) that depressive symptoms are associated with increased risk of developing mild cognitive impairment (MCI), a preclinical state that often precedes dementia, and (2) that the association between depressive symptoms and MCI is attributable to underlying vascular disease. DESIGN: Prospective, population-based, longitudinal study. SETTING: Random sample of adults 65 years or older recruited from 4 US communities. PARTICIPANTS: Subjects were 2220 participants in the Cardiovascular Health Study Cognition Study with high cognitive function at baseline. Depressive symptoms were measured at baseline using the 10-item Center for Epidemiological Studies Depression Scale and were classified as none (0-2 points), low (3-7 points), and moderate or high (>/=8 points). Vascular disease measures at baseline included confirmed history of stroke, transient ischemic attack, diabetes mellitus, or hypertension; carotid artery stenosis; ankle-arm blood pressure index; and small or large infarcts or white matter disease on cerebral magnetic resonance imaging. Mild cognitive impairment was diagnosed after 6 years of follow-up based on the consensus of a team of dementia experts using standard clinical criteria. MAIN OUTCOME MEASURE: Diagnosis of MCI. RESULTS: Depressive symptoms at baseline were associated with increased risk of MCI (10.0%, 13.3%, and 19.7% for those with no, low, and moderate or high depressive symptoms, respectively). This association was diminished only slightly by adjustment for vascular disease measures and demographics. Vascular disease measures also were associated with increased risk of MCI, and these associations were not diminished by adjustment for depressive symptoms or demographics. CONCLUSION: Depressive symptoms were associated with increased risk of MCI, and this association was independent of underlying vascular disease.

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PubMed2006

Positron emission tomography imaging of peripheral benzodiazepine receptor binding in human immunodeficiency virus-infected subjects with and without cognitive impairment.

The pathology associated with late-stage dementia in human immunodeficiency virus (HIV) infection has been studied extensively. Neuropathological examination has demonstrated abundant activation and infection of macrophages/microglia termed HIV encephalitis. For obvious reasons, less is known regarding the neuropathology of minor cognitive impairment seen in earlier stages of HIV infection. The authors examined the utility of the peripheral benzodiazepine receptor ligand PK11195 in positron emission tomography (PET) imaging to assess microglial/macrophage activation in the brains of HIV-infected subjects with minor neurocognitive impairment in a cross-sectional study of 12 HIV infected individuals and 5 age-matched noninfected controls. Subjects were given a battery of neuropsychological tests in addition to assessing CD4 T-cell count and peripheral viremia followed by contrast enhanced magnetic resonance imaging (MRI) and PET with [15O]H2O followed by [11C](R)-PK11195. Two of the six neurocognitively impaired HIV-infected subjects demonstrated plasma viral breakthrough, whereas only one of six nonimpaired individuals demonstrated plasma viral load near the limits of detection. MRI demonstrated no abnormal enhancement and although atrophy was more prominent in impaired subjects, it was also present though to a lesser extent in nonimpaired subjects. None of the 12 HIV-infected subjects demonstrated increased retention of [11C](R)-PK11195 in the brain parenchyma compared to the 5 controls. These results suggest that either [11C](R)-PK11195 PET assessment is insensitive to the degree of macrophage activation in HIV-associated minor neurocognitive impairment or macrophage activation is not the pathological substrate of this neurological condition.

AIDS Dementia Complex↗

PubMed2006

Prediction of psychosis onset in Alzheimer disease: The role of cognitive impairment, depressive symptoms, and further evidence for psychosis subtypes.

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.

Adult↗

PubMed2005

Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4+ T lymphocyte decline.

HIV/AIDS infection is the fourth leading cause of death worldwide, and one in every 100 adults aged 15-49 years is HIV-infected. Forty percent of AIDS patients suffer from neurological symptoms, but the selective profile of damage caused by HIV in the brain is not well understood. Here, we report 3D maps revealing how AIDS affects the human cerebral cortex, identifying the most vulnerable regions and where deficits link with cognitive decline and immune-system suppression. With high-resolution brain MRI scans, we created composite maps of cortical gray-matter thickness in 26 AIDS patients and 14 healthy controls to establish the selective pattern of brain deficits in AIDS. In AIDS, primary sensory, motor, and premotor cortices were 15% thinner. Thinner frontopolar and language cortex correlated with immune system deterioration measured through blood levels of CD4+ T lymphocytes. Prefrontal and parietal tissue loss correlated with cognitive/motor deficits. T cell depletion and cognitive impairment are, therefore, associated with specific 3D brain-deficit patterns visualized with MRI. These quantitative MRI-based maps reveal that HIV selectively damages the cortex. They provide an approach to gauge the impact of AIDS on the living brain and show that the brain is still vulnerable to infection even when patients are receiving antiretroviral therapy.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Alzheimer disease subjects with psychosis have increased schizotypal symptoms before dementia onset.

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.

Age of Onset↗

PubMed2005

Event-related functional magnetic resonance imaging investigation of executive control in very old individuals with mild cognitive impairment.

BACKGROUND: Attentional control of executive cognitive function (ECF) decreases in older individuals with Alzheimer Disease (AD). In order to examine early AD-related changes in the neural substrates of ECF attentional control, we measured activation dorsolateral prefrontal (dLPFC), posterior parietal (PPC), and anterior cingulate cortex (ACC) in adults with mild cognitively impairment (MCI) and in cognitively normal (CN) adults. METHODS: Functional magnetic resonance imaging analysis of brain activation in MCI (n = 8, mean age 79.5) and CN (n = 8 mean age 81.5) during increasing loads of attentional demands. RESULTS: MCI and CN older adults performed with similar accuracy and reaction time. MCI had greater activation than CN in PPC (right p = .03 and left p = .05) and dlPFC areas (right p = .002 and left p = .004), while activation in ACC was similar in the two groups. Response to increasing loads of the task differed by group: MCI selectively engaged bilateral PPC (right p = .03, left p = .04), while CN subjects increased bilateral dlPFC activation (right p = .005 and left p = .02) and ACC activation (p = .04). Among MCI, greater load-related changes in PPC activity were associated with smaller load-related changes in accuracy rates (r = -.85, p = .07) and greater increases in reaction times (r = .97, p = .01). In CN subjects, load-related change in PPC activation was associated with load-related change in reaction time (r = .76, p = .02) but not with changes in accuracy rates. CONCLUSIONS: PPC and dlPFC may show early functional changes associated with MCI.

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PubMed2005

Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study.

Physical activity may help preserve cognitive function and decrease dementia risk, but epidemiologic findings are inconsistent. The authors conducted a prospective study to determine the association between physical activity and risk of dementia, Alzheimer's disease, and vascular dementia. The US study population comprised 3,375 men and women aged 65 years or older, free of dementia at baseline, who participated in the Cardiovascular Health Cognition Study in 1992-2000. Leisure-time energy expenditure and an activity index reflecting number of different physical activities were calculated. Analyses were based on Cox proportional hazards models. There were 480 incident cases of dementia over an average of 5.4 years of follow-up. After multivariate adjustment, participants in the highest quartile of physical energy expenditure had a relative risk of dementia of 0.85 (95% confidence interval: 0.61, 1.19) compared with those in the lowest quartile, and participants engaging in >or=4 activities had a relative risk of dementia of 0.51 (95% confidence interval: 0.33, 0.79) compared with those engaging in 0-1 activity. These associations were more marked in apolipoprotein E genotype (APOE) epsilon4 allele noncarriers but were absent in carriers. A similar pattern was observed for Alzheimer's disease and vascular dementia. Mechanisms to explain the observed relations deserve further study.

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PubMed2005

Statin use and the risk of incident dementia: the Cardiovascular Health Study.

BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce cardiovascular risk through mechanisms that might affect the development of dementia. OBJECTIVE: To evaluate whether statin use is associated with a lower risk of dementia compared with never use of lipid-lowering agents (LLAs). DESIGN: Cohort study of community-dwelling adults 65 years and older. The analysis included 2798 participants free of dementia at baseline. MAIN OUTCOME MEASURES: Using Cox proportional hazards regression analysis, we estimated the risk of incident all-cause and type-specific dementia associated with time-dependent statin therapy compared with never use of LLAs. The primary analyses incorporated a 1-year lag between exposure and outcome. Secondary analyses included the final year of exposure and modeled statin use as current use vs nonuse to simulate a case-control approach. RESULTS: Compared with never use of LLAs, ever use of statins was not associated with the risk of all-cause dementia (multivariable-adjusted hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.77-1.52), Alzheimer disease alone (HR, 1.21; 95% CI, 0.76-1.91), mixed Alzheimer disease and vascular dementia (HR, 0.87; 95% CI, 0.44-1.72), or vascular dementia alone (HR, 1.36; 95% CI, 0.61-3.06). In contrast, in secondary analyses, current use of statins compared with nonuse of LLAs was associated with HRs of 0.69 (95% CI, 0.46-1.02) for all-cause dementia and 0.56 (95% CI, 0.35-0.92) for any Alzheimer disease. CONCLUSIONS: In this cohort study, statin therapy was not associated with a decreased risk of dementia. Methodological differences may explain why results of this cohort investigation differ from those of prior case-control studies. Additional investigation is needed to determine whether and for whom statin use may affect dementia risk.

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PubMed2005

Differential cortical atrophy in subgroups of mild cognitive impairment.

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.

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PubMed2005

Non-cognitive symptoms in mild cognitive impairment subjects.

The term mild cognitive impairment (MCI) is used to identify individuals with worse cognitive performance than those with normal aging, and who are at risk of dementia, especially Alzheimer's disease (AD). Although the MCI concept is based on the presence of specific cognitive deficits, several studies have shown that these subjects can develop depression, disruptive behaviors (e.g., agitation, aggression), and psychosis. In this study, we examined the baseline psychiatric characteristics of 228 MCI (Mean age: 71.2, Mini-mental State Examination [MMSE] score: 25.9) and 427 mildly demented Probable AD (Mean age: 73.2; Mean MMSE score: 23.5) subjects from a referral dementia clinic. The psychiatric assessment was conducted by geriatric psychiatrists using semi-structured interviews. The proportion of subjects with major depression (MCI: 7.5% vs. Probable AD: 8%) and aggression (MCI: 10% vs. Probable AD: 12.5%) was similar in the two groups. There were more Probable AD patients with psychomotor agitation (52% vs. 38%), delusions (29% vs. 14%), and hallucinations (9% vs. 4%) than MCI subjects. Within MCI groups, we did not observe any differences between MCI subjects with amnesic syndrome versus MCI subjects with a much broader cognitive deficit. These results showed that the MCI syndrome is not circumscribed to a neuropsychological definition, but occurs with a wide range of psychiatric syndromes. Furthermore, it is possible that the development of disruptive behaviors and psychosis, in MCI subjects with no previous history of psychiatric illness, constitutes a strong indication that there is an underlying neurodegenerative disorder.

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PubMed2005

Alteration of a clinically meaningful outcome in the natural history of Alzheimer's disease by cholinesterase inhibition.

OBJECTIVES: To describe the effect of cholinesterase inhibitors (CEIs) on the natural course of Alzheimer's disease (AD) using clinically meaningful outcomes. DESIGN: Cross-sectional and longitudinal study. SETTING: Referral dementia clinic. PARTICIPANTS: One hundred thirty-five matched pairs of patients with probable AD. MEASUREMENTS: The risk of AD patients being classified as slow progressors (Mini-Mental State Examination (MMSE) score change <or=2 at 1-year follow-up) was examined as a function of treatment with CEIs. A logistic regression analysis, controlling for age, sex, education level, MMSE score, Blessed Dementia Rating Scale (BDRS) for activities of daily living (ADLs), extrapyramidal signs, psychosis, major depression, and use of antidepressants, antipsychotics, and sedative/hypnotics determined the factors that best predict slow progression and nursing home admission. RESULTS: Eighty-one (60%) of the patients on CEIs and 53 (39%) of the patients who never used CEIs were considered slow progressors (P=.001) at 1-year follow-up. Slow progression was associated only with CEI use (relative risk (RR)=2.45, 95% confidence interval (CI)=1.45-4.16), and sedative/hypnotics use was associated with a MMSE change of 3 points or more (RR=0.35, 95% CI=0.13-0.93). CEI use had a protective effect on nursing home admission (RR=0.095, 95% CI=0.03-0.30), whereas higher scores on the BDRS for ADLs increased risk of admission at 24- and 36-month follow-up. CONCLUSION: CEI use had a clinically meaningful effect on the natural history of AD. Patients taking CEIs were 2.5 times more likely to progress slowly and had a lower risk of nursing home admission after 2 years, even after controlling for multiple factors that can alter the course of the disease, and a slower rate of decline during the first year of follow-up.

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