Severity Of Dementia In Alzheimer's Disease Research Articles

Cognition Mediates the Association Between Cerebrospinal Fluid Biomarkers of Amyloid and P-Tau and Neuropsychiatric Symptoms.

Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer's disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aβ1-42, p-tau181), cognitive function, and NPS. Primary models included 781 participants from the National Alzheimer's Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR®) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOEɛ4. The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau181/Aβ1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau181/Aβ1-42 ratio and CDR global impairment. With dementia excluded, p-tau181/Aβ1-42 ratio was no longer associated with the NPI-Q. NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia.

Dissociable Effects of Alzheimer's Disease-Related Cognitive Dysfunction and Aging on Functional Brain Network Segregation.

Alzheimer's disease (AD) is associated with changes in large-scale functional brain network organization. Individuals with AD exhibit less segregated resting-state brain networks compared with individuals without dementia. However, declines in brain network segregation are also evident as adult individuals grow older. Determining whether these observations reflect unique or overlapping alterations on the functional connectome of the brain is essential for understanding the impact of AD on network organization and incorporating measures of functional brain network organization toward AD characterization. Relationships between AD dementia severity and participant's age on resting-state brain system segregation were examined in 326 cognitively healthy and 275 cognitively impaired human individuals recruited through the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 601; age range, 55-96 years; 320 females). Greater dementia severity and increasing age were independently associated with lower brain system segregation. Further, dementia versus age relationships with brain network organization varied according to the processing roles of brain systems and types of network interactions. Aging was associated with alterations to association systems, primarily among within-system relationships. Conversely, dementia severity was associated with alterations that included both association systems and sensory-motor systems and was most prominent among cross-system interactions. Dementia-related network alterations were evident regardless of the presence of cortical amyloid burden, revealing that the measures of functional network organization are unique from this marker of AD-related pathology. Collectively, these observations demonstrate the specific and widespread alterations in the topological organization of large-scale brain networks that accompany AD and highlight functionally dissociable brain network vulnerabilities associated with AD-related cognitive dysfunction versus aging.SIGNIFICANCE STATEMENT Alzheimer's disease (AD)-associated cognitive dysfunction is hypothesized to be a consequence of brain network damage. It is unclear exactly how brain network alterations vary with dementia severity and whether they are distinct from alterations associated with aging. We evaluated functional brain network organization measured at rest among individuals who varied in age and dementia status. AD and aging exerted dissociable impacts on the brain's functional connectome. AD-associated brain network alterations were widespread and involved systems that subserve not only higher-order cognitive operations, but also sensory and motor operations. Notably, AD-related network alterations were independent of amyloid pathology. The research furthers our understanding of AD-related brain dysfunction and motivates refining existing frameworks of dementia characterization with measures of functional network organization.

Plasma total bilirubin in patients with Alzheimer’s disease: An observational study

AbstractBackgroundBilirubin, the primary end product of the heme cleavage pathway, is currently regarded as a major physiologic antioxidant with important cytoprotective properties. Oxidative stress is a well established contributing factor in the development of Alzheimer's disease (AD). In the present study, we aimed to compare serum bilirubin levels in patients with AD and healthy elderly controls, and to analyze the potential relationship between serum total bilirubin levels and dementia severity in AD patients.MethodMeasures of fasting serum total bilirubin levels were studied in 68 patients with AD (34 women; mean age 71.4±5.8 years; range 60‐82) (DSM‐IV; NINCDS‐ADRDA criteria) from a private ambulatory of neurology, recruited in a community elderly in Skikda‐Algeria (2017‐2020); and in 68 elderly controls (34 women; mean age 70.4±6.3 years; range 58‐82). Dementia severity was assessed by the clinical dementia rating scale‐CDR global score.ResultThe mean (±SD) plasma total bilirubin level was 0.72±0.13 (Range 0.49–1.08) among AD group and 0.66±0.11 (range 0.48–1.02) mg/dL among control group; (p= 0.0029). By gender, plasma total bilirubin level was higher in cases compared to controls both in men 0.75±0.14 vs. 0.67±0.13 mg/dL respectively, (p= 0.027); and in women 0.70±0.12 vs. 0.64±0.10 mg/dL; (p= 0.040). Patients with mild AD (Mean age 68±3.7 years) showed significantly higher levels of plasma total bilirubin compared with patients with moderate AD (Mean age 77.4±3.6 years): 0.77±0.13 vs. 0.64±0.09 mg/dL respectively (one way ANOVA, p= 0.0001). Plasma total bilirubin level was significantly negatively correlated with dementia severity, r= ‐0.4503; (95% CI for rho: ‐0.621; ‐0.238), p= 0.0001. By gender r= ‐3564; (p= 0.038) for men; and r= ‐0.5481, (p= 0.0007) for women.ConclusionThese data indicate that plasma total bilirubin level is increased in AD compared to controls, and inversely correlates with dementia severity. Patients with mild AD have higher total bilirubin levels (Within clinical normal range) than patients with moderate AD. These results suggest that serum total bilirubin level may provide additional information for predicting development of AD. We speculate that a possible beneficial physiologic antioxidant role for bilirubin could be operating during earlier stages of AD and gradually fades with disease progression.

Semantic Memory in the Clinical Progression of Alzheimer Disease.

Semantic memory measures may be useful in tracking and predicting progression of Alzheimer disease. We investigated relationships among semantic memory tasks and their 1-year predictive value in women with Alzheimer disease. We conducted secondary analyses of a randomized clinical trial of raloxifene in 42 women with late-onset mild-to-moderate Alzheimer disease. We assessed semantic memory with tests of oral confrontation naming, category fluency, semantic recognition and semantic naming, and semantic density in written narrative discourse. We measured global cognition (Alzheimer Disease Assessment Scale, cognitive subscale), dementia severity (Clinical Dementia Rating sum of boxes), and daily function (Activities of Daily Living Inventory) at baseline and 1 year. At baseline and 1 year, most semantic memory scores correlated highly or moderately with each other and with global cognition, dementia severity, and daily function. Semantic memory task performance at 1 year had worsened one-third to one-half standard deviation. Factor analysis of baseline test scores distinguished processes in semantic and lexical retrieval (semantic recognition, semantic naming, confrontation naming) from processes in lexical search (semantic density, category fluency). The semantic-lexical retrieval factor predicted global cognition at 1 year. Considered separately, baseline confrontation naming and category fluency predicted dementia severity, while semantic recognition and a composite of semantic recognition and semantic naming predicted global cognition. No individual semantic memory test predicted daily function. Semantic-lexical retrieval and lexical search may represent distinct aspects of semantic memory. Semantic memory processes are sensitive to cognitive decline and dementia severity in Alzheimer disease.

Costs and quality of life in community-dwelling patients with Alzheimer's disease in Spain: results from the GERAS II observational study.

Country-specific data on resource use and costs associated with Alzheimer's disease (AD) help inform governments about the increasing need for medical and financial support as the disease increases in prevalence. GERAS II, a prospective observational study, assessed resource use, costs, and health-related quality of life (HRQoL) among patients with AD and their caregivers in Spain. Community-dwelling patients aged ≥55 years with probable AD, and their primary caregivers, were recruited by study investigators during routine clinical practice and assessed as having mild, moderate, or moderately severe/severe (MS/S) AD dementia based on patient Mini-Mental State Examination scores. Costs of AD were calculated by applying costs to resource-use data obtained in caregiver interviews using the Resource Utilization in Dementia instrument. Total societal costs included patients' health and social care costs and caregiver informal care costs. Baseline results are presented. Total mean monthly societal costs/patient (2013 values) were €1514 for mild (n = 116), €2082 for moderate (n = 118), and €2818 for MS/S AD dementia (n = 146) (p value <0.001 between groups). Caregiver informal care costs comprised most of the total societal costs and differed significantly between groups (€1050, €1239, €1580, respectively; p value = 0.013), whereas patient healthcare costs did not. Across AD dementia severity groups, patient HRQoL (measured by proxy) decreased significantly (p value <0.001), caregiver subjective burden significantly increased (p value <0.001) and caregiver HRQoL was similar. Societal costs associated with AD in Spain were largely attributable to caregiver informal care costs and increased with increasing AD dementia severity.

Dependence Levels as Interim Clinical Milestones Along the Continuum of Alzheimer's Disease: 18-Month Results from the GERAS Observational Study.

While functional loss forms part of the current diagnostic criteria used to identify dementia due to Alzheimer's disease, the gradual and progressive nature of the disease makes it difficult to recognize clinically relevant signposts that could be helpful in making treatment and management decisions. Having previously observed a significant relationship between stages of functional dependence (the level of assistance patients require consequent to Alzheimer's disease deficits, derived from the Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale) and cognitive severity, we investigated whether measures of functional dependence could be utilized to identify clinical milestones of Alzheimer's disease progression. To describe the patterns of change in dependence over the course of 18 months in groups stratified according to cognitive Alzheimer's disease dementia severity (determined using the Mini-Mental State Examination score) and to identify characteristics associated with patients showing worsening dependence (progressors) versus those showing no change or improvement (non-progressors). Analysis of longitudinal data from the GERAS study. GERAS is an 18-month prospective, multicenter, naturalistic, observational cohort study reflecting the routine care of patients with Alzheimer's disease in France, Germany, and the United Kingdom. 1495 community-living patients, aged ≥55 years, diagnosed with probable Alzheimer's disease dementia, and their caregivers. Dependence levels, cognitive function, behavioral symptoms, caregiver burden, and cost were assessed at baseline and at 18 months. Of 971 patients having both baseline and 18-month data, 42% (408) were progressors and 563 (58%) were non-progressors. This general pattern held for all three levels of baseline Alzheimer's disease dementia severity - mild (Mini-Mental State Examination score 21-26), moderate (15-20) or moderately severe/severe (<15) - with 40-45% of each group identified as progressors and 55-60% as non-progressors. No baseline differences were seen between progressors and non-progressors in cognitive scores or behavioral symptoms, although progressors had significantly shorter times since diagnosis and showed milder functional impairment. Baseline factors predictive of increasing dependence over 18 months included more severe cognitive impairment, living with others, and having multiple caregivers. A higher level of initial dependence was associated with less risk of dependence progression. Total societal costs of care also increased with greater dependence. In this large cohort, 42% of Alzheimer's disease dementia patients at all levels of cognitive severity became more dependent within 18 months of observation while 58% did not progress. Dependence levels may be considered as meaningful interim clinical milestones that reflect Alzheimer's disease-related functional deficits, although a time frame that extends beyond 18 months may be necessary to observe changes if used in clinical trials or other longitudinal studies. Recognition of predictors of greater dependence offers opportunities for intervention.

Resource utilisation, costs and clinical outcomes in non-institutionalised patients with Alzheimer's disease: 18-month UK results from the GERAS observational study.

BackgroundAlzheimer’s disease (AD), the commonest cause of dementia, represents a significant cost to UK society. This analysis describes resource utilisation, costs and clinical outcomes in non-institutionalised patients with AD in the UK.MethodsThe GERAS prospective observational study assessed societal costs associated with AD for patients and caregivers over 18 months, stratified according to baseline disease severity (mild, moderate, or moderately severe/severe [MS/S]). All patients enrolled had an informal caregiver willing to participate in the study. Healthcare resource utilisation was measured using the Resource Utilization in Dementia instrument, and 18-month costs estimated by applying unit costs of services and products (2010 values). Total societal costs were calculated using an opportunity cost approach.ResultsOverall, 526 patients (200 mild, 180 moderate and 146 MS/S at baseline) were recruited from 24 UK centres. Mini-Mental State Examination (MMSE) scores deteriorated most markedly in the MS/S patient group, with declines of 3.6 points in the mild group, 3.5 points in the moderate group and 4.7 points in the MS/S group; between-group differences did not reach statistical significance. Patients with MS/S AD dementia at baseline were more likely to be institutionalised (Kaplan–Meier probability 28% versus 9% in patients with mild AD dementia; p < 0.001 for difference across all severities) and had a greater probability of death (Kaplan–Meier probability 15% versus 5%; p = 0.013) at 18 months. Greater disease severity at baseline was also associated with concomitant increases in caregiver time and mean total societal costs. Total societal costs of £43,560 over 18 months were estimated for the MS/S group, versus £25,865 for the mild group and £30,905 for the moderate group (p < 0.001). Of these costs, over 50% were related to informal caregiver costs at each AD dementia severity level.ConclusionsThis study demonstrated a mean deterioration in MMSE score over 18 months in patients with AD. It also showed that AD is a costly disease, with costs increasing with disease severity, even when managed in the community: informal caregiver costs represented the main contributor to societal costs.

Extrapyramidal Signs by Dementia Severity in Alzheimer Disease and Dementia With Lewy Bodies

Alzheimer disease (AD) and dementia with Lewy bodies (DLB) are common etiologies of dementia with overlapping clinical features. Our objective was to determine which extrapyramidal signs (EPSs) are most helpful in identifying DLB. We analyzed data from the National Alzheimer's Coordinating Center, including demographics, Unified Parkinson's Disease Rating Scale (UPDRS) scores, Mini-Mental State Examination (MMSE) scores, and clinical diagnosis. The subjects were divided into 3 groups: AD, DLB, or Lewy body variant (LBV). The UPDRS motor scores were totaled and analyzed within and across the MMSE strata using regression techniques. Further, we divided UPDRS subscores into 9 EPSs, dichotomized as either present or absent. Logistic regression analysis was used to compare each of the EPS in the AD and Lewy body (DLB+LBV) groups. DLB subjects (n=130) were more likely to be male individuals, younger, and have higher MMSE scores (P<0.001) compared with that in AD (n=1826) or LBV (n=105) subjects. Differences were found for total UPDRS score and number of EPSs (P<0.001), after controlling for age, sex, and MMSE. Logistic regression models demonstrated that masked facies best differentiated AD from Lewy body (odds ratio=6.5, P<0.001, 95% confidence interval, 3.8-11.1). If these findings are neuropathologically validated, then the presence of specific EPS may help clinicians better differentiate AD and DLB.

Cardiorespiratory fitness is associated with atrophy in Alzheimer's and aging over 2 years

We sought to describe change in cardiorespiratory (CR) fitness over 2 years in those with early-stage Alzheimer's disease (AD) and nondemented aging and assess the relationship of CR fitness with cognitive decline, brain atrophy, and dementia progression. Individuals with early-stage AD (n = 37) and without dementia (n = 53) attended clinical evaluations, cognitive and exercise tests, and magnetic resonance imaging (MRI) at baseline and 2 years later. CR fitness was lower in those with AD over the study period. Lower baseline CR fitness was associated with progression of dementia severity in AD. Declining CR fitness over 2 years was associated with brain atrophy in AD, especially in the parahippocampus. In nondemented participants, there was a trend for lower baseline fitness to be related to cognitive decline. Both lower baseline CR fitness and declining CR fitness over 2 years were associated with regional brain atrophy. We conclude that CR fitness is chronically reduced in those with AD. Further, in those with AD, CR fitness is associated with progression of dementia severity and brain atrophy in AD, suggesting a link between progression of dementia severity and cardiorespiratory health.

Bihemispheric Cerebral FDG PET Correlates of Cognitive Dysfunction as Assessed by the CERAD in Alzheimer's Disease

Alzheimer's disease (AD) is characterized by a variety of cognitive deficits which can be reliably assessed by the neuropsychological test battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), but the cerebral changes underlying the respective cognitive deficits are only partly understood. Measures of severity of dementia in AD as well as delayed episodic memory performance in mild cognitive impairment significantly correlated with bihemispheric cerebral glucose hypometabolism. We therefore hypothesized that the CERAD cognitive battery may represent cerebral dysfunction of both hemispheres in patients with AD. In 32 patients with AD, cerebral glucose metabolism was investigated using positron-emission-tomography with 18Fluorodeoxyglucose (FDG PET) and associated with the test scores of the CERAD cognitive battery by statistical parametric mapping. Episodic memory scores significantly correlated with temporopari etal glucose metabolism of both hemispheres while delayed episodic memory significantly was correlated with the right frontotemporal cortices. Verbal fluency and naming scores significantly correlated with glucose metabolism in left temporoparietal and right frontal cortices, whereas constructional praxis predominantly correlated significantly with the bilateral precuneus. In conclusion, the results of our study demonstrate that not only memory function but also functions of language and constructional praxis in AD are associated with glucose metabolism as revealed by FDG PET in subsets of uni- and bilateral brain areas. The findings of our study for the first time demonstrate that in AD neuropsychological deficits as assessed by the CERAD refer to different cerebral sites of both hemispheres.

New drug discovery for Alzheimer′s disease: Challenges and hopes

Byline: T. Sathyanarayana Rao, K. Rao Alzheimer's disease (AD) is a common neurodegenerative disease that affects cognitive function in the elderly. It is a common dementia related to aging and a fatal neurodegenerative disease, which is on rise in both the developed and the developing countries. The disease has a complex pathology and etiology. There are no biomarkers for early detection of the disease. There are no successful drugs either to cure or to manage the disease. It has affected 4.5 million people in the United States alone in 2000 and is expected to reach about 15 million by the year 2050 in spite of all the medical advancement. Patients develop progressive cognitive decline with psychiatric and behavioral problems that impair daily living activities and also passively affect quality of life of the patient and the family. The burden of AD has an extraordinary social and economic impact on the families and on the world itself. This makes the development of potential therapies a high priority area in biomedical research. The main challenge is to choose the right biochemical target for drug discovery because of complex neuropathology of the AD brain. The large extracellular beta-amyloid (A[sz] ) plaques and tau-containing intraneuronal neurofibrillary tangles characterize AD from a histopathologic perspective.[sup] [1] However, the severity of dementia in AD is more closely related to the degree of the associated neuronal and synaptic loss. It is not known how neurons die and synapses are lost in AD.[sup] [2] Most of the evidence indicates that precursor protein (APP) processing has a central role in the AD process. The A[sz] in the form of plaques is a metabolite of the APP that forms when an alternative (beta-secretase and then gamma-secretase enzymatic pathway) is utilized for processing. A total of six mutations have been described in the APP gene, which leads to AD by influencing APP metabolism.[sup] [3] One of the leading theories is that A[sz] in plaques leads to AD because A[sz] is directly toxic to the adjacent neurons. Other theories advance the notion that neuronal death is triggered by intracellular events that occur during APP processing or by extraneuronal preplaque A[sz] oligomers. Now, AD has been understood as a more general problem with protein processing, from accumulation of intraneuronal A[sz] or extracellular, preplaque A[sz] leading to neuronal cell death. However, recently functional imaging studies implied that functional decline in humans can occur separately from both neuronal loss and neurofibrillary tangles. A[sz] , a 39-43 aminoacid peptide derived from APP is the major component of senile plaques observed in AD. Evidences implicate a central role for A[sz] in the pathophysiology of AD. Av40 is the dominant species in human cerebrospinal fluid, accounting for approximately 90% of total A under normal conditions. There is a disease-specific increase in A[sz] 40 brain tissue levels compared with the A[sz] 42 change observed both in the aged and in the AD brain. It is now speculated that A[sz] pathological significance is also known to be associated with a-synuclein aggregation, a protein implicated in Parkinson's disease. A[sz] is a self-aggregating protein and the conformational transition from unfolded state to a beta sheet-rich conformation leads to deposition of protein aggregates. Although A[sz] deposits are primarily extracellular, studies have demonstrated an intraneuronal accumulation of A[sz] in AD-vulnerable regions. It is said that the amyloid is deposited first in the neuron and later in the extracellular space. Thus, neurodegeneration (ND) includes complex pathology and etiology. No animal model completely reflects human ND seen in the brain. The major challenges are how to choose the best neuronutraceuticals for clinical trials, what kind of preclinical study design is required and whether we can formulate a synthetic or modification of the natural compound best suited for the brain. …

Imaging β-amyloid burden in aging and dementia

To compare brain beta-amyloid (Abeta) burden measured with [(11)C]Pittsburgh Compound B (PIB) PET in normal aging, Alzheimer disease (AD), and other dementias. Thirty-three subjects with dementia (17 AD, 10 dementia with Lewy bodies [DLB], 6 frontotemporal dementia [FTD]), 9 subjects with mild cognitive impairment (MCI), and 27 age-matched healthy control subjects (HCs) were studied. Abeta burden was quantified using PIB distribution volume ratio. Cortical PIB binding was markedly elevated in every AD subject regardless of disease severity, generally lower and more variable in DLB, and absent in FTD, whereas subjects with MCI presented either an "AD-like" (60%) or normal pattern. Binding was greatest in the precuneus/posterior cingulate, frontal cortex, and caudate nuclei, followed by lateral temporal and parietal cortex. Six HCs (22%) showed cortical uptake despite normal neuropsychological scores. PIB binding did not correlate with dementia severity in AD or DLB but was higher in subjects with an APOE-epsilon4 allele. In DLB, binding correlated inversely with the interval from onset of cognitive impairment to diagnosis. Pittsburgh Compound B PET findings match histopathologic reports of beta-amyloid (Abeta) distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if Abeta deposition in nondemented subjects is preclinical AD are now feasible. Our findings also suggest that Abeta may influence the development of dementia with Lewy bodies, and therefore strategies to reduce Abeta may benefit this condition.

Low serum VEGF levels are associated with Alzheimer's disease

As vascular endothelial growth factor (VEGF) determines important neurotrophic and neuroprotective actions, we postulated serum VEGF levels could be abnormally low in patients with Alzheimer's disease (AD). We measured serum VEGF levels (VEGF(165) isoform by ELISA) in 51 patients with AD by National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorder Association criteria and compared with 66 age- and gender-matched non-demented controls. Patients with AD were stratified into levels of dementia severity by the Clinical Dementia Rating scale. Serum VEGF levels were stratified into upper (>309 pg/ml), middle (207-309 pg/ml), and lower (<207 pg/ml) tertiles. VEGF (-2,578) (rs 699,947) and VEGF (-634) (rs 2,010,963) polymorphisms were genotyped in patients with AD and controls. The mean concentration of VEGF in the serum of patients with AD (215.9 pg/ml, SD 101.5) was significantly lower than that of the controls (308.6 pg/ml, SD 223.9, P = 0.004), and decreased serum VEGF levels were associated with AD in a dose-dependent manner, the lower tertile of serum VEGF levels being associated with a fivefold increased risk for AD when compared with the upper tertile. There was no significant correlation between serum VEGF levels and age, sex, APOE alleles, AD dementia severity nor VEGF gene polymorphisms. Decrease in serum VEGF levels could contribute to the neurodegenerative process in AD.

Apolipoprotein E Genotype Influences Presence and Severity of Delusions and Aggressive Behavior in Alzheimer Disease

Aim: We investigated differences in the prevalence and severity of 10 neuropsychiatric and behavioral symptoms according to apolipoprotein E (APOE) genotype and dementia severity in Alzheimer disease (AD). Methods: Neuropsychiatric and behavioral symptoms of 110 AD patients were assessed using the Neuropsychatric Inventory. Dementia severity was assessed using the Mini Mental State Examination (MMSE). Results: There were 27 APOE-Ε4-negative patients, 65 heterozygous patients and 18 homozygous patients. There was a significant association between the number of APOE Ε4 alleles and prevalence and severity of neuropsychiatric and behavioral symptoms that was mainly attributable to delusions and agitation/aggression, which were more common and severer among homozygous APOE Ε4 carriers. In addition, the presence of hallucinations, anxiety, apathy and aberrant motor behavior increased with deteriorating MMSE score, independently of APOE Ε4 status. Conclusions: The present study showed that the APOE Ε4 genotype modifies neuropsychiatric and behavioral phenotype in AD. In particular, it was shown that delusions and agitation/aggression were more common and severer among homozygous APOE Ε4 carriers than among heterozygous or APOE-Ε4-negative patients.

Elevated cortical zinc in Alzheimer disease

To determine whether changes in brain biometals in Alzheimer disease (AD) and in normal brain tissue are tandemly associated with amyloid beta-peptide (Abeta) burden and dementia severity. The authors measured zinc, copper, iron, manganese, and aluminum and Abeta levels in postmortem neocortical tissue from patients with AD (n = 10), normal age-matched control subjects (n = 14), patients with schizophrenia (n = 26), and patients with schizophrenia with amyloid (n = 8). Severity of cognitive impairment was assessed with the Clinical Dementia Rating Scale (CDR). There was a significant, more than twofold, increase of tissue zinc in the AD-affected cortex compared with the other groups. Zinc levels increased with tissue amyloid levels. Zinc levels were significantly elevated in the most severely demented cases (CDR 4 to 5) and in cases that had an amyloid burden greater than 8 plaques/mm(2). Levels of other metals did not differ between groups. Brain zinc accumulation is a prominent feature of advanced Alzheimer disease (AD) and is biochemically linked to brain amyloid beta-peptide accumulation and dementia severity in AD.

In vivo imaging of region and cell type specific neocortical neurodegeneration in Alzheimer's disease. Perspectives of MRI derived corpus callosum measurement for mapping disease progression and effects of therapy. Evidence from studies with MRI, EEG and PET.

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

Beta-amyloid, neuronal death and Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disease that affects cognitive function in the elderly. Large extracellular beta-amyloid (Abeta) plaques and tau-containing intraneuronal neurofibrillary tangles characterize AD from a histopathologic perspective. However, the severity of dementia in AD is more closely related to the degree of the associated neuronal and synaptic loss. It is not known how neurons die and synapses are lost in AD; the current review summarizes what is known about this issue. Most evidence indicates that amyloid precursor protein (APP) processing is central to the AD process. The Abeta in plaques is a metabolite of the APP that forms when an alternative (beta-secretase and then gamma-secretase) enzymatic pathway is utilized for processing. Mutations of the APP gene lead to AD by influencing APP metabolism. One leading theory is that the Abeta in plaques leads to AD because Abeta is directly toxic to the adjacent neurons. Other theories advance the notion that neuronal death is triggered by intracellular events that occur during APP processing or by extraneuronal preplaque Abeta oligomers. Some investigators speculate that in many cases there is a more general disorder of protein processing in neurons that leads to cell death. In the later models, Abeta plaques are a byproduct of the disease process, rather than the direct cause of neuronal death. A direct correlation between Abeta plaque burden and neuronal (or synaptic) loss should occur in AD if Abeta plaques cause AD through a direct toxic effect. However, histopathologic studies indicate that the correlation between Abeta plaque burden and neuronal (or synaptic) loss is poor. We conclude that APP processing and Abeta formation is important to the AD process, but that neuronal alterations that underlie symptoms of AD are not due exclusively to a direct toxic effect of the Abeta deposits that occur in plaques. A more general problem with protein processing, damage due to the neuron from accumulation of intraneuronal Abeta or extracellular, preplaque Abeta may also be important as underlying factors in the dementia of AD.

Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer disease.

Synaptic pathology is proposed to be integral to the clinical expression of Alzheimer disease (AD). Most studies have assessed only the vesicle protein synaptophysin as a measure of synaptic integrity. The interrelationships of synaptophysin, other presynaptic proteins, the cholinergic system, and severity of dementia in AD remain unclear. We studied the presynaptic proteins synaptophysin, syntaxin and SNAP-25, along with choline acetyltransferase (ChAT) activity in prefrontal cortex (BA 46) samples from 18 subjects with AD and 16 controls. Mean values of presynaptic protein immunoreactivities were significantly reduced, by 21%-28%, and ChAT activity was reduced by 41% in the AD groups. Synaptic protein immunoreactivity and ChAT activity were correlated with Mini-Mental State Examination scores obtained 1 yr prior to death. When AD cases were subgrouped into mild/moderate and severe illness at time of death, all differences in presynaptic proteins and ChAT activity were significant between controls and severe cases. However, no significant differences were detected in BA 46 between controls and mild/moderate cases. Considerable synaptic reserve or plasticity remains in BA 46 until the late stages of AD. Synaptophysin and ChAT appear to be more vulnerable in severe AD than are syntaxin or SNAP-25.

The Presence of Isoaspartic Acid in β-Amyloid Plaques Indicates Plaque Age

Extracellular deposits of fibrillar β-amyloid are a characteristic neuropathology of Alzheimer's disease (AD). We have developed a novel antibody to a hypothesized “older isomer” of the amyloid protein. This antibody, raised against a synthetic β-amyloid peptide containing isoaspartic acid at position 7 (isoaspartic-7-Aβ), reacts with isoaspartic-7-Aβ, a nonenzymatic modification found in long-lived proteins. Plaques stained with this antibody are thioflavine positive and are found throughout the frontal and entorhinal cortices of AD cases. In frontal cortex, isoaspartic-7-Aβ plaques are clustered but have a widespread distribution in all cortical layers. Isoaspartic-7-Aβ is found primarily in the core of individual plaques surrounded by nonisomerized amyloid. Activated microglia are associated with plaques containing isomerized and nonisomerized amyloid. In contrast to AD, isoaspartic-7-Aβ plaques in Down's syndrome (DS) cases are found primarily in the superficial layers of frontal cortex. Using image analysis isoaspartic-7-Aβ deposition was correlated with dementia severity in AD and with age in DS. The results indicate that this antibody against altered aspartyl amyloid could be a useful indicator of the age of amyloid plaques.

Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype.

To study differences between subjects with Alzheimer disease (AD) and cognitively intact control subjects, with respect to brain histologic markers of AD, and the relationship of those markers in the AD group to severity of dementia, age at death, sex, and apolipoprotein E genotype. Washington University Alzheimer's Disease Research Center, St Louis, Mo. Consecutive neuropathologic series of 224 prospectively studied volunteer research subjects, 186 with dementia of the Alzheimer type (DAT) or "incipient" DAT and confirmed to have AD by postmortem examination and 13 cognitively intact subjects, confirmed to lack postmortem findings of AD. Brain densities (number per square millimeter) of senile plaques and neurofibrillary tangles, extent of cerebral amyloid angiopathy, cortical Lewy bodies, and apolipoprotein E genotype. Neocortical neurofibrillary tangle densities were substantially correlated with dementia severity, and to a greater degree than was true for senile plaque densities. When infarcts, hemorrhages, and Parkinson disease changes coexisted with AD, neurofibrillary tangle and senile plaque densities were lower. Plaque-predominant AD was found in a greater proportion of subjects with milder than more severe dementia. Entorhinal cortical Lewy bodies were no more frequent in plaque-predominant AD than in the remaining AD cases. Increasing age at death was negatively correlated with dementia severity and densities of senile plaques and neurofibrillary tangles. The apolipoprotein E epsilon4 allele frequency was greater in AD than in control subjects but decreased with increasing age. After controlling for dementia severity, senile plaque densities were only weakly related to epsilon4 allele frequency, and only in hippocampus. However, the degree of cerebral amyloid angiopathy was clearly related to epsilon4 allele frequency. Among subjects diagnosed during life as having DAT or incipient DAT, only 7% were found to have a neuropathologic disorder other than AD causing their dementia. (1) The order of the strength of relationships between densities of histologic markers and dementia severity in AD is neurofibrillary tangles greater than cored senile plaques greater than total senile plaques. (2) Advanced age at death is associated with somewhat less severe dementia and fewer senile plaques and neurofibrillary tangles. (3) Plaque-predominant AD may represent a developmental stage in AD. (4) Despite a substantial effect of apolipoprotein E epsilon4 as a risk factor for AD, on decreasing the age at AD onset, and increasing the amount of cerebral amyloid angiopathy, its effect on senile plaque densities is variable and complex, being confounded with age, dementia severity, and methodologic differences. (5) Stringent clinical diagnostic criteria for DAT, even in the very mild stage, and senile plaque-based neuropathologic criteria for AD are highly accurate.