Search

Brain imaging genetics intends to uncover associations between genetic markers and neuroimaging quantitative traits. Sparse canonical correlation analysis (SCCA) can discover bi-multivariate associations and select relevant features, and is becoming popular in imaging genetic studies. The L1-norm function is not only convex, but also singular at the origin, which is a necessary condition for sparsity. Thus most SCCA methods impose $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm onto the individual feature or the structure level of features to pursuit corresponding sparsity. However, the $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm penalty over-penalizes large coefficients and may incurs estimation bias. A number of non-convex penalties are proposed to reduce the estimation bias in regression tasks. But using them in SCCA remains largely unexplored. In this paper, we design a unified non-convex SCCA model, based on seven non-convex functions, for unbiased estimation and stable feature selection simultaneously. We also propose an efficient optimization algorithm. The proposed method obtains both higher correlation coefficients and better canonical loading patterns. Specifically, these SCCA methods with non-convex penalties discover a strong association between the APOE e4 rs429358 SNP and the hippocampus region of the brain. They both are Alzheimer’s disease related biomarkers, indicating the potential and power of the non-convex methods in brain imaging genetics.

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin., Whether Alzheimer's disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

Mild cognitive impairment (MCI) is a transitional state between normal cognitive functioning and dementia. A proposed MCI typology classifies individuals by the type and extent of cognitive impairment, yet few studies have characterized or compared these subtypes. Four hundred forty-seven women 65 years of age and older from the Women's Health Initiative Memory Study were classified into the 4 MCI subgroups and a "no impairment" group and compared on clinical, sociodemographic, and health variables. A cognitive deficit in at least 1 domain was present in 82.1% of participants, with most (74.3%) having deficits in multiple cognitive domains. Only 4.3% had an isolated memory deficit, whereas 21.3% had an isolated nonmemory deficit. Of the 112 women who met all MCI criteria examined, the most common subtype was amnestic multidomain MCI (42.8%), followed by nonamnestic multiple domain MCI (26.7%), nonamnestic single domain (24.1%), and amnestic single domain MCI (6.3%). Subtypes were similar with respect to education, health status, smoking, depression, and prestudy and onstudy use of hormone therapy. Despite the attention it receives in the literature, amnestic MCI is the least common type highlighting the importance of identifying and characterizing other nonamnestic and multidomain subtypes. Further research is needed on the epidemiology of MCI subtypes, clinical and biologic differences between them, and rates for conversion to dementia.

We applied the hippocampal radial atrophy mapping technique to the baseline and follow-up magnetic resonance image data of 169 amnestic mild cognitive impairment (MCI) participants in the imaging arm of the Alzheimer's Disease Cooperative Study MCI Donepezil/Vitamin E trial. Sixty percent of the subjects with none to mild hippocampal atrophy rated with the visual medial temporal atrophy rating scale (MTA score < 2) and 33.8% of the subjects with moderate to severe (MTA ≥ 2) hippocampal atrophy converted to Alzheimer's disease (AD) during 3-year follow-up. MTA ≥ 2 showed a trend for greater left sided hippocampal atrophy versus MTA < 2 groups at baseline (Pcorrected = 0.08). Higher MTA scores were associated with progressive atrophy of the subiculum and the CA1–3 subregions. The MTA < 2 group demonstrated significant bilateral atrophy progression at follow-up (left Pcorrected = 0.008; right Pcorrected = 0.05). Relative to MTA < 2 nonconverters, MTA < 2 converters showed further involvement of the subiculum and CA1 and additional involvement of CA2–3 at follow-up. Right CA1 atrophy was significantly associated with conversion to dementia (for 1 mm greater right CA1 radial distance subjects had 50% reduced hazard for conversion). Greater CA1 and subicular atrophy can be demonstrated early and is predictive of future conversion to AD, whereas CA2–3 involvement becomes more evident as the disease progresses.

Background: Immunization of patients with Alzheimers disease (AD) with synthetic amyloid-β peptide (Aβ42) (AN1792) was previously studied in a randomized, double-blind, placebo-controlled phase 2a clinical trial, Study AN1792(QS-21)-201. Treatment was discontinued following reports of encephalitis. One year follow-up revealed that AN1792 antibody responders showed improvements in cognitive measures as assessed by the neuropsychological test battery (NTB) and a decrease in brain volume compared with placebo. Methods: A follow-up study, Study AN1792(QS-21)-251, was conducted to assess the long-term functional, psychometric, neuroimaging, and safety outcomes of patients from the phase 2a study 4.6 years after immunization with AN1792. The results were analyzed by comparing patients originally identified as antibody responders in the AN1792 phase 2a study with placebo-treated patients. Results: One hundred and fifty-nine patients/caregivers (30 placebo; 129 AN1792) participated in this follow-up study. Of the 129 AN1792-treated patients, 25 were classified in the phase 2a study as antibody responders (anti-AN1792 titers 1:2,200 at any time after the first injection). Low but detectable, sustained anti- AN1792 titers were found in 17 of 19 samples obtained from patients classified as antibody responders in the phase 2a study. No detectable anti-AN1792 antibodies were found in patients not classified as antibody responders in the phase 2a study. Significantly less decline was observed on the Disability Assessment for Dementia scale among antibody responders than placebo-treated patients (p=0.015) after 4.6 years. Significant differences in favor of responders were also observed on the Dependence Scale (p=0.033). Of the small number of patients who underwent a follow-up MRI, antibody responders showed similar brain volume loss during the follow-up period subsequent to the AN1792 phase 2a study compared with placebo-treated patients. Conclusions: Approximately 4.6 years after immunization with AN1792, patients defined as responders in the phase 2a study maintained low but detectable, sustained anti-AN1792 antibody titers and demonstrated significantly reduced functional decline compared with placebo-treated patients. Brain volume loss in antibody responders was not significantly different from placebo-treated patients approximately 3.6 years from the end of the original study. No further cases of encephalitis were noted. These data support the hypothesis that Aβ immunotherapy may have long-term functional benefits.

Objectives Cognitive-discrepancy analysis has been shown to be a useful technique for detecting subtle cognitive deficits in normal-functioning elderly individuals who are genetically at-risk for Alzheimer disease (AD). However, studies that have used cognitive-discrepancy measures to date have used retrospective or cross-sectional designs, and the utility of this approach to predict cognitive decline has not been examined in a prospective investigation. Design Longitudinal study. Setting San Diego, CA, Veterans Administration Hospital. Participants Twenty-four normal-functioning elderly individuals participated in the study, with 16 subjects exhibiting no change in their Dementia Rating Scale (DRS) scores over an 1-year period (Stable Group), and 8 subjects exhibiting a decline in DRS scores over the 1-year period (Decline group). Measurements A cognitive-discrepancy measure isolating cognitive switching was computed that contrasted performance on a new higher-level task of executive functioning (a Stroop/Switching measure) relative to a composite measure of lower-level Stroop conditions. Results a) In the year before their cognitive changes, the Decline group exhibited a significantly larger cognitive-discrepancy (Stroop/Switching versus lower-level Stroop conditions) score compared with a control (Stable) group; and b ) the cognitive-discrepancy measure was superior to APOE genotype in predicting DRS decline. Conclusion Cognitive-discrepancy analysis isolating a component executive function ability not only seems to be a useful tool for identifying individuals at risk for cognitive deficits, but also shows promise in predicting individuals who may show subtle cognitive decline over time.

A recent clinical trial in patients with Mild Cognitive Impairment (MCI) found an increased rate of possible or probable Alzheimer's disease (AD) diagnoses in patients assigned to rofecoxib compared to placebo. This unexpected finding was difficult to interpret due to methodological issues and a lack of confirmation on secondary endpoints, as well as a lack of confirmation in trials in related populations. We performed additional post hoc analyses to explore explanations for the finding based on possible neuropathological, cardiovascular/cerebrovascular, or cognitive effects of rofecoxib. 1) Neuropathological hypothesis: Of the 189 incident cases of possible or probable AD, 154 were probable AD. In probable AD patients, the treatment hazard ratio was reduced compared to the primary analysis -- a concordant finding would have strengthened a conclusion that rofecoxib accelerated the underlying neuropathology of AD. The treatment hazard ratio was increased in the remaining 35 patients with less certain diagnoses, but there was no single predominant reason for the reduced certainty of diagnosis. 2) Cardiovascular hypothesis: Neither cardiovascular risk status nor mean arterial blood pressure had an overall effect on AD diagnosis or modified the treatment difference. 3) Cognitive side-effects hypothesis: The percentages of patients with non-specific NSAID-type central nervous system adverse events were similar between the treatment groups. In summary, the present analyses are limited by their post hoc nature but provided little support for any of the possible explanations explored. The significance of the observation that rofecoxib increased the rate of conversion from MCI to AD remains uncertain.

Objective: To compare volumetric MRI of whole brain and medial temporal lobe structures to clinical measures for predicting progression from amnestic mild cognitive impairment (MCI) to Alzheimer disease (AD). Methods: Baseline MRI scans from 129 subjects with amnestic MCI were obtained from participants in the Alzheimer9s Disease Cooperative Study group9s randomized, placebo-controlled clinical drug trial of donepezil, vitamin E, or placebo. Measures of whole brain, ventricular, hippocampal, and entorhinal cortex volumes were acquired. Participants were followed with clinical and cognitive evaluations until formal criteria for AD were met, or completion of 36 months of follow-up. Logistic regression modeling was done to assess the predictive value of all MRI measures, risk factors such as APOE genotype, age, family history of AD, education, sex, and cognitive test scores for progression to AD. Least angle regression modeling was used to determine which variables would produce an optimal predictive model, and whether adding MRI measures to a model with only clinical measures would improve predictive accuracy. Results: Of the four MRI measures evaluated, only ventricular volumes and hippocampal volumes were predictive of progression to AD. Maximal predictive accuracy using only MRI measures was obtained by hippocampal volumes by themselves (60.4%). When clinical variables were added to the model, the predictive accuracy increased to 78.8%. Use of MRI measures did not improve predictive accuracy beyond that obtained by cognitive measures alone. APOE status, MRI, or demographic variables were not necessary for the optimal predictive model. This optimal model included the Delayed 10-word list recall, New York University Delayed Paragraph Recall, and the Alzheimer9s Disease Assessment Scale–Cognitive Subscale total score. Conclusion: In moderate stages of amnestic mild cognitive impairment, common cognitive tests provide better predictive accuracy than measures of whole brain, ventricular, entorhinal cortex, or hippocampal volumes for assessing progression to Alzheimer disease.

Late-onset Alzheimer's disease (LOAD) and Parkinson's disease (PD) are the most common neurodegenerative disorders and in both diseases susceptibility is known to be influenced by genes. We set out to identify novel susceptibility genes for LOAD by performing a large scale, multi-tiered association study testing 4692 single nucleotide polymorphism (SNPs). We identified a SNP within a putative transcription factor binding site in the NEDD9 gene (neural precursor cell expressed, developmentally down-regulated), that shows good evidence of association with disease risk in four out of five LOAD samples [N = 3521, P = 5.38x10(-6), odds ratio (OR) = 1.38 (1.20-1.59)] and in addition, we observed a similar pattern of association in two PD sample sets [N = 1464, P = 0.0145, OR =1.31 (1.05-1.62)]. In exploring a potential mechanism for the association, we observed that expression of NEDD9 and APOE show a strong inverse correlation in the hippocampus of Alzheimer's cases. These data implicate NEDD9 as a novel susceptibility gene for LOAD and possibly PD. SB. 18.6.2013

Previous research suggests that patients with Alzheimer's disease exhibit cognitive impairment in the years preceding a clinical diagnosis. Memory impairments are particularly pronounced, but the relative degree to which other cognitive functions are impaired and the speed with which they decline during the preclinical years remains unclear. The authors report a detailed neuropsychological evaluation of 11 patients over the course of 3 years up to and including the 1st year of nonnormal diagnosis. The results suggest that performance falls off rapidly in all areas of cognitive functioning but that abilities thought to be subserved by the medial and lateral temporal lobes (episodic and semantic memory, respectively) appear to be substantially more impaired than those abilities thought to be subserved by the frontal lobes.

Objective: To study cycad-derived products as possible risk factors for dementia, mild cognitive impairment (MCI), and parkinsonism–dementia complex (PDC) on Guam. Methods: Complete risk factor data from in-person interviews of 166 cases of Guam dementia, 50 cases of amnestic MCI, and 21 cases of PDC were compared with 1,581 controls in the base population regarding exposure to cycad-derived products from a traditional food (fadang), consumption of fruit bats, and use of cycad-derived topical medicine. Results: Adjusted odds ratios (ORs) and 95% CIs for picking, processing, and eating fadang in young adulthood ranged from 1.42 (1.05 to 1.91) to 2.87 (1.48 to 5.56) and were consistently elevated and significant across all three diagnostic outcomes. Associations independent of exposure in young adulthood were for picking (OR 0.78, 95% CI 0.64 to 0.96) and processing (OR 0.77, 95% CI 0.63 to 0.94) fadang in childhood with Guam dementia. Men showed stronger and more consistent relations across exposure groups in young adulthood compared with women. No associations were found for consumption of fruit bats or exposure to cycad used as a topical medicine for any of the outcomes. Estimated adjusted population attributable risks suggest that exposure to eating fadang in young adulthood incurred the highest attributable risk percent. Conclusions: Environmental lifestyle and diet may contribute to the etiology of neurodegenerative diseases in the native population of Guam.

Objectives: To estimate the prevalence of dementia and its clinical subtypes among Chamorros on Guam aged 65 years or older and to examine associations with age, gender, education, and APOE genotype. Background: Chamorros, the indigenous people of Guam, had a high incidence of ALS and parkinsonism–dementia complex (PDC), in the 1950s. Over the next 50 years, ALS incidence declined markedly, but PDC only slightly. The prevalence of late life dementia in Chamorros and its relationship to ALS/PDC are unknown. Methods: Island-wide population-based survey of Chamorros aged 65 years or older as of January 1, 2003. Two-stage assessment: cognitive and motor screening, followed by neurologic and psychometric evaluation. Data were reviewed at consensus conference to make clinical diagnoses. Results: Of 2,789 Chamorros aged 65 years or older, 73% were enrolled; 27% declined participation, died before contact or screening, or moved off Guam. The point prevalence of all-cause dementia on February 1, 2004, was 12.2%. Prevalence data for subtypes were as follows: Guam dementia (clinically equivalent to AD), 8.8%; PDC, 1.5%; pure vascular dementia, 1.3%; other, 0.6%. The prevalence of dementia rose exponentially with age. Low education was significantly associated with dementia, but gender was not. There was a trend toward higher PDC prevalence among men. The APOE e4 allele was not associated with dementia. Conclusions: The prevalence of dementia among elderly Chamorros is relatively high. Guam dementia is the most common diagnosis and exceeds parkinsonism–dementia complex. Age and low education are strongly associated with dementia, but gender and APOE e4 are not. Incidence studies will allow risk factors for dementia to be clarified.

Objective: To assess the efficacy and tolerability of quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Methods: Multicenter randomized, double-blind, placebo-controlled parallel groups clinical trial involving 40 patients with dementia with Lewy bodies (n = 23), Parkinson disease (PD) with dementia (n = 9), or Alzheimer disease with parkinsonian features (n = 8). The main outcome measure for efficacy was change in the Brief Psychiatric Rating Scale (BPRS) from baseline to 10 weeks of therapy. For tolerability it was change in the Unified PD Rating Scale (UPDRS) motor section over the same time period. The trial was confounded by the need for a design change and incomplete recruitment. Results: No significant differences in the primary or secondary outcome measures of efficacy were observed. An unexpectedly large placebo effect, inadequate dosage (mean 120 mg/day), and inadequate power may have contributed to lack of demonstrable benefit. Quetiapine was generally well-tolerated and did not worsen parkinsonism, but was associated with a trend toward a decline on a measure of daily functioning. Conclusions: Quetiapine was well-tolerated and did not worsen parkinsonism. Although conclusions about efficacy may be limited, the drug in the dosages used did not show demonstrable benefit for treating agitation or psychosis in patients with dementia and parkinsonism. These findings are in keeping with prior studies reporting limited efficacy of various medications for reducing behavioral problems in demented patients.

Exogenously provided NGF enhances cognitive performance in impaired rodents and humans and is currently a promising compound for the treatment of dementia. To investigate whether NGF-dependent cognitive improvement may be due in part to increased hippocampal neurogenesis, adult and aged male rats were treated with NGF or vehicle intracerebroventricularly for 6 or 20 days followed by evaluation of cholinergic parameters and hippocampal neurogenesis. We show that NGF increases hippocampal cholinergic activity as rapidly as 3 days after initiation of treatment. NGF treatment for 6 days did not affect proliferation of progenitor cells in the dentate gyrus granule cell layer (GCL). However, continuous NGF infusion enhanced survival of new neurons in the GCL of young adult, but not aged rats. Taken together, these findings suggest that NGF, likely mediated through increased cholinergic tone, promotes neurogenesis in the adult hippocampus, which may relate to the nootropic action of NGF.

Objective: To investigate the neurocognitive measures that best predict progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD). Methods: We evaluated 539 participants with aMCI from the Alzheimer9s Disease Cooperative Study clinical drug trial of donepezil, vitamin E, or placebo. During the study period of 36 months, 212 aMCI participants progressed to AD. Using progression from aMCI to AD within 36 months as the dependent variable, a generalized linear model was fit to the data using the least absolute shrinkage and selection operator. Independent variables included in this analysis were age, sex, education, APOE-e4 (APOE4) status, family history of dementia, Mini-Mental State Examination score, Digits Backwards (Wechsler Memory Scale), Maze Time and Errors, Number Cancellation, Delayed Recall of Alzheimer9s Disease Assessment Scale Word List, New York University Paragraph Recall Test (Immediate and Delayed), Boston Naming Test, Category Fluency, Clock Drawing Test, and the Alzheimer9s Disease Assessment Scale–Cognitive subscale (ADAS-cog). Results: The model that best predicted progression from aMCI to AD over 36 months included APOE4 status, the Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), and the ADAS-cog total score. When APOE4 was removed from the analysis the resulting model had a similar estimated predictive accuracy as the full model. As determined by cross-validation, the estimated predictive accuracy of the final model was 80%. Conclusion: Progression from amnestic mild cognitive impairment to Alzheimer disease in this cohort was best determined by combining four common, easily administered, cognitive measures.

Plans are underway in Nevada to conduct a comprehenive, statewide initiative that will identify people at risk for ementia, Alzheimer’s disease (AD), or other memory disrders. The Nevada Vital Aging (NVA) Initiative will enroll s many as 12,000 volunteers older than 45 years in Nevada uring the next 5 years for the long-term exploration of actors that lead to memory problems ranging from mild emory loss to dementia. At a September 2006 think tank orkshop convened by Keep Memory Alive, the foundation or the Lou Ruvo Brain Institute of Las Vegas, Nevada, a roup of researchers and clinicians who specialize in AD or n conducting large-scale observational trials met to begin esigning the Initiative, which is expected to begin enrollng volunteers in the summer of 2007. Spearheading this Initiative is Zaven S. Khachaturian, hD, former Director of the Office of Alzheimer’s Disease esearch at the National Institutes of Health and now the resident and chief executive officer of Keep Memory live. Leon Thal, MD, and Lewis Kuller, MD, DrPH, o-chair the initiative. Thal heads the Alzheimer’s Disease esearch Center at the University of California, San Diego; uller is a professor of epidemiology at the University of ittsburgh Graduate School of Public Health. Other particpants at the workshop included Keith Bowman, MD, John reitner, MD, MPH, Denis Evans, MD, Lindsey Farrer, hD, Richard Frank, MD, Walter Kukull, PhD, Javier Nito, MD, PhD, Ronald Petersen, PhD, MD, Mark Sager, D, and Paul Scherr, PhD, DSc. These scientists and cliicians will form the core advisory group for the Initiative. lso participating in the workshop were John A. McDonald

Patients with autopsy-confirmed frontotemporal dementia (FTD; n = 16) and Alzheimer's disease (AD; n = 32) were compared on first-letter and semantic category fluency tasks. Despite being matched on age, education, and dementia severity, FTD patients performed worse overall and showed similar impairment in letter and semantic category fluency, whereas AD patients showed greater impairment in semantic category than letter fluency. A measure of the disparity between letter and semantic category fluency (the semantic index) was effective in differentiating FTD from AD patients, and this disparity increased with increasing severity of dementia. These unique patterns of letter and semantic category fluency deficits may be indicative of differences in the relative contribution of frontal-lobe-mediated retrieval deficits and temporal-lobe-mediated semantic deficits in FTD and AD.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions., Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Background The modified Telephone Interview for Cognitive Status (TICS-m) assesses cognitive status via the telephone and has been used to recruit for clinical trials by screening for amnestic mild cognitive impairment (aMCI). The utility of screening for aMCI has not been validated, and it is unknown which questions best predict aMCI. Methods The Alzheimer's Disease Cooperative Study (ADCS) used the TICS-m to recruit for an aMCI clinical trial. If telephone respondents screened positive for aMCI on the TICS-m, they were referred to a clinical site where they were assessed for the operational criteria of aMCI. Univariate analyses identified the TICS-m questions that best predicted aMCI, creating a final model using forward stepwise logistic regression. Results Of 52,722 calls, 16,312 were screened for trial entry. Of these, 4,883 received the TICS-m. The 2,431 that screened positive for aMCI were referred to a clinic, and 527 arrived for clinical assessment. Of these, 266 met operational criteria for aMCI. The positive predictive value of the TICS-m in this population is 50.9% (95% confidence interval [CI], 46.2% to 54.8%). The final model included 5 variables: (1) 10-word list delayed recall ( p p = 0.002), (3) season ( p = 0.009), (4) last name of current president ( p = 0.020), and (5) month ( p = 0.036). This model has a predictive accuracy of 0.61 (95% CI, 0.51 to 0.71) which is similar to the entire TICS-m. The predictive accuracy of the 10-word list delayed recall alone was 0.63 (95% CI, 0.54 to 0.72). Conclusion The TICS-m is not optimally efficient for recruitment of subjects for aMCI clinical trials. The 10-word delayed recall has a predictive accuracy similar to that of the entire TICS-m.

The objective of the present study was to determine whether a systematic optimization of Morris water maze (mwm) testing parameters could reveal a significant role of the septohippocampal cholinergic system in spatial working memory. Young adult rats were lesioned using 192 IgG-saporin infused bilaterally into the medial septum. Lesions were near complete as measured by choline acetyltransferase (ChAT) activity and immunohistochemistry. Behavioral testing was performed in three phases. In the first, lesioned and unlesioned rats were trained in the mwm focusing on working memory, which was tested using novel platform locations daily. In the second phase, the optimal locations were retested with increasing intertrial intervals (ITI). In the third phase, intracerebroventricular infusions of nerve growth factor (NGF) were employed to enhance cholinergic activity of the unlesioned rats and potentially further separate group performance. Neither the standard or increased ITI resulted in a consistent significant difference in spatial working memory between groups. In addition, NGF treatment also failed to induce a significant difference in behavioral performance. In conclusion, impairments in working memory as assessed by the mwm could not be revealed despite a greater than 90% loss of hippocampal ChAT and the use of optimal testing parameters and NGF treatment.

To determine which clinical feature(s) [among visual hallucinations (VH), extrapyramidal signs (EPS) and visuospatial impairment] in the earliest stages of disease best predicted a diagnosis of dementia with Lewy bodies (DLB) at autopsy, first-visit data of 23 pathologically proven DLB and 94 Alzheimer's disease cases were compared. There were no group differences with regard to age, gender, education or global severity of dementia at presentation (mean Mini-Mental State Examination: 24.0 versus 25.0, mean Dementia Rating Scale: 123.6 versus 125.7). DLB patients at initial presentation displayed an increased frequency of VH (P = 0.001), but not EPS (P = 0.3), compared to Alzheimer's disease patients. However, only a minority of DLB cases had either VH (22%), EPS (26%) or both (13%). In contrast, although not a core feature, visuospatial/constructional impairment was observed in most of the DLB cases (74%). Among clinical variables, presence/recent history of VH was the most specific to DLB (99%), and visuospatial impairment was the most sensitive (74%). As a result, VH at presentation were the best positive predictor of DLB at autopsy (positive predictive value: 83% versus 32% or less for all other variables), while lack of visuospatial impairment was the best negative predictor (negative predictive value: 90%). We conclude that the best model for differentiating DLB from Alzheimer's disease in the earliest stages of disease includes VH and visuospatial/constructional dysfunction, but not spontaneous EPS, as predictors. This suggests that clinical history plus a brief assessment of visuospatial function may be of the greatest value in correctly identifying DLB early during the course of disease.

Regulatable gene therapy systems provide a method to alter neurotransmitter levels in vivo. We developed a rodent fibroblast cell line expressing the choline acetyltransferase (ChAT) cDNA that is silenced by doxycycline (DOX) administration. The ability of the cell line to improve cognition was tested by grafting after cholinergic lesions. Ibotenic acid was injected bilaterally into the nucleus basalis of rats, which were distributed into three groups. One group received no treatment, while the second group received cortical transplants (Graft). The third group received identical grafts but was treated with DOX to turn off ChAT expression (Graft/DOX). An unlesioned group served as control. Water maze acquisition was significantly better in the Graft group compared to the Graft/DOX group, an effect also seen in the retention and spatial probe trials. However, cognitive enhancement was restricted to spatial tasks, as inhibitory avoidance or open-field activity measures were unchanged. Molecular and biochemical analyses confirmed that DOX regulated transgene transcription and ACh levels. This study demonstrates that regulatable gene therapy has therapeutic value for single-gene disorders and also provides a mechanism to deliver small molecules in a spatiotemporal pattern to delineate the role of these compounds in discrete behavioral tasks.

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10–specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P

Objective: Three placebo-controlled clinical trials have suggested the benefit of valproate for treatment of agitation associated with dementia; one was used as the basis for this multicenter trial, conducted by the Alzheimer’s Disease (AD) Cooperative Study. It addresses the efficacy, safety, and tolerability of divalproex sodium for the treatment of agitation associated with dementia. Methods: This was a randomized, double-blind, placebo-controlled clinical trial in 153 nursing home residents with probable or possible AD complicated by agitation; 110 (72%) completed the trial. Participants were randomized to treatment with divalproex sodium at a target dose of 750 mg/day (N 75) or placebo (N 78) for 6 weeks. The primary outcome measure was change from baseline on the Brief Psychiatric Rating Scale (BPRS) Agitation factor. Secondary outcomes included total BPRS, Clinical Global Impression of Change, Cohen-Mansfield Agitation Inventory score, and measures of safety and tolerability. Results: Compliance averaged 88%. Participants receiving divalproex achieved a mean dose of 800 mg/day. Change in mean BPRS Agitation factor scores did not differ between patients treated with divalproex and placebo, nor did secondary behavioral measures. Measures of safety and tolerability did not reveal clinically important drug/ placebo differences. Conclusions: This multicenter trial showed no benefit of divalproex sodium for treatment for agitation in dementia at a mean dose of 800 mg/day over 6 weeks. The results do not support findings from previous trials indicating possible benefit. (Am J Geriatr Psychiatry 2005; 13:942–949)

Objective Three placebo-controlled clinical trials have suggested the benefit of valproate for treatment of agitation associated with dementia; one was used as the basis for this multicenter trial, conducted by the Alzheimer's Disease (AD) Cooperative Study. It addresses the efficacy, safety, and tolerability of divalproex sodium for the treatment of agitation associated with dementia. Methods This was a randomized, double-blind, placebo-controlled clinical trial in 153 nursing home residents with probable or possible AD complicated by agitation; 110 (72%) completed the trial. Participants were randomized to treatment with divalproex sodium at a target dose of 750 mg/day (N = 75) or placebo (N = 78) for 6 weeks. The primary outcome measure was change from baseline on the Brief Psychiatric Rating Scale (BPRS) Agitation factor. Secondary outcomes included total BPRS, Clinical Global Impression of Change, Cohen-Mansfield Agitation Inventory score, and measures of safety and tolerability. Results Compliance averaged 88%. Participants receiving divalproex achieved a mean dose of 800 mg/day. Change in mean BPRS Agitation factor scores did not differ between patients treated with divalproex and placebo, nor did secondary behavioral measures. Measures of safety and tolerability did not reveal clinically important drug/placebo differences. Conclusions This multicenter trial showed no benefit of divalproex sodium for treatment for agitation in dementia at a mean dose of 800 mg/day over 6 weeks. The results do not support findings from previous trials indicating possible benefit.

A relatively early and substantial loss of basal forebrain cholinergic neurons is a constant feature of Alzheimer's disease (AD). However, the mechanisms that contribute to the selective vulnerability of these neurons are not fully delineated. In the present series of experiments, we determined the possible contribution of apoptotic processes and other pathologic cascades to the degeneration of the cholinergic neurons of the nucleus basalis of Meynert (NBM) in AD. In contrast to neurons in the frontal cortex which showed prominent DNA fragmentation as detected by the TUNEL method, no DNA fragmentation was observed within the NBM in any of the AD or normal brains. Similarly, immunoreactivity for the apoptotic signals Fas, Fas-ligand, Bax, Bcl-x, caspase-8, caspase-9 and caspase-3 was absent from the NBM of AD and control brains. In contrast, a substantial subpopulation of cholinergic neurons within the NBM in AD displayed prominent immunoreactivity for the apoptotic signal Fas-associated death domain (FADD) in the form of tangles. FADD immunoreactivity was also present in dystrophic neurites. FADD-positive tangle-like structures were localized in neurons which contained immunoreactivity for the cholinergic marker choline acetyltransferase (ChAT) and the low affinity neurotrophin receptor p75NTR. While many of the NBM cholinergic neurons in control brains contained immunoreactivity for the calcium binding protein calbindin-D28K (CB), the NBM neurons in AD displayed a substantial loss of CB immunoreactivity. Importantly, most of FADD-immunoreactive cholinergic neurons were devoid of CB immunoreactivity, and, conversely, most CB-positive cholinergic neurons had no FADD immunoreactivity. FADD immunoreactivity within the basal forebrain was colocalized with phosphorylated tau immunoreactive tangles and dystrophic neurites. In contrast, FADD immunoreactivity did not appear to be related to the primarily diffuse amyloid-beta deposits intermingled between cholinergic neurons in AD NBM. Finally, many CD68-positive microglia were observed surrounding the NBM cholinergic neurons in AD. In conclusion, the findings of the present study indicate that, while the FADD apoptotic signaling pathway may be triggered within the basal forebrain cholinergic neurons in AD, the apoptotic cascade is most likely aborted as no DNA fragmentation was detected and the executioner caspase-3 was not up-regulated within these neurons. The findings also suggest possible relationships between loss of CB, FADD expression and phosphorylation of tau within the basal forebrain cholinergic neurons in AD.

Background: Olfactory abnormalities are reported in Alzheimer’s disease and Parkinson’s disease. Anosmia appears to be common in dementia with Lewy bodies but not in pure Alzheimer’s disease. Objective: To determine whether anosmia improves discrimination between the Lewy body variant (LBV) of Alzheimer’s disease and “pure” Alzheimer’s disease. Methods: 106 cases of necropsy confirmed pure Alzheimer’s disease (n = 89) or LBV (n = 17) were reviewed. All had received butanol odour threshold testing. Anosmia was defined as a score ⩽1.0 on a 0–9 point scale. Logistic regression analysis was used to model potential predictors (for example, parkinsonism, smoking, hallucinations) of neuropathological diagnosis and anosmia. Results: LBV cases had an increased prevalence of anosmia (65%) compared with Alzheimer’s disease (23%; odds ratio (OR) = 6.3, p = 0.00045), or normal elderly people (6.7%). Within the dementia cases, the negative predictive value (92%) and specificity (78%) of anosmia were both good; sensitivity for detecting LBV was 65%, but the positive predictive value (PPV) was only 35%. Logistic regression models showed anosmia (OR = 5.4, p = 0.005) and visual hallucinations (OR = 7.3, p = 0.007) were strong independent predictors of Lewy body pathology. When anosmia was added as a core feature to consensus diagnostic criteria for probable Lewy body dementia, five additional cases of LBV were detected (29% increased sensitivity), but with four additional false positives (1% increased discrimination, 4% decreased specificity, 33% decreased PPV). Conclusions: Anosmia is very common in LBV. Adding anosmia as a core feature improved sensitivity for detecting LBV, but did not improve discrimination between Alzheimer’s disease and LBV owing to a concomitant increase in false positives.

Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.

Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and might be mediated via the COX-2 enzyme. Previous studies with the selective COX-2 inhibitors, rofecoxib and celecoxib, have shown that they do not alter the progression of AD. We conducted a double-blind study to investigate whether rofecoxib could delay a diagnosis of AD in patients with mild cognitive impairment (MCI), a group with an expected annual AD diagnosis rate of 10-15%. MCI patients > or =65 years were randomized to rofecoxib 25 mg (N=725) or placebo (N=732) daily for up to 4 years. The primary end point was the percentage of patients with a clinical diagnosis of AD. The estimated annual AD diagnosis rate was lower than the anticipated 10-15%: 6.4% in the rofecoxib group vs 4.5% in the placebo group (rofecoxib : placebo hazard ratio=1.46 (95% CI: 1.09, 1.94), p=0.011). Analyses of secondary end points, including measures of cognition (eg the cognitive subscale of the AD Assessment Scale (ADAS-Cog)) and global function (eg the Clinical Dementia Rating (CDR)), did not demonstrate differences between treatment groups. There was also no consistent evidence that rofecoxib differed from placebo in post hoc analyses comparing ADAS-Cog and CDR-sum of boxes scores in overlapping subgroups of patients who had Mini Mental State Exam scores of 24-26 in the present MCI study and in a previous AD treatment study with a similar design. The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD. In conjunction with the lack of effects observed in previous AD studies, the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD.

Alzheimer disease (AD) is a complex neurodegenerative disorder predisposed by multiple genetic factors. Mutations in amyloid beta precursor protein (APP) are known to be associated with autosomal dominant, early onset familial AD and possibly also late onset AD (LOAD). A number of genes encoding proteins capable of binding to APP have been identified, but their contribution to AD pathobiology remains unclear. Conceivably, mutations in these genes may play a role in affecting AD susceptibility, which appears to be substantiated by some genetic studies. Here we report results of the first genetic association study with APBB2, an APP binding protein (also known as FE65L), and LOAD, in three independently collected case-control series totaling approximately 2,000 samples. Two SNPs were significantly associated with LOAD in two sample series and in meta-analyses of all three sample sets (for rs13133980: odds ratio [OR](hom)=1.36 [95% CI: 1.05-1.75], OR(het)=1.32 [95% CI: 1.04-1.67], minor allele frequency=43%, P=0.041; and for hCV1558625: OR(hom)=1.37 [95% CI: 1.06-1.77], OR(het)=1.02 [95% CI: 0.82-1.26], minor allele frequency=48%, P=0.026). One of these SNPs, located in a region conserved between the human and mouse genome, showed a significant interaction with age of disease onset. For this marker, the association with LOAD was most pronounced in subjects with disease onset before 75 years of age (OR(hom)=2.43 [95% CI: 1.61-3.67]; OR(het)=2.15 [95% CI: 1.46-3.17]; P=0.00006) in the combined sample set. Our data raise the possibility that genetic variations in APBB2 may affect LOAD susceptibility.

Several studies have reported evidence for linkage of late-onset Alzheimer's disease (LOAD) to chromosome 9. Recently, an intronic polymorphism affecting alternative splicing of exon 8 of ubiquilin 1 (UBQLN1) was reported to be associated with LOAD. We attempted to replicate this observation by genotyping this polymorphism, rs12344615 (also known as UBQ-8i), in a large sample of 1,544 LOAD cases and 1,642 nondemented controls. We did not find any evidence that this single nucleotide polymorphism, or any of six others tested in UBQLN1, increases risk for LOAD. Williams J, Goate A.

Little is known about possible differences in the memory deficits that occur in Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We compared 24 autopsy-confirmed DLB and 24 age-, education-, and MMSE-matched autopsy-confirmed AD patients on the California Verbal Learning Test (CVLT) and the Wechsler Memory Scale-Revised Logical Memory subtest. The DLB and AD groups were similarly impaired on CVLT Total Learning (Trials 1–5) and Long Delayed Free Recall, but the DLB group demonstrated relative improvement in Savings scores and on recognition testing compared to the AD group. Likewise, the patient groups were equally impaired on Logical Memory immediate and delayed recall, but the DLB group's Saving scores were significantly better than those of the AD patients. These results indicate that while both DLB and AD patients exhibit significant memory impairment, the ability to consolidate information may be less severely impaired in DLB patients than in AD patients. (JINS, 2004, 10, 689–697.)

Genetic association of ABCA1 or the ATP-binding cassette A1 transporter with late-onset Alzheimer's disease (LOAD) has recently been proposed for a haplotype comprised of three single nucleotide polymorphisms (SNPs). We have genotyped these and other ABCA1 SNPs in a LOAD case-control series of 796 individuals (419 cases versus 377 controls) collected at Washington University. While our sample series is larger and thus presumably has greater power than any of the series used to implicate ABCA1, we were unable to replicate the published association, using either single markers or multiple marker haplotypes. Further, we did not observe significant and replicated association of other ABCA1 SNPs we examined with the disease, thus these ABCA1 variants do not appear to influence the risk of LOAD in this study.

A rat fibroblast cell line was modified to contain the Drosophila choline acetyltransferase (ChAT) cDNA under the control of a tetracycline-regulated system. Several clonal lines were assessed in vitro and in vivo to establish the optimal clone for gene therapy experiments. The influence of in vitro cell density on ChAT expression was compared to biological activity detected after grafting to the rat brain. While each clone had different ChAT activity patterns, all clones had low activity immediately post-grafting which increased over time, reaching a plateau between 1 and 2 months which was maintained for at least 1 year. The clones expressed a high basal ChAT activity level in vitro that was repressed in a dose- and time-dependent manner with doxycycline (DOX) treatment. In the absence of DOX, high levels of ChAT activity were maintained for at least 2 months in vitro. DOX induced a rapid and strong (200-fold) suppression of ChAT activity within 48 h. A dose–response curve indicated that the fibroblasts were very sensitive to low concentrations of DOX (ED50 12 pg/ml). Removal of DOX led to a derepression of ChAT activity within 2 days. These cells will be useful for ex vivo gene therapy of the cholinergic system.

Objective: To determine the relation of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) to the development and evolution of Alzheimer disease (AD). Methods: An autopsy series of 102 patients with dementia and pathologically confirmed AD and 29 normal control subjects (NCs) was studied. AD cases were stratified according to their last Mini-Mental State Examination (MMSE) before death as mild, moderate, severe, or very severe. NPs and NFTs were enumerated in the midfrontal (MF), inferior parietal (IP), superior temporal (ST), hippocampal (Hip), or entorhinal cortices using thioflavin-S preparations. Results: Most (87%) of the NCs had allocortical NFTs, whereas only a minority (37%) displayed neocortical NPs, and even fewer (19%) showed Hip NPs. In contrast, none of the NCs exhibited neocortical NFTs, except one case with a single ST tangle. However, neocortical NFTs were not detected in even 10% of the patients with AD and, in particular, were absent in nearly 50% of those with mild disease at death. Thus, their sensitivity as a marker of AD was lower than that of NPs, which, conversely, were found in all patients with AD. Comparing NCs and patients with mild AD, significant differences were found for numbers of NPs only. Across the AD groups, in contrast, although NP and NFT density increased with dementia severity, significant differences consistently emerged for NFTs alone. Conclusions: Deterioration in Alzheimer disease appears to be driven by neuritic plaques and neurofibrillary tangles at different stages of the disease. The significant increase in neuritic plaques, but not neurofibrillary tangles, in patients with even mild Alzheimer disease at death compared with normal control subjects suggests that only neuritic plaques are associated with the earliest symptoms of Alzheimer disease.

Objective: To determine the effect of idebenone on the rate of decline in Alzheimer’s disease (AD). Methods: A 1-year, multicenter, double-blind, placebo-controlled, randomized trial was conducted. Subjects were over age 50 with a diagnosis of probable AD and had Mini-Mental State Examination (MMSE) scores between 12 and 25. Subjects were treated with idebenone 120, 240, or 360 mg tid, each of which was compared with placebo. Primary outcome measures were the Alzheimer’s Disease Assessment Scale–Cognitive Subcomponent (ADAS-Cog) and a Clinical Global Impression of Change (CGIC). Secondary outcome measures included measurements of activities of daily living, the Behavioral Pathology in Alzheimer’s Disease Rating Scale, and the MMSE. Results: Five hundred thirty-six subjects were enrolled and randomized to the four groups. Except for a slight difference in age, there were no differences in patient characteristics at baseline. For the primary outcome measures, there were no significant overall differences between the treatment groups in the prespecified four-group design. In an exploratory two-group analysis comparing all three treated groups combined with placebo, drug-treated patients performed better on the ADAS-Cog in both the intent-to-treat (ITT) and completers analyses. There were no differences in the CGIC scores for the ITT or completers analyses in either the four-group or the two-group analyses. There were no overall differences on any of the secondary outcome measures in any of the analyses. Conclusion: Idebenone failed to slow cognitive decline in AD that was of sufficient magnitude to be clinically significant.

The Sleep Disorders Inventory (SDI) is an expanded version of one item of the Neuropsychiatric Inventory (NPI). It describes the frequency, severity, and caregiver burden of sleep-disturbed behaviors during a period prior to its administration. We carried out post hoc analyses on baseline responses to the SDI in 104 persons with Alzheimer's disease (AD) and live-in caregivers who had been recruited for a trial of melatonin in the treatment of sleep disturbance. These patient-participants averaged

Background: Cross-sectional studies in Alzheimer’s disease (AD) show a strong relationship between extrapyramidal motor signs and presence of psychosis, yet it remains unclear whether neuromotor abnormalities precede and therefore can predict development of psychosis in AD. Objective: To identify cognitive and motor risk factors for the development of psychosis in patients with AD. Methods: Baseline clinical motor ratings and instrumental measures of neuromuscular function were obtained from 54 nonpsychotic patients with AD who were evaluated annually for 2 years for the development of psychosis. Survival analyses were performed to identify incidence and risks associated with psychosis. Results: The incidence of new onset psychosis in our sample was 32.5% in 2 years. Patients with abnormal agonist muscle burst amplitudes during rapid alternating movements of the hand were more likely to develop psychosis than those without (OR = 4.31; p = 0.007). Women with AD also had a higher risk of developing psychosis within 2 years than men (OR = 1.33; p = 0.01). Conclusions: Using simple noninvasive instrumental procedures for assessing neuromotor function, it may be possible to identify an individual’s level of risk for developing psychosis during the course of AD.

Background: Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology. Objective: To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain. Methods: The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects. Results: Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden ρ2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation. Conclusions: Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.

Background: The neurodegenerative process in Alzheimer’s disease (AD) and in the Lewy body variant of AD (LBV) patients is characterized by cholinergic dysfunction and deposition of amyloid β-peptide (Aβ) 1–40 and 1–42; however, the differential effects of Aβ species on the cholinergic system are not completely clear. Objective: To better understand the relationship between levels of Aβ1–40 and 1–42 on cholinergic deficits in AD and LBV patients. Methods: Levels of choline acetyltransferase (ChAT) activity and ChAT immunoreactivity in the plaques in the frontal cortex of patients with AD and LBV were correlated with Aβ1–42 and 1–40 levels determined by ELISA and with neuropathologic and neurologic markers. Results: Although the overall levels of ChAT activity were reduced in AD and LBV cases, there was a direct correlation with Aβ1–42 levels. Furthermore, patients with high Aβ1–42 levels had more abundant cholinergic dystrophic neurites in the plaques than cases with lower Aβ1–42. Conclusion: Aβ1–42 may also trigger cholinergic dysfunction by promoting aberrant neuritic sprouting.

Both monoamine oxidase (MAO) A and MAO B in the brain have been implicated in the etiology of Alzheimer's disease. MAO B is elevated in plaque-associated glia in Alzheimer brain. Elevations in MAO A in Alzheimer neurons have been linked to increases in neurotoxic metabolites and neuron loss. We investigated the relationship between cognitive function in Alzheimer patients and post-mortem prefrontal cortex MAO A and B activities. Prefrontal cortex tissue from 92 Alzheimer patients and 74 neurologically normal subjects was obtained at autopsy and analyzed for activities of MAO A and B by radioenzymatic methods. Mini Mental Status Exam was performed on Alzheimer patients within 1 year of death. Alzheimer brains were analyzed for Braak stage, tangles, plaques and choline acetyltransferase activity. Prefrontal cortex MAO B activity was significantly increased by 16% in Alzheimer patients versus normals, whereas MAO A activity was significantly decreased by 17% in these same patients. Neither MAO A nor MAO B activities correlated with cognitive function (MMSE score), choline acetyltransferase activity, plaques, neurofibrillary tangles, Braak stage, or age of disease onset in the Alzheimer patients. With increasing Alzheimer duration or increasing Braak stage, MMSE scores and choline acetyltransferase activity declined, but levels of MAO A and B in prefrontal cortex were unchanged. Patients in the upper quintile for MAO A or B activity did not differ significantly from those in the lowest quintile with respect to MMSE scores or age of Alzheimer disease onset. We conclude that the changes in MAO A and B in the prefrontal cortex occur very early in Alzheimer's disease and remain relatively constant as the disease progresses.

The profiles of neuropsychological deficits associated with Alzheimer's disease (AD) in Young-Old (M age < 70) and Very-Old (M age > 80) patients were compared, along with possible modifying effects of apolipoprotein E (APOE) genotype on these profiles. A comprehensive battery of neuropsychological tests was administered to the two AD patient groups (Young-Old: n = 33; Very-Old: n = 48) and their respective age-matched normal control (NC) groups who remained free of dementia on follow-up examinations over a 1 to 10 year period (Young-Old: n = 43; Very-Old: n = 36). AD and NC groups did not differ in education levels or gender distributions. Young-Old AD and Very-Old AD groups were comparable in education, gender, dementia severity, and disease duration. Results showed that both AD groups achieved comparable raw scores on all the neuropsychological measures. However, when scores were standardized on the basis of performance of their respective NC groups (i.e., age-corrected z scores), Very-Old AD patients significantly outperformed Young-Old AD patients on tests of executive functions, visuospatial skills, and delayed memory. Furthermore, the relationship between age and memory and executive function deficits in AD was modified by APOE genotype. These data suggest that the profile of neuropsychological deficits associated with AD in the Very-Old lacks the disproportionate saliency of episodic memory and executive function deficits typical of the Young-Old. (JINS, 2003, 9, 783–795.)

Mild cognitive impairment (MCI) appears to be a transitional stage in the development of Alzheimer's disease (AD). Patients with MCI show impaired memory performance and hippocampal atrophy relative to normal elderly controls. Prior studies indicate that the degree of hippocampal atrophy in MCI patients predicts conversion to AD. In contrast to patients with MCI who have deficits primarily in memory, AD patients have clinically evident impairments in both memory and nonmemory cognitive domains. One explanation for the observation that a smaller hippocampal volume predicts conversion to AD might be that hippocampal atrophy is associated with early impairment in nonmemory cognitive areas as well as memory. A link between hippocampal volume and nonmemory function could occur if hippocampal atrophy was correlated with AD pathology in other brain regions. We therefore sought to determine the relationship of hippocampal volume with performance on memory and nonmemory tasks in patients with MCI. Although we found a significant correlation between hippocampal volume and memory performance, we did not find a significant correlation between hippocampal volume and nonmemory performance. We conclude that the relationship between hippocampal volume and risk of AD is likely tied to reduced memory performance and not associated with impairment in nonmemory cognitive domains.

Glucose and insulin may play an important role in the pathophysiology and symptomatology of Alzheimers disease (AD), and prior studies suggest interactions among glucose, insulin, gender and apolipoprotein E genotype. We analyzed the relationship between steroid-induced glucose elevation and gender, presence of the apolipoprotein E epsilon 4 (APOE-4) allele and cognition using data from a multicenter trial of prednisone therapy in AD. The low-dose prednisone regimen (initial dose: 20 mg/day, maintenance dose: 10 mg/day) caused a moderate increase in random blood glucose (mean post-baseline glucose 115 mg/dl). There was a significant interaction between rise in glucose, gender and presence of the APOE-4 allele. There was no important relationship between glucose and cognitive function at baseline or with prednisone treatment. Meta-analysis including data from three other AD trials showed a small influence of random blood glucose on cognitive scores. These results support a relationship between gender, apolipoprotein E genotype and glucose metabolism, but do not indicate that mild changes in glucose have an important impact on cognitive function.

The non-Abeta component of Alzheimer's disease amyloid precursor protein (NACP) is predominantly a neuron-specific presynaptic protein that may play a central role in neurodegeneration because NACP fragments are found in Alzheimer's disease amyloid and a mutation in the NACP gene is associated with familial Parkinson's disease. In addition, NACP may play an important role during synaptogenesis and CNS development. To understand better the patterns of NACP expression during development, we analyzed the levels of this protein as well as the levels of another synaptic protein (synaptophysin) by ribonuclease protection assay, western blotting, and immunocytochemistry in fetal, juvenile, and adult mouse brain. From embryonic day 12 to 15, there was a slight increase, which was then followed by a more dramatic increase at later time points. Immunocytochemical staining for NACP increases throughout these stages as well. Although NACP appeared early in CNS development, synaptophysin levels started to rise at a later stage. These findings support the contention that NACP might be important for CNS development. Furthermore, the cytosolic component of NACP precedes the particulate component in development, indicating that a redistribution of the protein to the membrane fraction may be important for events later in neuronal development and in synaptogenesis.

Nerve growth factor (NGF) ameliorates deficits in models of cholinergic hypofunction. However, notable adverse effects of intracerebroventricular (ICV) infusion of NGF include weight loss, Schwann cell hyperplasia (SCH), and aberrant sensory and sympathetic sprouting. In order to maintain efficacy on the cholinergic basal forebrain (CBF) and minimize these detrimental effects, intraparenchymal NGF infusion was compared with ICV administration to assess morphological and functional measures. NGF was delivered intraparenchymally (Intra-NGF) or intracerebroventricularly (ICV-NGF) for 3 and 6 months. Hypertrophy of cholinergic nucleus basalis neurons at 3 and 6 months was not different between both routes of administration, indicating similar efficacy for the CBF. SCH surrounding the medulla was observed in both Intra- and ICV-NGF animals due to the widespread distribution of NGF from the infusion site. The thickness of SCH reached a plateau at 3 months in ICV-NGF animals, while further proliferation occurred in Intra-NGF animals. More importantly, ectopic Schwann cells and aberrant sensory and sympathetic sprouting within the medulla oblongata were found solely in ICV-NGF animals. Differential changes in sensory processing were evident by an exaggerated response to acoustic stimuli in Intra-NGF animals and a decrease in thermal pain threshold in ICV-NGF-treated animals. Intra-NGF treatment did not produce the reduction in body weight exhibited by ICV-NGF-treated rats. These results indicate that different routes of NGF administration are identically efficacious for CBF neurons, but differentially modulate behaviors and structures leading to distinct profiles of adverse effects. Thus, current trophic factor delivery methods require further refinement to abolish detrimental effects.

Background: The growing propensity to diagnose AD in individuals with very mild cognitive impairment increases the danger of false-positive diagnostic errors. Unfortunately, there is little systematically acquired information about the accuracy of the AD diagnosis in very mildly impaired patients. Objective: To determine the accuracy of the diagnosis of AD in very mildly impaired patients and to identify objective measures that effectively distinguish these patients from elderly normal controls (NC). Methods: Consecutive patients with Mini-Mental State Examination scores of ≥24 who received a clinical diagnosis of AD were evaluated annually for at least 3 years. The initial diagnosis was verified or refuted by autopsy or by information obtained in subsequent evaluations. Initial neuropsychological test scores of verified AD patients were compared with those of NC subjects to identify effective diagnostic measures. Results: The diagnosis of AD was confirmed in 98 of 110 (89%) very mildly impaired patients (33/36 by autopsy, 65/74 by disease progression). The diagnosis was inaccurate in 12 patients (11%): Seven were subsequently diagnosed with other neurologic disorders, and five were ultimately found to be normal. Neuropsychological measures of delayed recall, verbal fluency, and global cognitive status (i.e., Mattis Dementia Rating Scale) provided excellent sensitivity (≥96%) and specificity (≥93%) for differentiating between very mildly impaired AD patients and NC subjects. Conclusions: When comprehensive assessment procedures are employed, AD can be diagnosed with reasonably high accuracy in very mildly impaired individuals. However, the dementia evaluation should be repeated after approximately 1 year to ensure the accuracy of the initial diagnosis.

It has been reported that patients with amnesia have a reduced effect of word repetition upon the late positive component of the event related potential (ERP), which peaks at around 600 ms after word onset.To study a word repetition ERP paradigm in subjects with mild cognitive impairment.14 patients with mild cognitive impairment (mean mini-mental state examination score = 27); 14 normal elderly controls.Auditory category statements were each followed by a single visual target word (50% "congruous" category exemplars, 50% "incongruous") while ERPs were recorded. N400 (an ERP component elicited by semantically "incongruous" words) and LPC amplitude data were submitted to analysis of variance.The latency of the N400 was slower in mild cognitive impairment. In normal controls, the ERPs to "congruous" targets showed a late positive component to new words, which was greatly diminished with repetition. This repetition effect in normal subjects started before 300 ms at right frontal sites, and peaked at approximately 600 ms post-stimulus over posterior sites. In contrast, the group with mild cognitive impairment had a reduced repetition effect (p0.02), which started around 500 ms, with a more central distribution. Further comparisons within the cognitive impairment group showed no appreciable congruous word repetition effect among seven individuals who subsequently converted to probable Alzheimer's disease. The congruous word repetition effect in the group with mild cognitive impairment was almost entirely accounted for by the non-converters. The amplitude of the congruous late positive component word repetition effect was significantly correlated (0.38or = ror = 0.73) with several verbal memory measures.The congruous word repetition ERP effect appears sensitive to the memory impairment in mild cognitive impairment and could have value in predicting incipient Alzheimer's disease.