Alzheimer Disease: Schmitt FA

Mendiondo MS, Kryscio RJ, Schmitt FA. · No affiliation provided · Neurology. · Pubmed #11571313 No free full text.

This publication has no abstract.

Karlawish JH, Schmitt FA. · No affiliation provided · J Am Geriatr Soc. · Pubmed #10968311 No free full text.

This publication has no abstract.

Nelson PT, Smith CD, Abner EA, Schmitt FA, Scheff SW, Davis GJ, Keller JN, Jicha GA, Davis D, Wang-Xia W, Hartman A, Katz DG, Markesbery WR. · Department of Pathology, Division of Neuropathology, University of Kentucky Medical Center, Sanders-Brown Center on Aging and Alzheimer's Disease Center, University of Kentucky, Lexington, KY 40536-0230, USA. · Biochim Biophys Acta. · Pubmed #18789386 No free full text.

Abstract: The cerebral neuropathology of Type 2 diabetes (CNDM2) has not been positively defined. This review includes a description of CNDM2 research from before the 'Pubmed Era'. Recent neuroimaging studies have focused on cerebrovascular and white matter pathology. These and prior studies about cerebrovascular histopathology in diabetes are reviewed. Evidence is also described for and against the link between CNDM2 and Alzheimer's disease pathogenesis. To study this matter directly, we evaluated data from University of Kentucky Alzheimer's Disease Center (UK ADC) patients recruited while non-demented and followed longitudinally. Of patients who had come to autopsy (N = 234), 139 met inclusion criteria. These patients provided the basis for comparing the prevalence of pathological and clinical indices between well-characterized cases with (N = 50) or without (N = 89) the premortem diagnosis of diabetes. In diabetics, cerebrovascular pathology was more frequent and Alzheimer-type pathology was less frequent than in non-diabetics. Finally, a series of photomicrographs demonstrates histopathological features (including clinical-radiographical correlation) observed in brains of persons that died after a history of diabetes. These preliminary, correlative, and descriptive studies may help develop new hypotheses about CNDM2. We conclude that more work should be performed on human material in the context of CNDM2.

Caban-Holt A, Bottiggi K, Schmitt FA. · Sanders-Brown Center on Aging, University of Kentucky Chandler Medical Center, Lexington, KY 40536-0284, USA. · Geriatrics. · Pubmed #16025769 No free full text.

Abstract: Alzheimer's disease (AD) is a progressive disorder that negatively impacts cognitive, behavioral, and functional abilities. Because of the complex nature of this disease, it is crucial to design assessment procedures that accurately track disease progression across a wide variety of symptom domains. One important use of such techniques is to assess the effectiveness of therapeutic compounds in AD clinical trials. A number of outcome measures that assess cognitive, behavioral, functional, or global ability have been developed for this purpose. This paper describes the assessment measures that are most commonly used in AD trials. The inherent strengths and limitations of each evaluative technique are summarized, as well as how these outcome measures are useful to the practicing clinician.

Schmitt FA, Cragar D, Ashford JW, Reisberg B, Ferris S, Möbius HJ, Stöffler A. · Sanders-Brown Center on Aging, Department of Psychiatry, University of Kentucky Medical Center, Lexington, KY 40536-0230, USA. · J Neural Transm Suppl. · Pubmed #12456059 No free full text.

Abstract: Measurement of cognitive dysfunction and treatment response in the early stages of Alzheimer's disease (AD) has used such scales as the Mini-Mental State Examination (MMSE) and the AD Assessment Scale (ADAS). With the exception of clinical rating scales, however, there are only a few objective measures of cognition for tracking progression in advanced AD. Given renewed interest in potential therapies for advanced AD, objective measures of cognition are important for the adequate evaluation of change due to AD progression or therapy. Several cognitive measures for advanced AD are reviewed. One measure, the Severe Impairment Battery (SIB) is reviewed in detail. Preliminary analyses from a trial of memantine show significant change on the SIB in memory (p < 0.001) and visuospatial functions (p < 0.02) over six-months with a trend for language and praxis. Data from a donepezil trial also highlight the importance of accurate assessment in advanced AD.

Ashford JW, Schmitt FA. · Department of Psychiatry, Sanders-Brown Center on Aging, University of Kentucky, 101 Sanders-Brown Building, Lexington, KY 40536-0230, USA. · Curr Psychiatry Rep. · Pubmed #11177755 No free full text.

Abstract: Alzheimer's disease (AD) progresses from a preclinical period, through a middle phase of cognitive deterioration, to a late, profound state. The temporal progression of disability can be modeled with a horologic (time-based) function using "time-index" (TI) intervals (day- or year-units) to quantify an individual's disability across multiple cognitive and functional domains relative to a reference AD population. Clinicians and researchers can use TI quantification to assess dementia severity and initial therapy benefits. Rate of progression and confidence intervals require at least two successive measurements. Rate of progression measures can be used to support diagnosis and to investigate disease-course-modifying therapies.

Feldman HH, Schmitt FA, Olin JT, Anonymous00305. · Division of Neurology, University of British Columbia, Vancouver, BC, Canada. · Alzheimer Dis Assoc Disord. · Pubmed #17132971 No free full text.

Abstract: In moderate-to-severe Alzheimer disease (AD), there are significant losses of activities of daily living (ADL). In a recent prospective, randomized, placebo-controlled trial, memantine treatment lessened the overall functional decline in AD patients already on stable donepezil therapy. In this trial, patients (n=404) with Mini-Mental State Examination scores of 5 to 14 receiving stable donepezil treatment were randomized to double-blind treatment with memantine (10 mg b.i.d.; n=203) or placebo (n=201). A primary outcome measure was the 19-item Alzheimer's Disease Cooperative Study--Activities of Daily Living Inventory (ADCS-ADL(19)). To further evaluate the treatment effects of memantine on function, we performed post hoc analyses of ADCS-ADL(19) data from this trial, including ADL items and new subscales derived from factor analysis. Using mixed model analyses, patients receiving memantine had statistically significant less decline in total ADCS-ADL(19) scores compared with placebo. An item analysis revealed statistically significant benefits of memantine on grooming, toileting, conversing, watching television, and being left alone. Statistically significant improvements were noted in subscales evaluating higher-level functions and connectedness/autonomy with memantine compared with placebo. These post hoc analyses in moderate-to-severe AD patients receiving stable donepezil treatment suggest that memantine may impact overall functional levels, and some of the cognitive processing underlying ADL performance.

Schmitt FA, van Dyck CH, Wichems CH, Olin JT, Anonymous00304. · Department of Neurology, University of Kentucky Medical Center, Sanders-Brown Center on Aging, Lexington, KY 40536, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17132970 No free full text.

Abstract: OBJECTIVE: To investigate the cognitive effects of the N-methyl-D-aspartate receptor antagonist, memantine, with a post-hoc exploratory reanalysis of a 24-week randomized, double-blind, placebo-controlled, parallel group clinical trial comparing memantine (20 mg per day) to placebo in patients with moderate to severe Alzheimer disease (AD) receiving treatment with the cholinesterase inhibitor, donepezil. METHODS: The effects of memantine on individual items of the Severe Impairment Battery (SIB), subscale performance, and 3 post-hoc-derived aggregate subscales were investigated. Analyses were based on the intention-to-treat population using last observation carried forward and observed cases approaches. The SIB components were assessed at baseline, weeks 4, 8, 12, 18, and 24. RESULTS: The mean change from baseline by visit and at study end point on the SIB showed statistically significant differences between the memantine and placebo groups at all visits beginning at week 8 (last observation carried forward and observed cases). The SIB subscale analysis showed statistically significantly greater effects of memantine than placebo on memory, language, and praxis. When the SIB domains were aggregated using a face valid approach to create 3 higher-order subscales, memantine treatment resulted in statistically significant differences on memory, language, and praxis compared with placebo. CONCLUSIONS: These post-hoc analyses support the beneficial effects of memantine on cognition observed in a previously reported clinical trial. The results presented here suggest an effect of memantine on memory, language, and praxis in patients with moderate to severe AD and support the efficacy of memantine for the treatment of cognitive deficits in AD.

Scheff SW, Price DA, Schmitt FA, Mufson EJ. · Sanders-Brown Center on Aging and the Alzheimer's Disease Research Center, University of Kentucky College of Medicine, 101 Sanders-Brown, Lexington, KY 40536-0230, USA. · Neurobiol Aging. · Pubmed #16289476 No free full text.

Abstract: One of the major neuropathological findings in the brains of individuals with Alzheimer's disease (AD) is a loss of synaptic contacts in both the neocortex and hippocampus. Here we report, for the first time, an estimate of the total number of synapses in the outer molecular layer (OML) of the human dentate gyrus, in individuals with early Alzheimer's disease (eAD), mild cognitive impairment (MCI), or no cognitive impairment (NCI). An unbiased stereologic sampling scheme coupled with transmission electron microscopy to directly visualize synaptic contacts, was used to estimate the total number of synapses in short postmortem autopsy tissue. Individuals with eAD had significantly fewer synapses than the other two diagnostic groups. Seventy-five percent of the individuals with MCI had synaptic values that were lower than the NCI group mean. The number of synapses showed a significant correlation with the subject's Mini-Mental State score and with cognitive tests involving delayed recall. Synaptic loss showed no relationship to Braak stage or to apoE genotype. The volume of the OML was significantly reduced in eAD compared to the other two diagnositic groups that were not different from each other. These data suggest that a loss of afferents from the entorhinal cortex underlie the synapse loss seen in eAD. This study supports the concept that synapse loss is an early event in the disease process and suggests that MCI may be a transition stage between eAD and NCI with synaptic loss a structural correlate involved in cognitive decline.

Smith CD, Andersen AH, Kryscio RJ, Schmitt FA, Kindy MS, Blonder LX, Avison MJ. · Department of Neurology, Magnetic Resonance Imaging and Spectroscopy Center, University of Kentucky College of Medicine, Lexington 40536, USA. · Neurology. · Pubmed #11971086 No free full text.

Abstract: BACKGROUND: Imaging studies have shown disparities in resting metabolism and in functional activation between cognitively normal individuals at high and low risk for AD. A recent study has shown increased parietal activation in high-risk subjects during a paired associates recall task, which the authors postulated might overlap activation typically observed in verbal fluency. OBJECTIVE: To determine whether parietal activation is altered in a letter fluency task in cognitively normal individuals at high risk for AD. METHODS: fMRI was used to compare cortical activation between two groups of cognitively normal women differing in their risk for developing AD. A letter fluency task was used, which activates left frontal and parietal regions. The risk groups differed in family history of AD and APOE allele status but were matched in age, education, and measures of cognitive performance. Average age of the study participants was 53 years. RESULTS: The regional patterns of brain activation were similar between groups and similar to patterns observed by other investigators. However, the high-risk group showed significantly increased activation in the left parietal region despite identical letter fluency performance between risk groups. CONCLUSIONS: Cognitively normal individuals at high risk for AD show increased brain activation in the left parietal region with letter fluency, a region adjacent to that observed by others using a recall task. This convergence of results indicates disruption of functional circuits involving the left parietal lobe in asymptomatic individuals at increased risk for AD.

Ashford JW, Borson S, O'Hara R, Dash P, Frank L, Robert P, Shankle WR, Tierney MC, Brodaty H, Schmitt FA, Kraemer HC, Buschke H. · Stanford / VA Alzheimer Center, Department of Psychiatry, Palo Alto VA Health Care System, Palo Alto, CA, USA. · Alzheimers Dement. · Pubmed #19595860 No free full text.

Abstract: The question of whether to screen for dementia and Alzheimer's disease (AD) has been discussed in many forums throughout the world. Generally, medical advisory groups and policy-making groups have recognized the importance of early diagnosis but have uniformly avoided making recommendations to screen at-risk populations. This presentation reflects the support for reconsidering the importance of screening individuals at risk or above a certain age. In this statement, the majority of the authors support the consideration of dementia risk factors in individuals at age 50, with routine yearly screening after 75. Other authors remain concerned that the benefits of treatments of early disease do not yet support a general screening recommendation. These statements are made to encourage progress toward the development of a consensus regarding the widespread institution of screening policy. Accordingly, members of the worldwide scientific community are invited to add their perspective by contributing short commentaries (1500 words) on this subject.

Nelson PT, Abner EL, Schmitt FA, Kryscio RJ, Jicha GA, Santacruz K, Smith CD, Patel E, Markesbery WR. · Department of Pathology and Division of Neuropathology, Univerisity of Kentucky, Lexington, Kentucky 40536-0230, USA. · J Neuropathol Exp Neurol. · Pubmed #19535994 No free full text.

Abstract: Brains that have many neurofibrillary tangles (NFTs) in medial temporal lobe structures (Braak stage III or IV) but no cortical neuritic plaques (NPs) may be a diagnostic dilemma; they also raise questions about the amyloid cascade hypothesis of Alzheimer disease (AD) in which NFT development is thought to occur downstream of the development of amyloid plaques. To determine the clinical, demographic, and biological factors related to NFT+/NP- cases, we analyzed 26 NFT+/NP- patient brains identified from the University of Kentucky AD Center autopsy cohort (n=502); most of these patients were at least 85 years old and lacked profound antemortem cognitive impairment. A subset of the cases had NFTs in the medulla oblongata. Aberrant trans-activator regulatory DNA-binding protein 43 immunohistochemical staining was seen in 5 of the 26 cases with the clinical diagnoses of AD or mild cognitive impairment. We also queried cases in the National Alzheimer's Coordinating Center Registry (n=5,108) and found 219 NFT+/NP- cases. Those patients had a relatively high likelihood of belonging to a birth cohort with the highest incidence of influenza infection during the 1918 to 1919 pandemic. This observation may link the pathogenesis in NFT+/NP- cases to encephalitis during childhood. We conclude that NFT+/NP- cases comprise approximately 5% of aged individuals in multiple data sets; these cases are not necessarily within the spectrum of AD.

Markesbery WR, Jicha GA, Liu H, Schmitt FA. · Alzheimer's Disease Center and the Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA. · J Neuropathol Exp Neurol. · Pubmed #19535990 links to  free full text

Abstract: Lewy bodies and Lewy neurites are the hallmark neuropathologic findings in Parkinson disease, Parkinson disease with dementia, dementia with Lewy bodies, and other alpha-synucleinopathies. They have also been described in the brains of normal older individuals and referred to as incidental Lewy body disease. The purpose of this study was to determine the prevalence of Lewy bodies and Lewy neurites (Lewy body pathology [LBP]) in 139 autopsies from our normal volunteer control group of the University of Kentucky Alzheimer's Disease Center. All subjects were followed longitudinally and were cognitively normal and without any type of movement disorder, neuropsychiatric features, or other CNS findings. The brains of 33 of 139 normal subjects contained LBP in various regions. The most common regions involved were the medulla (26%), amygdala (24%), pons (20%), and midbrain (20%). No mean statistical differences were found between those with and without LBP on any demographic or cognitive variable, Braak stage, or neurofibrillary tangle and neuritic plaque quantitation. An explanation for the high prevalence of LBP in our elderly, well-educated study group is not clear, although it does not seem to be related to aging or the presence of Alzheimer disease pathology. Overall, our findings support the concept that incidental Lewy body disease most likely represents preclinical or presymptomatic Parkinson disease, Parkinson disease with dementia, or dementia with Lewy bodies.

Price JL, McKeel DW, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC. · Department of Anatomy and Neurobiology, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. · Neurobiol Aging. · Pubmed #19376612 No free full text.

Abstract: OBJECTIVE: To determine the frequency and possible cognitive effect of histological Alzheimer's disease (AD) in autopsied older nondemented individuals. DESIGN: Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer's Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions. SETTING: Washington University Alzheimer's Disease Research Center. PARTICIPANTS: Ninety-seven nondemented participants who were age 60 years or older at death (mean=84 years). RESULTS: About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs. CONCLUSIONS: Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80-85 years, many nondemented older adults have substantial AD pathology.

Nelson PT, Kryscio RJ, Abner EL, Schmitt FA, Jicha GA, Mendiondo MS, Cooper G, Smith CB, Markesbery WR. · Department of Pathology, University of Kentucky Medical Center, University of Kentucky, Lexington, KY, USA. · J Alzheimers Dis. · Pubmed #19158418 links to  free full text

Abstract: Dementia can be caused by different diseases including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or both (AD + DLB). University of Kentucky AD Center pathologically-diagnosed AD and AD + DLB cases were evaluated who had three or more longitudinal antemortem mental status examinations (n = 156). Patients with important concomitant pathology (n = 5) or patients that were profoundly demented at recruitment (intake MMSE < 20; n = 86) were excluded to strengthen our ability to test the association of specific clinical and pathological indices. Patients with pathologically-diagnosed AD + DLB (n = 25) lost cognitive capacity faster than patients with AD alone (n = 40). In both diseases, treatment with acetylcholinesterase inhibitors was associated with a slower rate of cognitive decline.

Dassel KB, Schmitt FA. · Department of the Graduate Center for Gerontology, University of Kentucky, Lexington, USA. · Gerontologist. · Pubmed #19139251 No free full text.

Abstract: PURPOSE: The initial diagnosis and treatment of cognitive disorders such as mild cognitive impairment and Alzheimer's disease is highly dependent on caregiver reports of patient performance of activities of daily living (ADLs). However, these reports may not always be reliable. We investigated the cognitive skills of caregivers, specifically their executive functioning (EF), as a potential explanatory variable of discrepancies between caregiver report of and patient performance on ADLs. DESIGN AND METHODS: Forty spousal dyads consisting of one cognitively unimpaired spouse and one spouse with either mild cognitive impairment (n = 20) or mild to moderate Alzheimer's disease (n = 20) were included in the study. Caregivers completed eight measures of EF and reported on their spouses' ADL performance, which was then directly assessed. Caregiver education and a composite EF score were then used to predict the difference in ADL ratings. RESULTS: Regression analyses revealed that caregiver EF composite score (beta =.33; p =.04) and level of education (beta = -.11; p <.05) were significant predictors of the discrepancies between caregiver ADL reports and directly assessed patient performance on ADLs (R(2) =.11; p =.04). IMPLICATIONS: The findings of this study suggest that the executive skills of spousal caregivers may influence the accuracy of subjectively reported ADL measures. Physicians should be aware of such potential biases when evaluating patients for memory disorders and should consider using objective measures for assessing functional impairment within their patient population. Future studies should investigate whether cognitive training and educational programs for caregivers increase the accuracy of their ADL reports.

Nelson PT, Abner EL, Scheff SW, Schmitt FA, Kryscio RJ, Jicha GA, Smith CD, Patel E, Markesbery WR. · Department of Pathology and Division of Neuropathology, University of Kentucky Medical Center, Sanders-Brown Center on Aging and Alzheimer's Disease Center, University of Kentucky, Lexington, KY 40536, USA. · Neurosci Lett. · Pubmed #19010392 No free full text.

Abstract: We studied Alzheimer's disease (AD) pathology in the precuneus and surrounding brain areas. Anatomically, the precuneus corresponds to the medial portion of human cerebral cortical Brodmann Area 7. This study utilized patients from the University of Kentucky Alzheimer's Disease Center autopsy cohort. Data from 47 brains were used comprising patients of differing antemortem cognitive impairment severities, each with longitudinal clinical data and extensive neuropathological data. We assessed whether the precuneus and surrounding areas are differentially vulnerable to AD-type pathological lesions (diffuse amyloid plaques, neuritic amyloid plaques, and neurofibrillary tangles). Eleven areas of brain were evaluated for each case: amygdala, hippocampal CA1, subiculum, entorhinal cortex, frontal cortex, superior and middle temporal gyri, inferior parietal lobule, occipital cortex, posterior cingulate gyrus, Brodmann Area 31, and the precuneus proper. Like other areas of neocortex, the precuneus demonstrated increased diffuse and neuritic amyloid plaques early in the evolution in AD, and increased neurofibrillary tangles late in AD. Correcting for the antemortem cognitive status of the patients, there was no evidence of an increase in the density of AD-type pathology in the precuneus or neighboring areas relative to other areas of cerebral neocortex. Our results are not consistent with the idea that the precuneus is involved in a special way with plaques or tangles relative to other areas of neocortex.

Jicha GA, Abner E, Schmitt FA, Cooper GE, Stiles N, Hamon R, Carr S, Smith CD, Markesbery WR. · Department of Neurology, University of Kentucky College of Medicine, Lexington, KY, USA. · Dement Geriatr Cogn Disord. · Pubmed #18724049 links to  free full text

Abstract: OBJECTIVE: Comparative analysis of subjects with mild cognitive impairment (MCI) diagnosed in a primary research setting and those seen in a tertiary care memory disorders clinic. METHODS: Subjects who received a diagnosis of MCI between July 1, 2005, and December 31, 2006, in a longitudinal research study of normal cognition (n = 48) and patients diagnosed in a tertiary care referral clinic (n = 34) were evaluated using similar methodologies. Comparative analyses of detailed medical, neurological and neuropsychological data are presented. RESULTS: The diagnosis of MCI was not accepted by 13 of 48 subjects (27%) classified as MCI in the primary research setting. Nondegenerative, potentially treatable causes of cognitive decline were found in 3 of 34 subjects (9%) seen in the tertiary referral clinic and in 11 of 35 subjects (31%) identified as MCI in the primary research setting (p = 0.02, Fisher's exact test). MCI subjects identified in the primary research setting were older than those referred to the memory clinic (mean +/- SD, 79.7 +/- 7.0 vs. 71.5 +/- 9.0 years, p < 0.0001, t test) and had more years of education (16.0 +/- 3.2 vs. 13.6 +/- 4.2 years, p < 0.01, t test). MCI subjects in the primary research setting appeared to be in a milder stage of disease, characterized by higher Mini-Mental State Examination scores (28.2 +/- 1.8 vs. 25.7 +/- 1.8, p < 0.0001), and a tendency towards single domain involvement, predominantly memory (mean number of domains involved, 1.0 vs. 2.5, p < 0.0001). More advanced stages of MCI, seen in the tertiary referral population, had additional involvement of attention (p < 0.0001, Fisher's exact test) and visuospatial domains (p < 0.0002, Fisher's exact test). Semiquantitative grading of hippocampal and medial temporal lobe atrophy did not differ between groups (p = 0.81, Mann-Whitney U test). CONCLUSIONS: The diagnosis of MCI may be unwelcome in naïve persons. Remedial causes of MCI should be actively investigated. Demographic and clinical characteristics of MCI differ between research subjects and patients referred to a tertiary care clinic.

Nelson PT, Jicha GA, Schmitt FA, Liu H, Davis DG, Mendiondo MS, Abner EL, Markesbery WR. · Department of Pathology and Division of Neuropathology, University of Kentucky, Lexington, Kentucky 40536-0230, USA. · J Neuropathol Exp Neurol. · Pubmed #18090922 No free full text.

Abstract: There is uncertainty regarding the association of cognitive decline in Alzheimer disease (AD) with classic histopathologic features- neurofibrillary tangles (NFTs) and "neuritic" amyloid plaques (NPs). This uncertainty fuels doubts about the diagnostic importance of NFTs and NPs and leads to confusion regarding hypotheses of AD pathogenesis. Three hundred ninety subjects who underwent longitudinal premortem clinical workup and postmortem quantitative neuropathologic assessment served as the group to address this issue. Subjects with concomitant brain disease(s) were analyzed independently to more accurately assess the contribution of distinct pathologies to cognitive decline. More than 60% of patients of all age groups had important non-AD brain pathologies. However, subjects without superimposed brain diseases showed strong correlations between AD-type pathology counts (NFTs > NPs) and premortem Mini-Mental State Examination scores. The observed correlation was stronger in isocortex than in allocortex and was maintained across age groups including patients older than 90 years. A theoretical model is proposed in which our results are interpreted to support the "amyloid cascade hypothesis" of AD pathogenesis. Our data show that there are many important contributory causes to cognitive decline in older persons. However, NFTs and NPs should not be dismissed as irrelevant in AD based on clinicopathologic correlation.

Weycker D, Taneja C, Edelsberg J, Erder MH, Schmitt FA, Setyawan J, Oster G. · Policy Analysis Inc., Brookline, Massachusetts 02445, USA. · Curr Med Res Opin. · Pubmed #17519086 No free full text.

Abstract: OBJECTIVE: The efficacy and safety of memantine in patients with moderate-to-severe Alzheimer's disease (AD) receiving stable doses of donepezil were recently demonstrated in a phase III trial. The cost-effectiveness of such therapy is unknown. RESEARCH DESIGN AND METHODS: A microsimulation model was developed to depict AD progression over time and associated clinical and economic outcomes. AD progression was measured in terms of decline in cognitive function, as assessed by the Severe Impairment Battery (SIB). At model entry, patients were assumed to have moderate-to-severe AD, to be on stable doses of donepezil, and to begin combination therapy with memantine, or continue to receive donepezil alone; duration of therapy was assumed to be 1 year. Drug efficacy was based on data from a phase III trial. Key assumptions of the model included: (1) efficacy of study drugs would extend to 1 year; (2) measures of cognitive function could be mapped to one another, as well as to global measures of disease severity; and (3) following therapy discontinuation, cognitive function would revert immediately to natural history levels. Cost-effectiveness was assessed in terms of cost (2005 US$) per quality-adjusted life-year (QALY) gained over a lifetime (3% discount rate). RESULTS: SIB scores were estimated to improve by 3.3 over 1 year from therapy with memantine plus donepezil (vs. donepezil alone). While pharmacotherapy costs were estimated to increase by $1250 during the year of memantine treatment, costs of formal and informal services were estimated to decrease by $1240 over this period and by $1493 (discounted present value) over a lifetime. Findings were sensitive to the assumed SIB score at therapy initiation; cost-effectiveness was better for patients with higher initial SIB scores (i.e., less severe disease). CONCLUSION: In patients with moderate-to-severe AD already receiving donepezil, treatment with memantine results in improved clinical outcomes and reduced total costs of care.

Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. · Sanders-Brown Center on Aging and Alzheimer Disease Research Center, University of Kentucky College of Medicine, Lexington, KY 40536-0230, USA. · Neurology. · Pubmed #17470753 No free full text.

Abstract: OBJECTIVE: To evaluate the total number of synapses in the stratum radiatum (str rad) of the human hippocampal CA1 subfield in individuals with mild Alzheimer disease (mAD), mild cognitive impairment (MCI), or no cognitive impairment (NCI) and determine if synapse loss is an early event in the progression of the disease. METHODS: Short postmortem autopsy tissue was obtained, and an unbiased stereologic sampling scheme coupled with transmission electron microscopy was used to directly visualize synaptic contacts. RESULTS: Individuals with mAD had fewer synapses (55%) than the other two diagnostic groups. Individuals with MCI had a mean synaptic value that was 18% lower than the NCI group mean. The total number of synapses showed a correlation with several cognitive tests including those involving both immediate and delayed recall. Total synaptic numbers showed no relationship to the subject's Braak stage or to APOE genotype. The volume of the str rad was reduced in mAD vs the other two diagnostic groups that were not different from each other. CONCLUSION: These results strongly support the concept that synapse loss is a structural correlate involved very early in cognitive decline in mild Alzheimer disease (mAD) and supports mild cognitive impairment as a transitional stage between mAD and no cognitive impairment.

Smith CD, Chebrolu H, Wekstein DR, Schmitt FA, Jicha GA, Cooper G, Markesbery WR. · MRISC, Room 62, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536. · Neurology. · Pubmed #17438217 No free full text.

Abstract: OBJECTIVE: To determine whether alterations of brain structure in normal aged individuals precede the development of mild cognitive impairment (MCI) or Alzheimer disease (AD). BACKGROUND: Persons with MCI and AD demonstrate cortical volume losses vs asymptomatic aged individuals, particularly in the hippocampus, amygdala, and entorhinal cortex. It is unknown whether these losses or other volumetric changes are present, and to what degree, in cognitively normal individuals before the clinical diagnosis of MCI. METHODS: Structural MRI was performed on a cross-section of 136 longitudinally examined normal aged subjects. All subjects were cognitively normal at the time of their scan, but 23 later developed MCI, and 9 of these 23 went on to an AD diagnosis. Extracted volumes from voxel-based morphometric analysis were combined with clinical data to compare the 23 subjects who eventually developed MCI to 113 subjects who remained cognitively normal over an average follow-up of 5.4 years. RESULTS: Initially normal subjects who eventually developed MCI demonstrated decreased gray matter volumes in the anteromedial temporal lobes bilaterally and left angular gyrus while still cognitively normal. CONCLUSION: Structural brain changes in anatomic areas involved in higher cognitive processes precede clinical signs and symptoms in longitudinally followed normal subjects destined to develop mild cognitive impairment.

Schneider LS, Clark CM, Doody R, Ferris SH, Morris JC, Raman R, Reisberg B, Schmitt FA. · Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17135806 No free full text.

Abstract: BACKGROUND: Because primary prevention trials will require large samples and modest treatment effects are expected, the use of standard clinician-administered, clinic-based measures are unlikely to be feasible. There is a need for proxy-administered outcome measures. The goal of the Alzheimer's Disease Cooperative Study (ADCS) Prevention Instrument Project was to conduct a simulated Alzheimer disease prevention trial in 650 nondemented elderly (Ferris et al, 2006). This involved comparison of data acquisition from both home and clinic and the use of both informant-ratings and self-ratings. Important outcomes included clinical global impressions of change (CGIC) as indicators of clinically meaningful change. Such ratings provide verification that the effects of a medication as measured on rating scales are readily observable and clinically meaningful. One objective was to develop self-rated and study partner-rated CGICs optimized for nondemented elderly or people with very early Alzheimer disease. An important consideration was whether global assessments are specific and sensitive measures of change during a prevention trial. METHODS: A self-administered CGIC and a study partner-rated CGIC were developed to be used either in the clinic or at home. Using 3-month follow-up data, we determined its reliability and validity with 317 subject-partner pairs. We compared subject-ratings with partner-ratings, clinic-based with home-based ratings, and ratings based on severity as determined by the Clinical Dementia Rating scale. RESULTS: There were no differences between clinic and home ratings. Overall, 24% of subjects rated themselves, and 10% of study partners rated the subjects, as minimally to markedly improved. Subjects and partners agreed to within 1 point of their ratings 83% of the time on the 7-point scale. There were weak correlations, generally <0.20, with change scores of selected clinical rating scales. DISCUSSION: The CGICs behaved as expected, showing no overall change over 3 months, no difference between administrations at home compared with clinics, and concurrent validity. Some subjects tended to rate themselves better than their partners rated them. These analyses show the potential for using home-based CGICs which can be completed with minimal supervision and allow assessments of potential preventative interventions.

Mitchell DB, Schmitt FA. · WellStar College of Health and Human Services, Kennesaw State University, GA 30144, USA. · Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. · Pubmed #16887792 No free full text.

Abstract: Implicit memory processes were investigated via picture naming in healthy young and older adults and in persons with mild Alzheimer's disease (AD). Repetition priming in picture-naming was intact in all groups over the course of a short retention interval (seconds), and only the AD group revealed a deficit over a longer interval (72 hours). In addition, the AD group showed impaired procedural memory, with no benefit of practice on picture-naming. Impaired long-term priming was related to severity of AD. Both theoretical and methodological implications are discussed.

Smith CD, Chebrolu H, Wekstein DR, Schmitt FA, Markesbery WR. · Department of Biomedical Engineering, University of Kentucky, Lexington, KY 40536-0098, United States. · Neurobiol Aging. · Pubmed #16774798 No free full text.

Abstract: The adult human brain shrinks slowly with age, but the regional specificity and tissue class specificity of this loss is unclear. Subjects (n=122) were healthy aged participants in a longitudinal cohort who undergo periodic standardized cognitive and clinical examination. Multi-spectral segmentation of magnetic resonance images into grey matter (GM), white matter (WM) and CSF was performed on cross-sectional image data using a custom template and calculated prior probability maps. Global differences were evaluated by fitting a regression model for absolute and normalized subject GM, WM, and CSF values. Global and regional patterns of GM, WM and CSF differences were assessed using optimized voxel-based morphometry (VBM). GM volume decreased with age at a rate of 2.4 cm(3)/year (-0.18%/year); CSF increased by 2.5 cm(3)/year (0.20%/year). Regression analyses showed no significant decrease in WM volume, but a focal WM decrease with age was detected in the anterior corpus callosum using VBM. Diffuse reductions of GM volume were seen with age in the frontal, parietal, and temporal cortex, cerebellum and basal ganglia. Relative regional differences in cortical GM volume with age occurred in the frontal, parietal and temporal lobes, but not in medial temporal lobe or in posterior cingulate. We did not observe significant gender effects. These findings establish a baseline for comparison with pathologic changes in human brain volume between ages 58 and 95 years.