Alzheimer Disease: Clark CM

Clark CM, Davatzikos C, Borthakur A, Newberg A, Leight S, Lee VM, Trojanowski JQ. · Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA. · Neurosignals. · Pubmed #18097155 No free full text.

Abstract: The increasing prevalence of Alzheimer's disease and the devastating consequences of late-life dementia motivates the drive to develop diagnostic biomarkers to reliably identify the pathology associated with this disorder. Strategies to accomplish this include the detection of altered levels of tau and amyloid in cerebrospinal fluid, the use of structural MRI to identify disease-specific patterns of regional atrophy and MRI T(1)rho to detect disease-related macromolecular protein aggregation, and the direct imaging of amyloid deposits using positron emission tomography and single photon emission computerized tomography. Success will facilitate the ability to reliably diagnose Alzheimer's disease while the symptoms of brain failure are mild and may provide objective measures of disease-modifying treatment efficacy.

Shaw LM, Korecka M, Clark CM, Lee VM, Trojanowski JQ. · Department of Pathology and Laboratory Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. · Nat Rev Drug Discov. · Pubmed #17347655 No free full text.

Abstract: Rapid progress towards understanding the molecular underpinnings of neurodegenerative disorders such as Alzheimer's disease is revolutionizing drug discovery for these conditions. Furthermore, the development of models for these disorders is accelerating efforts to translate insights related to neurodegenerative mechanisms into disease-modifying therapies. However, there is an urgent need for biomarkers to diagnose neurodegenerative disorders early in their course, when therapy is likely to be most effective, and to monitor responses of patients to new therapies. As research related to this need is currently most advanced for Alzheimer's disease, this Review focuses on progress in the development and validation of biomarkers to improve the diagnosis and treatment of Alzheimer's disease and related disorders.

Cotter VT, Clark CM, Karlawish JH. · Adult Health & Gerontology Nurse Practitioner Programs, School of Nursing, Alzheimer's Disease Center, University of Pennsylvania, USA. · J Am Acad Nurse Pract. · Pubmed #12640943 No free full text.

Abstract: PURPOSE: To describe brief assessments of functional performance and cognition to detect Alzheimer's disease (AD) and depression in older adults for the primary care provider. DATA SOURCES: Review of the literature. CONCLUSIONS: It is important for the clinician to interview both the patient and a knowledgeable informant to assess changes in the patients' functioning in daily life tasks and to administer brief screening tests to detect cognitive impairment and depression in older adults. Several suggested instruments for use in the primary care setting are included. IMPLICATIONS FOR PRACTICE: Standardized assessments of functional performance and brief cognitive tests identify individuals with clinically meaningful cognitive impairment and provide baseline measurement against which to compare future assessments.

Karlawish JH, Clark CM. · University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Ann Intern Med. · Pubmed #12614094 links to  free full text

Abstract: This case-based discussion focuses on the clinical presentation and diagnostic assessment of a uniquely challenging group of elderly patients: those with symptoms of mild memory problems. Such patients present a challenge to clinicians because of flux in our understandings of normal, age-related cognitive changes; of cognitive changes due to neurodegenerative illnesses; and of the relationships between depression and cognitive impairment. In addition, symptoms of memory problems may be reported by an observer rather than by the patient. These challenges warrant stepwise evaluation of elderly patients who present with symptoms of memory loss.

Clark CM, Karlawish JH. · Memory Disorders Clinic, Penn-Ralston Center, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, Pennsylvania 19104, USA. · Ann Intern Med. · Pubmed #12614093 links to  free full text

Abstract: Alzheimer disease is a complex neurodegenerative dementing illness. It has become a major public health problem because of its increasing prevalence, long duration, high cost of care, and lack of disease-modifying therapy. Over the past few years, however, remarkable advances have taken place in understanding both the genetic and molecular biology associated with the intracellular processing of amyloid and tau and the changes leading to the pathologic formation of extracellular amyloid plaques and the intraneuronal aggregation of hyperphosphorylated tau into neurofibrillary tangles. The identification of disease-causing autosomal dominant mutations as well as gene polymorphisms that alter the risk for pathology indicate that Alzheimer disease is a genetically complex disorder. This progress in our understanding of the molecular pathology has set the stage for clinically meaningful advances in diagnosis and treatment. Emerging diagnostic methods that are based on biochemical and imaging biomarkers of disease-specific pathology hold the potential for accurately diagnosing Alzheimer disease at the earliest stage of the illness--the time when disease-modifying treatment will be most effective. Currently available cholinesterase inhibition therapy targets the cognitive symptoms. However, the goal of new therapies under development is halting the pathologic cascade and potentially reversing the course of the disease. If these new therapies are successful, they will represent a remarkable medical advance for patients and the families who care for them.

Karlawish JH, Clark CM. · Department of Medicine, Division of Geriatrics, Alzheimer's Disease Center, Center for Bioethics and Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia 19104, USA. · Neurobiol Aging. · Pubmed #12470801 No free full text.

Abstract: This essay addresses the challenges of clinical trials to develop treatments for Alzheimer's Disease (AD). The issues covered are enrolling subjects, defining clinically meaningful endpoints, and making the claim that a drug slows the progression of the disease. The perspective to address these challenges is that dementia research should embrace a biopsychosocial model for drug development. In this model, the patient and caregiver are seen as interrelated subjects of both treatment and research and outcome measures reflect biomarkers of the disease, the functional morbidity of AD and the distress of caregiving.

Kawas CH, Clark CM, Farlow MR, Knopman DS, Marson D, Morris JC, Thal LJ, Whitehouse PJ. · Department of Neurology and Alzheimer's Disease Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10485569 No free full text.

Abstract: During the past 10 years, there has been a rapidly growing number of pharmaceutical industry-sponsored drug trials for treatment of Alzheimer disease (AD) and other neurodegenerative diseases. As public awareness and concerns about AD have grown, so has interest in developing drug therapies for retarding symptom progression, delaying onset, and ultimately curing the disease. Ethical debate on the use of placebo control trials in AD research has come of age in the United States with the availability of treatments approved by the Food and Drug Administration. The experts and the public agree that more effective therapies are necessary, and new therapeutic options are being developed as rapidly as possible. The arguments on each side of the debate are provocative and important but do not provide unequivocal justification for either the abandonment or the maintenance of placebo-controlled trials in all AD research. Clinical trials differ with respect to scientific and practical goals, and these factors inherently affect the ethical priorities of each study. We present these contrasting points of view to delineate some of the issues rather than to make specific recommendations other than to urge that all clinical trials in AD should be designed with careful consideration of the ethical issues surrounding the use of placebo controls. As new and more effective treatments emerge, the ethical framework for placebo use in AD studies will require frequent re-examination. To make wise choices, patients, caregivers, physicians, and ethicists (among others) must have a voice in this continuing discussion.

Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, Farlow MR, Galvin JE, Peskind ER, Quinn JF, Sherzai A, Sowell BB, Aisen PS, Thal LJ. · University of California, San Diego, La Jolla, CA 92037, USA. · Arch Neurol. · Pubmed #18695053 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN: Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. SETTING: Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES: Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. RESULTS: Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. CONCLUSIONS: LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.

Higdon R, Foster NL, Koeppe RA, DeCarli CS, Jagust WJ, Clark CM, Barbas NR, Arnold SE, Turner RS, Heidebrink JL, Minoshima S. · University of Washington, Seattle, USA. · Stat Med. · Pubmed #14716732 No free full text.

Abstract: Flurodeoxyglucose positron emission tomography (FDG-PET) is being explored to determine its ability to differentiate between a diagnosis of Alzheimer's disease (AD) and fronto-temporal dementia (FTD). We have examined statistical discrimination procedures to help achieve this purpose and compared the results to visual ratings of FDG-PET images. The methods are applied to a data set of 48 subjects with autopsy confirmed diagnoses of AD or FTD (these subjects come from a multi-centre collaborative study funded by the National Alzheimer's Coordinating Center). FDG-PET images are composed of thousands of voxels (volume elements) so one is left with a situation where there are vastly more variables than subjects. Therefore, it is necessary to perform a data reduction before a statistical procedure can be applied. Approaches using both the entire image and summary statistics calculated on a number of volumes of interest (VOI) are examined. We performed the data reduction techniques of principal components analysis (PCA) and partial least-squares (PLS) on the entire image and then used linear discriminant analysis (LDA), quadratic (QDA) or logistic regression (LR) to classify subjects as having AD or FTD. Some of these methods achieve diagnostic accuracy (as assessed by leave-one-out cross-validation) that is similar to visual ratings by expert raters. Methods using PLS appear to be more successful. Averaging or using VOI data may also be helpful.

Glosser G, Gallo JL, Clark CM, Grossman M. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA. · Neuropsychology. · Pubmed #11949711 No free full text.

Abstract: Memory encoding and retrieval strategies were assessed in patients with behavior-executive variant frontotemporal dementia (FTD), language variant FTD, and Alzheimer's disease (AD) using verbal and visuospatial supraspan learning tests. FTD patients obtained higher free recall, cued recall, and recognition scores than AD patients. Comparison of free recall scores with cued recall and recognition scores was similar in the 3 dementia groups. Groups did not differ in semantic clustering strategies during learning, but serial-order recall was more common in FTD patients. These data do not support the idea that FTD patients' poor memory is due to a selective retrieval disorder, though FTD patients may fail to implement sophisticated organizational strategies during learning. FTD patients' retained capacity for encoding new information into long-term declarative memory is likely due to relatively spared medial temporal lobe involvement.

Doody RS, Dunn JK, Clark CM, Farlow M, Foster NL, Liao T, Gonzales N, Lai E, Massman P. · Baylor College of Medicine Alzheimer's Disease Research Center (AGO-8664), Houston, Tex 77030-3498, USA. · Dement Geriatr Cogn Disord. · Pubmed #11351141 No free full text.

Abstract: OBJECTIVE: To compare rates of cognitive decline between probable Alzheimer's disease (AD) patients treated with long-duration cholinesterase inhibitors (ChE-Is) and those who remained untreated. BACKGROUND: ChE-Is, including donepezil and tracrine, have shown beneficial effects on cognition and global functioning in patients with AD. The duration of these benefits is unknown because the longest double-blind placebo-controlled studies reported were only approximately 6 months long. Ethical concerns regarding randomization of patients to placebo for long periods make it difficult to undertake trials of longer duration. METHODS: We identified patients in 4 AD centers who were or were not consistently treated with ChE-Is and who had demographic, psychometric and follow-up data. We compared 205 ChE-I-treated and 218 untreated AD patients on baseline variables hypothesized to differ between these groups, on baseline Mini Mental Status Examination (MMSE) scores and on rates of MMSE change at 1 year. The analysis was performed initially with all ChE-I-treated patients as a single group versus untreated subjects, and then with donepezil versus untreated subjects and tacrine versus untreated subjects. RESULTS: As expected, treated and untreated patients differed with respect to age, education, ethnicity, percentage of community dwelling and exact days of follow-up (ANOVA and chi2) in several comparisons, but did not differ on baseline MMSE score. These baseline variables were highly intercorrelated. MMSE scores declined significantly more slowly after 1 year of ChE-I treatment compared to untreated patients (p = 0.05) after controlling for baseline differences in age, education, ethnicity and percentage of community dwelling. Slowing of decline was significant in the donepezil-treated patients (p = 0.007) but not in the tacrine-treated group (p = 0.33). CONCLUSIONS: This study, utilizing concurrent, nonrandomized controls, suggests that donepezil continues to have efficacy over at least the first year of therapy. Other studies are needed to determine whether the benefits are maintained beyond 1 year.

Clark CM, Sheppard L, Fillenbaum GG, Galasko D, Morris JC, Koss E, Mohs R, Heyman A. · Department of Neurology, Alzheimer's Disease Center, University of Pennsylvania, Philadelphia 19104, USA. · Arch Neurol. · Pubmed #10404988 links to  free full text

Abstract: OBJECTIVE: To determine the variability in annual Mini-Mental State Examination scores of patients with Alzheimer disease enrolled in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). PATIENTS: A total of 372 patients with probable Alzheimer disease with 1 or more years of follow-up. SETTING: Twenty-one CERAD clinical sites throughout the United States. RESULTS: An average annual decline of 3.4 points in CERAD patients returning for longitudinal reassessments was close to the SD of the measurement error of 2.8 points for the Mini-Mental State Examination. There was wide variability in individual rates of decline. Even with 4 years of follow-up, 15.8% of the patients had no clinically meaningful decline in Mini-Mental State Examination score (defined as a change in initial score >3, ie, 1 SD of measurement error). Validity of measurements of the rate of change in Mini-Mental State Examination scores improved with longer observation intervals and was reliable for most patients when observations were separated by 3 or more years. CONCLUSIONS: Although the Mini-Mental State Examination is a useful screening instrument to assess level of cognitive function, it has limited value in measuring the progression of Alzheimer disease in individual patients for periods less than 3 years because of a large measurement error and substantial variation in change in annual score.

Haris M, McArdle E, Fenty M, Singh A, Davatzikos C, Trojanowski JQ, Melhem ER, Clark CM, Borthakur A. · MMRRCC, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6100, USA. · J Magn Reson Imaging. · Pubmed #19388096 No free full text.

Abstract: PURPOSE: To evaluate the T1rho (T(1rho)) MRI relaxation time in hippocampus in the brain of Alzheimer's disease (AD), mild cognitive impairment (MCI), and control, and to determine whether the T(1rho) shows any significant difference between these cohorts. MATERIALS AND METHODS: With informed consent, AD (n = 49), MCI (n = 48), and age-matched control (n = 31) underwent T(1rho) MRI on a Siemens 1.5T Scanner. T(1rho) values were automatically calculated from the left and right hippocampus region using in-house developed software. Bonferroni post-hoc multiple comparisons was performed to compare the T(1rho) value among the different cohorts. RESULTS: Significantly higher T(1rho) values were observed both in AD (P = 0.000) and MCI (P = 0.037) cohorts compared to control; also, the T(1rho) in AD was significantly high over (P = 0.032) MCI. Hippocampus T(1rho) was 13% greater in the AD patients than control, while in MCI it was 7% greater than control. Hippocampus T(1rho) in AD patients was 6% greater than MCI. CONCLUSION: Higher hippocampus T(1rho) values in the AD patients might be associated with the increased plaques burden. A follow-up study would help to determine the efficacy of T(1rho) values as a predictor of developing AD in the control and MCI individuals.

Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee VM, Trojanowski JQ, Anonymous00044. · Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Ann Neurol. · Pubmed #19296504 links to  free full text

Abstract: OBJECTIVE: Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. METHODS: Amyloid-beta 1 to 42 peptide (A beta(1-42)), total tau (t-tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy-confirmed AD cases and 52 age-matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t-tau and A beta(1-42) in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy-confirmed CSF data. RESULTS: CSF A beta(1-42) was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for A beta(1-42), t-tau, and APO epsilon 4 allele count provided the best assessment delineation of mild AD. An AD-like baseline CSF profile for t-tau/A beta(1-42) was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study. INTERPRETATION: The CSF biomarker signature of AD defined by A beta(1-42) and t-tau in the autopsy-confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD.

Mellon EA, Pilkinton DT, Clark CM, Elliott MA, Witschey WR, Borthakur A, Reddy R. · Department of Radiology, MMRRCC, University of Pennsylvania, Philadelphia, PA, USA. · AJNR Am J Neuroradiol. · Pubmed #19213826 No free full text.

Abstract: BACKGROUND AND PURPOSE: There is significant interest in the development of novel noninvasive techniques for the diagnosis of Alzheimer disease (AD) and tracking its progression. Because MR imaging has detected alterations in sodium levels that correlate with cell death in stroke, we hypothesized that there would be alterations of sodium levels in the brains of patients with AD, related to AD cell death. MATERIALS AND METHODS: A total of 10 volunteers (5 with mild AD and 5 healthy control subjects) were scanned with a 20-minute sodium (23Na) MR imaging protocol on a 3T clinical scanner. RESULTS: After normalizing the signal intensity from the medial temporal lobes corresponding to the hippocampus with the ventricular signal intensity, we were able to detect a 7.5% signal intensity increase in the brains of patients with AD (AD group, 68.25% +/- 3.4% vs control group, 60.75% +/- 2.9%; P < .01). This signal intensity enhancement inversely correlated with hippocampal volume (AD group, 3.22 +/- 0.50 cm3 vs control group, 3.91 +/- 0.45 cm3; r2 = 0.50). CONCLUSIONS: This finding suggests that sodium imaging may be a clinically useful tool to detect the neuropathologic changes associated with AD.

Patel T, Polikar R, Davatzikos C, Clark CM. · Signal Processing and Pattern Recognition Laboratory of the Electrical and Computer Eng. Dept. at Rowan University, Glassboro, NJ 08028, USA. · Conf Proc IEEE Eng Med Biol Soc. · Pubmed #19163020 No free full text.

Abstract: The prevalence of Alzheimer's disease (AD) is rising alarmingly as the average age of our population increases. There is no treatment to halt or slow the pathology responsible for AD, however, new drugs are promising to reduce the rate of progression. On the other hand, the efficacy of these new medications critically depends on our ability to diagnose AD at the earliest stage. Currently AD is diagnosed through longitudinal clinical evaluations, which are available only at specialized dementia clinics, hence beyond financial and geographic reach of most patients. Automated diagnosis tools that can be made available to community hospitals would therefore be very beneficial. To that end, we have previously shown that the event related potentials obtained from different scalp locations can be effectively used for early diagnosis of AD using an ensemble of classifiers based decision fusion approach. In this study, we expand our data fusion approach to include MRI based measures of regional brain atrophy. Our initial results indicate that ERPs and MRI carry complementary information, and the combination of these heterogeneous data sources using a decision fusion approach can significantly improve diagnostic accuracy.

Fillenbaum GG, van Belle G, Morris JC, Mohs RC, Mirra SS, Davis PC, Tariot PN, Silverman JM, Clark CM, Welsh-Bohmer KA, Heyman A. · Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA. · Alzheimers Dement. · Pubmed #18631955 No free full text.

Abstract: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of Alzheimer's disease (AD). The present report describes the measures that CERAD developed during its first decade and their continued use in their original and translated forms. These measures include clinical, neuropsychological, neuropathologic, and behavioral assessments of AD and also assessment of family history and parkinsonism in AD. An approach to evaluating neuroimages did not meet the standards desired. Further evaluations that could not be completed because of lack of funding (but where some materials are available) include evaluation of very severe AD and of service use and need by patient and caregiver. The information that was developed in the U.S. and abroad permits standardized assessment of AD in clinical practice, facilitates epidemiologic studies, and provides information valuable for individual and public health planning. CERAD materials and data remain available for those wishing to use them.

Connolly J, Siderowf A, Clark CM, Mu D, Pratico D. · Department of Neurology, Parkinson's Disease and Movement Disorders Center, Pennsylvania Hospital, Philadelphia, PA 19107, USA. · Cogn Behav Neurol. · Pubmed #18541983 No free full text.

Abstract: OBJECTIVE: To determine the utility of 8,12-isoprostaneF2alpha-VI (iP), a specific and sensitive index of lipid peroxidation, as a biomarker for dementia in Parkinson disease (PD). BACKGROUND: iP is a member of the F2-isoprostanes family that has been shown to be promising biomarker for Alzheimer disease. However, iP levels have not been studied in patients with clinical diagnosis of PD or Parkinson disease with dementia (PDD). METHODS: PD and PDD patient plasma and urine iP levels were compared with age-matched and sex-matched controls. Clinical measures including demographics and tests of motor function, affect, and cognition were assessed and compared with iP levels. RESULTS: There were no differences in plasma iP levels between PD subjects and controls (299 vs. 306 pg/mL; P=0.6). Urine iP levels were higher in cases than controls (2.8 vs. 2.1 ng/mg Cr; P=0.003), but levels were lower than those seen in Alzheimer disease patients in prior studies. Within PD subjects, there was no association of iP levels in either the plasma or urine with performance on any clinical measure. CONCLUSIONS: Plasma and urine iP levels do not seem to be substantially elevated in PD and are not associated with severity of cognitive impairment in PDD.

Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, Miller BL, Kretzschmar HA, Lee VM, Trojanowski JQ, Neumann M. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine,University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. · J Neuropathol Exp Neurol. · Pubmed #18520774 No free full text.

Abstract: Pathologic TAR-DNA-binding protein 43 (TDP-43) is a disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. We studied the presence, frequency, and distribution of TDP-43 pathology by immunohistochemistry and biochemistry in a series of clinically well-characterized tauopathy patient brains, including 182 Alzheimer disease (AD), 39 corticobasal degeneration, 77 progressive supranuclear palsy, and 12 Pick disease cases and investigated the clinical impact of concomitant TDP-43 pathology in these cases. TAR-DNA-binding protein 43 pathology was found in 25.8% of AD cases. It was restricted to the dentate gyrus and entorhinal cortex in approximately 75% of cases; approximately 25% showed more widespread TDP-43 pathology in frontal and temporal cortices, resembling the FTLD-U subtype associated with progranulin mutations. TAR-DNA-binding protein 43 pathology in AD was associated with significantly longer disease duration, but there was no association with the clinical presentation (148 cases diagnosed as AD and 34 cases diagnosed as frontotemporal lobar degeneration). Progressive supranuclear palsy and Pick disease cases showed no TDP-43 inclusions and no biochemical alterations of TDP-43. There was, however, a unique, predominantly glial TDP-43 pathology with staining of astrocytic plaque-like structures and coiled bodies in 15.4% of corticobasal degeneration cases; this was associated with biochemical TDP-43 changes similar to those in FTLD-U. These findings provide further insight into the burden and clinical significance of TDP-43 pathology in disorders other than FTLD-U and amyotrophic lateral sclerosis.

Borthakur A, Sochor M, Davatzikos C, Trojanowski JQ, Clark CM. · MMRRCC, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104-6100, USA. · Neuroimage. · Pubmed #18479942 links to  free full text

Abstract: Alzheimer's disease (AD) is the most common form of dementia in the elderly. Classic symptoms of the disease include memory loss and confusion associated with the hallmark neuro-pathologic lesions of neurofibrillary tangles (NFT) and senile plaques (SP) and their sequelae, gray matter atrophy. Volumetric assessment methods measure tissue atrophy, which typically follows early biochemical changes. An alternate MRI contrast mechanism to visualize the early pathological changes is T1rho (or "T-1-rho"), the spin lattice relaxation time constant in the rotating frame, which determines the decay of the transverse magnetization in the presence of a "spin-lock" radio-frequency field. Macromolecular changes (in plaques and tangles) that accompany early AD are expected to alter bulk water T1rho relaxation times. In this work, we measure T1rho MRI on patients with clinically diagnosed AD, MCI and in age-matched cognitively normal control subjects in order to compare T1rho values with changes in brain volume in the same regions of the brain and demonstrate that T1rho can potentially constitute an important biomarker of AD.

Davatzikos C, Resnick SM, Wu X, Parmpi P, Clark CM. · Section of Biomedical Image Analysis, Department of Radiology, University of Pennsylvania, 3600 Market street, Suite 380, Philadelphia, PA 19104, USA. · Neuroimage. · Pubmed #18474436 links to  free full text

Abstract: The purpose of this study is to determine the diagnostic accuracy of MRI-based high-dimensional pattern classification in differentiating between patients with Alzheimer's disease (AD), Frontotemporal Dementia (FTD), and healthy controls, on an individual patient basis. MRI scans of 37 patients with AD and 37 age-matched cognitively normal elderly individuals, as well as 12 patients with FTD and 12 age-matched cognitively normal elderly individuals, were analyzed using voxel-based analysis and high-dimensional pattern classification. Diagnostic sensitivity and specificity of spatial patterns of regional brain atrophy found to be characteristic of AD and FTD were determined via cross-validation and via split-sample methods. Complex spatial patterns of relatively reduced brain volumes were identified, including temporal, orbitofrontal, parietal and cingulate regions, which were predominantly characteristic of either AD or FTD. These patterns provided 100% diagnostic accuracy, when used to separate AD or FTD from healthy controls. The ability to correctly distinguish AD from FTD averaged 84.3%. All estimates of diagnostic accuracy were determined via cross-validation. In conclusion, AD- and FTD-specific patterns of brain atrophy can be detected with high accuracy using high-dimensional pattern classification of MRI scans obtained in a typical clinical setting.

Bian H, Van Swieten JC, Leight S, Massimo L, Wood E, Forman M, Moore P, de Koning I, Clark CM, Rosso S, Trojanowski J, Lee VM, Grossman M. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Neurology. · Pubmed #18458217 links to  free full text

Abstract: OBJECTIVE: To evaluate the diagnostic value of CSF biomarkers in patients with known pathology due to frontotemporal lobar degeneration (FTLD). BACKGROUND: It is important to distinguish FTLD from other neurodegenerative diseases like Alzheimer disease (AD), but this may be difficult clinically because of atypical presentations. METHODS: Patients with FTLD (n = 30) and AD (n = 19) were identified at autopsy or on the basis of genetic testing at University of Pennsylvania and Erasmus University Medical Center. CSF was obtained during a diagnostic lumbar puncture and was analyzed using assays for total tau and amyloid-beta 1-42 (A beta(42)). Patients also were assessed with a brief neuropsychological battery. RESULTS: CSF total tau level and the ratio of CSF total tau to A beta(42) (tau/A beta(42)) were significantly lower in FTLD than in AD. Receiver operating characteristic curve analyses confirmed that the CSF tau/A beta(42) ratio is sensitive and specific at discriminating between FTLD and AD, and is more successful at this than CSF total tau alone. Although some neuropsychological measures are significantly different in autopsy-proven FTLD and AD, combining these neuropsychological measures with CSF biomarkers did not improve the ability to distinguish FTLD from AD. CONCLUSIONS: The ratio of CSF tau/A beta(42) is a sensitive and specific biomarker at discriminating frontotemporal lobar degeneration from Alzheimer disease in patients with known pathology.

Bekris LM, Millard SP, Galloway NM, Vuletic S, Albers JJ, Li G, Galasko DR, DeCarli C, Farlow MR, Clark CM, Quinn JF, Kaye JA, Schellenberg GD, Tsuang D, Peskind ER, Yu CE. · Geriatric Research, Education, and Clinical Center (GRECC), VA Puget Sound Health Care System, Seattle, WA 98108, USA. · J Alzheimers Dis. · Pubmed #18430993 No free full text.

Abstract: The epsilon4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer's disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21-87 years of age (n=134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE epsilon4 and correlation between SNPs (linkage disequilibrium). APOE epsilon4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.

Fan Y, Batmanghelich N, Clark CM, Davatzikos C, Anonymous00453. · Section of Biomedical Image Analysis, Department of Radiology, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA. · Neuroimage. · Pubmed #18053747 No free full text.

Abstract: Spatial patterns of brain atrophy in mild cognitive impairment (MCI) and Alzheimer's disease (AD) were measured via methods of computational neuroanatomy. These patterns were spatially complex and involved many brain regions. In addition to the hippocampus and the medial temporal lobe gray matter, a number of other regions displayed significant atrophy, including orbitofrontal and medial-prefrontal grey matter, cingulate (mainly posterior), insula, uncus, and temporal lobe white matter. Approximately 2/3 of the MCI group presented patterns of atrophy that overlapped with AD, whereas the remaining 1/3 overlapped with cognitively normal individuals, thereby indicating that some, but not all, MCI patients have significant and extensive brain atrophy in this cohort of MCI patients. Importantly, the group with AD-like patterns presented much higher rate of MMSE decline in follow-up visits; conversely, pattern classification provided relatively high classification accuracy (87%) of the individuals that presented relatively higher MMSE decline within a year from baseline. High-dimensional pattern classification, a nonlinear multivariate analysis, provided measures of structural abnormality that can potentially be useful for individual patient classification, as well as for predicting progression and examining multivariate relationships in group analyses.

Grossman M, Libon DJ, Forman MS, Massimo L, Wood E, Moore P, Anderson C, Farmer J, Chatterjee A, Clark CM, Coslett HB, Hurtig HI, Lee VM, Trojanowski JQ. · Department of Neurology, 2 Gibson, University of Pennsylvania School of Medicine, 3400 Spruce St, Philadelphia, PA 19104-4283, USA. · Arch Neurol. · Pubmed #17998442 links to  free full text

Abstract: BACKGROUND: Clinical-pathologic studies are crucial to understanding brain-behavior relations and improving diagnostic accuracy in neurodegenerative diseases. OBJECTIVE: To establish clinical, neuropsychological, and imaging features of clinically diagnosed patients with frontotemporal dementia (FTD) that help discriminate between pathologically determined tau-positive FTD, tau-negative FTD, and frontal-variant Alzheimer disease. DESIGN: Retrospective clinical-pathologic survey. SETTING: Academic medical center. Patients Sixty-one participants with the clinical diagnosis of a frontotemporal spectrum disorder who underwent a neuropsychological evaluation and had an autopsy-confirmed disease. MAIN OUTCOME MEASURES: Neuropsychological performance and high-resolution structural magnetic resonance imaging (MRI). RESULTS: Distinguishing features of patients with tau-positive FTD include visual perceptual-spatial difficulty and an extrapyramidal disorder significantly more often than other patients, significant cortical atrophy in the frontal and parietal regions as evidenced on MRI, and the burden of pathology is greatest in the frontal and parietal regions. Patients with tau-negative FTD are distinguished by their greater difficulties with social, language, and verbally mediated executive functions, significant cortical atrophy in the frontal and temporal regions as evidenced on MRI, and significant frontal and temporal pathology. Patients with Alzheimer disease at autopsy have significantly impaired delayed recall during episodic memory testing; atrophy that involves temporal areas, including the hippocampus, as evidenced on MRI; and widely distributed pathology including the medial temporal structures. A discriminant function analysis grouped patients on the basis of clinical and neuropsychological features with 87.5% accuracy. CONCLUSION: Clinical, neuropsychological, and imaging profiles can contribute to accurate antemortem diagnosis in FTD.