Alzheimer Disease: Trojanowski JQ

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ, Anonymous00019. · Department of Neurology, Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University School of Medicine, 338 Krieger Hall, 3400 N Charles St, Baltimore, MD 21218-2685, USA. · Arch Neurol. · Pubmed #11708987 links to  free full text

Abstract: An international group of clinical and basic scientists participated in the Frontotemporal Dementia and Pick's Disease Criteria Conference at the National Institutes of Health in Bethesda, Md, on July 7, 2000, to reassess clinical and neuropathological criteria for the diagnosis of frontotemporal dementia (FTD). Previous criteria for FTD have primarily been designed for research purposes. The goal of this meeting was to propose guidelines that would enable clinicians (particularly neurologists, psychiatrists, and neuropsychologists) to recognize patients with FTD and, if appropriate, to expedite their referral to a diagnostic center. In addition, recommendations for the neuropathological criteria of FTD were reviewed, relative to classical neuropathology and modern molecular biology.

Petersen RC, Trojanowski JQ. · No affiliation provided · JAMA. · Pubmed #19622825 No free full text.

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Trojanowski JQ, Smith AB, Huryn D, Lee VM. · No affiliation provided · Expert Opin Pharmacother. · Pubmed #15934894 No free full text.

Abstract: Increasing evidence implicates impairments of axonal transport in mechanisms underlying diverse neurodegenerative disease. This evidence includes discoveries of mutations in genes encoding human motor proteins or proteins involved in stabilising the microtubule (MT) network required for maintenance of axonal transport in familial neurodegenerative disorders, as well as data from in vivo and in vitro model systems. Moreover, in sporadic neurodegenerative disorders such as Alzheimer's disease (AD), pathological alterations of the MT-binding protein tau are linked to impaired axonal transport and brain degeneration. Because MT-stabilising compounds hold promise for counteracting the loss of tau function in AD and sustaining effective axonal transport, we conclude that MT-binding/stabilising drugs show potential therapeutic utility for the treatment of AD and other neurodegenerative disorders characterised by altered MTs and impaired axonal transport.

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.

Ballatore C, Lee VM, Trojanowski JQ. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104-4283, USA. · Nat Rev Neurosci. · Pubmed #17684513 No free full text.

Abstract: Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies.

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.

Lee VM, Trojanowski JQ. · The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and Institute on Aging, The University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · J Alzheimers Dis. · Pubmed #16914864 No free full text.

Abstract: The landmark description of neurofibrillary tangles (NFTs) and senile plaques as the pathological hallmarks of an unusual form of dementia 100 years ago by Alois Alzheimer launched the quest to understand a neurodegenerative disorder that now has become a scourge in the 21st Century due to the unprecedented increase in human life expectancy since 1900. Indeed, while there are many benefits to individuals and society as a whole that will accrue from the remarkable gains in longevity since 1900, the risk of developing Alzheimer's disease (AD) increases exponentially with advancing age beyond the 7th decade of life. Hence, the prevalence of AD will rise inexorably in the coming decades unless effective interventions are developed to delay the onset or progression of AD. Widespread international recognition of the urgency of this problem has accelerated research to discover meaningful therapies for AD, and growing evidence implicates impairments of axonal transport in mechanisms underlying AD due to pathological alterations in tau, the building block proteins of NFTs. This brief review summarizes insights into mechanisms whereby pathological alterations in tau impair axonal transport resulting in neurodegeneration and how these insights are being exploited now to develop novel therapeutic interventions for the treatment of AD.

Mueller SG, Weiner MW, Thal LJ, Petersen RC, Jack C, Jagust W, Trojanowski JQ, Toga AW, Beckett L. · Department of Radiology, University of California, San Francisco, CA, USA. · Neuroimaging Clin N Am. · Pubmed #16443497 links to  free full text

Abstract: With increasing life expectancy in developed countries, the incidence of Alzheimer's disease (AD) and its socioeconomic impact are growing. Increasing knowledge of the mechanisms of AD facilitates the development of treatment strategies aimed at slowing down or preventing neuronal death. AD treatment trials using clinical outcome measures require long observation times and large patient samples. There is increasing evidence that neuroimaging and cerebrospinal fluid and blood biomarkers may provide information that may reduce sample sizes and observation periods. The Alzheimer's Disease Neuroimaging Initiative will help identify clinical, neuroimaging, and biomarker outcome measures that provide the highest power for measurement of longitudinal changes and for prediction of transitions.

Forman MS, Trojanowski JQ, Lee VM. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania, 36th and Spruce Streets, Maloney Building, 3rd Floor, Philadelphia, Pennsylvania 19104-4283, USA. · Nat Med. · Pubmed #15459709 No free full text.

Abstract: A wide variety of neurodegenerative diseases are characterized by the accumulation of intracellular or extracellular protein aggregates. More recently, the genetic identification of mutations in familial counterparts to the sporadic disorders, leading to the development of in vitro and in vivo model systems, has provided insights into disease pathogenesis. The effect of many of these mutations is the abnormal processing of misfolded proteins that overwhelms the quality-control systems of the cell, resulting in the deposition of protein aggregates in the nucleus, cytosol and/or extracellular space. Further understanding of mechanisms regulating protein processing and aggregation, as well as of the toxic effects of misfolded neurodegenerative disease proteins, will facilitate development of rationally designed therapies to treat and prevent these disorders.

Forman MS, Lee VM, Trojanowski JQ. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3600 Spruce Street, Maloney Building, 3rd Floor, Philadelphia, PA 19104, USA. · Trends Neurosci. · Pubmed #12900170 No free full text.

Abstract: The endoplasmic reticulum responds to stress by initiating a cascade of events known as the 'unfolded-protein response' (UPR). The accumulation of misfolded proteins in the leukodystrophy Pelizaeus-Merzbacher disease activates this stress response, resulting in apoptosis of oligodendrocytes. Although it remains uncertain whether the UPR plays a mechanistic role in prototypical neurodegenerative disorders such as Alzheimer's disease, this is plausible because misfolded proteins are directly implicated in the pathogenesis of these disorders.

Frank RA, Galasko D, Hampel H, Hardy J, de Leon MJ, Mehta PD, Rogers J, Siemers E, Trojanowski JQ, Anonymous00193. · Pharmacia Corporation, Mailstop 134, Peapack, NJ 07977, USA. · Neurobiol Aging. · Pubmed #12714109 No free full text.

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Trojanowski JQ. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Ann Neurol. · Pubmed #12205637 No free full text.

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Trojanowski JQ, Lee VM. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Maloney Building, 3rd Floor, HUP, Philadelphia, PA 19104, USA. · Med Clin North Am. · Pubmed #12168561 No free full text.

Abstract: Despite earlier uncertainties about the role of tau pathology in AD, the discovery of multiple mutations in the tau gene that lead to the abnormal aggregation of tau and the onset/progression of FTDP-17 demonstrates that tau dysfunction is sufficient to produce neurodegenerative disease. The mutations lead to specific cellular alterations, including altered expression, function and biochemistry of tau. The finding that specific tau gene mutations lead to diverse FTDP-17 phenotypes raises the possibility that the clinical and pathological expression of hereditary and related sporadic tauopathies may be influenced by tau gene polymorphisms, other genetic factors and epigenetic events. However, the precise mechanisms whereby tau assembles into filaments and causes neurodegeneration in the human brain remain to be elucidated, but further investigation into the mechanisms of tau dysfunction, as well as the identification of potential disease-modifying factors, will provide additional insight into novel strategies for the treatment and prevention of AD and related disorders. Moreover, development of additional animal models of tauopathies that more closely recapitulate human diseases will facilitate this undertaking, and this is likely to have implications for other neurodegenerative disorders since the aggregation of tau in AD and and related tauopathies is an example of abnormal protein-protein interactions resulting in the intracellular accumulation of filamentous proteins that is a common feature of many fatal CNS diseases characterized by relentlessly progressive brain degeneration [1-3]. Thus, the fibrillization and aggregation of proteins in the brain is a common theme in a diverse group of neurodegenerative disorders and insight into the pathogenesis of any one of these disorders may have implications for understanding the mechanisms that underlie all these diseases as well as for the discovery of better strategies to treat them [1-3].

Giasson BI, Ischiropoulos H, Lee VM, Trojanowski JQ. · Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA 19104-4283, USA. · Free Radic Biol Med. · Pubmed #12057764 No free full text.

Abstract: Alzheimer's (AD) and Parkinson's diseases (PD) are late-onset neurodegenerative diseases that have tremendous impact on the lives of affected individuals, their families, and society as a whole. Remarkable efforts are being made to elucidate the dominant factors that result in the pathogenesis of these disorders. Extensive postmortem studies suggest that oxidative/nitrative stresses are prominent features of these diseases, and several animal models support this notion. Furthermore, it is likely that protein modifications resulting from oxidative/nitrative damage contribute to the formation of intracytoplasmic inclusions characteristic of each disease. The frequent presentation of both AD and PD in individuals and the co-occurrence of inclusions characteristic of AD and PD in several other neurodegenerative diseases suggests the involvement of a common underlying aberrant process. It can be surmised that oxidative/nitrative stress, which is cooperatively influenced by environmental factors, genetic predisposition, and senescence, may be a link between these disorders.

Trojanowski JQ, Lee VM. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP, Maloney Building, 3rd Floor, Philadelphia, Pennsylvania 19104-4283, USA. · Ann N Y Acad Sci. · Pubmed #11193803 No free full text.

Abstract: Abnormal protein-protein interactions that result in the formation of intracellular and extracellular aggregates of proteinacious fibrils are common neuropathological features of many, albeit diverse, neurodegenerative disorders, such as sporadic and familial Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and prion encephalopathies. Indeed, increasing evidence suggests that abnormal protein-protein interactions and/or the lesions that result from the aggregation of pathological protein fibrils could play a mechanistic role in the dysfunction and death of neurons or glial cells in neurodegenerative diseases. Here we propose that "fatal attractions" between brain proteins are the key pathological events underlying Alzheimer's disease and a large number of other seemingly diverse neurodegenerative disorders. This hypothesis predicts that the abnormal interaction between normal brain proteins alters their conformation and promotes the assembly of these pathological conformers into filaments that progressively accumulate as intracellular or extracellular fibrous deposits in the central nervous system. Further, the transformation of the normal proteins into pathological conformers is predicted to result in losses of critical functions, and the disease proteins or their progressive accumulation into filamentous aggregates are predicted to acquire neurotoxic properties, all of which culminate in the dysfunction and death of affected brain cells. Thus, the "fatal attractions" hypothesis describes a plausible unifying mechanism that accounts for the onset/progression of Alzheimer's disease and a large number of other seemingly unrelated neurodegenerative disorders characterized neuropathologically by filamentous brain lesions formed by different proteins.

Higuchi M, Tashiro M, Arai H, Okamura N, Hara S, Higuchi S, Itoh M, Shin RW, Trojanowski JQ, Sasaki H. · Department of Geriatric Medicine, Tohoku University School of Medicine, Miyagi, Sendai, 980, Japan. · Exp Neurol. · Pubmed #10739631 No free full text.

Abstract: Cerebral glucose metabolism using positron emission tomography (PET) with (18)F-fluorodeoxyglucose was examined in 11 patients with probable Alzheimer's disease (AD), 6 patients with probable, and 1 patient with autopsy-confirmed dementia with Lewy bodies (DLB) as well as in 10 age-matched normal control subjects. Among widespread cortical regions showing glucose hypometabolism in the DLB group, the metabolic reduction was most pronounced in the visual association cortex compared to that in the AD group. Using a metabolic ratio of 0.92 in the visual association cortex as a cutoff (mean-2 SD of normal control subjects), DLB could be distinguished from AD with a sensitivity of 86% and a specificity of 91%. In contrast, apolipoprotein E4 allele frequency and cerebrospinal fluid tau levels did not differ significantly between the two groups. In order to further dissect out neuropathological correlates of the dysfunctional occipital lobe, postmortem brains from 19 patients with AD and 17 with DLB as well as 11 brains from normal controls were examined. A distinct and extensive spongiform change with coexisting gliosis was variably noted throughout cerebral white matter with relative sparing of gray matter in DLB. Notably, the white matter spongiform change and gliosis was most prominently and consistently found in the occipital region of DLB, and the severity of the spongiform change in each brain region generally paralleled to the regional difference in reduced glucose metabolism between the living AD and DLB patients. These findings suggest that (1) among several potential antemortem biomarkers in the diagnosis of DLB, measures of the glucose metabolism in the occipital cortex may be an informative diagnostic aid to distinguish DLB from AD; and (2) a pathological process that generates widespread spongiform change and gliosis in long projection fibers may contribute, at least in part, to the characteristic imaging features of DLB.

Schenk D, Carrillo MC, Trojanowski JQ. · Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA. · Alzheimers Dement. · Pubmed #19595899 No free full text.

Abstract: The Alzheimer's Association Research Roundtable, a consortium of Association senior scientists and leaders from pharmaceutical, biotech, and imaging companies, met to discuss strategies for developing novel therapeutics for the treatment of Alzheimer's disease (AD). The goal of the meeting was to address, primarily, strategies that do not hinge on directly modulating levels of beta-amyloid. The identification of beta-amyloid as the major constituent of senile plaques and the subsequent discovery that familial AD can be caused by mutations in either the beta-amyloid precursor protein or presenilins, proteases that cleaves beta-amyloid from its precursor, has spawned numerous therapeutic strategies for treating AD. These include passive and active vaccines for clearing beta-amyloid from the brain and the development of small molecule inhibitors of beta- and gamma-secretases that can attenuate the production of beta-amyloid. But the field recognizes that there is more to AD than beta-amyloid alone. What role do neurofibrillary tangles play in the disease, for example, and how are they influenced by beta-amyloid? What lies upstream of beta-amyloid production in the sporadic AD brain, and how do apolipoproteins and cholesterol influence disease progression? Are there environmental or behavioral factors that contribute to the initiation or progression of sporadic AD? Because of the complexity of AD, the field is continually looking to other therapeutic strategies that may complement or substitute for therapies that target beta-amyloid. This roundtable meeting was charged with discussing and evaluating some of those strategies.

Jedrziewski MK, Lee VM, Trojanowski JQ. · The Institute on Aging, Penn Ralston House, University of Pennsylvania School of Medicine, 3615 Chestnut Street, Philadelphia, PA 19104; Marian S. Ware Alzheimer Program, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. · Alzheimers Dement. · Pubmed #19595848 No free full text.

Abstract: BACKGROUND: The increasing prevalence of Alzheimer's disease (AD) and other aging-related dementias as the population ages will have a dramatic impact on both provision of health care and the economy if nothing is done to prevent or delay the onset of AD or to slow its progression. METHODS: A comprehensive review of the literature in several promising areas of inquiry, other than those representing Food and Drug Administration (FDA)-approved AD- or dementia-specific pharmacologic therapies, that may impact the risk or progression of AD and related dementias was undertaken. RESULTS: Results highlight a number of factors associated with AD and dementia. These include education and occupation, cognitive and leisure activities, exercise, cholesterol and statins, and head trauma. CONCLUSIONS: Factors associated with AD and dementia may have potential as strategies useful in preventing or delaying AD and dementia or slowing its progression. Further research is needed to determine the validity and strength of the associations and to ascertain causality.

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.

Khachaturian ZS, Snyder PJ, Doody R, Aisen P, Comer M, Dwyer J, Frank RA, Holzapfel A, Khachaturian AS, Korczyn AD, Roses A, Simpkins JW, Schneider LS, Albert MS, Egge R, Deves A, Ferris S, Greenberg BD, Johnson C, Kukull WA, Poirier J, Schenk D, Thies W, Gauthier S, Gilman S, Bernick C, Cummings JL, Fillit H, Grundman M, Kaye J, Mucke L, Reisberg B, Sano M, Pickeral O, Petersen RC, Mohs RC, Carrillo M, Corey-Bloom JP, Foster NL, Jacobsen S, Lee V, Potter WZ, Sabbagh MN, Salmon D, Trojanowski JQ, Wexler N, Bain LJ. · Lou Ruvo Brain Institute, Las Vegas, NV 89106, USA. · Alzheimers Dement. · Pubmed #19328434 No free full text.

Abstract: This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

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.

Leow AD, Yanovsky I, Parikshak N, Hua X, Lee S, Toga AW, Jack CR, Bernstein MA, Britson PJ, Gunter JL, Ward CP, Borowski B, Shaw LM, Trojanowski JQ, Fleisher AS, Harvey D, Kornak J, Schuff N, Alexander GE, Weiner MW, Thompson PM, Anonymous00037. · Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095-1769, USA. · Neuroimage. · Pubmed #19280686 links to  free full text

Abstract: Tensor-based morphometry can recover three-dimensional longitudinal brain changes over time by nonlinearly registering baseline to follow-up MRI scans of the same subject. Here, we compared the anatomical distribution of longitudinal brain structural changes, over 12 months, using a subset of the ADNI dataset consisting of 20 patients with Alzheimer's disease (AD), 40 healthy elderly controls, and 40 individuals with mild cognitive impairment (MCI). Each individual longitudinal change map (Jacobian map) was created using an unbiased registration technique, and spatially normalized to a geometrically-centered average image based on healthy controls. Voxelwise statistical analyses revealed regional differences in atrophy rates, and these differences were correlated with clinical measures and biomarkers. Consistent with prior studies, we detected widespread cerebral atrophy in AD, and a more restricted atrophic pattern in MCI. In MCI, temporal lobe atrophy rates were correlated with changes in mini-mental state exam (MMSE) scores, clinical dementia rating (CDR), and logical/verbal learning memory scores. In AD, temporal atrophy rates were correlated with several biomarker indices, including a higher CSF level of p-tau protein, and a greater CSF tau/beta amyloid 1-42 (ABeta42) ratio. Temporal lobe atrophy was significantly faster in MCI subjects who converted to AD than in non-converters. Serial MRI scans can therefore be analyzed with nonlinear image registration to relate ongoing neurodegeneration to a variety of pathological biomarkers, cognitive changes, and conversion from MCI to AD, tracking disease progression in 3-dimensional detail.

Chou YY, Leporé N, Avedissian C, Madsen SK, Parikshak N, Hua X, Shaw LM, Trojanowski JQ, Weiner MW, Toga AW, Thompson PM, Anonymous00026. · Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095-7332, USA. · Neuroimage. · Pubmed #19236926 links to  free full text

Abstract: We aimed to improve on the single-atlas ventricular segmentation method of (Carmichael, O.T., Thompson, P.M., Dutton, R.A., Lu, A., Lee, S.E., Lee, J.Y., Kuller, L.H., Lopez, O.L., Aizenstein, H.J., Meltzer, C.C., Liu, Y., Toga, A.W., Becker, J.T., 2006. Mapping ventricular changes related to dementia and mild cognitive impairment in a large community-based cohort. IEEE ISBI. 315-318) by using multi-atlas segmentation, which has been shown to lead to more accurate segmentations (Chou, Y., Leporé, N., de Zubicaray, G., Carmichael, O., Becker, J., Toga, A., Thompson, P., 2008. Automated ventricular mapping with multi-atlas fluid image alignment reveals genetic effects in Alzheimer's disease, NeuroImage 40(2): 615-630); with this method, we calculated minimal numbers of subjects needed to detect correlations between clinical scores and ventricular maps. We also assessed correlations between emerging CSF biomarkers of Alzheimer's disease pathology and localizable deficits in the brain, in 80 AD, 80 mild cognitive impairment (MCI), and 80 healthy controls from the Alzheimer's Disease Neuroimaging Initiative. Six expertly segmented images and their embedded parametric mesh surfaces were fluidly registered to each brain; segmentations were averaged within subjects to reduce errors. Surface-based statistical maps revealed powerful correlations between surface morphology and 4 variables: (1) diagnosis, (2) depression severity, (3) cognitive function at baseline, and (4) future cognitive decline over the following year. Cognitive function was assessed using the mini-mental state exam (MMSE), global and sum-of-boxes clinical dementia rating (CDR) scores, at baseline and 1-year follow-up. Lower CSF Abeta(1-42) protein levels, a biomarker of AD pathology assessed in 138 of the 240 subjects, were correlated with lateral ventricular expansion. Using false discovery rate (FDR) methods, 40 and 120 subjects, respectively, were needed to discriminate AD and MCI from normal groups. 120 subjects were required to detect correlations between ventricular enlargement and MMSE, global CDR, sum-of-boxes CDR and clinical depression scores. Ventricular expansion maps correlate with pathological and cognitive measures in AD, and may be useful in future imaging-based clinical trials.

Ji B, Maeda J, Sawada M, Ono M, Okauchi T, Inaji M, Zhang MR, Suzuki K, Ando K, Staufenbiel M, Trojanowski JQ, Lee VM, Higuchi M, Suhara T. · Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Chiba 263-8555, Japan. · J Neurosci. · Pubmed #19020019 links to  free full text

Abstract: We demonstrate the significance of peripheral benzodiazepine receptor (PBR) imaging in living mouse models of Alzheimer's disease (AD) as biomarkers and functional signatures of glial activation. By radiochemically and immunohistochemically analyzing murine models of the two pathological hallmarks of AD, we found that AD-like Abeta deposition is concurrent with astrocyte-dominant PBR expression, in striking contrast with nonastroglial PBR upregulation in accumulations of AD-like phosphorylated tau. Because tau-induced massive neuronal loss was distinct from the marginal neurodegeneration associated with Abeta plaques in these models, cellular localization of PBR reflected deleterious and beneficial glial reactions to tau versus Abeta pathologies, respectively. This notion was subsequently examined in models of various non-AD neuropathologies, revealing the following reactive glial dynamics underlying differential PBR upregulation: (1) PBR(-) astrogliosis uncoupled with microgliosis or coupled with PBR(+) microgliosis associated with irreversible neuronal insults; and (2) PBR(+) astrogliosis coupled with PBR(- or +/-) microgliosis associated with minimal or reversible neuronal toxicity. Intracranial transplantation of microglia also indicated that nontoxic microglia drives astroglial PBR expression. Moreover, levels of glial cell line-derived neurotrophic factor (GDNF) in astrocytes were correlated with astroglial PBR, except for increased GDNF in PBR(-) astrocytes in the model of AD-like tau pathology, thereby suggesting that PBR upregulation in astrocytes is an indicator of neurotrophic support. Together, PBR expressions in astrocytes and microglia reflect beneficial and deleterious glial reactions, respectively, in diverse neurodegenerative disorders including AD, pointing to new applications of PBR imaging for monitoring the impact of gliosis on the pathogenesis and treatment of AD.