516 results on '"Jagust WJ"'
Search Results
2. Amyloid in dementia associated with familial FTLD: not an innocent bystander
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Naasan, G, Rabinovici, GD, Ghosh, P, Elofson, JD, Miller, BL, Coppola, G, Karydas, A, Fong, J, Perry, D, Lee, SE, Yokoyama, JS, Seeley, WW, Kramer, JH, Weiner, MW, Schuff, N, Jagust, WJ, Grinberg, LT, Pribadi, M, Yang, Z, Sears, R, Klein, E, Wojta, K, and Rosen, HJ
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Clinical Sciences ,Psychology ,Cognitive Sciences ,Experimental Psychology ,Neurosciences ,Biological psychology ,Clinical and health psychology - Abstract
Patients with frontotemporal lobar degeneration (FTLD) can show superimposed amyloid pathology, though the impact of amyloid on the clinical presentation of FTLD is not well characterized. This cross-sectional case–control study compared clinical features, fluorodeoxyglucose-positron emission tomography metabolism and gray matter volume loss in 30 patients with familial FTLD in whom amyloid status was confirmed with autopsy or Pittsburgh compound B-PET. Compared to the amyloid-negative patients, the amyloid-positive patients performed significantly worse on several cognitive tests and showed hypometabolism and volume loss in more temporoparietal regions. Our results suggest that in FTLD amyloid positivity is associated with a more Alzheimer’s disease-like pattern of neurodegeneration.
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- 2016
3. Tau and beta-amyloid-The malignant duo
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Jagust, WJ
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Clinical Sciences ,Neurosciences ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Published
- 2016
4. APOE effect on Alzheimer's disease biomarkers in older adults with significant memory concern
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Risacher, SL, Kim, S, Nho, K, Foroud, T, Shen, L, Petersen, RC, Jack, CR, Beckett, LA, Aisen, PS, Koeppe, RA, Jagust, WJ, Shaw, LM, Trojanowski, JQ, Weiner, MW, Saykin, AJ, and Alzheimer's Disease Neuroimaging Initiative (ADNI)
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Clinical Sciences ,Neurosciences ,Geriatrics ,Clinical sciences ,Biological psychology - Abstract
Introduction This study assessed apolipoprotein E (APOE) ε4 carrier status effects on Alzheimer's disease imaging and cerebrospinal fluid (CSF) biomarkers in cognitively normal older adults with significant memory concerns (SMC). Methods Cognitively normal, SMC, and early mild cognitive impairment participants from Alzheimer's Disease Neuroimaging Initiative were divided by APOE ε4 carrier status. Diagnostic and APOE effects were evaluated with emphasis on SMC. Additional analyses in SMC evaluated the effect of the interaction between APOE and [18F]Florbetapir amyloid positivity on CSF biomarkers. Results SMC ε4+ showed greater amyloid deposition than SMC ε4-, but no hypometabolism or medial temporal lobe (MTL) atrophy. SMC ε4+ showed lower amyloid beta 1-42 and higher tau/p-tau than ε4-, which was most abnormal in APOE ε4+ and cerebral amyloid positive SMC. Discussion SMC APOE ε4+ show abnormal changes in amyloid and tau biomarkers, but no hypometabolism or MTL neurodegeneration, reflecting the at-risk nature of the SMC group and the importance of APOE in mediating this risk.
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- 2015
5. Loss of functional connectivity is greater outside the default mode network in nonfamilial early-onset Alzheimer's disease variants
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Lehmann, M, Madison, C, Ghosh, PM, Miller, ZA, Greicius, MD, Kramer, JH, Coppola, G, Miller, BL, Jagust, WJ, Gorno-Tempini, ML, Seeley, WW, and Rabinovici, GD
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Clinical Sciences ,Neurosciences ,Neurology & Neurosurgery - Abstract
The common and specific involvement of brain networks in clinical variants of Alzheimer's disease (AD) is not well understood. We performed task-free ("resting-state") functional imaging in 60 nonfamilial AD patients, including 20 early-onset AD (age at onset
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- 2015
6. Tau, amyloid, and hypometabolism in a patient with posterior cortical atrophy
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Ossenkoppele, R, Schonhaut, DR, Baker, SL, O'Neil, JP, Janabi, M, Ghosh, PM, Santos, M, Miller, ZA, Bettcher, BM, Gorno-Tempini, ML, Miller, BL, Jagust, WJ, and Rabinovici, GD
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Neurology & Neurosurgery ,Clinical Sciences ,Neurosciences - Abstract
Determining the relative contribution of amyloid plaques and neurofibrillary tangles to brain dysfunction in Alzheimer disease is critical for therapeutic approaches, but until recently could only be assessed at autopsy. We report a patient with posterior cortical atrophy (visual variant of Alzheimer disease) who was studied using the novel tau tracer [18F]AV-1451 in conjunction with [11C]Pittsburgh compound B (PIB; amyloid) and [18F]fluorodeoxyglucose (FDG) positron emission tomography. Whereas [11C]PIB bound throughout association neocortex, [18F]AV-1451 was selectively retained in posterior brain regions that were affected clinically and showed markedly reduced [18F]FDG uptake. This provides preliminary in vivo evidence that tau is more closely linked to hypometabolism and symptomatology than amyloid.
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- 2015
7. b-Amyloid deposition in the human brain disrupts NREM slow wave sleep and associated hippocampus-dependent long term memory
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Mander, BA, Marks, SM, Vogel, JW, Rao, V, Lu, B, Saletin, JM, Ancoli-Israel, S, Jagust, WJ, and Walker, MP
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Neurosciences ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Published
- 2015
8. The Centiloid project: Standardizing quantitative amyloid plaque estimation by PET
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Klunk, WE, Koeppe, RA, Price, JC, Benzinger, TL, Devous, MD, Jagust, WJ, Johnson, KA, Mathis, CA, Minhas, D, Pontecorvo, MJ, Rowe, CC, Skovronsky, DM, and Mintun, MA
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Geriatrics ,Neurosciences ,Clinical Sciences - Abstract
Although amyloid imaging with PiB-PET ([C-11]Pittsburgh Compound-B positron emission tomography), and now with F-18-labeled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (≤45 years) and typical Alzheimer's disease patients. The units of this scale have been named "Centiloids." Basically, we describe a "standard" method of analyzing PiB PET data and then a method for scaling any "nonstandard" method of PiB PET analysis (or any other tracer) to the Centiloid scale.
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- 2015
9. Amyloid PET imaging in Alzheimer's disease: a comparison of three radiotracers.
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Landau, SM, Thomas, BA, Thurfjell, L, Schmidt, M, Margolin, R, Mintun, M, Pontecorvo, M, Baker, SL, Jagust, WJ, and Alzheimer’s Disease Neuroimaging Initiative
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Alzheimer’s Disease Neuroimaging Initiative ,Cerebral Cortex ,Humans ,Alzheimer Disease ,Amyloid ,Radiopharmaceuticals ,Positron-Emission Tomography ,Image Processing ,Computer-Assisted ,Aged ,Female ,Male ,White Matter ,Alzheimer's disease ,PET imaging ,Neurology ,Aging ,Brain Disorders ,Clinical Research ,Acquired Cognitive Impairment ,Bioengineering ,Neurodegenerative ,Dementia ,Neurosciences ,Alzheimer's Disease ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Biomedical Imaging ,Nuclear Medicine & Medical Imaging ,Other Physical Sciences ,Clinical Sciences - Abstract
PurposeThe increasing use of amyloid PET in Alzheimer's disease research and clinical trials has motivated efforts to standardize methodology. We compared retention of the (11)C radiotracer Pittsburgh Compound B (PiB) and that of two (18)F amyloid radiotracers (florbetapir and flutemetamol) using two study populations. We also examined the feasibility of converting between tracer-specific measures, using PiB as the common link between the two (18)F tracers.MethodsOne group of 40 subjects underwent PiB and flutemetamol imaging sessions and a separate group of 32 subjects underwent PiB and florbetapir imaging sessions. We compared cortical and white matter retention for each (18)F tracer relative to that of PiB, as well as retention in several reference regions and image analysis methods. Correlations between tracer pairs were used to convert tracer-specific threshold values for amyloid positivity between tracers.ResultsCortical retention for each pair of tracers was strongly correlated regardless of reference region (PiB-flutemetamol, ρ = 0.84-0.99; PiB-florbetapir, ρ = 0.83-0.97) and analysis method (ρ = 0.90-0.99). Compared to PiB, flutemetamol had higher white matter retention, while florbetapir had lower cortical retention. Two previously established independent thresholds for amyloid positivity were highly consistent when values were converted between tracer pairs.ConclusionDespite differing white and grey matter retention characteristics, cortical retention for each (18)F tracer was highly correlated with that of PiB, enabling conversion of thresholds across tracer measurement scales with a high level of internal consistency. Standardization of analysis methods and measurement scales may facilitate the comparison of amyloid PET data obtained using different tracers.
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- 2014
10. Safety and tolerability of putaminal AADC gene therapy for Parkinson diseaseSYMBOL
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Christine, CW, Starr, PA, Larson, PS, Eberling, JL, Jagust, WJ, Hawkins, RA, VanBrocklin, HF, Wright, JF, Bankiewicz, KS, and Aminoff, MJ
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Medical Biotechnology ,Biomedical and Clinical Sciences ,Clinical Sciences ,Brain Disorders ,Clinical Research ,Aging ,Gene Therapy ,Neurodegenerative ,Genetics ,Neurosciences ,Parkinson's Disease ,Prevention ,Neurological ,Aged ,Aromatic-L-Amino-Acid Decarboxylases ,Cohort Studies ,Dyskinesias ,Female ,Follow-Up Studies ,Genetic Therapy ,Humans ,Intracranial Hemorrhages ,Male ,Middle Aged ,Neurosurgical Procedures ,Parkinson Disease ,Positron-Emission Tomography ,Putamen ,Severity of Illness Index ,Time Factors ,Treatment Outcome ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
BackgroundIn Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial.MethodsPatients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [(18)F]fluoro-L-m-tyrosine (FMT) were performed as a measure of gene expression.ResultsThe gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort.ConclusionThis study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson's Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.
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- 2009
11. Amyloid Imaging in Aging and Dementia: Testing the Amyloid Hypothesis In Vivo
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Rabinovici, GD and Jagust, WJ
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Biological Psychology ,Psychology ,Acquired Cognitive Impairment ,Aging ,Clinical Research ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Dementia ,Neurosciences ,Alzheimer's Disease ,Neurodegenerative ,Biomedical Imaging ,4.1 Discovery and preclinical testing of markers and technologies ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Alzheimer Disease ,Amyloid beta-Peptides ,Biomarkers ,Brain ,Brain Mapping ,Cognition Disorders ,Humans ,Image Processing ,Computer-Assisted ,Radionuclide Imaging ,Behavioral and Social Science ,Amyloid imaging ,PET ,PIB ,beta-amyloid ,brain aging ,MCI ,Alzheimer's disease ,Clinical Sciences ,Cognitive Sciences ,Experimental Psychology ,Allied health and rehabilitation science ,Biological psychology - Abstract
Amyloid imaging represents a major advance in neuroscience, enabling the detection and quantification of pathologic protein aggregations in the brain. In this review we survey current amyloid imaging techniques, focusing on positron emission tomography (PET) with (11)carbon-labelled Pittsburgh Compound-B ((11)C-PIB), the most extensively studied and best validated tracer. PIB binds specifically to fibrillar beta-amyloid (Abeta) deposits, and is a sensitive marker for Abeta pathology in cognitively normal older individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). PIB-PET provides us with a powerful tool to examine in vivo the relationship between amyloid deposition, clinical symptoms, and structural and functional brain changes in the continuum between normal aging and AD. Amyloid imaging studies support a model in which amyloid deposition is an early event on the path to dementia, beginning insidiously in cognitively normal individuals, and accompanied by subtle cognitive decline and functional and structural brain changes suggestive of incipient AD. As patients progress to dementia, clinical decline and neurodegeneration accelerate and proceed independently of amyloid accumulation. In the future, amyloid imaging is likely to supplement clinical evaluation in selecting patients for anti-amyloid therapies, while MRI and FDG-PET may be more appropriate markers of clinical progression.
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- 2009
12. Neuropsychological characteristics of mild cognitive impairment subgroups
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Lopez, OL, Becker, JT, Jagust, WJ, Fitzpatrick, A, Carlson, MC, DeKosky, ST, Breitner, J, Lyketsos, CG, Jones, B, Kawas, C, and Kuller, LH
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Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Behavioral and Social Science ,Aging ,Neurodegenerative ,Dementia ,Alzheimer's Disease ,Clinical Research ,Mental Health ,Rehabilitation ,Brain Disorders ,Acquired Cognitive Impairment ,Neurosciences ,Aetiology ,2.1 Biological and endogenous factors ,2.3 Psychological ,social and economic factors ,Mental health ,Neurological ,Aged ,Aged ,80 and over ,Alzheimer Disease ,Amnesia ,Cognition Disorders ,Female ,Humans ,Male ,Neuropsychological Tests ,Psychometrics ,Reference Values ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
ObjectiveTo describe the neuropsychological characteristics of mild cognitive impairment (MCI) subgroups identified in the Cardiovascular Health Study (CHS) cognition study.MethodsMCI was classified as MCI-amnestic type (MCI-AT): patients with documented memory deficits but otherwise normal cognitive function; and MCI-multiple cognitive deficits type (MCI-MCDT): impairment of at least one cognitive domain (not including memory), or one abnormal test in at least two other domains, but who had not crossed the dementia threshold. The MCI subjects did not have systemic, neurological, or psychiatric disorders likely to affect cognition.ResultsMCI-AT (n = 10) had worse verbal and non-verbal memory performance than MCI-MCDT (n = 28) or normal controls (n = 374). By contrast, MCI-MCDT had worse language, psychomotor speed, fine motor control, and visuoconstructional function than MCI-AT or normal controls. MCI-MCDT subjects had memory deficits, though they were less pronounced than in MCI-AT. Of the MCI-MCDT cases, 22 (78.5%) had memory deficits, and 6 (21.5%) did not. MCI-MCDT with memory disorders had more language deficits than MCI-MCDT without memory disorders. By contrast, MCI-MCDT without memory deficits had more fine motor control deficits than MCI-MCDT with memory deficits.ConclusionsThe most frequent form of MCI was the MCI-MCDT with memory deficits. However, the identification of memory impaired MCI groups did not reflect the true prevalence of MCI in a population, as 16% of all MCI cases and 21.5% of the MCI-MCDT cases did not have memory impairment. Study of idiopathic amnestic and non-amnestic forms of MCI is essential for an understanding of the aetiology of MCI.
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- 2006
13. Classification of vascular dementia in the Cardiovascular Health Study Cognition Study
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Lopez, OL, Kuller, LH, Becker, JT, Jagust, WJ, DeKosky, ST, Fitzpatrick, A, Breitner, J, Lyketsos, C, Kawas, C, and Carlson, M
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Neurodegenerative ,Cardiovascular ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aging ,Dementia ,Alzheimer's Disease ,Neurosciences ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Good Health and Well Being ,Aged ,Aged ,80 and over ,Alzheimer Disease ,Brain ,Cerebral Arteries ,Cohort Studies ,Dementia ,Vascular ,Diagnosis ,Differential ,Disease Progression ,Female ,Humans ,Magnetic Resonance Imaging ,Male ,Predictive Value of Tests ,Stroke ,United States ,Clinical Sciences ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
ObjectiveTo describe the diagnostic classification of subjects with incident vascular dementia (VaD) participating in the Cardiovascular Health Study (CHS) Cognition Study.MethodsThe CHS classified 480 incident cases between 1994 and 1999 among 3,608 CHS participants who had brain MRI in 1992 through 1994 and in 1997 through 1998. The patients were diagnosed before and after reviewing the brain MRI.ResultsThe pre-MRI classification showed that 52 participants had VaD and 76 had both Alzheimer disease (AD) and VaD. The post-MRI classification showed that the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria classified 61 subjects as having VaD, the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria classified 43 subjects as having probable VaD and 10 as possible VaD, and the State of California Alzheimer's Disease Diagnostic and Treatment Center (ADDTC) criteria classified 117 as having probable VaD and 96 as possible. The combination of the ADDTC and National Institute of Neurological and Communication Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria was used to examine the spectrum of vascular disease in dementia. The dementia was attributable to only vascular factors in 56 cases (probable VaD); VaD coexisted with AD in 61 cases, although the VaD component was the leading cause of dementia (probable VaD with AD); AD was the leading cause of dementia in 61 cases (possible VaD and probable AD); and in 29 cases, it was not clear that either AD or VaD was the primary diagnosis (possible AD and possible VaD).ConclusionsNone of the clinical criteria for VaD identified the same group of subjects. The diagnosis of vascular dementia is difficult in epidemiologic studies because poststroke dementia can be due to Alzheimer disease (AD) and evidence of vascular disease can be found in the MRI of dementia cases without clinical strokes. Whether the clinical progression is related to AD pathology or vascular disease is difficult to establish.
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- 2005
14. Determinants of vascular dementia in the Cardiovascular Health Cognition Study
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Kuller, LH, Lopez, OL, Jagust, WJ, Becker, JT, DeKosky, ST, Lyketsos, C, Kawas, C, Breitner, JCS, Fitzpatrick, A, and Dulberg, C
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Biomedical Imaging ,Prevention ,Neurosciences ,Dementia ,Stroke ,Neurodegenerative ,Alzheimer's Disease ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aging ,Vascular Cognitive Impairment/Dementia ,Cardiovascular ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Good Health and Well Being ,Age Factors ,Aged ,Aged ,80 and over ,Alzheimer Disease ,Atrophy ,Brain ,Cardiovascular Diseases ,Cerebral Arteries ,Cerebral Infarction ,Cohort Studies ,Comorbidity ,Dementia ,Vascular ,Female ,Humans ,Lateral Ventricles ,Magnetic Resonance Imaging ,Male ,Nerve Fibers ,Myelinated ,Neuropsychological Tests ,Racial Groups ,Risk Factors ,Sex Factors ,Clinical Sciences ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
ObjectiveThe authors evaluated 3,375 participants without dementia at the time of MRI in 1991 to 1994 over 5.7 years for incident dementia and type of dementia.MethodsIncidence of and risk factors for vascular dementia (VaD) were measured using both pre-MRI and modified State of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) post-MRI review and further classified Alzheimer disease (AD) by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria.ResultsApproximately 44% (213) of 480 incident dementia cases were classified as possible or probable VaD by ADDTC. The incidence of VaD increased with age and was greater in blacks than whites. Risk factors for VaD included age, Modified Mini-Mental State Examination, high white matter grade, number of MRI infarcts, ventricular size, and history of stroke.ConclusionsVascular disease in the brain is prevalent among incident dementia cases. There is a substantial overlap between cases classified as Alzheimer disease by Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association and vascular dementia (VaD) by modified State of California Alzheimer's Disease Diagnostic and Treatment Centers criteria. The substantial contribution of vascular disease would be missed without inclusion of MRI. Treatment of risk factors for VaD could have an important impact on incidence of dementia.
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- 2005
15. Clinical and MRI factors for vascular dementia in the Cardiovascular Health Study Cognition Study
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Kuller, LH, Lopez, OL, Jagust, WJ, Becker, JT, DeKosky, ST, Lyketsos, C, Kawas, C, Breitner, JCS, Fitzpatrick, A, and Dulberg, B
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Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Alzheimer's Disease ,Alzheimer's Disease Related Dementias (ADRD) ,Cerebrovascular ,Vascular Cognitive Impairment/Dementia ,Acquired Cognitive Impairment ,Biomedical Imaging ,Neurodegenerative ,Dementia ,Aging ,Brain Disorders ,Cardiovascular ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurological ,Good Health and Well Being ,Clinical Sciences ,Neurology & Neurosurgery ,Biological psychology - Published
- 2004
16. Classification of vascular dementia in the Cardiovascular Health Study Cognition Study
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Lopez, OL, Kuller, LH, Becker, JT, Jagust, WJ, DeKosky, ST, Fitzpatrick, A, Dulberg, C, Breitner, J, Lyketsos, C, Kawas, C, and Carlson, M
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Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Clinical Sciences ,Neurology & Neurosurgery ,Biological psychology - Published
- 2004
17. Dopamine Synthesis Capacity is Associated with D2/3 Receptor Binding but Not Dopamine Release
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Berry, AS, Shah, VD, Furman, DJ, White, RL, Baker, SL, O'Neil, JP, Janabi, M, D'Esposito, M, and Jagust, WJ
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Adult ,Male ,Adolescent ,Dopamine ,Medical and Health Sciences ,Young Adult ,Dopamine Uptake Inhibitors ,Receptors ,Dopamine D2 ,Dopamine D3 ,Humans ,Psychiatry ,Brain Mapping ,Psychology and Cognitive Sciences ,Neurosciences ,Corpus Striatum ,Brain Disorders ,Mental Health ,Raclopride ,Aromatic-L-Amino-Acid Decarboxylases ,Positron-Emission Tomography ,Methylphenidate ,Dopamine Antagonists ,Biomedical Imaging ,Female ,Radiopharmaceuticals ,Protein Binding - Abstract
©The Author(s) 2018. Positron Emission Tomography (PET) imaging allows the estimation of multiple aspects of dopamine function including dopamine synthesis capacity, dopamine release, and D2/3 receptor binding. Though dopaminergic dysregulation characterizes a number of neuropsychiatric disorders including schizophrenia and addiction, there has been relatively little investigation into the nature of relationships across dopamine markers within healthy individuals. Here we used PET imaging in 40 healthy adults to compare, within individuals, the estimates of dopamine synthesis capacity (K i) using 6-[ 18 F]fluoro-l-m-tyrosine ([ 18 F]FMT; a substrate for aromatic amino acid decarboxylase), baseline D2/3 receptor-binding potential using [ 11 C]raclopride (a weak competitive D2/3 receptor antagonist), and dopamine release using [ 11 C]raclopride paired with oral methylphenidate administration. Methylphenidate increases synaptic dopamine by blocking the dopamine transporter. We estimated dopamine release by contrasting baseline D2/3 receptor binding and D2/3 receptor binding following methylphenidate. Analysis of relationships among the three measurements within striatal regions of interest revealed a positive correlation between [ 18 F]FMT K i and the baseline (placebo) [ 11 C]raclopride measure, such that participants with greater synthesis capacity showed higher D2/3 receptor-binding potential. In contrast, there was no relationship between [ 18 F]FMT and methylphenidate-induced [ 11 C]raclopride displacement. These findings shed light on the nature of regulation between pre-and postsynaptic dopamine function in healthy adults, which may serve as a template from which to identify and describe alteration with disease.
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- 2018
18. Head to head comparison of [18F] AV-1451 and [18F] THK5351 for tau imaging in Alzheimer’s disease and frontotemporal dementia
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Jang, YK, Lyoo, CH, Park, S, Oh, SJ, Cho, H, Oh, M, Ryu, YH, Choi, JY, Rabinovici, GD, Kim, HJ, Moon, SH, Jang, H, Lee, JS, Jagust, WJ, Na, DL, Kim, JS, and Seo, SW
- Abstract
© 2017, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Tau accumulation is a core pathologic change in various neurodegenerative diseases including Alzheimer’s disease and frontotemporal lobar degeneration-tau. Recently, tau positron emission tomography tracers such as [18F] AV-1451 and [18F] THK5351 have been developed to detect tau deposition in vivo. In the present study, we performed a head to head comparison of these two tracers in Alzheimer’s disease and frontotemporal dementia cases and aimed to investigate which tracers are better suited to image tau in these disorders. Methods: A cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We recruited eight participants (two Alzheimer’s disease, four frontotemporal dementia and two normal controls) who underwent magnetic resonance image, amyloid positron emission tomography with [18F]-Florbetaben and tau positron emission tomography with both THK5351 and AV-1451. To measure regional AV1451 and THK5351 uptakes, we used the standardized uptake value ratios by dividing mean activity in target volume of interest by mean activity in the cerebellar hemispheric gray matter. Results: Although THK5351 and AV-1451 uptakes were highly correlated, cortical uptake of AV-1451 was more striking in Alzheimer’s disease, while cortical uptake of THK5351 was more prominent in frontotemporal dementia. THK5351 showed higher off-target binding than AV-1451 in the white matter, midbrain, thalamus, and basal ganglia. Conclusions: AV-1451 is more sensitive and specific to Alzheimer’s disease type tau and shows lower off-target binding, while THK5351 may mirror non-specific neurodegeneration.
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- 2018
19. Associations between [F-18]AV1451 tau PET and CSF measures of tau pathology in a clinical sample
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La Joie, R, Bejanin, A, Fagan, AM, Ayakta, N, Baker, SL, Bourakova, V, Boxer, AL, Cha, J, Karydas, A, Jerome, G, Maass, A, Mensing, A, Miller, ZA, O'Neil, JP, Pham, J, Rosen, HJ, Tsai, R, Visani, AV, Miller, BL, Jagust, WJ, and Rabinovici, GD
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- 2018
20. Association of cerebral amyloid-β Aggregation with cognitive functioning in persons without dementia
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Jansen, WJ, Ossenkoppele, R, Tijms, BM, Fagan, AM, Hansson, O, Klunk, WE, Van Der Flier, WM, Villemagne, VL, Frisoni, GB, Fleisher, AS, Lleó, A, Mintun, MA, Wallin, A, Engelborghs, S, Na, DL, Chételat, G, Molinuevo, JL, Landau, SM, Mattsson, N, Kornhuber, J, Sabri, O, Rowe, CC, Parnetti, L, Popp, J, Fladby, T, Jagust, WJ, Aalten, P, Lee, DY, Vandenberghe, R, De Oliveira, CR, Kapaki, E, Froelich, L, Ivanoiu, A, Gabryelewicz, T, Verbeek, MM, Sanchez-Juan, P, Hildebrandt, H, Camus, V, Zboch, M, Brooks, DJ, Drzezga, A, Rinne, JO, Newberg, A, De Mendonça, A, Sarazin, M, Rabinovici, GD, Madsen, K, Kramberger, MG, Nordberg, A, Mok, V, Mroczko, B, Wolk, DA, Meyer, PT, Tsolaki, M, Scheltens, P, Verhey, FRJ, Visser, PJ, Aarsland, D, Alcolea, D, Alexander, M, Almdahl, IS, Arnold, SE, Baldeiras, I, Barthel, H, Van Berckel, BNM, Blennow, K, Van Buchem, MA, Cavedo, E, Chen, K, Chipi, E, Cohen, AD, Förster, S, Fortea, J, Frederiksen, KS, Freund-Levi, Y, Gkatzima, O, Gordon, MF, Grimmer, T, Hampel, H, Hausner, L, Hellwig, S, Herukka, SK, Johannsen, P, Klimkowicz-Mrowiec, A, Köhler, S, and Koglin, N
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mental disorders - Abstract
IMPORTANCE Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. OBJECTIVE To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. MAIN OUTCOMES AND MEASURES Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. RESULTS Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4%[95%CI, 0%-7%] at 72 years and 21% [95%CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3%[95%CI, -1%to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16%[95%CI, 12%-20%], P < .001) and low MMSE (mean difference, 14%[95%CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. CONCLUSIONS AND RELEVANCE Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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- 2018
21. Association of Cerebral Amyloid-beta Aggregation With Cognitive Functioning in Persons Without Dementia
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Jansen, WJ, Ossenkoppele, R, Tijms, BM, Fagan, AM, Hansson, O, Klunk, WE, van der Flier, WM, Villemagne, VL, Frisoni, GB, Fleisher, AS, Lleo, A, Mintun, MA, Wallin, A, Engelborghs, S, Na, DL, Chetelat, G, Molinuevo, JL, Landau, SM, Mattsson, N, Kornhuber, J, Sabri, O, Rowe, CC, Parnetti, L, Popp, J, Fladby, T, Jagust, WJ, Aalten, P, Lee, DY, Vandenberghe, R, de Oliveira, CR, Kapaki, E, Froelich, L, Ivanoiu, A, Gabryelewicz, T, Verbeek, MM, Sanchez-Juan, P, Hildebrandt, H, Camus, V, Zboch, M, Brooks, DJ, Drzezga, A, Rinne, JO, Newberg, A, de Mendonca, A, Sarazin, M, Rabinovici, GD, Madsen, K, Kramberger, MG, Nordberg, A, Mok, V, Mroczko, B, Wolk, DA, Meyer, PT, Tsolaki, M, Scheltens, P, Verhey, FRJ, Visser, PJ, and Amyloid Biomarker Study Grp
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mental disorders - Abstract
IMPORTANCE Cerebral amyloid-beta aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. OBJECTIVE To investigate whether amyloid-beta aggregation is associated with cognitive functioning in persons without dementia. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. MAIN OUTCOMES AND MEASURES Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score
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- 2018
22. Old Brains Come Uncoupled in Sleep: Slow Wave-Spindle Synchrony, Brain Atrophy, and Forgetting
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Helfrich, RF, Mander, BA, Jagust, WJ, Knight, RT, and Walker, MP
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Male ,Aging ,overnight forgetting ,1.1 Normal biological development and functioning ,Neurodegenerative ,Basic Behavioral and Social Science ,Young Adult ,atrophy ,hippocampus-dependent memory consolidation ,Clinical Research ,Underpinning research ,Behavioral and Social Science ,directional cross-frequency coupling ,Acquired Cognitive Impairment ,Humans ,2.1 Biological and endogenous factors ,Psychology ,Aetiology ,hierarchical nesting ,Aged ,Memory Consolidation ,prefrontal cortex ,Neurology & Neurosurgery ,Neurosciences ,Brain ,sleep spindles ,Brain Disorders ,age-related memory decline ,Neurological ,Female ,Mental health ,Cognitive Sciences ,Sleep ,Sleep Research ,slow oscillation - Abstract
© 2017 Elsevier Inc. The coupled interaction between slow-wave oscillations and sleep spindles during non-rapid-eye-movement (NREM) sleep has been proposed to support memory consolidation. However, little evidence in humans supports this theory. Moreover, whether such dynamic coupling is impaired as a consequence of brain aging in later life, contributing to cognitive and memory decline, is unknown. Combining electroencephalography (EEG), structural MRI, and sleep-dependent memory assessment, we addressed these questions in cognitively normal young and older adults. Directional cross-frequency coupling analyses demonstrated that the slow wave governs a precise temporal coordination of sleep spindles, the quality of which predicts overnight memory retention. Moreover, selective atrophy within the medial frontal cortex in older adults predicted a temporal dispersion of this slow wave-spindle coupling, impairing overnight memory consolidation and leading to forgetting. Prefrontal-dependent deficits in the spatiotemporal coordination of NREM sleep oscillations therefore represent one pathway explaining age-related memory decline. Helfrich et al. demonstrate that the precise coupling between sleeping brainwaves, called slow waves and spindles, supports memory retention. However, this brainwave coupling during sleep is impaired in older adults due to loss of tissue in the medial frontal lobe, resulting in next-day forgetting.
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- 2018
23. Considerations and code for partial volume correcting [18F]-AV-1451 tau PET data
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Baker, SL, Maass, A, and Jagust, WJ
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© 2017 The Authors [18F]-AV-1451 is a leading tracer used with positron emission tomography (PET) to quantify tau pathology. However, [18F]-AV-1451 shows “off target” or non-specific binding, which we define as binding of the tracer in unexpected areas unlikely to harbor aggregated tau based on autopsy literature [1]. Along with caudate, putamen, pallidum and thalamus non-specific binding [2,3], we have found binding in the superior portion of the cerebellar gray matter, leading us to use inferior cerebellar gray as the reference region. We also addressed binding in the posterior portion of the choroid plexus. PET signal unlikely to be associated with tau also occurs in skull, meninges and soft tissue (see e.g. [4]). We refer to [18F]-AV-1451 binding in the skull and meninges as extra-cortical hotspots (ECH) and find them near lateral and medial orbitofrontal, lateral occipital, inferior and middle temporal, superior and inferior parietal, and inferior cerebellar gray matter. Lastly, the choroid plexus also shows non-specific binding that bleeds into hippocampus. We are providing the code (http://www.runmycode.org/companion/view/2798) used to create different regions of interest (ROIs) that we then used to perform Partial Volume Correction (PVC) using the Rousset geometric transfer matrix method (GTM, [5]). This method was used in the companion article, “Comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer's Disease” ([6], DOI 10.1016/j.neuroimage.2017.05.058).
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- 2017
24. 18F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study
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Schonhaut, DR, McMillan, CT, Spina, S, Dickerson, BC, Siderowf, A, Devous, MD, Tsai, R, Winer, J, Russell, DS, Litvan, I, Roberson, ED, Seeley, WW, Grinberg, LT, Kramer, JH, Miller, BL, Pressman, P, Nasrallah, I, Baker, SL, Gomperts, SN, Johnson, KA, Grossman, M, Jagust, WJ, Boxer, AL, and Rabinovici, GD
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eye diseases - Abstract
© 2017 American Neurological Association Objective: 18F-flortaucipir (formerly 18F-AV1451 or 18F-T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo 18F-flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26). Methods: Participants underwent magnetic resonance imaging and positron emission tomography for amyloid-β (11C-PiB or 18F-florbetapir) and tau (18F-flortaucipir). 18F-flortaucipir standardized uptake value ratios were calculated (t = 80–100 minutes, cerebellum gray matter reference). Voxelwise and region-of-interest group comparisons were performed in template space, with receiver operating characteristic curve analyses to assess single-subject discrimination. Qualitative comparisons with postmortem tau are reported in 1 patient who died 9 months after 18F-flortaucipir. Results: Clinical PSP patients showed bilaterally elevated 18F-flortaucipir uptake in globus pallidus, putamen, subthalamic nucleus, midbrain, and dentate nucleus relative to controls and PD patients (voxelwise p < 0.05 family wise error corrected). Globus pallidus binding best distinguished PSP patients from controls and PD (area under the curve [AUC] = 0.872 vs controls, AUC = 0.893 vs PD). PSP clinical severity did not correlate with 18F-flortaucipir in any region. A patient with clinical PSP and pathological diagnosis of corticobasal degeneration had severe tau pathology in PSP-related brain structures with good correspondence between in vivo 18F-flortaucipir and postmortem tau neuropathology. Interpretation: 18F-flortaucipir uptake was elevated in PSP versus controls and PD patients in a pattern consistent with the expected distribution of tau pathology. Ann Neurol 2017;82:622–634.
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- 2017
25. Amyloid and tau PET demonstrate region-specific associations in normal older people
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Lockhart, SN, Schöll, M, Baker, SL, Ayakta, N, Swinnerton, KN, Bell, RK, Mellinger, TJ, Shah, VD, O'Neil, JP, Janabi, M, and Jagust, WJ
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Male ,Aging ,Amyloid ,tau Proteins ,Neurodegenerative ,Alzheimer's Disease ,Medical and Health Sciences ,Polypathology ,Computer-Assisted ,mental disorders ,80 and over ,Acquired Cognitive Impairment ,Humans ,Carbon Radioisotopes ,Image Interpretation ,Aged ,Aniline Compounds ,Amyloid beta-Peptides ,Neurology & Neurosurgery ,Psychology and Cognitive Sciences ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Magnetic Resonance Imaging ,Temporal Lobe ,Brain Disorders ,Thiazoles ,PET ,Positron-Emission Tomography ,Neurological ,Biomedical Imaging ,Female ,Dementia ,Radiopharmaceuticals ,Tau ,Carbolines - Abstract
© 2017 Elsevier Inc. β-amyloid (Aβ) and tau pathology become increasingly prevalent with age, however, the spatial relationship between the two pathologies remains unknown. We examined local (same region) and non-local (different region) associations between these 2 aggregated proteins in 46 normal older adults using [18F]AV-1451 (for tau) and [11C]PiB (for Aβ) positron emission tomography (PET) and 1.5 T magnetic resonance imaging (MRI) images. While local voxelwise analyses showed associations between PiB and AV-1451 tracer largely in the temporal lobes, k-means clustering revealed that some of these associations were driven by regions with low tracer retention. We followed this up with a whole-brain region-by-region (local and non-local) partial correlational analysis. We calculated each participant's mean AV-1451 and PiB uptake values within 87 regions of interest (ROI). Pairwise ROI analysis demonstrated many positive PiB—AV-1451 associations. Importantly, strong positive partial correlations (controlling for age, sex, and global gray matter fraction, p
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- 2017
26. Tau and β-Amyloid Are Associated with Medial Temporal Lobe Structure, Function, and Memory Encoding in Normal Aging
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Marks, SM, Lockhart, SN, Baker, SL, and Jagust, WJ
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Adult ,Male ,Aging ,Adolescent ,hippocampus ,1.1 Normal biological development and functioning ,tau Proteins ,and over ,Neurodegenerative ,Alzheimer's Disease ,Medical and Health Sciences ,Young Adult ,Memory ,80 and over ,Acquired Cognitive Impairment ,Humans ,2.1 Biological and endogenous factors ,Alzheimer's Disease including Alzheimer's Disease Related Dementias ,tau ,Aged ,Amyloid beta-Peptides ,Neurology & Neurosurgery ,fMRI ,Psychology and Cognitive Sciences ,Neurosciences ,amyloid ,episodic memory ,Middle Aged ,Temporal Lobe ,Brain Disorders ,PET ,Mental Health ,Neurological ,Female ,Dementia ,Episodic ,psychological phenomena and processes - Abstract
Normal aging is associated with a decline in episodic memory and also with aggregation of the β-amyloid (Aβ) and tau proteins and atrophy of medial temporal lobe (MTL) structures crucial to memory formation. Although some evidence suggests that Aβ is associated with aberrant neural activity, the relationships among these two aggregated proteins, neural function, and brain structure are poorly understood. Using in vivo human Aβ and tau imaging, we demonstrate that increased Aβ and tau are both associated with aberrant fMRI activity in the MTL during memory encoding in cognitively normal older adults. This pathological neural activity was in turn associated with worse memory performance and atrophy within the MTL. A mediation analysis revealed that the relationship with regional atrophy was explained by MTL tau. These findings broaden the concept of cognitive aging to include evidence of Alzheimer's disease-related protein aggregation as an underlying mechanism of age-related memory impairment.SIGNIFICANCE STATEMENT Alterations in episodic memory and the accumulation of Alzheimer's pathology are common in cognitively normal older adults. However, evidence of pathological effects on episodic memory has largely been limited to β-amyloid (Aβ). Because Aβ and tau often cooccur in older adults, previous research offers an incomplete understanding of the relationship between pathology and episodic memory. With the recent development of in vivo tau PET radiotracers, we show that Aβ and tau are associated with different aspects of memory encoding, leading to aberrant neural activity that is behaviorally detrimental. In addition, our results provide evidence linking Aβ- and tau-associated neural dysfunction to brain atrophy.
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- 2017
27. Reference tissue-based kinetic evaluation of 18F-AV-1451 for tau imaging
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Baker, SL, Lockhart, SN, Price, JC, He, M, Huesman, RH, Schonhaut, D, Faria, J, Rabinovici, G, and Jagust, WJ
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Copyright © 2017 SNMMI; all rights reserved. The goal of this paper was to evaluate the in vivo kinetics of the novel tau-specific PET radioligand 18F-AV-1451 in cognitively healthy control (HC) and Alzheimer disease (AD) subjects, using reference region analyses. Methods: 18F-AV-1451 PET imaging was performed on 43 subjects (5 young HCs, 23 older HCs, and 15 AD subjects). Data were collected from 0 to 150 min after injection, with a break from 100 to 120 min. T1-weighted MR images were segmented using FreeSurfer to create 14 bilateral regions of interest (ROIs). In all analyses, cerebellar gray matter was used as the reference region. Nondisplaceable binding potentials (BPNDs) were calculated using the simplified reference tissue model (SRTM) and SRTM2; the Logan graphical analysis distribution volume ratio (DVR) was calculated for 30-150 min (DVR30-150). These measurements were compared with each other and used as reference standards for defining an appropriate 20-min window for the SUV ratio (SUVR). Pearson correlations were used to compare the reference standards to 20-min SUVRs (start times varied from 30 to 130 min), for all values, for ROIs with low 18F-AV-1451 binding (lROIs, mean of BPND + 1 and DVR30-150 < 1.5), and for ROIs with high 18F-AV- 1451 binding (hROIs, mean of BPND + 1 and DVR30-150 > 1.5). Results: SRTM2 BPND + 1 and DVR30-150 were in good agreement. Both were in agreement with SRTM BPND + 1 for lROIs but were greater than SRTM BPND + 1 for hROIs, resulting in a nonlinear relationship. hROI SUVRs increased from 80-100 to 120-140 min by 0.24 ± 0.15. The SUVR time interval resulting in the highest correlation and slope closest to 1 relative to the reference standards for all values was 120-140 min for hROIs, 60-80 min for lROIs, and 80-100 min for lROIs and hROIs. There was minimal difference between methods when statistical significance between ADs and HCs was calculated. Conclusion: Despite later time periods providing better agreement between reference standards and SUVRs for hROIs, a good compromise for studying lROIs and hROIs is SUVR80-100. The lack of SUVR plateau for hROIs highlights the importance of precise acquisition time for longitudinal assessment.
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- 2017
28. Regional correlations between [11C]PIB PET and post-mortem burden of amyloid-beta pathology in a diverse neuropathological cohort
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Seo, SW, Ayakta, N, Grinberg, LT, Villeneuve, S, Lehmann, M, Reed, B, DeCarli, C, Miller, BL, Rosen, HJ, Boxer, AL, O'Neil, JP, Jin, LW, Seeley, WW, Jagust, WJ, and Rabinovici, GD
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mental disorders - Abstract
© 2016 The Authors Imaging-pathological correlation studies show that in vivo amyloid-β (Aβ) positron emission tomography (PET) strongly predicts the presence of significant Aβ pathology at autopsy. We sought to determine whether regional PiB-PET uptake would improve sensitivity for amyloid detection in comparison with global measures (experiment 1), and to estimate the relative contributions of different Aβ aggregates to in vivo PET signal (experiment 2). In experiment 1, 54 subjects with [11C] PiB-PET during life and postmortem neuropathologic examination (85.2% with dementia, interval from PET to autopsy 3.1 ± 1.9 years) were included. We assessed Thal amyloid phase (N = 36) and CERAD score (N = 54) versus both global and regional PiB SUVRs. In experiment 2 (N = 42), PiB SUVR and post-mortem amyloid β burden was analyzed in five customized regions of interest matching regions sampled at autopsy. We assessed the relative contribution of neuritic plaques (NPs), diffuse plaques (DPs) and cerebral amyloid angiopathy (CAA) to regional PIB SUVR using multi-linear regression. In experiment 1, there were no differences in Area Under the Curve for amyloid phase ≥ A2 and CERAD score ≥ C2 between global and highest regional PiB SUVR (p = 0.186 and 0.230). In experiment 2, when NPs, DPs, and/or CAA were included in the same model, moderate to severe NPs were independently correlated with PiB SUVR in all regions except for the inferior temporal and calcarine ROI (β = 0.414–0.804, p < 0.05), whereas DPs were independently correlated with PiB SUVR in the angular gyrus ROI (β = 0.446, p = 0.010). CAA was also associated with PiB SUVR in the inferior temporal and calcarine ROI (β = 0.222–0.355, p < 0.05). In conclusion, global PiB-PET SUVR performed as well as regional values for amyloid detection in our cohort. The substrate-specific binding of PiB might differ among the brain specific regions.
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- 2017
29. Aging Affects Dopaminergic Neural Mechanisms of Cognitive Flexibility
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Berry, AS, Shah, VD, Baker, SL, Vogel, JW, O’Neil, JP, Janabi, M, Schwimmer, HD, Marks, SM, and Jagust, WJ
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Adult ,Male ,Aging ,1.2 Psychological and socioeconomic processes ,Dopamine ,1.1 Normal biological development and functioning ,and over ,Neuropsychological Tests ,Neurodegenerative ,Basic Behavioral and Social Science ,Medical and Health Sciences ,cognitive flexibility ,Young Adult ,Executive Function ,Cognition ,Clinical Research ,Parietal Lobe ,Behavioral and Social Science ,Reaction Time ,80 and over ,Humans ,2.1 Biological and endogenous factors ,Aged ,Neurology & Neurosurgery ,Dopaminergic Neurons ,fMRI ,Psychology and Cognitive Sciences ,Neurosciences ,Brain ,task switching ,Magnetic Resonance Imaging ,Frontal Lobe ,Brain Disorders ,Neostriatum ,PET ,Mental Health ,Positron-Emission Tomography ,Neurological ,Biomedical Imaging ,Female - Abstract
Aging is accompanied by profound changes in the brain's dopamine system that affect cognitive function. Evidence of powerful individual differences in cognitive aging has sharpened focus on identifying biological factors underlying relative preservation versus vulnerability to decline. Dopamine represents a key target in these efforts. Alterations of dopamine receptors and dopamine synthesis are seen in aging, with receptors generally showing reduction and synthesis demonstrating increases. Using the PET tracer 6-[18F]fluoro-l-m-tyrosine, we found strong support for upregulated striatal dopamine synthesis capacity in healthy older adult humans free of amyloid pathology, relative to young people. We next used fMRI to define the functional impact of elevated synthesis capacity on cognitive flexibility, a core component of executive function. We found clear evidence in young adults that low levels of synthesis capacity were suboptimal, associated with diminished cognitive flexibility and altered frontoparietal activation relative to young adults with highest synthesis values. Critically, these relationships between dopamine, performance, and activation were transformed in older adults with higher synthesis capacity. Variability in synthesis capacity was related to intrinsic frontoparietal functional connectivity across groups, suggesting that striatal dopamine synthesis influences the tuning of networks underlying cognitive flexibility. Together, these findings define striatal dopamine's association with cognitive flexibility and its neural underpinnings in young adults, and reveal the alteration in dopamine-related neural processes in aging.Significance statementFew studies have combined measurement of brain dopamine with examination of the neural basis of cognition in youth and aging to delineate the underlying mechanisms of these associations. Combining in vivo PET imaging of dopamine synthesis capacity, fMRI, and a sensitive measure of cognitive flexibility, we reveal three core findings. First, we find evidence supporting older adults' capacity to upregulate dopamine synthesis. Second, we define relationships between dopamine, cognition, and frontoparietal activity in young adults indicating high levels of synthesis capacity are optimal. Third, we demonstrate alteration of these relationships in older adults, suggesting neurochemical modulation of cognitive flexibility changes with age.
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- 2016
30. Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults
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Risacher, SL, McDonald, BC, Tallman, EF, West, JD, Farlow, MR, Unverzagt, FW, Gao, S, Boustani, M, Crane, PK, Petersen, RC, Jack, CR, Jagust, WJ, Aisen, PS, Weiner, MW, Saykin, AJ, Trojanowki, JQ, Toga, AW, Beckett, L, Green, RC, Morris, J, Shaw, LM, Khachaturian, Z, Sorensen, G, Carrillo, M, Kuller, L, Raichle, M, Paul, S, Davies, P, Fillit, H, Hefti, F, Holtzman, D, Mesulam, MM, Potter, W, Snyder, PJ, Schwartz, A, Montine, T, Thomas, RG, Donohue, M, Walter, S, Gessert, D, Sather, T, Jiminez, G, Balasubramanian, AB, Mason, J, Sim, I, Harvey, D, Bernstein, M, Fox, N, Thompson, P, Schuff, N, DeCarli, C, Borowski, B, Gunter, J, Senjem, M, Vemuri, P, Jones, D, Kantarci, K, Ward, C, Koeppe, RA, Foster, N, Reiman, EM, Chen, K, Mathis, C, Landau, S, Cairns, NJ, Householder, E, Taylor-Reinwald, L, Lee, V, Korecka, M, Figurski, M, Crawford, K, and Neu, S
- Abstract
Copyright 2016 American Medical Association. All rights reserved. IMPORTANCE The use of anticholinergic (AC) medication is linked to cognitive impairment and an increased risk of dementia. To our knowledge, this is the first study to investigate the association between AC medication use and neuroimaging biomarkers of brain metabolism and atrophy as a proxy for understanding the underlying biology of the clinical effects of AC medications. OBJECTIVE To assess the association between AC medication use and cognition, glucose metabolism, and brain atrophy in cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Indiana Memory and Aging Study (IMAS). DESIGN, SETTING, AND PARTICIPANTS The ADNI and IMAS are longitudinal studies with cognitive, neuroimaging, and other data collected at regular intervals in clinical and academic research settings. For the participants in the ADNI, visits are repeated 3, 6, and 12 months after the baseline visit and then annually. For the participants in the IMAS, visits are repeated every 18 months after the baseline visit (402 cognitively normal older adults in the ADNI and 49 cognitively normal older adults in the IMAS were included in the present analysis). Participants were either taking (hereafter referred to as the AC+ participants [52 from the ADNI and 8 from the IMAS]) or not taking (hereafter referred to as the AC- participants [350 from the ADNI and 41 from the IMAS]) at least 1 medication with medium or high AC activity. Data analysis for this study was performed in November 2015. MAIN OUTCOMES AND MEASURES Cognitive scores, mean fludeoxyglucose F 18 standardized uptake value ratio (participants from the ADNI only), and brain atrophy measures from structural magnetic resonance imaging were compared between AC+ participants and AC- participants after adjusting for potential confounders. The total AC burden score was calculated and was related to target measures. The association of AC use and longitudinal clinical decline (mean [SD] follow-up period, 32.1 [24.7] months [range, 6-108 months]) was examined using Cox regression. RESULTS The 52 AC+ participants (mean [SD] age, 73.3 [6.6] years) from the ADNI showed lower mean scores onWeschler Memory Scale-Revised Logical Memory Immediate Recall (raw mean scores: 13.27 for AC+ participants and 14.16 for AC- participants; P = .04) and the Trail Making Test Part B (raw mean scores: 97.85 seconds for AC+ participants and 82.61 seconds for AC- participants; P = .04) and a lower executive function composite score (raw mean scores: 0.58 for AC+ participants and 0.78 for AC- participants; P = .04) than the 350 AC- participants (mean [SD] age, 73.3 [5.8] years) from the ADNI. Reduced total cortical volume and temporal lobe cortical thickness and greater lateral ventricle and inferior lateral ventricle volumes were seen in the AC+ participants relative to the AC- participants. CONCLUSIONS AND RELEVANCE The use of AC medication was associated with increased brain atrophy and dysfunction and clinical decline. Thus, use of AC medication among older adults should likely be discouraged if alternative therapies are available.
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- 2016
31. Accelerating rates of cognitive decline and imaging markers associated with β-amyloid pathology
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Insel, PS, Mattsson, N, Mackin, RS, Schöll, M, Nosheny, RL, Tosun, D, Donohue, MC, Aisen, PS, Jagust, WJ, Weiner, MW, Stern, Yaakov, and Alzheimer's, Disease, Neuroimaging, Initiative
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- 2016
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32. Alzheimer risk genes modulate the relationship between plasma apoE and cortical PiB binding
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Lazaris, A, Hwang, KS, Goukasian, N, Ramirez, LM, Eastman, J, Blanken, AE, Teng, E, Gylys, K, Cole, G, Saykin, AJ, Shaw, LM, Trojanowski, JQ, Jagust, WJ, Weiner, MW, and Apostolova, LG
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Alzheimer's Disease Neuroimaging Initiative - Abstract
© 2015 American Academy of Neurology. Objective: We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association. Methods: Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [11C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes. Results: Low plasma apoE was significantly associated with high PiB SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preservedonly in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A. Conclusions: Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction.
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- 2015
33. GWAS of longitudinal amyloid accumulation on18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP
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Ramanan, VK, Risacher, SL, Nho, K, Kim, S, Shen, L, McDonald, BC, Yoder, KK, Hutchins, GD, West, JD, Tallman, EF, Gao, S, Foroud, TM, Farlow, MR, De Jager, PL, Bennett, DA, Aisen, PS, Petersen, RC, Jack, CR, Toga, AW, Green, RC, Jagust, WJ, Weiner, MW, and Saykin, AJ
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© 2015 The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. Brain amyloid deposition is thought to be a seminal event in Alzheimer's disease. To identify genes influencing Alzheimer's disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by18F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10-9) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer's disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical11C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.
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- 2015
34. β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation
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Mander, BA, Marks, SM, Vogel, JW, Rao, V, Lu, B, Saletin, JM, Ancoli-Israel, S, Jagust, WJ, and Walker, MP
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musculoskeletal, neural, and ocular physiology ,mental disorders ,psychological phenomena and processes - Abstract
© 2015 Nature America, Inc. Independent evidence associates β-amyloid pathology with both non-rapid eye movement (NREM) sleep disruption and memory impairment in older adults. However, whether the influence of β-amyloid pathology on hippocampus-dependent memory is, in part, driven by impairments of NREM slow wave activity (SWA) and associated overnight memory consolidation is unknown. Here we show that β-amyloid burden in medial prefrontal cortex (mPFC) correlates significantly with the severity of impairment in NREM SWA generation. Moreover, reduced NREM SWA generation was further associated with impaired overnight memory consolidation and impoverished hippocampal-neocortical memory transformation. Furthermore, structural equation models revealed that the association between mPFC β-amyloid pathology and impaired hippocampus-dependent memory consolidation was not direct, but instead statistically depended on the intermediary factor of diminished NREM SWA. By linking β-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a mechanistic pathway through which β-amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly.
- Published
- 2015
35. Prevalence of cerebral amyloid pathology in persons without dementia: A meta-analysis
- Author
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Jansen, WJ, Ossenkoppele, R, Knol, DL, Tijms, BM, Scheltens, P, Verhey, FRJ, Visser, PJ, Aalten, P, Aarsland, D, Alcolea, D, Alexander, M, Almdahl, IS, Arnold, SE, Baldeiras, I, Barthel, H, Van Berckel, BNM, Bibeau, K, Blennow, K, Brooks, DJ, Van Buchem, MA, Camus, V, Cavedo, E, Chen, K, Chetelat, G, Cohen, AD, Drzezga, A, Engelborghs, S, Fagan, AM, Fladby, T, Fleisher, AS, Van Der Flier, WM, Ford, L, Forster, S, Fortea, J, Foskett, N, Frederiksen, KS, Freund-Levi, Y, Frisoni, GB, Froelich, L, Gabryelewicz, T, Gill, KD, Gkatzima, O, Gomez-Tortosa, E, Gordon, MF, Grimmer, T, Hampel, H, Hausner, L, Hellwig, S, Herukka, SK, Hildebrandt, H, Ishihara, L, Ivanoiu, A, Jagust, WJ, Johannsen, P, Kandimalla, R, Kapaki, E, Klimkowicz-Mrowiec, A, Klunk, WE, Kohler, S, Koglin, N, Kornhuber, J, Kramberger, MG, Van Laere, K, Landau, SM, Lee, DY, De Leon, M, Lisetti, V, Lleo, A, Madsen, K, Maier, W, Marcusson, J, Mattsson, N, De Mendonca, A, Meulenbroek, O, Meyer, PT, Mintun, MA, Mok, V, Molinuevo, JL, Mollergard, HM, Morris, JC, Mroczko, B, Van Der Mussele, S, Na, DL, Newberg, A, Nordberg, A, Nordlund, A, Novak, GP, Paraskevas, GP, and Parnetti, L
- Subjects
mental disorders - Abstract
Copyright 2015 American Medical Association. All rights reserved. IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE andWeb of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION: AND SYNTHESIS: Individual recordswere provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95%CI, 8%-13%) to 44%(95%CI, 37%-51%) among participants with normal cognition; from 12%(95%CI, 8%-18%) to 43%(95%CI, 32%-55%) among patients with SCI; and from 27%(95%CI, 23%-32%) to 71%(95%CI, 66%-76%) among patients with MCI. APOE-ϵ4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ϵ4ϵ4 carriers, 50 years for ϵ2ϵ4 carriers, 55 years for ϵ3ϵ4 carriers, 65 years for ϵ3ϵ3 carriers, and 95 years for ϵ2ϵ3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.
- Published
- 2015
36. Comparison of visual and quantitative florbetapir F 18 positron emission tomography analysis in predicting mild cognitive impairment outcomes
- Author
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Schreiber, S, Landau, SM, Fero, A, Schreiber, F, and Jagust, WJ
- Abstract
Copyright 2015 American Medical Association. All rights reserved. IMPORTANCE: The applicability of ß-amyloid peptide (Aß) positron emission tomography (PET) as a biomarker in clinical settings to aid in selection of individuals at preclinical and prodromal Alzheimer disease (AD) will depend on the practicality of PET image analysis. In this context, visual-based Aß PET assessment seems to be the most feasible approach. OBJECTIVES: To determine the agreement between visual and quantitative Aß PET analysis and to assess the ability of both techniques to predict conversion from mild cognitive impairment (MCI) to AD. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal study was conducted among the Alzheimer's Disease Neuroimaging Initiative (ADNI) sites in the United States and Canada during a1.6-year mean follow-up period. The study was performed from September 21, 2010, to August 11, 2014; data analysis was conducted from September 21, 2014, to May 26, 2015. Participants included 401 individuals with MCI receiving care at a specialty clinic (219 [54.6%] men; mean [SD] age, 71.6 [7.5] years; 16.2 [2.7] years of education). All participants were studied with florbetapir F 18 [18F] PET. The standardized uptake value ratio (SUVR) positivity threshold was 1.11, and one reader rated all images, with a subset of 125 scans rated by a second reader. MAINOUTCOMES ANDMEASURES: Sensitivity and specificity of positive and negative [18F] florbetapir PET categorization, which was estimated with cerebrospinal fluid Aß1-42 as the reference standard. Risk for conversion to AD was assessed using Cox proportional hazards regression models. RESULTS: The frequency of Aß positivity was 48.9% (196 patients; visual analysis), 55.1% (221 patients; SUVR), and 64.8% (166 patients; cerebrospinal fluid), yielding substantial agreement between visual and SUVR data (κ = 0.74) and between all methods (Fleiss κ = 0.71). For approximately 10% of the 401 participants in whom visual and SUVR data disagreed, interrater reliability was moderate (κ = 0.44), but it was very high if visual and quantitative results agreed (κ = 0.92). Visual analysis had a lower sensitivity (79% vs 85%) but higher specificity (96% vs 90%), respectively, compared with SUVR. The conversion rate was 15.2% within a mean of 1.6 years, and a positive [18F] florbetapir baseline scan was associated with a 6.91-fold (SUVR) or 11.38-fold (visual) greater hazard for AD conversion, which changed only modestly after covariate adjustment for apolipoprotein e4, concurrent fludeoxyglucose F 18 PET scan, and baseline cognitive status. CONCLUSIONS AND RELEVANCE: Visual and SUVR Aß PET analysis maybe equivalently used to determine Aß status for individuals with MCI participating in clinical trials, and both approaches add significant value for clinical course prognostication.
- Published
- 2015
37. Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease
- Author
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Mattsson, N, Insel, PS, Donohue, M, Landau, S, Jagust, WJ, Shaw, LM, Trojanowski, JQ, Zetterberg, H, Blennow, K, and Weiner, MW
- Subjects
mental disorders - Abstract
© 2015 The Author. Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE e4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE e4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE e4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P50.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P50.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that cerebrospinal fluid and positron emission tomography amyloid-β provide partially independent information about a wide range of Alzheimer's measures supports the theory that these modalities represent partly different aspects of Alzheimer's pathology. The fact that mismatch, with positive cerebrospinal fluid amyloid-β but normal positron emission tomography amyloid-β, is relatively common in cognitively healthy people may be considered when using these biomarkers to identify early stage Alzheimer's disease. Reduced cerebrospinal fluid amyloid-β may be more strongly related to early stage Alzheimer's disease, whereas increased positron emission tomography amyloid-β may be more strongly related to disease progression.
- Published
- 2015
38. Measurement of longitudinal β-amyloid change with 18F-florbetapir PET and standardized uptake value ratios
- Author
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Landau, SM, Fero, A, Baker, SL, Koeppe, R, Mintun, M, Chen, K, Reiman, EM, and Jagust, WJ
- Subjects
sense organs - Abstract
COPYRIGHT © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc. The accurate measurement of β-amyloid (Aβ) change using amyloid PET imaging is important for Alzheimer disease research and clinical trials but poses several unique challenges. In particular, reference region measurement instability may lead to spurious changes in cortical regions of interest. To optimize our ability to measure 18F-florbetapir longitudinal change, we evaluated several candidate regions of interest and their influence on cortical florbetapir change over a 2-y period in participants from the Alzheimer Disease Neuroimaging Initiative (ADNI). Methods: We examined the agreement in cortical florbetapir change detected using 6 candidate reference regions (cerebellar gray matter, whole cerebellum, brain stem/pons, eroded subcortical white matter [WM], and 2 additional combinations of these regions) in 520 ADNI subjects. We used concurrent cerebrospinal fluid Aβ1-42 measurements to identify subgroups of ADNI subjects expected to remain stable over follow-up (stable Aβgroup; n = 14) and subjects expected to increase (increasing Aβ group; n = 91). We then evaluated reference regions according to whether cortical change was minimal in the stable Aβgroup and cortical retention increased in the increasing Aβgroup. Results: There was poor agreement across reference regions in the amount of cortical change observed across all 520 ADNI subjects. Within the stable Aβ group, however, cortical florbetapir change was 1%- 2% across all reference regions, indicating high consistency. In the increasing Aβ group, cortical increases were significant with all reference regions. Reference regions containing WM (as opposed to cerebellum or pons) enabled detection of cortical change that was more physiologically plausible and more likely to increase over time. Conclusion: Reference region selection has an important influence on the detection of florbetapir change. Compared with cerebellum or pons alone, reference regions that included subcortical WM resulted in change measurements that are more accurate. In addition, because use of WM-containing reference regions involves dividing out cortical signal contained in the reference region (via partial-volume effects), use of these WM-containing regions may result in more conservative estimates of actual change. Future analyses using different tracers, tracer - kinetic models, pipelines, and comparisons with other biomarkers will further optimize our ability to accurately measure Aβ changes over time.
- Published
- 2015
39. Improved power for characterizing longitudinal amyloid-βPET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region
- Author
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Chen, K, Roontiva, A, Thiyyagura, P, Lee, W, Liu, X, Ayutyanont, N, Protas, H, Luo, JL, Bauer, R, Reschke, C, Bandy, D, Koeppe, RA, Fleisher, AS, Caselli, RJ, Landau, S, Jagust, WJ, Weiner, MW, and Reiman, EM
- Abstract
COPYRIGHT © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc. In this article, we describe an image analysis strategy with improved power for tracking longitudinal amyloid-β (Aβ) PET changes and evaluating Aβ-modifying treatments. Methods: Our aims were to compare the power of template-based cerebellar, pontine, and cerebral white matter reference regions to track 24-mo florbetapir standardized uptake value (SUV) ratio (SUVR) changes; to relate those changes to 24-mo clinical declines; and to evaluate Aβ-modifying treatments in Aβ-positive (Aβ+) and Aβ-negative (Aβ-) patients with probable Alzheimer dementia (pAD), in patients with mild cognitive impairment (MCI), in cognitively normal controls (NCs), and in cognitively normal apolipoprotein E4 (APOE4) carriers and noncarriers. We used baseline and follow-up (∼24 mo) florbetapir PET scans from 332 Aβ+ and Aβ- subjects participating in the multicenter Alzheimer's Disease Neuroimaging Initiative. Each of the proposed analyses included 31 pAD patients, 187 MCI patients, and 114 NCs. Cerebral-to-white matter, cerebellar, and pontine SUVRs were characterized in terms of their longitudinal variability; their power to track longitudinal fibrillar Aβ increases in Aβ+ and Aβ- subgroups and cognitively normal APOE4 carriers and noncarriers; the sample sizes needed to detect attenuated accumulation of or clearance of fibrillar Aβ accumulation in randomized clinical trials; and their ability to relate 24-mo fibrillar Aβ increases to clinical declines. Results: As predicted, cerebral-to-white matter SUVR changes were significantly less variable and had significantly greater power to detect 24-mo fibrillar Aβ increases and evaluate Aβ-modifying treatment effects in Aβ+ pAD, MCI, and NC subjects and cognitively normal APOE4 carriers. They were also distinguished by the ability to detect significant associations between 24-mo Aβ increases and clinical declines. Conclusion: A cerebral white matter reference region may improve the power to track longitudinal fibrillar Aβincreases, to characterize their relationship to longitudinal clinical declines, and to evaluate Aβ-modifying treatments in randomized clinical trials.
- Published
- 2015
40. Neuroprotective pathways: lifestyle activity, brain pathology, and cognition in cognitively normal older adults
- Author
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Wirth, M, Haase, CM, Villeneuve, S, Vogel, J, and Jagust, WJ
- Subjects
Male ,Aging ,Amyloid beta-Peptides ,Neurology & Neurosurgery ,Physical activity ,Clinical Sciences ,Cognitive activity ,Neurosciences ,Brain ,Motor Activity ,Beta-amyloid ,Magnetic Resonance Imaging ,Cognitive aging ,Cognition ,Alzheimer Disease ,White matter lesion ,Positron-Emission Tomography ,Surveys and Questionnaires ,80 and over ,Humans ,Female ,PIB-PET ,Life Style ,Aged - Abstract
This study used path analysis to examine effects of cognitive activity and physical activity on cognitive functioning in older adults, through pathways involving beta-amyloid (Aβ) burden, cerebrovascular lesions, and neural injury within the brain regions affected in Alzheimer's disease (AD). Ninety-two cognitively normal older adults (75.2 ± 5.6years) reported lifetime cognitive activity and current physical activity using validated questionnaires. For each participant, we evaluated cortical Aβ burden (using [11C] labeled Pittsburgh-Compound-B positron emission tomography), cerebrovascular lesions (using magnetic resonance imaging-defined white matter lesion [WML]), and neural integrity within AD regions (using a multimodal neuroimaging biomarker). Path models (adjusted for age, gender, and education) indicated that higher lifetime cognitive activity and higher current physical activity was associated with fewer WMLs. Lower WML volumes were in turn related to higher neural integrity and higher global cognitive functioning. As shown previously, higher lifetime cognitive activity was associated with lower [11C] labeled Pittsburgh-Compound-B retention, which itself moderated the impact of neural integrity on cognitive functioning. Lifestyle activity may thus promote cognitive health in aging by protecting against cerebrovascular pathology and Aβ pathology thought to be relevant to AD development. © 2014 Elsevier Inc.
- Published
- 2014
41. PET studies of functional compensation in a primate model of Parkinsonʼs disease
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Jamie L. Eberling, Krys S. Bankiewicz, Jordan S, Jagust Wj, and Henry F. VanBrocklin
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Fluorine Radioisotopes ,Retrograde Degeneration ,Monoamine Oxidase Inhibitors ,Parkinson's disease ,Dopamine Agents ,Neurotoxins ,Nigrostriatal pathway ,Substantia nigra ,chemistry.chemical_compound ,Dopamine ,medicine ,Animals ,Parkinson Disease, Secondary ,General Neuroscience ,MPTP ,Putamen ,Dopaminergic ,medicine.disease ,Macaca mulatta ,Corpus Striatum ,Neuroprotective Agents ,medicine.anatomical_structure ,Pargyline ,nervous system ,chemistry ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,Disease Progression ,Tyrosine ,Psychology ,Neuroscience ,Tomography, Emission-Computed ,medicine.drug - Abstract
MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is a neurotoxin that produces degeneration of nigrostriatal dopaminergic neurons and a chronic parkinsonian condition in primates. Positron emission tomography (PET) studies of rhesus macaques at various time points following unilateral MPTP administration demonstrated a different time course of degeneration in the dopaminergic terminals in the putamen and in the cell bodies in the substantia nigra, consistent with other evidence of retrograde degeneration. In addition, the substantia nigra showed a transient upregulation in dopaminergic function in the lesioned hemisphere indicating functional compensation. This plasticity has important implications for the therapeutic effects of growth factors and other potential treatments for neurodegenerative diseases.
- Published
- 1997
42. Temporoparietal hypometabolism in frontotemporal lobar degeneration and associated imaging diagnostic errors
- Author
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Womack, KB, Diaz-Arrastia, R, Aizenstein, HJ, Arnold, SE, Barbas, NR, Boeve, BF, Clark, CM, DeCarli, CS, Jagust, WJ, Leverenz, JB, Peskind, ER, Turner, RS, Zamrini, EY, Heidebrink, JL, Burke, JR, DeKosky, ST, Farlow, MR, Gabel, MJ, Higdon, R, Kawas, CH, Koeppe, RA, Lipton, AM, and Foster, NL
- Subjects
mental disorders - Abstract
Objective: To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomographic scans with fludeoxyglucose F 18 (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and patients with Alzheimer disease (AD). Design: Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere - frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex, and posterior cingulate cortex. Results were compared with neuropathological diagnoses. Setting: Academic medical centers. Patients: Forty-five patients with pathologically confirmed FTLD (n=14) or AD (n=31). Results: Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27 of 31 patients [87%]) than in patients with FTLD (7 of 14 patients [50%]) (P=.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 scans lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD. Conclusions: Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism but rather must take into account the relative hypometabolism of all brain regions. ©2011 American Medical Association. All rights reserved.
- Published
- 2011
43. Validation of consensus panel diagnosis in dementia
- Author
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Gabel, MJ, Foster, NL, Heidebrink, JL, Higdon, R, Aizenstein, HJ, Arnold, SE, Barbas, NR, Boeve, BF, Burke, JR, Clark, CM, DeKosky, ST, Farlow, MR, Jagust, WJ, Kawas, CH, Koeppe, RA, Leverenz, JB, Lipton, AM, Peskind, ER, Turner, RS, Womack, KB, and Zamrini, EY
- Abstract
Background: The clinical diagnosis of dementing diseases largely depends on the subjective interpretation of patient symptoms. Consensus panels are frequently used in research to determine diagnoses when definitive pathologic findings are unavailable. Nevertheless, research on group decision making indicates that many factors can adversely affect panel performance. Objective: To determine conditions that improve consensus panel diagnosis. Design: Comparison of neuropathologic diagnoses with individual and consensus panel diagnoses based on clinical scenarios only, fludeoxyglucose F 18 positron emission tomography images only, and scenarios plus images. Setting: Expert and trainee individual and consensus panel deliberations using a modified Delphi method in a pilot research study of the diagnostic utility of fludeoxyglucose F 18 positron emission tomography. Patients: Forty-five patients with pathologically confirmed Alzheimer disease or frontotemporal dementia. Main Outcome Measures: Statistical measures of diagnostic accuracy, agreement, and confidence for individual raters and panelists before and after consensus deliberations. Results: The consensus protocol using trainees and experts surpassed the accuracy of individual expert diagnoses when clinical information elicited diverse judgments. In these situations, consensus was 3.5 times more likely to produce positive rather than negative changes in the accuracy and diagnostic certainty of individual panelists. A rule that forced group consensus was at least as accurate as majority and unanimity rules. Conclusions: Using a modified Delphi protocol to arrive at a consensus diagnosis is a reasonable substitute for pathologic information. This protocol improves diagnostic accuracy and certainty when panelist judgments differ and is easily adapted to other research and clinical settings while avoiding the potential pitfalls of group decision making. ©2010 American Medical Association. All rights reserved.
- Published
- 2010
44. PET 6-[18F]fluoro-L-m-tyrosine studies of dopaminergic function in human and nonhuman primates
- Author
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Eberling, JL, Bankiewicz, KS, O'Neil, JP, and Jagust, WJ
- Abstract
Although positron emission tomography (PET) and the aromatic L-amino acid decarboxylase (AADC) tracer 6-[18F]fluoro-L-m-tyrosine (FMT) has been used to assess the integrity of the presynaptic dopamine system in the brain, relatively little has been published in terms of brain FMT uptake values especially for normal human subjects. Twelve normal volunteer subjects were scanned using PET and FMT to determine the range of normal striatal uptake values using Patlak graphical analysis. For comparison, seven adult rhesus monkeys were studied and the data analyzed in the same way. A subset of monkeys that were treated with a unilateral intracarotid artery infusion of the dopamine neurotoxin MPTP showed an 87% decrease in striatal FMT uptake. These findings support the use of PET and FMT to image AADC distribution in both normal and diseased brains using Patlak graphical analysis and tissue input functions. © 2008 Eberling, Bankiewicz, O'Neil and Jagust.
- Published
- 2008
45. Abstract P3-11-01: Prospective study of cognitive function in women with early stage breast cancer: Predictors of cognitive decline and relationship to cognitive complaints
- Author
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Heflin, LH, primary, Fang, S, additional, DeLuca, A, additional, Melisko, MM, additional, Moasser, M, additional, Park, JW, additional, Chien, AJ, additional, Munster, P, additional, Landau, SM, additional, Kramer, JH, additional, Jagust, WJ, additional, and Rugo, HS, additional
- Published
- 2013
- Full Text
- View/download PDF
46. Diagnostic accuracy of FDG-PET in evaluation of dementia: International multicenter pooled brain scan and autopsy data
- Author
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Silverman, Dh, Small, Gw, de Aburto MAK, Hoffman, Jm, Salmon, E, de Leon MJ, Mielke, R, Jagust, Wj, Pietrini, Pietro, Alexander, G, Czernin, J, and Phelps, Me
- Published
- 2000
47. Relative contributions of biomarkers in Alzheimer's disease.
- Author
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Haight TJ, Jagust WJ, Alzheimer's Disease Neuroimaging Initiative, Haight, Thaddeus J, Jagust, William J, and Alzheimer’s Disease Neuroimaging Initiative
- Abstract
Purpose: To assess relationships between biomarkers for Alzheimer's disease (AD) and their potential contributions to AD.Methods: Biomarkers and cognitive evaluations were assessed longitudinally in 179 patients with mild cognitive impairment, from the Alzheimer's Disease Neuroimaging Initiative from 2003 to 2006, and were used to examine, at any given time, the joint contributions of hippocampal volume, whole brain volume, and brain glucose metabolism on clinical AD progression, using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Marginal structural models were applied, and an inverse-probability of treatment weight estimation was used to account for time-dependent confounding between study variables.Results: At any given time, population-level differences (e.g., 1-standard deviation [SD] increase) in brain glucose metabolism (-1.036; 95% confidence interval [95% CI], -1.608, -0.464) and hippocampal volume (-1.537; 95% CI, -2.399, -0.674) independently reduced mean (ADAS-Cog), whereas a 1-SD increase in whole brain volume did not (0.372; 95% CI, -0.283, 1.027). The effects of brain glucose metabolism differed in subgroups defined by baseline covariates (e.g., age), but no subgroup effects were observed for hippocampal volume and brain volume.Conclusions: Brain glucose metabolism and hippocampal volume represent relevant biological markers in subjects at risk for AD. [ABSTRACT FROM AUTHOR]- Published
- 2012
- Full Text
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48. Vascular burden and Alzheimer disease pathologic progression.
- Author
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Lo RY, Jagust WJ, Alzheimer's Disease Neuroimaging Initiative, Lo, Raymond Y, and Jagust, William J
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- 2012
- Full Text
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49. Predicting missing biomarker data in a longitudinal study of Alzheimer disease.
- Author
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Lo RY, Jagust WJ, Alzheimer's Disease Neuroimaging Initiative, Lo, Raymond Y, and Jagust, William J
- Published
- 2012
- Full Text
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50. Amyloid pathway-based candidate gene analysis of [(11)C]PiB-PET in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.
- Author
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Swaminathan S, Shen L, Risacher SL, Yoder KK, West JD, Kim S, Nho K, Foroud T, Inlow M, Potkin SG, Huentelman MJ, Craig DW, Jagust WJ, Koeppe RA, Mathis CA, Jack CR Jr, Weiner MW, Saykin AJ, Alzheimer's Disease Neuroimaging Initiative, and Swaminathan, Shanker
- Abstract
Amyloid imaging with [(11)C]Pittsburgh Compound-B (PiB) provides in vivo data on plaque deposition in those with, or at risk for, Alzheimer's disease (AD). We performed a gene-based association analysis of 15 quality-controlled amyloid-pathway associated candidate genes in 103 Alzheimer's Disease Neuroimaging Initiative participants. The mean normalized PiB uptake value across four brain regions known to have amyloid deposition in AD was used as a quantitative phenotype. The minor allele of an intronic SNP within DHCR24 was identified and associated with a lower average PiB uptake. Further investigation at whole-brain voxel-wise level indicated that non-carriers of the minor allele had higher PiB uptake in frontal regions compared to carriers. DHCR24 has been previously shown to confer resistance against beta-amyloid and oxidative stress-induced apoptosis, thus our findings support a neuroprotective role. Pathway-based genetic analysis of targeted molecular imaging phenotypes appears promising to help elucidate disease pathophysiology and identify potential therapeutic targets. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
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