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1. Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals

Author

Öhrfelt, Annika, Benedet, Andréa L, Ashton, Nicholas J, Kvartsberg, Hlin, Vandijck, Manu, Weiner, Michael W, Trojanowski, John Q, Shaw, Leslie M, Zetterberg, Henrik, Blennow, Kaj, and Initiative, for the Alzheimer's Disease Neuroimaging

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, Dementia, Behavioral and Social Science, Aging, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Clinical Research, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Humans, Alzheimer Disease, Amyloid beta-Peptides, GAP-43 Protein, Retrospective Studies, tau Proteins, Cognitive Dysfunction, Biomarkers, Amyloidogenic Proteins, Atrophy, Positron-Emission Tomography, Disease Progression, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Background and objectivesTo test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally.MethodsIn this retrospective study, GAP-43 was measured in participants from the AD Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (amyloid beta [Aβ] and tau pathologies, neurodegeneration, and cognition) adjusted by age, sex, and diagnosis. Linear mixed-effect models evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline over time. Cox proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time.ResultsThis study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (nCU- = 197); CU Aβ-positive (nCU+ = 55), mild cognitively impaired (MCI) Aβ-negative (nMCI- = 228), MCI Aβ-positive (nMCI+ = 193), and AD dementia Aβ-positive (nAD = 113). CSF GAP-43 levels were increased in Aβ-positive compared with Aβ-negative participants, independent of the cognitive status. In Aβ-positive participants, high baseline GAP-43 levels led to worse brain metabolic decline (p = 0.01), worse brain atrophy (p = 8.8 × 10-27), and worse MMSE scores (p = 0.03) over time, as compared with those with low GAP-43 levels. Similarly, Aβ-positive participants with high baseline GAP-43 had the highest risk to convert to AD dementia (hazard ratio [HR = 8.56, 95% CI 4.94-14.80, p = 1.5 × 10-14]). Despite the significant association with Aβ pathology (η2 Aβ PET = 0.09, P Aβ PET < 0.001), CSF total tau (tTau) and phosphorylated tau (pTau) had a larger effect size on GAP43 than Aβ PET (η2 pTau-181 = 0.53, P pTau-181 < 0.001; η2 tTau = 0.59, P tTau < 0.001).DiscussionHigh baseline levels of CSF GAP-43 are associated with progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline, and increased risk of converting to dementia.

Published
2023

2. Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques

Author

Li, Yan, Schindler, Suzanne E, Bollinger, James G, Ovod, Vitaliy, Mawuenyega, Kwasi G, Weiner, Michael W, Shaw, Leslie M, Masters, Colin L, Fowler, Christopher J, Trojanowski, John Q, Korecka, Magdalena, Martins, Ralph N, Janelidze, Shorena, Hansson, Oskar, and Bateman, Randall J

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Prevention, Brain Disorders, Neurodegenerative, Biomedical Imaging, Acquired Cognitive Impairment, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Aging, Clinical Research, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Good Health and Well Being, Alzheimer Disease, Amyloid beta-Peptides, Biomarkers, Humans, Peptide Fragments, Plaque, Amyloid, Positron-Emission Tomography, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Background and objectivesTo determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols.MethodsPlasma samples (n = 465) were obtained from 3 large Alzheimer disease (AD) research cohorts in the United States (n = 182), Australia (n = 183), and Sweden (n = 100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40.ResultsIn the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ε4 carrier status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ε4 status. These findings were consistent across the 3 cohorts, despite differences in protocols. The assay performed similarly in both cognitively unimpaired and impaired individuals.DiscussionPlasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials.Classification of evidenceThis study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants.

Published
2022

3. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts

Author

Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van der Zee, Julie, and Van Broeckhoven, Christine

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Genetics, Brain Disorders, Aging, Aphasia, Neurodegenerative, Rare Diseases, Alzheimer's Disease Related Dementias (ADRD), Dementia, Frontotemporal Dementia (FTD), Acquired Cognitive Impairment, Neurological, Age of Onset, Aged, Aged, 80 and over, Aphasia, Primary Progressive, C9orf72 Protein, Cohort Studies, DNA Repeat Expansion, Europe, Female, Frontotemporal Dementia, Frontotemporal Lobar Degeneration, Geography, Humans, Male, Mediterranean Region, Middle Aged, Principal Component Analysis, Scandinavian and Nordic Countries, Syndrome, International FTD-Genetics Consortium, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveWe sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.MethodsWe evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.ResultsWe found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.ConclusionsOur results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

Published
2020

4. Serum triglycerides in Alzheimer disease: Relation to neuroimaging and CSF biomarkers.

Author

Bernath, Megan M, Bhattacharyya, Sudeepa, Nho, Kwangsik, Barupal, Dinesh Kumar, Fiehn, Oliver, Baillie, Rebecca, Risacher, Shannon L, Arnold, Matthias, Jacobson, Tanner, Trojanowski, John Q, Shaw, Leslie M, Weiner, Michael W, Doraiswamy, P Murali, Kaddurah-Daouk, Rima, and Saykin, Andrew J

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Dementia, Biomedical Imaging, Neurodegenerative, Cerebrovascular, Clinical Research, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease, Vascular Cognitive Impairment/Dementia, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Aging, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Biomarkers, Cognition, Cognitive Dysfunction, Disease Progression, Female, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Neuroimaging, Neuropsychological Tests, Triglycerides, Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Metabolomics Consortium, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo investigate the association of triglyceride (TG) principal component scores with Alzheimer disease (AD) and the amyloid, tau, neurodegeneration, and cerebrovascular disease (A/T/N/V) biomarkers for AD.MethodsSerum levels of 84 TG species were measured with untargeted lipid profiling of 689 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including 190 cognitively normal older adults (CN), 339 with mild cognitive impairment (MCI), and 160 with AD. Principal component analysis with factor rotation was used for dimension reduction of TG species. Differences in principal components between diagnostic groups and associations between principal components and AD biomarkers (including CSF, MRI and [18F]fluorodeoxyglucose-PET) were assessed with a generalized linear model approach. In both cases, the Bonferroni method of adjustment was used to correct for multiple comparisons.ResultsThe 84 TGs yielded 9 principal components, 2 of which, consisting of long-chain, polyunsaturated fatty acid-containing TGs (PUTGs), were significantly associated with MCI and AD. Lower levels of PUTGs were observed in MCI and AD compared to CN. PUTG principal component scores were also significantly associated with hippocampal volume and entorhinal cortical thickness. In participants carrying the APOE ε4 allele, these principal components were significantly associated with CSF β-amyloid1-42 values and entorhinal cortical thickness.ConclusionThis study shows that PUTG component scores were significantly associated with diagnostic group and AD biomarkers, a finding that was more pronounced in APOE ε4 carriers. Replication in independent larger studies and longitudinal follow-up are warranted.

Published
2020

5. Early vs late age at onset frontotemporal dementia and frontotemporal lobar degeneration

Author

Seo, Sang Won, Thibodeau, Marie-Pierre, Perry, David C, Hua, Alice, Sidhu, Manu, Sible, Isabel, Vargas, Jose Norberto S, Gaus, Stephanie E, Rabinovici, Gil D, Rankin, Katherine D, Boxer, Adam L, Kramer, Joel H, Rosen, Howard J, Gorno-Tempini, Maria Luisa, Grinberg, Lea T, Huang, Eric J, DeArmond, Stephen J, Trojanowski, John Q, Miller, Bruce L, and Seeley, William W

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Alzheimer's Disease Related Dementias (ADRD), Aging, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Rare Diseases, Dementia, Neurodegenerative, Neurological, Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Comorbidity, Diagnostic Errors, Female, Frontotemporal Lobar Degeneration, Humans, Male, Prevalence, Prospective Studies, Supranuclear Palsy, Progressive, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo examine clinicopathologic correlations in early vs late age at onset frontotemporal dementia (FTD) and frontotemporal lobar degeneration (FTLD).MethodsAll patients were clinically evaluated and prospectively diagnosed at the UCSF Memory and Aging Center. Two consecutive series were included: (1) patients with a clinically diagnosed FTD syndrome who underwent autopsy (cohort 1) and (2) patients with a primary pathologic diagnosis of FTLD, regardless of the clinical syndrome (cohort 2). These series were divided by age at symptom onset (cutoff 65 years).ResultsIn cohort 1, 48 (25.3%) were 65 years or older at symptom onset. Pathologic causes of behavioral variant FTD (bvFTD) were similar in the early age at onset (EO) and late age at onset (LO) bvFTD groups. In corticobasal syndrome (CBS), however, the most common pathologic substrate differed according to age at onset: progressive supranuclear palsy (42.9%) in LO-CBS and Alzheimer disease (AD; 40.7%) in EO-CBS. In cohort 2, 57 (28.4%) were classified as LO-FTLD. Regarding FTLD major molecular classes, FTLD with transactive response DNA-binding protein of 43 kDa was most common in EO-FTLD (44.4%), whereas FTLD-tau (58.3%) was most common in LO-FTLD. Antemortem diagnosis of a non-FTD syndrome, usually AD-type dementia, was more frequent in LO-FTLD than EO-FTLD (19.3% vs 7.7%, p = 0.017). LO-FTLD was also associated with more prevalent comorbid pathologic changes. Of these, moderate to severe AD neuropathologic change and argyrophilic grain disease were overrepresented among patients who received an antemortem diagnosis of AD-type dementia.ConclusionPatients with FTD and FTLD often develop symptoms after age 65, and age at onset represents an important consideration when making antemortem neuropathologic predictions.

Published
2018

6. Anosognosia predicts default mode network hypometabolism and clinical progression to dementia

Author

Therriault, Joseph, Ng, Kok Pin, Pascoal, Tharick A, Mathotaarachchi, Sulantha, Kang, Min Su, Struyfs, Hanne, Shin, Monica, Benedet, Andrea L, Walpola, Ishan C, Nair, Vasavan, Gauthier, Serge, Rosa-Neto, Pedro, Initiative, For the Alzheimer's Disease Neuroimaging, Initiative, Alzheimer's Disease Neuroimaging, Weiner, Michael W, Aisen, Paul, Petersen, Ronald, Jack, Clifford, Jagust, William, Morris, John C, Saykin, Andrew J, Trojanowski, John Q, Toga, Arthur W, and Beckett, Laurel

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Clinical Research, Alzheimer's Disease, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Dementia, Behavioral and Social Science, Neurodegenerative, Mental Health, 2.1 Biological and endogenous factors, Neurological, Aged, Agnosia, Amyloid, Aniline Compounds, Apolipoprotein E4, Biomarkers, Brain, Cognitive Dysfunction, Disease Progression, Ethylene Glycols, Female, Fluorodeoxyglucose F18, Follow-Up Studies, Humans, Male, Prognosis, Radiopharmaceuticals, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment.MethodsWe stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [18F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [18F]fluorodeoxyglucose at baseline and at 24-month follow-up. Multivariate logistic regression tested the association of awareness status with conversion from amnestic mild cognitive impairment to dementia.ResultsWe found that participants with impaired awareness had lower [18F]fluorodeoxyglucose uptake and increased [18F]florbetapir uptake in the posterior cingulate cortex at baseline. In addition, impaired awareness in mild cognitive impairment predicted [18F]fluorodeoxyglucose hypometabolism in the posterior cingulate cortex, left basal forebrain, bilateral medial temporal lobes, and right lateral temporal lobe over 24 months. Furthermore, participants with impaired awareness had a nearly 3-fold increase in likelihood of conversion to dementia within a 2-year time frame.ConclusionsOur results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment.

Published
2018

7. Diagnosis and management of dementia with Lewy bodies

Author

McKeith, Ian G, Boeve, Bradley F, Dickson, Dennis W, Halliday, Glenda, Taylor, John-Paul, Weintraub, Daniel, Aarsland, Dag, Galvin, James, Attems, Johannes, Ballard, Clive G, Bayston, Ashley, Beach, Thomas G, Blanc, Frédéric, Bohnen, Nicolaas, Bonanni, Laura, Bras, Jose, Brundin, Patrik, Burn, David, Chen-Plotkin, Alice, Duda, John E, El-Agnaf, Omar, Feldman, Howard, Ferman, Tanis J, Ffytche, Dominic, Fujishiro, Hiroshige, Galasko, Douglas, Goldman, Jennifer G, Gomperts, Stephen N, Graff-Radford, Neill R, Honig, Lawrence S, Iranzo, Alex, Kantarci, Kejal, Kaufer, Daniel, Kukull, Walter, Lee, Virginia MY, Leverenz, James B, Lewis, Simon, Lippa, Carol, Lunde, Angela, Masellis, Mario, Masliah, Eliezer, McLean, Pamela, Mollenhauer, Brit, Montine, Thomas J, Moreno, Emilio, Mori, Etsuro, Murray, Melissa, O'Brien, John T, Orimo, Sotoshi, Postuma, Ronald B, Ramaswamy, Shankar, Ross, Owen A, Salmon, David P, Singleton, Andrew, Taylor, Angela, Thomas, Alan, Tiraboschi, Pietro, Toledo, Jon B, Trojanowski, John Q, Tsuang, Debby, Walker, Zuzana, Yamada, Masahito, and Kosaka, Kenji

Subjects
Brain Disorders, Clinical Research, Acquired Cognitive Impairment, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease Related Dementias (ADRD), Lewy Body Dementia, Alzheimer's Disease, Prevention, Aging, Dementia, Neurodegenerative, Neurological, Biomarkers, Humans, Lewy Body Disease, Practice Guidelines as Topic, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Published
2017

8. Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease

Author

Ng, Kok Pin, Pascoal, Tharick A, Mathotaarachchi, Sulantha, Chung, Chang-Oh, Benedet, Andréa L, Shin, Monica, Kang, Min Su, Li, Xiaofeng, Ba, Maowen, Kandiah, Nagaendran, Rosa-Neto, Pedro, Gauthier, Serge, Weiner, Michael W, Aisen, Paul, Petersen, Ronald, Jack, Clifford, Jagust, William, Morris, John C, Saykin, Andrew J, Trojanowski, John Q, Toga, Arthur W, and Beckett, Laurel

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Mental Health, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Clinical Research, Behavioral and Social Science, Alzheimer's Disease, Prevention, Biomedical Imaging, Dementia, Aging, Neurodegenerative, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Neurological, Aged, Alzheimer Disease, Aniline Compounds, Apolipoprotein E4, Biomarkers, Brain, Brain Mapping, Ethylene Glycols, Female, Fluorodeoxyglucose F18, Follow-Up Studies, Humans, Irritable Mood, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Positron-Emission Tomography, Prodromal Symptoms, Prognosis, Radiopharmaceuticals, Sleep, tau Proteins, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD).MethodsWe stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET.ResultsIndividuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction.ConclusionsThe magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.

Published
2017

9. Plasma tau in Alzheimer disease

Author

Mattsson, Niklas, Zetterberg, Henrik, Janelidze, Shorena, Insel, Philip S, Andreasson, Ulf, Stomrud, Erik, Palmqvist, Sebastian, Baker, David, Tan Hehir, Cristina A, Jeromin, Andreas, Hanlon, David, Song, Linan, Shaw, Leslie M, Trojanowski, John Q, Weiner, Michael W, Hansson, Oskar, and Blennow, Kaj

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Acquired Cognitive Impairment, Alzheimer's Disease, Clinical Research, Dementia, Alzheimer's Disease Related Dementias (ADRD), Aging, Behavioral and Social Science, Brain Disorders, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biomedical Imaging, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, 4.2 Evaluation of markers and technologies, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Brain, Cognition Disorders, Cohort Studies, Female, Fluorodeoxyglucose F18, Humans, Male, Neuropsychological Tests, Positron-Emission Tomography, Psychiatric Status Rating Scales, tau Proteins, ADNI Investigators, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo test whether plasma tau is altered in Alzheimer disease (AD) and whether it is related to changes in cognition, CSF biomarkers of AD pathology (including β-amyloid [Aβ] and tau), brain atrophy, and brain metabolism.MethodsThis was a study of plasma tau in prospectively followed patients with AD (n = 179), patients with mild cognitive impairment (n = 195), and cognitive healthy controls (n = 189) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and cross-sectionally studied patients with AD (n = 61), mild cognitive impairment (n = 212), and subjective cognitive decline (n = 174) and controls (n = 274) from the Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study at Lund University, Sweden. A total of 1284 participants were studied. Associations were tested between plasma tau and diagnosis, CSF biomarkers, MRI measures, 18fluorodeoxyglucose-PET, and cognition.ResultsHigher plasma tau was associated with AD dementia, higher CSF tau, and lower CSF Aβ42, but the correlations were weak and differed between ADNI and BioFINDER. Longitudinal analysis in ADNI showed significant associations between plasma tau and worse cognition, more atrophy, and more hypometabolism during follow-up.ConclusionsPlasma tau partly reflects AD pathology, but the overlap between normal aging and AD is large, especially in patients without dementia. Despite group-level differences, these results do not support plasma tau as an AD biomarker in individual people. Future studies may test longitudinal plasma tau measurements in AD.

Published
2016

10. Memory, executive, and multidomain subtle cognitive impairment

Author

Toledo, Jon B, Bjerke, Maria, Chen, Kewei, Rozycki, Martin, Jack, Clifford R, Weiner, Michael W, Arnold, Steven E, Reiman, Eric M, Davatzikos, Christos, Shaw, Leslie M, Trojanowski, John Q, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Leon, Sue, Schneider, Stacy, Marson, Daniel, Griffith, Randall, and Clark, David

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Biomedical Imaging, Brain Disorders, Prevention, Acquired Cognitive Impairment, Alzheimer's Disease, Dementia, Aging, Behavioral and Social Science, Clinical Research, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, 4.2 Evaluation of markers and technologies, Mental health, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Biomarkers, Brain, Cognition Disorders, Cognitive Dysfunction, Disease Progression, Executive Function, Female, Humans, Magnetic Resonance Imaging, Male, Memory Disorders, Multimodal Imaging, Positron-Emission Tomography, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveWe studied the biomarker signatures and prognoses of 3 different subtle cognitive impairment (SCI) groups (executive, memory, and multidomain) as well as the subjective memory complaints (SMC) group.MethodsWe studied 522 healthy controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cutoffs for executive, memory, and multidomain SCI were defined using participants who remained cognitively normal (CN) for 7 years. CSF Alzheimer disease (AD) biomarkers, composite and region-of-interest (ROI) MRI, and fluorodeoxyglucose-PET measures were compared in these participants.ResultsUsing a stringent cutoff (fifth percentile), 27.6% of the ADNI participants were classified as SCI. Most single ROI or global-based measures were not sensitive to detect differences between groups. Only MRI-SPARE-AD (Spatial Pattern of Abnormalities for Recognition of Early AD), a quantitative MRI pattern-based global index, showed differences between all groups, excluding the executive SCI group. Atrophy patterns differed in memory SCI and SMC. The CN and the SMC groups presented a similar distribution of preclinical dementia stages. Fifty percent of the participants with executive, memory, and multidomain SCI progressed to mild cognitive impairment or dementia at 7, 5, and 2 years, respectively.ConclusionsOur results indicate that (1) the different SCI categories have different clinical prognoses and biomarker signatures, (2) longitudinally followed CN subjects are needed to establish clinical cutoffs, (3) subjects with SMC show a frontal pattern of brain atrophy, and (4) pattern-based analyses outperform commonly used single ROI-based neuroimaging biomarkers and are needed to detect initial stages of cognitive impairment.

Published
2015

11. Sleep-disordered breathing advances cognitive decline in the elderly

Author

Osorio, Ricardo S, Gumb, Tyler, Pirraglia, Elizabeth, Varga, Andrew W, Lu, Shou-en, Lim, Jason, Wohlleber, Margaret E, Ducca, Emma L, Koushyk, Viachaslau, Glodzik, Lidia, Mosconi, Lisa, Ayappa, Indu, Rapoport, David M, de Leon, Mony J, Weiner, Michael W, Aisen, Paul, Petersen, Ronald, Jack, Clifford, Jagust, William, Morris, John C, Saykin, Andrew J, Trojanowski, John Q, Toga, Arthur W, and Beckett, Laurel

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Lung, Dementia, Acquired Cognitive Impairment, Neurodegenerative, Neurosciences, Behavioral and Social Science, Brain Disorders, Sleep Research, Aging, Cerebrovascular, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Neurological, Age Distribution, Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Causality, Cognitive Dysfunction, Cohort Studies, Comorbidity, Continuous Positive Airway Pressure, Disease Progression, Female, Humans, Incidence, Longitudinal Studies, Male, Middle Aged, Retrospective Studies, Risk Factors, Sleep Apnea, Obstructive, Survival Rate, Treatment Outcome, United States, Alzheimer's Disease Neuroimaging Initiative, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier age at mild cognitive impairment (MCI) or Alzheimer disease (AD)-dementia onset in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We also examined whether continuous positive airway pressure (CPAP) use is associated with delayed onset of cognitive decline.MethodsFrom the ADNI cohort, 3 subsets with progressively stringent criteria were created in a step-wise manner. Age at MCI or AD-dementia onset was the main outcome variable. Analyses were performed separately for each subset in untreated SDB+ vs SDB- and untreated SDB+ vs CPAP+ groups. Chi-square and t tests were performed to examine between-group differences. Survival analyses were performed using the Kaplan-Meier method, compared by the log-rank test, and assessed by multivariate Cox regression adjusting for potential confounders.ResultsSDB+ patients had a younger age at MCI onset in all subsets (MC1: 72.63 vs 83.67; MC2: 72.15 vs 83.45; MC3: 77.40 vs 89.89; p < 0.01). SDB+ patients had a younger age at AD-dementia onset only in our most conservative subset (AC3: 83.46 vs 88.13; p < 0.05). In a combined outcome analysis, SDB+ patients had a younger age at onset to MCI or AD-dementia in all subsets. In subsets 1 and 2, CPAP use delayed the age at MCI onset (CMC1: 72.63 vs 82.10; CMC2: 72.11 vs 82.10; p < 0.01).ConclusionsConsistent with our hypothesis, the presence of SDB was associated with an earlier age at cognitive decline. Our findings in CPAP+ participants suggest that CPAP treatment of SDB may delay progression of cognitive impairment.

Published
2015

12. PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease

Author

Beecham, Gary W, Dickson, Dennis W, Scott, William K, Martin, Eden R, Schellenberg, Gerard, Nuytemans, Karen, Larson, Eric B, Buxbaum, Joseph D, Trojanowski, John Q, Van Deerlin, Vivianna M, Hurtig, Howard I, Mash, Deborah C, Beach, Thomas G, Troncoso, Juan C, Pletnikova, Olga, Frosch, Matthew P, Ghetti, Bernardino, Foroud, Tatiana M, Honig, Lawrence S, Marder, Karen, Vonsattel, Jean Paul, Goldman, Samuel M, Vinters, Harry V, Ross, Owen A, Wszolek, Zbigniew K, Wang, Liyong, Dykxhoorn, Derek M, Pericak-Vance, Margaret A, Montine, Thomas J, Leverenz, James B, Dawson, Ted M, and Vance, Jeffery M

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Parkinson's Disease, Clinical Research, Aging, Genetics, Brain Disorders, Human Genome, Neurodegenerative, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Chromosomes, Human, Pair 1, Female, Genetic Loci, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Parkinson Disease, Polymorphism, Single Nucleotide, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls.MethodsFour hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis.ResultsA small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.2 × 10(-8)). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1.ConclusionsWe confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.

Published
2015

13. Brain amyloidosis ascertainment from cognitive, imaging, and peripheral blood protein measures

Author

Apostolova, Liana G, Hwang, Kristy S, Avila, David, Elashoff, David, Kohannim, Omid, Teng, Edmond, Sokolow, Sophie, Jack, Clifford R, Jagust, William J, Shaw, Leslie, Trojanowski, John Q, Weiner, Michael W, Thompson, Paul M, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jagust, Wiliam, Trojanowki, JQ, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Gamst, Anthony, Sakin, Andrew J, Morris, John, Potter, William Z, Montine, Tom, Donohue, Michael, Walter, Sarah, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Shaw, Lee, Lee, Virginia M-Y, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Harvey, Danielle, Kornak, John, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Tang, Cheuk, Marzloff, George, deToledo-Morrell, Leyla, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Robers, Peggy, Albert, Marilyn S, Kozauer, Nicholas, Zerrate, Maria, Rusinek, Henry, de Leon, Mony J, De Santi, Susan M, Doraiswamy, P Murali, Petrella, Jeffrey R, Aiello, Marilyn, Arnold, Steve, and Karlawish, Jason H

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Dementia, Acquired Cognitive Impairment, Neurodegenerative, Behavioral and Social Science, Clinical Research, Brain Disorders, Aging, Biomedical Imaging, Clinical Trials and Supportive Activities, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 4.1 Discovery and preclinical testing of markers and technologies, 4.2 Evaluation of markers and technologies, Neurological, Aged, Algorithms, Alzheimer Disease, Amyloid beta-Peptides, Amyloidosis, Aniline Compounds, Biomarkers, Brain, Cognition, Cognitive Dysfunction, Cohort Studies, Databases, Factual, Disease Progression, Female, Humans, Male, Neuropsychological Tests, Pattern Recognition, Automated, Peptide Fragments, Positron-Emission Tomography, Sensitivity and Specificity, Thiazoles, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundThe goal of this study was to identify a clinical biomarker signature of brain amyloidosis in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) mild cognitive impairment (MCI) cohort.MethodsWe developed a multimodal biomarker classifier for predicting brain amyloidosis using cognitive, imaging, and peripheral blood protein ADNI1 MCI data. We used CSF β-amyloid 1-42 (Aβ42) ≤ 192 pg/mL as proxy measure for Pittsburgh compound B (PiB)-PET standard uptake value ratio ≥ 1.5. We trained our classifier in the subcohort with CSF Aβ42 but no PiB-PET data and tested its performance in the subcohort with PiB-PET but no CSF Aβ42 data. We also examined the utility of our biomarker signature for predicting disease progression from MCI to Alzheimer dementia.ResultsThe CSF training classifier selected Mini-Mental State Examination, Trails B, Auditory Verbal Learning Test delayed recall, education, APOE genotype, interleukin 6 receptor, clusterin, and ApoE protein, and achieved leave-one-out accuracy of 85% (area under the curve [AUC] = 0.8). The PiB testing classifier achieved an AUC of 0.72, and when classifier self-tuning was allowed, AUC = 0.74. The 36-month disease-progression classifier achieved AUC = 0.75 and accuracy = 71%.ConclusionsAutomated classifiers based on cognitive and peripheral blood protein variables can identify the presence of brain amyloidosis with a modest level of accuracy. Such methods could have implications for clinical trial design and enrollment in the near future.Classification of evidenceThis study provides Class II evidence that a classification algorithm based on cognitive, imaging, and peripheral blood protein measures identifies patients with brain amyloid on PiB-PET with moderate accuracy (sensitivity 68%, specificity 78%).

Published
2015

14. In vivo signatures of nonfluent/agrammatic primary progressive aphasia caused by FTLD pathology

Author

Caso, Francesca, Mandelli, Maria Luisa, Henry, Maya, Gesierich, Benno, Bettcher, Brianne M, Ogar, Jennifer, Filippi, Massimo, Comi, Giancarlo, Magnani, Giuseppe, Sidhu, Manu, Trojanowski, John Q, Huang, Eric J, Grinberg, Lea T, Miller, Bruce L, Dronkers, Nina, Seeley, William W, and Gorno-Tempini, Maria Luisa

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Acquired Cognitive Impairment, Dementia, Aging, Aphasia, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Rare Diseases, Alzheimer's Disease Related Dementias (ADRD), Behavioral and Social Science, Neurodegenerative, Frontotemporal Dementia (FTD), 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Aged, Aged, 80 and over, Aphasia, Broca, Apraxias, Atrophy, DNA-Binding Proteins, Female, Frontal Lobe, Frontotemporal Lobar Degeneration, Humans, Male, Middle Aged, Primary Progressive Nonfluent Aphasia, Prospective Studies, tau Proteins, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo identify early cognitive and neuroimaging features of sporadic nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) caused by frontotemporal lobar degeneration (FTLD) subtypes.MethodsWe prospectively collected clinical, neuroimaging, and neuropathologic data in 11 patients with sporadic nfvPPA with FTLD-tau (nfvPPA-tau, n = 9) or FTLD-transactive response DNA binding protein pathology of 43 kD type A (nfvPPA-TDP, n = 2). We analyzed patterns of cognitive and gray matter (GM) and white matter (WM) atrophy at presentation in the whole group and in each pathologic subtype separately. We also considered longitudinal clinical data.ResultsAt first evaluation, regardless of pathologic FTLD subtype, apraxia of speech (AOS) was the most common cognitive feature and atrophy involved the left posterior frontal lobe. Each pathologic subtype showed few distinctive features. At presentation, patients with nfvPPA-tau presented with mild to moderate AOS, mixed dysarthria with prominent hypokinetic features, clear agrammatism, and atrophy in the GM of the left posterior frontal regions and in left frontal WM. While speech and language deficits were prominent early, within 3 years of symptom onset, all patients with nfvPPA-tau developed significant extrapyramidal motor signs. At presentation, patients with nfvPPA-TDP had severe AOS, dysarthria with spastic features, mild agrammatism, and atrophy in left posterior frontal GM only. Selective mutism occurred early, when general neurologic examination only showed mild decrease in finger dexterity in the right hand.ConclusionsClinical features in sporadic nfvPPA caused by FTLD subtypes relate to neurodegeneration of GM and WM in frontal motor speech and language networks. We propose that early WM atrophy in nfvPPA is suggestive of FTLD-tau pathology while early selective GM loss might be indicative of FTLD-TDP.

Published
2014

15. Practical utility of amyloid and FDG-PET in an academic dementia center

Author

Sánchez-Juan, Pascual, Ghosh, Pia M, Hagen, Jayne, Gesierich, Benno, Henry, Maya, Grinberg, Lea T, O'Neil, James P, Janabi, Mustafa, Huang, Eric J, Trojanowski, John Q, Vinters, Harry V, Gorno-Tempini, Marilu, Seeley, William W, Boxer, Adam L, Rosen, Howard J, Kramer, Joel H, Miller, Bruce L, Jagust, William J, and Rabinovici, Gil D

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Dementia, Aging, Clinical Research, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Biomedical Imaging, Neurosciences, Acquired Cognitive Impairment, Neurodegenerative, 4.2 Evaluation of markers and technologies, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Aniline Compounds, Brain, Cognition Disorders, Female, Fluorodeoxyglucose F18, Humans, Male, Middle Aged, Outcome Assessment, Health Care, Positron-Emission Tomography, Radiopharmaceuticals, Retrospective Studies, Severity of Illness Index, Thiazoles, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo evaluate the effect of amyloid imaging on clinical decision making.MethodsWe conducted a retrospective analysis of 140 cognitively impaired patients (mean age 65.0 years, 46% primary β-amyloid (Aβ) diagnosis, mean Mini-Mental State Examination 22.3) who underwent amyloid (Pittsburgh compound B [PiB]) PET as part of observational research studies and were evaluated clinically before and after the scan. One hundred thirty-four concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed for changes between the pre- and post-PET clinical diagnosis (from Aβ to non-Aβ diagnosis or vice versa) and Alzheimer disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ(2) and multivariate logistic regression. Postmortem diagnosis was available for 24 patients (17%).ResultsConcordance between scan results and baseline diagnosis was high (PiB 84%, FDG 82%). The primary diagnosis changed after PET in 13/140 patients (9%) overall but in 5/13 (38%) patients considered pre-PET diagnostic dilemmas. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (unadjusted p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (adjusted p = 0.00013). Changes in treatment were associated with discordant PiB in patients with non-Aβ diagnoses (adjusted p = 0.028), while FDG had no effect on therapy. Both PiB (96%) and FDG (91%) showed high agreement with autopsy diagnosis.ConclusionsPET had a moderate effect on clinical outcomes. Discordant PiB had a greater effect than discordant FDG, and influence on diagnosis was greater than on treatment. Prospective studies are needed to better characterize the clinical role of amyloid PET.

Published
2014

16. C9orf72, AAO and ancestry help discriminating behavioural from language variants in FTLD cohorts

Author

Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van der Zee, Julie, Van Broeckhoven, Christine, van Rooij, Jeroen, Van Swieten, John C, Veronesi, Arianna, Vitale, Emilia, Waldö, Maria L, Woodward, Cathy, Yokoyama, Jennifer, Escott-Price, Valentina, Polke, James M, and Ferrari, Raffaele

Published
2020
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19. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, Ganesh, Adams, Hieab H.H., Satizabal, Claudia L., Bis, Joshua C., Teumer, Alexander, Sargurupremraj, Muralidharan, Hofer, Edith, Trompet, Stella, Hilal, Saima, Smith, Albert Vernon, Jian, Xueqiu, Malik, Rainer, Traylor, Matthew, Pulit, Sara L., Amouyel, Philippe, Mazoyer, Bernard, Zhu, Yi-Cheng, Kaffashian, Sara, Schilling, Sabrina, Beecham, Gary W., Montine, Thomas J., Schellenberg, Gerard D., Kjartansson, Olafur, Guðnason, Vilmundur, Knopman, David S., Griswold, Michael E., Windham, B. Gwen, Gottesman, Rebecca F., Mosley, Thomas H., Schmidt, Reinhold, Saba, Yasaman, Schmidt, Helena, Takeuchi, Fumihiko, Yamaguchi, Shuhei, Nabika, Toru, Kato, Norihiro, Rajan, Kumar B., Aggarwal, Neelum T., De Jager, Philip L., Evans, Denis A., Psaty, Bruce M., Rotter, Jerome I., Rice, Kenneth, Lopez, Oscar L., Liao, Jiemin, Chen, Christopher, Cheng, Ching-Yu, Wong, Tien Y., Ikram, Mohammad K., van der Lee, Sven J., Amin, Najaf, Chouraki, Vincent, DeStefano, Anita L., Aparicio, Hugo J., Romero, Jose R., Maillard, Pauline, DeCarli, Charles, Wardlaw, Joanna M., Hernández, Maria del C. Valdés, Luciano, Michelle, Liewald, David, Deary, Ian J., Starr, John M., Bastin, Mark E., Muñoz Maniega, Susana, Slagboom, P. Eline, Beekman, Marian, Deelen, Joris, Uh, Hae-Won, Lemmens, Robin, Brodaty, Henry, Wright, Margaret J., Ames, David, Boncoraglio, Giorgio B., Hopewell, Jemma C., Beecham, Ashley H., Blanton, Susan H., Wright, Clinton B., Sacco, Ralph L., Wen, Wei, Thalamuthu, Anbupalam, Armstrong, Nicola J., Chong, Elizabeth, Schofield, Peter R., Kwok, John B., van der Grond, Jeroen, Stott, David J., Ford, Ian, Jukema, J. Wouter, Vernooij, Meike W., Hofman, Albert, Uitterlinden, André G., van der Lugt, Aad, Wittfeld, Katharina, Grabe, Hans J., Hosten, Norbert, von Sarnowski, Bettina, Völker, Uwe, Levi, Christopher, Jimenez-Conde, Jordi, Sharma, Pankaj, Sudlow, Cathie L.M., Rosand, Jonathan, Woo, Daniel, Cole, John W., Meschia, James F., Slowik, Agnieszka, Thijs, Vincent, Lindgren, Arne, Melander, Olle, Grewal, Raji P., Rundek, Tatjana, Rexrode, Kathy, Rothwell, Peter M., Arnett, Donna K., Jern, Christina, Johnson, Julie A., Benavente, Oscar R., Wasssertheil-Smoller, Sylvia, Lee, Jin-Moo, Wong, Quenna, Mitchell, Braxton D., Rich, Stephen S., McArdle, Patrick F., Geerlings, Mirjam I., van der Graaf, Yolanda, de Bakker, Paul I.W., Asselbergs, Folkert W., Srikanth, Velandai, Thomson, Russell, McWhirter, Rebekah, Moran, Chris, Callisaya, Michele, Phan, Thanh, Rutten-Jacobs, Loes C.A., Bevan, Steve, Tzourio, Christophe, Mather, Karen A., Sachdev, Perminder S., van Duijn, Cornelia M., Worrall, Bradford B., Dichgans, Martin, Kittner, Steven J., Markus, Hugh S., Ikram, Mohammad A., Fornage, Myriam, Launer, Lenore J., Seshadri, Sudha, Longstreth, W.T., Jr, Debette, Stéphanie, Almgren, Peter, Anderson, Christopher D., Arnett, Donna K., Attia, John, Ay, Hakan, Benavente, Oscar R., Bevan, Steve, Brown, Robert D., Bustamante, Mariana, Cheng, Yu-Ching, Cole, John W., Cotlarciuc, Ioana, Cruchaga, Carlos, de Bakker, Paul IW., Delavaran, Hossein, Dichgans, Martin, Engström, Gunnar, Fornage, Myriam, Grewal, Raji P., Heitsch, Laura, Holliday, Elizabeth, Ibanez, Laure, Ilinca, Andreea, Irvin, Marguerite R., Jackson, Rebecca D., Jern, Christina, Jimenez-Conde, Jordi, Johnson, Julie A., Jood, Katarina, Kissela, Brett M., Kittner, Steven J., Kleindorfer, Dawn O., Labovitz, Daniel, Laurie, Cathy C., Lee, Jin-Moo, Lemmens, Robin, Levi, Christopher, Li, Linxin, Lindgren, Arne G., Maguire, Jane, Markus, Hugh S., McArdle, Patrick F., Melander, Olle, Meschia, James F., Mitchell, Braxton D., Müller-Nurasyid, Martina, Norrving, Bo, Peddareddygari, Leema Reddy, Pera, Joanna, Pulit, Sara L., Rexrode, Kathryn, Ribasés, Marta, Roquer, Jaume, Rost, Natalia S., Rothwell, Peter M., Rundek, Tatjana, Sacco, Ralph L., Schmidt, Reinhold, Sharma, Pankaj, Slowik, Agnieszka, Soriano-Tárraga, Carolina, Stanne, Tara, Stauch, Konstantin, Stine, O C., Sudlow, Cathie LM., Thijs, Vincent N.S., Wasssertheil-Smoller, Sylvia, Weir, David, Williams, Stephen R., Wong, Quenna, Woo, Daniel, Worrall, Bradford B., Xu, Huichun, Seshadri, Sudha, Hyacinth, Hyacinth I, Marini, Sandro, Nyquist, Paul, Lewis, Cathryn, Hansen, Bjorn, Norrving, Bo, Rosand, Jonathan, Biffi, Alessandro, Kourkoulis, Christina, Anderson, Chris, Giese, Anne-Katrin, Sacco, Ralph, Sharma, Pankaj, Chung, Jong-Won, Kim, Gyeong-Moon, Lubitz, Steven, Bourcier, Romain, Howson, Joanna, Granata, Alessandra, Drazyk, Anna, Markus, Hugh, Wardlaw, Joanna, Mitchell, Braxton, Cole, John, Hopewell, Jemma, Walters, Robin, Turnbull, Iain, Worrall, Bradford, Bis, Josh, Reiner, Alex, Dhar, Raj, Heitsch, Laura, Lee, Jin-Moo, Prasad, Kameshwar, Sarnowski, Chloé, Aparicio, Hugo Javier, Yang, Qiong, Chasman, Daniel, Rexrode, Kathryn, Phuah, Chia-Ling, Liu, Guiyou, Elkind, Mitchell, Lange, Leslie, Rost, Natalia, James, Michael, Stewart, Jill, Vojinovic, Dina, Thijs, Vincent, Parati, Eugenio, Boncoraglio, Giorgio, Zand, Ramin, Bijlenga, Philippe, Selim, Magdy, Grond-Ginsbach, Caspar, Strbian, Daniel, Tomppo, Liisa, Sallinen, Hanne, Pfeiffer, Dorothea, Torres, Nuria, Barboza, Miguel, Laarman, Melanie, Carriero, Roberta, Holliday, Elizabeth, Jimenez-Conde, Jordi, Soriano, Carolina, Gill, Dipender, Debette, Stephanie, Mishra, Aniket, Wu, Jer-Yuarn, Ko, Tai-Ming, Bione, Silvia, Jood, Katarina, Tatlisumak, Turgut, Holmegaard, Lukas, Yue, Suo, bersano, Anna, Pera, Joanna, Slowik, Agnieszka, Levi, Christopher, Schlicht, Kristina, Lemmens, Robin, Ninomiya, Toshiharu, Oberstein, Saskia Lesnik, Lee, Tsong-Hai, Malik, Rainer, Dichgans, Martin, Lindgren, Arne, Wasselius, Johan, Drake, Mattias, Melander, Olle, Stenman, Martin, Ilinca, Andreea, Crawford, Katherine, Lena, Umme, Mateen, Farrah, Ay, Hakan, Wu, Ona, Schirmer, Markus, Cramer, Steve, Golland, Polina, Brown, Robert, Meschia, James, Ross, Owen A., Pare, Guillaume, Chong, Mike, Rundek, Tatjana, Gwinn, Katrina, Chen, Christopher, Koenig, Jim, Giralt, Eva, Saleheen, Danish, de Leeuw, Frank-Erik, Klijn, Karin, Kamatani, Yoichiro, Kubo, Michiaki, Okada, Yukinori, Pedersen, Annie, Olsson, Maja, Martín, Juan José, Xu, Huichun, Tan, Eng King, Frid, Petrea, Lee, Chaeyoung, Tregouet, David, Leung, Thomas, Choy, Richard, Jern, Christina, Loo, Keat Wei, Rinkel, Gabriel, Franca, Paulo, Cendes, Iscia, Carrera, Caty, Fernandez-Cadenas, Israel, Montaner, Joan, Kim, Helen, Owolabi, Mayowa, Sofat, Reecha, Bakker, Mark, Ruigrok, Ynte, Hauer, Allard, Pulit, Sara L., van der Laan, Sander W., Irvin, Ryan, Sargurupremraj, Murali, Pezzini, Alessandro, Abd-Allah, Foad, Liebeskind, David, Traylor, Matthew, Tan, Rhea, Danesh, John, Rutten-Jacobs, Loes, Donatti, Amanda, Avelar, Wagner, Broderick, Joseph, Woo, Daniel, Sudlow, Cathie, Rannikmae, Kristiina, McDonough, Caitrin Wheeler, van Agtmael, Tom, Walters, Matthew, Söderholm, Martin, Lorentzen, Erik, Olsson, Sandra, Stanne, Tara, Olsson, Martina, Akinyemi, Rufus, Cotlatciuc, Ioana, McArdle, Patrick, Dave, Tushar, Kittner, Steven, Attia, John, Faber, James E, Millwood, Iona, Márquez, Elsa Valdés, Mancuso, Michelangelo, Vibo, Riina, Korv, Janika, Maguire, Jane, Fornage, Myriam, Majersik, Jennifer, DeHavenon, Adam, Alexander, Matthew, Sale, Michele, Southerland, Andrew, Owens, Debra, Psaty, Bruce, Longstreth, W. T., Jr, Wolfe, Stacey Quintero, Langefeld, Carl, Cruchaga, Carlos, Konrad, Jan, Sheth, Kevin, Falcone, Guido, Donahue, Kathleen, Simpkins, Alexis N, Liang Byorn, Tan Wei, Chan, Bernard, Clatworthy, Phil, Florez, Jose, Harshfield, Eric, Hozawa, Atsushi, Hsu, Chung, Hu, Chaur-Jong, Ibanez, Laure, Ihara, Masafumi, Lange, Marcos, Lee, Soo Ji, Lee, I-Hui, Musolino, Patricia, Nakatomi, Hirofumi, Park, Kwang-Yeol, Rich, Stephen S, Riley, Chris, Sung, Joohon, Suzuki, Hideaki, Vo, Katie, Washida, Kazuo, Ibenez, Laura Garcia, Slowik, Agnieszka, Hofman, Albert, Algra, Ale, Reiner, Alex P, Doney, Alexander S F, Gschwendtner, Andreas, Ilinca, Andreea, Giese, Anne-Katrin, Lindgren, Arne, Vicente, Astrid M, Norrving, Bo, Nordestgaard, Børge G, Mitchell, Braxton D, Worrall, Bradford B, Psaty, Bruce M, Carty, Cara L, Sudlow, Cathie, Anderson, Christopher D, Levi, Christopher, Satizabal, Claudia L, Palmer, Colin N A, Gamble, Dale M, Woo, Daniel, Saleheen, Danish, Ringelstein, E Bernd, Valdimarsson, Einar, Holliday, Elizabeth, Davies, Gail, Chauhan, Ganesh, Pasterkamp, Gerard, Boncoraglio, Giorgio, Kuhlenbäumer, Gregor, Thorleifsson, Gudmar, Falcone, Guido J, Pare, Guillame, Schmidt, Helena, Delavaran, Hossein, Markus, Hugh S, Aparicio, Hugo J, Deary, Ian, Cotlarciuc, Ioana, Fernandez-Cadenas, Israel, Meschia, James, Hopewell, Jemma C, Liu, Jingmin, Montaner, Joan, Pera, Joanna, Cole, John, Attia, John R, Rosand, Jonathan, Ferro, Jose M, Bis, Joshua, Furie, Karen, Stefansson, Kari, Berger, Klaus, Kostulas, Konstantinos, Rannikmae, Kristina, Ikram, M Arfan, Benn, Marianne, Dichgans, Martin, Farrall, Martin, Pandolfo, Massimo, Traylor, Matthew, Walters, Matthew, Sale, Michele, Nalls, Mike, Fornage, Myriam, van Zuydam, Natalie R, Sharma, Pankaj, Abrantes, Patricia, de Bakker, Paul IW, Higgins, Peter, Lichtner, Peter, Rothwell, Peter M, Amouyel, Philippe, Yang, Qiong, Malik, Rainer, Schmidt, Reinhold, Clarke, Robert, Lemmens, Robin, van der Laan, Sander W, Pulit, Sara L, Abboud, Sherine, Oliveira, Sofia A, Gretarsdottir, Solveig, Debette, Stephanie, Williams, Stephen R, Bevan, Steve, Kittner, Steven J, Seshadri, Sudha, Mosley, Thomas, Battey, Thomas WK, Tatlisumak, Turgut, Thorsteinsdottir, Unnur, Thijs, Vincent NS, Longstreth, W T, Zhao, Wei, Chen, Wei-Min, Cheng, Yu-Ching, Albert, Marilyn S., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barmada, M. Michael, Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Beecham, Gary W., Beekly, Duane, Bennett, David A., Bigio, Eileen H., Bird, Thomas D., Blacker, Deborah, Boeve, Bradley F., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Byrd, Goldie S., Cai, Guiqing, Cairns, Nigel J., Cantwell, Laura B., Cao, Chuanhai, Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., Cruchaga, Carlos, De Jager, Philip L., DeCarli, Charles, Demirci, F. Yesim, Dick, Malcolm, Dickson, Dennis W., Duara, Ranjan, Ertekin-Taner, Nilufer, Evans, Denis A., Faber, Kelley M., Fallin, M. Daniele, Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Farrer, Lindsay A., Ferris, Steven, Foroud, Tatiana M., Frosch, Matthew P., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilbert, John R., Go, Rodney C.P., Goate, Alison M., Graff-Radford, Neill R., Green, Robert C., Griffith, Patrick, Growdon, John H., Haines, Jonathan L., Hakonarson, Hakon, Hamilton, Ronald L., Hamilton-Nelson, Kara L., Haroutunian, Vahram, Harrell, Lindy E., Honig, Lawrence S., Huebinger, Ryan M., Hulette, Christine M., Hyman, Bradley T., Jicha, Gregory A., Jin, Lee-Way, Jun, Gyungah, Kamboh, M. Ilyas, Karydas, Anna, Kauwe, John S.K., Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., Kukull, Walter A., Kunkle, Brian W., LaFerla, Frank M., Lah, James J., Lang-Walker, Rosalyn, Larson, Eric B., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Logue, Mark W., Lopez, Oscar L., Lunetta, Kathryn L., Lyketsos, Constantine G., Mack, Wendy J., Manly, Jennifer J., Marson, Daniel C., Martin, Eden R., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, Mayeux, Richard, McKee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Montine, Thomas J., Morris, John C., Murrell, Jill R., Naj, Adam C., Obisesan, Thomas O., Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Partch, Amanda, Paulson, Henry L., Pericak-Vance, Margaret A., Perry, William, Peskind, Elaine, Petersen, Ronald C., Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raj, Towfique, Raskind, Murray, Reiman, Eric M., Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., Sano, Mary, Saykin, Andrew J., Schellenberg, Gerard D., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Tsuang, Debby W., Valladares, Otto, Van Deerlin, Vivianna M., Van Eldik, Linda J., Vardarajan, Badri N., Vinters, Harry V., Vonsattel, Jean Paul, Wang, Li-San, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Williamson, Jennifer, Wingo, Thomas S., Wishnek, Sarah, Woltjer, Randall L., Wright, Clinton B., Younkin, Steven G., Yu, Chang-En, Yu, Lei, Chauhan, Ganesh, Chu, Audrey Y., Fornage, Myriam, Bis, Joshua C., Havulinna, Aki S., Sargurupremraj, Muralidharan, Smith, Albert Vernon, Adams, Hieab H.H., Choi, Seung Hoan, Trompet, Stella, Garcia, Melissa E., Manichaikul, Ani, Teumer, Alexander, Gustafsson, Stefan, Bartz, Traci M., Bellenguez, Céline, Vidal, Jean Sebastien, Jian, Xueqiu, Kjartansson, Olafur, Wiggins, Kerri L., Satizabal, Claudia L., Xue, Flora, Ripatti, Samuli, Liu, Yongmei, Deelen, Joris, Hoed, Marcel den, Heckbert, Susan R., Rice, Kenneth, Smith, Nicholas L., Wong, Quenna, Aparicio, Hugo J., Buring, Julie E., Ridker, Paul M, Berr, Claudine, Dartigues, Jean-François, Hamsten, Anders, Magnusson, Patrik K., Pedersen, Nancy L., Lannfelt, Lars, Lind, Lars, Lindgren, Cecilia M., Morris, Andrew P., Hofman, Albert, Koudstaal, Peter J., Portegies, Marileen LP., Uitterlinden, André G., de Craen, Anton JM, Ford, Ian, Jukema, J. Wouter, Stott, David J, Allen, Norrina B., Sale, Michele M., Johnson, Andrew D, Bennett, David A., De Jager, Philip L., White, Charles C., Grabe, Hans Jörgen, Paulista Markus, Marcello Ricardo, Lopez, Oscar L, Rotter, Jerome I., Nalls, Michael A., Gottesman, Rebecca F., Griswold, Michael E., Knopman, David S., Windham, B. Gwen, Beiser, Alexa, Vartiainen, Erkki, French, Curtis R., Kurth, Tobias, Psaty, Bruce M., Harris, Tamara B., Rich, Stephen S, deStefano, Anita L., Schmidt, Carsten Oliver, Salomaa, Veikko, Mosley, Thomas H., Ingelsson, Erik, van Duijn, Cornelia M., Tzourio, Christophe, Launer, Lenore J, Ikram, M. Arfan, Chasman, Daniel I., Longstreth, W. T., Jr, Seshadri, Sudha, Debette, Stéphanie, Verhaaren, Benjamin F.J., Debette, Stéphanie, Bis, Joshua C., Smith, Jennifer A., Ikram, M. Kamran, Adams, Hieab H., Beecham, Ashley H., Rajan, Kumar B., Lopez, Lorna M., Barral, Sandra, van Buchem, Mark A., van der Grond, Jeroen, Smith, Albert V., Hegenscheid, Katrin, Aggarwal, Neelum T., de Andrade, Mariza, Atkinson, Elizabeth J., Beekman, Marian, Beiser, Alexa S., Blanton, Susan H., Boerwinkle, Eric, Brickman, Adam M., Bryan, R. Nick, Chauhan, Ganesh, Chen, Christopher P.L.H., Chouraki, Vincent, de Craen, Anton J.M., Crivello, Fabrice, Deary, Ian J., Deelen, Joris, De Jager, Philip L., Dufouil, Carole, Elkind, Mitchell S.V., Evans, Denis A., Freudenberger, Paul, Gottesman, Rebecca F., Guðnason, Vilmundur, Habes, Mohamad, Heckbert, Susan R., Heiss, Gerardo, Hilal, Saima, Hofer, Edith, Hofman, Albert, Ibrahim-Verbaas, Carla A., Knopman, David S., Lewis, Cora E., Liao, Jiemin, Liewald, David C.M., Luciano, Michelle, van der Lugt, Aad, Martinez, Oliver O., Mayeux, Richard, Mazoyer, Bernard, Nalls, Mike, Nauck, Matthias, Niessen, Wiro J., Oostra, Ben A., Psaty, Bruce M., Rice, Kenneth M., Rotter, Jerome I., von Sarnowski, Bettina, Schmidt, Helena, Schreiner, Pamela J., Schuur, Maaike, Sidney, Stephen S., Sigurdsson, Sigurdur, Slagboom, P. Eline, Stott, David J.M., van Swieten, John C., Teumer, Alexander, Töglhofer, Anna Maria, Traylor, Matthew, Trompet, Stella, Turner, Stephen T., Tzourio, Christophe, Uh, Hae-Won, Uitterlinden, André G., Vernooij, Meike W., Wang, Jing J., Wong, Tien Y., Wardlaw, Joanna M., Windham, B. Gwen, Wittfeld, Katharina, Wolf, Christiane, Wright, Clinton B., Yang, Qiong, Zhao, Wei, Zijdenbos, Alex, Jukema, J. Wouter, Sacco, Ralph L., Kardia, Sharon L.R., Amouyel, Philippe, Mosley, Thomas H., Longstreth, W. T., Jr, DeCarli, Charles C., van Duijn, Cornelia M., Schmidt, Reinhold, Launer, Lenore J., Grabe, Hans J., Seshadri, Sudha S., Ikram, M. Arfan, Fornage, Myriam, Bis, Joshua C., Kavousi, Maryam, Franceschini, Nora, Isaacs, Aaron, Abecasis, Gonçalo R, Schminke, Ulf, Post, Wendy, Smith, Albert V., Cupples, L. Adrienne, Markus, Hugh S, Schmidt, Reinhold, Huffman, Jennifer E., Lehtimäki, Terho, Baumert, Jens, Münzel, Thomas, Heckbert, Susan R., Dehghan, Abbas, North, Kari, Oostra, Ben, Bevan, Steve, Stoegerer, Eva-Maria, Hayward, Caroline, Raitakari, Olli, Meisinger, Christa, Schillert, Arne, Sanna, Serena, Völzke, Henry, Cheng, Yu-Ching, Thorsson, Bolli, Fox, Caroline S., Rice, Kenneth, Rivadeneira, Fernando, Nambi, Vijay, Halperin, Eran, Petrovic, Katja E., Peltonen, Leena, Wichmann, H. Erich, Schnabel, Renate B., Dörr, Marcus, Parsa, Afshin, Aspelund, Thor, Demissie, Serkalem, Kathiresan, Sekar, Reilly, Muredach P., Taylor, Kent, Uitterlinden, Andre, Couper, David J., Sitzer, Matthias, Kähönen, Mika, Illig, Thomas, Wild, Philipp S., Orru, Marco, Lüdemann, Jan, Shuldiner, Alan R., Eiriksdottir, Gudny, White, Charles C., Rotter, Jerome I., Hofman, Albert, Seissler, Jochen, Zeller, Tanja, Usala, Gianluca, Ernst, Florian, Launer, Lenore J., DʼAgostino, Ralph B., Sr, OʼLeary, Daniel H., Ballantyne, Christie, Thiery, Joachim, Ziegler, Andreas, Lakatta, Edward G., Chilukoti, Ravi Kumar, Harris, Tamara B., Wolf, Philip A., Psaty, Bruce M., Polak, Joseph F, Li, Xia, Rathmann, Wolfgang, Uda, Manuela, Boerwinkle, Eric, Klopp, Norman, Schmidt, Helena, Wilson, James F, Viikari, Jorma, Koenig, Wolfgang, Blankenberg, Stefan, Newman, Anne B., Witteman, Jacqueline, Heiss, Gerardo, van Duijn, Cornelia, Scuteri, Angelo, Homuth, Georg, Mitchell, Braxton D., Gudnason, Vilmundur, and O’Donnell, Christopher J.

Published
2019
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21. CSF Biomarkers of Alzheimer Disease in Patients With Concomitant α-Synuclein Pathology

Author

Cousins, Katheryn Alexandra Quilico, Arezoumandan, Sanaz, Shellikeri, Sanjana, Ohm, Daniel, Shaw, Leslie M., Grossman, Murray, Wolk, David, McMillan, Corey T., Chen-Plotkin, Alice, Lee, Edward, Trojanowski, John Q., Zetterberg, Henrik, Blennow, Kaj, and Irwin, David John

Subjects
Neurology (clinical), Research Article
Abstract

Background and Objectives:Cerebrospinal fluid (CSF) biomarkers amyloid-β42 (Aβ42), phosphorylated tau (p-tau181), total tau (t-tau) and neurogranin (Ng) can diagnose Alzheimer’s disease (AD) in life. However, it is unknown if CSF concentrations, and thus their accuracies, are affected by concomitant pathologies common in AD, such as α-synuclein (αSyn). Our primary goal was to test if biomarkers in patients with AD are altered by concomitant αSyn. We compared CSF Aβ42, p-tau181, t-tau and Ng levels across autopsy-confirmed AD and concomitant AD and αSyn (AD+αSyn). Antemortem CSF levels were related to postmortem accumulations of αSyn. Finally, we tested how concommitant AD+αSyn affected diagnostic accuracy of two CSF-based strategies: the ATN framework and the t-tau/Aβ42 ratio.Methods:Inclusion criteria were neuropathologic diagnoses of AD, mixed AD+αSyn, and αSyn. A convenience sample of non-impaired controls were selected with available CSF and a mini mental state exam (MMSE)≥27. αSyn without AD and controls were included as reference groups. Analyses of covariance (ANCOVAs) tested planned comparisons were CSF Aβ42, p-tau181, t-tau, and Ng differences across AD and AD+αSyn. Linear models tested how biomarkers were altered by αSyn accumulation in AD, accounting for pathologic amyloid-β and tau. Receiver operating characteristic and area under the curve (AUC), including 95% confidence intervals (CI), evaluated diagnostic accuracy.Results:Participants were 61 AD, 39 mixed AD+αSyn, 20 αSyn, and 61 Controls. AD had similar median age (73 [IQR=12]), MMSE (23 [IQR=9]), and sex distribution (Male=49%) compared to AD+αSyn age (70 [IQR=13]; p=0.3), MMSE (25 [IQR=9.5]; p=0.19), and sex distribution (Male=69%; p=0.077). ANCOVAs showed AD+αSyn had lower p-tau181 (F(1,94)=17, p=0), t-tau (F(1,93)=11, p=0.0004), and Ng levels (F(1,50)=12, p=0.0004) than AD; there was no difference in Aβ42 (p=0.44). Models showed increasing αSyn related to lower p-tau181 (β=-0.26, SE=0.092, p=0.0065), t-tau (β=-0.19, SE=0.092, p=0.041), and Ng levels (β=-0.2, SE=0.066, p=0.0046); αSyn was not a significant factor for Aβ42 (p=1). T-tau/Aβ42 had the highest accuracy when detecting AD, including mixed AD+αSyn cases (AUC=0.95; CI=0.92 to 0.98).Discussion:Findings demonstrate that concomitant αSyn pathology in AD is associated with lower CSF p-tau181, t-tau, and Ng levels, and can affect diagnositic accuracy in AD patients.

Published
2022
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23. CSF Biomarkers of Alzheimer Disease in Patients With Concomitant α-Synuclein Pathology

Author

Quilico Cousins, Katheryn Alexandra, primary, Arezoumandan, Sanaz, additional, Shellikeri, Sanjana, additional, Ohm, Daniel, additional, Shaw, Leslie M, additional, Grossman, Murray, additional, Wolk, David, additional, McMillan, Corey T, additional, Chen-Plotkin, Alice, additional, Lee, Edward, additional, Trojanowski, John Q., additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, and Irwin, David John, additional

Published
2022
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24. Chromatin accessibility differences between African and European Alzheimer Disease brains. (P2-3.002)

Author

Celis, Katrina, primary, Griswold, Anthony J., additional, Rajabli, Farid, additional, Hamilton-Nelson, Kara, additional, Weintraub, Sandra, additional, Gearing, Marla, additional, Geula, Changiz, additional, Trojanowski, John, additional, Dalgard, Clifton, additional, Bennett, David, additional, Pericak-Vance, Margaret, additional, young, Juan, additional, and Vance, Jeffery, additional

Published
2022
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25. Computational modeling of tau pathology spread reveals genetic correlates of regional vulnerability and the impact of a LRRK2 mutation (P9-3.005)

Author

Cornblath, Eli, primary, Li, Howard, additional, Changolkar, Lakshmi, additional, Zhang, Bin, additional, Brown, Hannah, additional, Gathagan, Ronald, additional, Olufemi, Modupe, additional, Trojanowski, John, additional, Bassett, Dani, additional, Lee, Virginia, additional, and Henderson, Michael, additional

Published
2022
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26. Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques

Author

Li, Yan, primary, Schindler, Suzanne E., additional, Bollinger, James G., additional, Ovod, Vitaliy, additional, Mawuenyega, Kwasi G., additional, Weiner, Michael W., additional, Shaw, Leslie M., additional, Masters, Colin L., additional, Fowler, Christopher J., additional, Trojanowski, John Q., additional, Korecka, Magdalena, additional, Martins, Ralph N., additional, Janelidze, Shorena, additional, Hansson, Oskar, additional, and Bateman, Randall J., additional

Published
2021
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27. Non-Tremor Motor Dysfunction is Associated with Alzheimer’s Disease Biomarkers in Lewy Body Dementias (2971)

Author

Walker, Ian, primary, Shaw, Sarah, additional, Vaishnavi, Sanjeev, additional, Wolk, David, additional, Dahodwala, Nabila, additional, Morley, James, additional, Duda, John, additional, Chen-Plotkin, Alice, additional, Siderowf, Andrew, additional, Shaw, Leslie, additional, Lee, Edward, additional, Trojanowski, John, additional, Grossman, Murray, additional, Weintraub, Daniel, additional, and Irwin, David, additional

Published
2021
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28. Association of Mitochondrial DNA Genomic Variation With Risk of Pick Disease

Author

Valentino, Rebecca R., primary, Heckman, Michael G., additional, Johnson, Patrick W., additional, Baker, Matthew C., additional, Soto-Beasley, Alexandra I., additional, Walton, Ronald L., additional, Koga, Shunsuke, additional, Roemer, Shanu F., additional, Suh, EunRan, additional, Uitti, Ryan J., additional, Trojanowski, John Q., additional, Grossman, Murray, additional, Van Deerlin, Vivianna M., additional, Rademakers, Rosa, additional, Wszolek, Zbigniew K., additional, Dickson, Dennis W., additional, and Ross, Owen A., additional

Published
2021
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29. Cognitive Profile and Markers of Alzheimer Disease–Type Pathology in Patients With Lewy Body Dementias

Author

Howard, Erica, primary, Irwin, David J., additional, Rascovsky, Katya, additional, Nevler, Naomi, additional, Shellikeri, Sanjana, additional, Tropea, Thomas F., additional, Spindler, Meredith, additional, Deik, Andres, additional, Chen-Plotkin, Alice, additional, Siderowf, Andrew, additional, Dahodwala, Nabila, additional, Weintraub, Daniel, additional, Shaw, Leslie M., additional, Trojanowski, John Q., additional, Vaishnavi, Sanjeev N., additional, Wolk, David A., additional, Mechanic-Hamilton, Dawn, additional, Morley, James F., additional, Duda, John E., additional, Grossman, Murray, additional, and Cousins, Katheryn A.Q., additional

Published
2021
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31. APOE ɛ4-related differences in visuospatial impairment in female Parkinson’s Disease patients (743)

Author

Rawls, Ashley, primary, Yang, Laurice, additional, Chung, Kathryn, additional, Hiller, Amie, additional, Espay, Alberto, additional, Revilla, Fredy, additional, Devoto, Johnna, additional, Goldman, Jennifer, additional, Stebbins, Glenn, additional, Bernard, Bryan, additional, Wszolek, Zbigniew, additional, Ross, Owen, additional, Dickson, Dennis, additional, Rosenthal, Liana, additional, Dawson, Ted, additional, Albert, Marilyn, additional, Factor, Stewart, additional, Weintraub, Daniel, additional, Trojanowski, John, additional, Van Deerlin, Vivianna, additional, Simuni, Tanya, additional, Lubbe, Steven, additional, Mencacci, Niccolo, additional, Hu, Shu-Ching, additional, Leverenz, James, additional, Quinn, Joseph, additional, Montine, Thomas, additional, Zabetian, Cyrus, additional, Poston, Kathleen, additional, and Cholerton, Brenna, additional

Published
2020
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32. Confrontation Naming Deficit in Lewy Body Dementia Patients with Alzheimer’s Disease Co-Pathology (4234)

Author

Howard, Erica, primary, Cousins, Katheryn, additional, Rascovsky, Katya, additional, Nevler, Naomi, additional, Tropea, Thomas, additional, Chen-Plotkin, Alice, additional, Siderowf, Andrew, additional, Weintraub, Daniel, additional, Shaw, Leslie, additional, Trojanowski, John, additional, Grossman, Murray, additional, and Irwin, David, additional

Published
2020
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34. Hippocampal tau pathology burden in Lewy body disorders (P1.1-014)

Author

Ittyerah, Ranjit, primary, Coughlin, David G., additional, Phillips, Jeffrey, additional, Miller, Simon, additional, Lee, Edward B., additional, Trojanowski, John Q., additional, Weintraub, Daniel, additional, Siderowf, Andrew, additional, Duda, John E., additional, Hurtig, Howard I., additional, Wolk, David A., additional, Yushkevich, Paul, additional, Grossman, Murray, additional, and Irwin, David J., additional

Published
2019
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41. Characterization of Sequence Variants in Downstream Flanking Region of C9orf72 Hexanucleotide Repeat in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis (P3.1-008)

Author

Grando, Kaitlyn, primary, Suh, EunRan, additional, Neal, Donald, additional, Richardson, Hayley, additional, Hennessey, Laura, additional, McMillan, Corey, additional, Irwin, David, additional, Lee, Edward B., additional, Grossman, Murray, additional, McCluskey, Leo, additional, Elman, Lauren, additional, Xie, Sharon, additional, Trojanowski, John Q., additional, and Van Deerlin, Vivianna, additional

Published
2019
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43. Divergent Bi-hemispheric Patterns of FTLD-TDP and FTLD-Tau Neuropathologies in Primary Progressive Aphasia (P1.185)

Author

Giannini, Lucia, primary, Liang, Mendy, additional, McMillan, Corey, additional, Williams, Andrew, additional, Jester, Charles, additional, Rascovsky, Katya, additional, Wolk, David, additional, Ash, Sharon, additional, Lee, Edward, additional, Trojanowski, John, additional, Grossman, Murray, additional, and Irwin, David, additional

Published
2018
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49. Sporadic FTLD TDP type C is a distinct clinicopathological entity from FTLD types A/B (S7.007)

Author

Baer, G Michael, primary, Byrne, Matthew, additional, Cooper, Felicia, additional, Suh, Eunran, additional, McCluskey, Leo, additional, Elman, Lauren, additional, Wolk, David, additional, Van Deerlin, Vivianna, additional, Lee, Virginia, additional, Lee, Edward, additional, Grossman, Murray, additional, Trojanowski, John, additional, and Irwin, David, additional

Published
2017
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