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102


Multimodal Hippocampal Subfield Grading For Alzheimer's Disease Classification

Hett, Kilian; Vinh-Thong Ta; Catheline, Gwenaelle; Tourdias, Thomas; Manjon, Jose V.; Coupe, Pierrick; Weiner, Michael W.; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowki, John Q.; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Shaw, Leslie M.; Khachaturian, Zaven; Sorensen, Greg; Carrillo, Maria; Kuller, Lew; Raichle, Marc; Paul, Steven; Davies, Peter; Fillit, Howard; Hefti, Franz; Holtzman, Davie; Mesulam, M. Marcel; Potter, William; Snyder, Peter; Montine, Tom; Thomas, Ronald G.; Donohue, Michael; Walter, Sarah; Sather, Tamie; Jiminez, Gus; Balasubramanian, Archana B.; Mason, Jennifer; Sim, Iris; Harvey, Danielle; Bernstein, Matthew; Fox, Nick; Thompson, Paul; Schuff, Norbert; Decarli, Charles; Borowski, Bret; Gunter, Jeff; Senjem, Matt; Vemuri, Prashanthi; Jones, David; Kantarci, Kejal; Ward, Chad; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Mathis, Chet; Landau, Susan; Cairns, Nigel J.; Householder, Erin; Taylor-Reinwald, Lisa; Lee, Virginia; Korecka, Magdalena; Figurski, Michal; Crawford, Karen; Neu, Scott; Foroud, Tatiana M.; Potkin, Steven; Shen, Li; Faber, Kelley; Kim, Sungeun; Nho, Kwangsik; Thal, Lean; Frank, Richard; Hsiao, John; Kaye, Jeffrey; Quinn, Joseph; Silbert, Lisa; Lind, Betty; Carter, Raina; Dolen, Sara; Ances, Beau; Carroll, Maria; Creech, Mary L.; Franklin, Erin; Mintun, Mark A.; Schneider, Stacy; Oliver, Angela; Schneider, Lon S.; Pawluczyk, Sonia; Beccera, Mauricio; Teodoro, Liberty; Spann, Bryan M.; Brewer, James; Vanderswag, Helen; Fleisher, Adam; Marson, Daniel; Griffith, Randall; Clark, David; Geldmacher, David; Brockington, John; Roberson, Erik; Love, Marissa Natelson; Heidebrink, Judith L.; Lord, Joanne L.; Mason, Sara S.; Albers, Colleen S.; Knopman, David; Johnson, Kris; Grossman, Hillel; Mitsis, Effie; Shah, Raj C.; deToledo-Morrell, Leyla; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Rountree, Susan; Dang, Mimi; Duara, Ranjan; Varon, Daniel; Greig, Maria T.; Roberts, Peggy; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Albert, Marilyn; Onyike, Chiadi; D\Agostino, Daniel; Kielb, Stephanie; Galvin, James E.; Cerbone, Brittany; Michel, Christina A.; Pogorelec, Dana M.; Rusinek, Henry; de Leon, Mony J.; Glodzik, Lidia; De Santi, Susan; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Borges-Neto, Salvador; Wong, Terence Z.; Coleman, Edward; Levey, Allan I.; Lah, James J.; Cella, Janet S.; Burns, Jeffrey M.; Swerdlow, Russell H.; Brooks, William M.; Arnold, Steven E.; Karlawish, Jason H.; Wolk, David; Clark, Christopher M.; Apostolova, Liana; Tingus, Kathleen; Woo, Ellen; Silverman, Daniel H. S.; Lu, Po H.; Bartzokis, George; Smith, Charles D.; Jicha, Greg; Hardy, Peter; Sinha, Partha; Oates, Elizabeth; Conrad, Gary; Graff-Radford, Neill R.; Parfitt, Francine; Kendall, Tracy; Johnson, Heather; Lopez, Oscar L.; Oakley, MaryAnn; Simpson, Donna M.; Farlow, Martin R.; Hake, Ann Marie; Matthews, Brandy R.; Brosch, Jared R.; Herring, Scott; Hunt, Cynthia; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Mulnard, Ruth A.; Thai, Gaby; Mc-Adams-Ortiz, Catherine; van Dyck, Christopher H.; Carson, Richard E.; MacAvoy, Martha G.; Varma, Pradeep; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Hsiung, Ging-Yuek Robin; Feldman, Howard; Mudge, Benita; Assaly, Michele; Finger, Elizabeth; Pasternack, Stephen; Rachisky, Irina; Trost, Dick; Kertesz, Andrew; Bernick, Charles; Munic, Donna; Lipowski, Kristine; Weintraub, M. A. Sandra; Bonakdarpour, Borna; Kerwin, Diana; Wu, Chuang-Kuo; Johnson, Nancy; Sadowsky, Carl; Villena, Teresa; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A.; Johnson, Keith A.; Marshall, Gad; Yesavage, Jerome; Taylor, Joy L.; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan N.; Belden, Christine M.; Jacobson, Sandra A.; Sirrel, Sherye A.; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Johnson, Patricia Lynn; Obisesan, Thomas O.; Wolday, Saba; Allard, Joanne; Lerner, Alan; Ogrocki, Paula; Tatsuoka, Curtis; Fatica, Parianne; Fletcher, Evan; Maillard, Pauline; Olichney, John; Carmichael, Owen; Kittur, Smita; Borrie, Michael; Lee, T-Y; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Burke, Anna; Trncic, Nadira; Fleisher, Adam; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W.; Kataki, Maria; Adeli, Anahita; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Flashman, Laura A.; Seltzer, Marc; Hynes, Mary L.; Santulli, Robert B.; Sink, Kaycee M.; Gordineer, Leslie; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J.; Miller, Bruce L.; Perry, David; Mintzer, Jacobo; Spicer, Kenneth; Bachman, David; Finger, Elizabether; Pasternak, Stephen; Rachinsky, Irina; Rogers, John; Drost, Dick; Pomara, Nunzio; Hernando, Raymundo; Sarrael, Antero; Schultz, Susan K.; Ponto, Laura L. Boles; Shim, Hyungsub; Smith, Karen Ekstam; Relkin, Norman; Chaing, Gloria; Lin, Michael; Ravdin, Lisa; Smith, Amanda; Raj, Balebail Ashok; Fargher, Kristin
ISI:000487586600036
ISSN: 2045-2322
CID: 4155602

Imaging Alzheimer's Disease: The Evolution of Biomarkers

Chapter by: de Leon, MJ; Glodzik, L; Mosconi, L; Osorio, R; Kamer, A; De Santi, S; Shulman, M; Li, Y; Tsui, W; Butler, T; Okamura, N; Rusinek, H
in: Brain Mapping: An Encyclopedic Reference by
pp. 619-623
ISBN: 9780123970251
CID: 1842822

Assessing cognition and function in Alzheimer's disease clinical trials: Do we have the right tools?

Snyder, Peter J; Kahle-Wrobleski, Kristin; Brannan, Stephen; Miller, David S; Schindler, Rachel J; DeSanti, Susan; Ryan, J Michael; Morrison, Glenn; Grundman, Michael; Chandler, Julie; Caselli, Richard J; Isaac, Maria; Bain, Lisa; Carrillo, Maria C
Several lines of evidence from Alzheimer's disease (AD) research continue to support the notion that the biological changes associated with AD are occurring possibly several decades before an individual will experience the cognitive and functional changes associated with the disease. The National Institute on Aging-Alzheimer's Association revised criteria for AD provided a framework for this new thinking. As a result of this growing understanding, several research efforts have launched or will be launching large secondary prevention trials in AD. These and other efforts have clearly demonstrated a need for better measures of cognitive and functional change in people with the earliest changes associated with AD. Recent draft guidance from the US Food and Drug Administration further elevated the importance of cognitive and functional assessments in early stage clinical trials by proposing that even in the pre-symptomatic stages of the disease, approval will be contingent on demonstrating clinical meaningfulness. The Alzheimer's Association's Research Roundtable addressed these issues at its fall meeting October 28-29, 2013, in Washington, D.C. The focus of the discussion included the need for improved cognitive and functional outcome measures for clinical of participants with preclinical AD and those diagnosed with Mild Cognitive Impairment due to AD.
PMID: 25458309
ISSN: 1552-5260
CID: 1370752

Beyond amyloid: getting real about nonamyloid targets in Alzheimer's disease [Meeting Abstract]

Herrup, Karl; Carrillo, Maria C; Schenk, Dale; Cacace, Angela; Desanti, Susan; Fremeau, Robert; Bhat, Ratan; Glicksman, Marcie; May, Patrick; Swerdlow, Russell; Van Eldik, Linda J; Bain, Lisa J; Budd, Samantha
For decades, researchers have focused primarily on a pathway initiated by amyloid beta aggregation, amyloid deposition, and accumulation in the brain as the key mechanism underlying the disease and the most important treatment target. However, evidence increasingly suggests that amyloid is deposited early during the course of disease, even prior to the onset of clinical symptoms. Thus, targeting amyloid in patients with mild to moderate Alzheimer's disease (AD), as past failed clinical trials have done, may be insufficient to halt further disease progression. Scientists are investigating other molecular and cellular pathways and processes that contribute to AD pathogenesis. Thus, the Alzheimer's Association's Research Roundtable convened a meeting in April 2012 to move beyond amyloid and explore AD as a complex multifactorial disease, with the goal of using a more inclusive perspective to identify novel treatment strategies.
PMCID:3983562
PMID: 23809366
ISSN: 1552-5260
CID: 960132

A preliminary, randomized, double-blind, placebo-controlled trial of l-carnosine to improve cognition in schizophrenia

Chengappa, K N Roy; Turkin, Scott R; Desanti, Susan; Bowie, Christopher R; Brar, Jaspreet S; Schlicht, Patricia J; Murphy, Sherry L; Hetrick, Michelle L; Bilder, Robert; Fleet, David
BACKGROUND: Targeting glutamatergic dysfunction provides an exciting opportunity to improve cognitive impairment in schizophrenia. One treatment approach has targeted inadequate antioxidant defenses at glutamatergic synapses. Animal and human data suggest NMDA antagonists worsen executive cognitive controls - e.g. increase perseverative responses and impair set-shifting. We conducted a preliminary study to test the hypothesis that l-carnosine, an antioxidant and anti-glycation agent which is co-localized and released with glutamate would improve executive dysfunction, a cognitive domain associated with glutamate. METHODS: Seventy-five symptomatically stable adults with chronic schizophrenia were randomly assigned to l-carnosine as adjunctive treatment (2g/day) or a matched placebo in a double-blind manner for 3months. Cognitive domains (executive dysfunction, memory, attention and motor speed) were assessed using a computerized battery at baseline, 4 and 12weeks, along with psychopathology ratings and safety parameters. RESULTS: The l-carnosine group performed significantly faster on non-reversal condition trials of the set-shifting test compared with placebo but reversal reaction times and errors were not significantly different between treatments. On the strategic target detection test, the l-carnosine group displayed significantly improved strategic efficiency and made fewer perseverative errors compared with placebo. Other cognitive tests showed no significant differences between treatments. Psychopathology scores remained stable. The carnosine group reported more adverse events (30%) compared with the placebo group (14%). Laboratory indices remained within acceptable ranges. CONCLUSIONS: These preliminary findings suggest that l-carnosine merits further consideration as adjunctive treatment to improve executive dysfunction in persons with schizophrenia.
PMID: 23099060
ISSN: 1573-2509
CID: 203392

Alzheimer's disease markers, hypertension, and gray matter damage in normal elderly

Glodzik L; Mosconi L; Tsui W; de Santi S; Zinkowski R; Pirraglia E; Rich KE; McHugh P; Li Y; Williams S; Ali F; Zetterberg H; Blennow K; Mehta P; de Leon MJ
It is not well known whether Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers are associated with brain damage in cognitively normal elderly. The combined influence of CSF biomarkers and hypertension (HTN) on the gray matter (GM) is also not well described. One hundred fifteen cognitively healthy subjects (mean age 62.6 +/- 9.5%, 62% women) received clinical assessment, a high resolution magnetic resonance imaging (MRI), and a lumbar puncture. The CSF levels of total tau (t-tau), hyperphosphorylated tau (p-tau(231)), amyloid beta (Abeta42/Abeta40), p-tau(231)/Abeta42, and t-tau/Abeta42 were dichotomized as 'high' and 'low' based on accepted cut off values. Statistical parametric mapping was used to examine MRI scans for regional GM density, studied as a function of the CSF markers, HTN, and combination of both. Global and medial temporal lobe (MTL) GM was also assessed. Voxel based morphometry revealed that higher t-tau was associated with lower GM density in the precunei. Subjects with higher p-tau(231) and p-tau(231)/Abeta42 had less GM in temporal lobes. Low Abeta42/Abeta40 was related to less GM in the thalami, caudate, and midbrain. Subjects with hypertension showed more GM atrophy in the cerebellum, occipital, and frontal regions. Simultaneous presence of elevated CSF AD biomarkers and HTN was associated with more GM atrophy than either marker individually, but no interaction effects were identified. In conclusion, in normal elderly CSF tau markers were associated predominantly with lower GM estimates in structures typically affected early in the AD process. In this presymptomatic stage when no cognitive impairment is present, AD biomarkers and HTN have additive effects on gray matter damage
PMCID:3179821
PMID: 21530003
ISSN: 1558-1497
CID: 140516

Maternal age affects brain metabolism in adult children of mothers affected by Alzheimer's disease

Mosconi L; Tsui W; Murray J; McHugh P; Li Y; Williams S; Pirraglia E; Glodzik L; De Santi S; Vallabhajosula S; de Leon MJ
Cognitively normal (NL) individuals with a maternal history of late-onset Alzheimer's disease (MH) show reduced brain glucose metabolism on FDG-PET as compared to those with a paternal history (PH) and those with negative family history (NH) of Alzheimer's disease (AD). This FDG-PET study investigates whether metabolic deficits in NL MH are associated with advancing maternal age at birth. Ninety-six NL individuals with FDG-PET were examined, including 36 MH, 24 PH, and 36 NH. Regional-to-whole brain gray matter standardized FDG uptake value ratios were examined for associations with parental age across groups using automated regions-of-interest and statistical parametric mapping. Groups were comparable for clinical and neuropsychological measures. Brain metabolism in AD-vulnerable regions was lower in MH compared to NH and PH, and negatively correlated with maternal age at birth only in MH. There were no associations between paternal age and metabolism in any group. Evidence for a maternally inherited, maternal age-related mechanism provides further insight on risk factors and genetic transmission in late-onset AD
PMCID:3155000
PMID: 21514691
ISSN: 1558-1497
CID: 140517

Presence of the APOE-4 allele decreases fertility in men but not women [Meeting Abstract]

McHugh, P; Pirraglia, E; Mosconi, L; Green, A; Cummings, M; De, Santi S; De, Leon M
Background: Recent reports have linked reproductive behavior with severity and age of onset of Alzheimer's Disease (AD) in women but not men, suggesting a gender disparity in disease process which is affected by reproductive functions. We attempted to shed further light on this interaction by examining the relationship of a known genetic risk factor for AD, the presence of the ApoE4 allele, with study participants' reproductive histories. Methods: 467 participants in ongoing outpatient AD studies were retrospectively evaluated for apoE status and number of children. SPSS (version 19.0, Chicago, IL) was used for data analyses. Participants' diagnoses were not factored into the analyses. All participants were past reproductive age and belonged to the same generational group. Results: In a logistic regression analysis predicting the probability of having none vs. 1 or more children with covariates of marital status, year of birth, education, and race, there was a significant interaction between gender and ApoE status (P=0.035). The male ApoE4 carrier group included significantly less individuals with children (n = 31 58%) compared to male ApoE4 non carriers (n = 69, 70%), (X2 (2)=4.3 P=0.04 odds ratio, OR=2.4 95% C.I.: 1.0-5.7) after accounting for covariates. Conversely, there was no relationship between ApoE4 status and whether or not a subject had children in the female group (n = 132 or 63% of the ApoE4 non carrier women, and n = 74 or 70% of the ApoE4 carrier women, n.s.). Conclusions: ApoE4 a known genetic risk factor for AD, negatively affects fertility in men than women. Thus it is more likely to be transmitted to future generations through the maternal line than the paternal line. These findings lend further evidence to a connection between reproductive function and the development and transmission of AD
EMBASE:70860891
ISSN: 1552-5260
CID: 178075

Maternal historyand impaired memory predict decline to dementia in cognitively normal individuals [Meeting Abstract]

Pirraglia, E; Murray, J; De, Santi S; Mosconi, L; Glodzik, L; De, Leon M
Background: Cognitively normal individuals with a maternal history (MHnl) of late-onset Alzheimer's disease (AD) show reduced hippocampal glucose metabolism, increased fibrillar amyloid beta burden, and reduced gray matter volume as compared to normal individuals with a paternal history of AD (PHnl) or no history (noHnl). However, it remains unknown whether MHnl decline to AD at higher rates compared to those with no maternal history. This study examines whether there is a correlation between family history and the probability of decline to mild cognitive impairment (MCI) or AD. Methods: This 5-year longitudinal study, used three independently collected data sets to investigate subjects that were cognitively normal at baseline and either remained normal at follow-up (stable- NL) or progressed MCI or AD at follow-up (decliners). All data sets used the same neuropsychological measure of delayed memory (WMS-R Logical Memory II). The New York University and Washington University data sets were combined to comprise 210 stable NL and 44 decliners. The National Alzheimer's Coordinating Center (NACC) data set included 1347 stable NL and 98 decliners. Logistic regression was used to predict future clinical decline based on family history and baseline delayed memory performance as well as the interaction between them. The last evaluation before clinical decline was used as a baseline for decliners resulting in an interval of approximately 2 years. Results: In both samples, family history alone was not a significant predictor of future clinical decline. However, in both samples there was a significant interaction between MHnl and delayed memory performance such that subjects with reduced memory and a positive MH showed a greater probability of future clinical decline ( I x 2 =5.2, p<.05 Odds Ratio=8.7, 95%CI: 1.3-58.4). There was no relationship between PHn1 or noHnl in their interaction with delayed memory on clinical decline. Conclusions: These results indicate that a maternal history of dementia in combination with reduced delayed memory increase the risk of developing MCI and dementia. The use of neuropsychological testing appears to be an effective method to determine risk for clinical decline in this subset of atrisk individuals
EMBASE:70860590
ISSN: 1552-5260
CID: 178078

Phosphorylated tau 231, memory decline and medial temporal atrophy in normal elders

Glodzik L; de Santi S; Tsui WH; Mosconi L; Zinkowski R; Pirraglia E; Wang HY; Li Y; Rich KE; Zetterberg H; Blennow K; Mehta P; de Leon MJ
Little is known whether cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) can predict both memory decline and associated longitudinal medial temporal lobe (MTL) gray matter (GM) reductions in cognitively healthy individuals. Fifty-seven normal elderly subjects received comprehensive evaluation at baseline and 2 years later. The baseline phosphorylated tau(231) (p-tau(231)), total tau, the amyloid beta (Abeta) Abeta42/Abeta40, t-tau/Abeta42 and p-tau(231)/Abeta42 ratios were examined as predictors of memory change and reductions in the global and MTL GM, determined from T1-weighted MRI. Twenty out of 57 participants experienced reduced memory performance at follow-up. The group with decreased memory performance showed higher baseline p-tau(231) (Z=-2.2, p=0.03), lower Abeta42/Abeta40 (t=-2.2 [55], p=0.04) and greater longitudinal MTL GM reductions (t([52])=-2.70, p=0.01). Higher baseline p-tau(231) was also associated with the absolute decrease in memory scores (rho=-0.30, p=0.02) and with longitudinal MTL GM reduction (F([2,52])=4.4, p=0.04, age corrected). Our results indicate that in normal individuals, elevated p-tau(231), a marker of neurofibrillary pathology is related to both a decrease in declarative memory and progressive atrophy of the MTL, suggesting its diagnostic potential in preclinical stage
PMCID:3179835
PMID: 20133017
ISSN: 1558-1497
CID: 138221