Authors: Abrahamson, Eric E. | Poloyac, Samuel M. | Dixon, C. Edward | Dekosky, Steven T. | Ikonomovic, Milos D.
Article Type: Research Article
Abstract: Background: Altered glutamatergic neurotransmission after traumatic brain injury (TBI) contributes to excitotoxic cell damage and death. Prevention or suppression of such changes is a desirable goal for treatment of TBI. Memantine (3,5-dimethyl-1-adamantanamine), an uncompetitive NMDA receptor antagonist with voltage-dependent open channel blocking kinetics, was reported to be neuroprotective in preclinical models of excitotoxicity, brain ischemia, and in TBI when administered prophylactically, immediately, or within minutes after injury. Methods: The current study examined effects of memantine administered by single intraperitoneal injection to adult male rats at a more clinically relevant delay of one hour after moderate-severe controlled cortical impact (CCI) injury …or sham surgery. Histopathology was assessed on days 1, 7, 21, and 90, vestibulomotor function (beam balance and beam walk) was assessed on days 1–5 and 71–75, and spatial memory (Morris water maze test, MWM) was assessed on days 14–21 and 83–90 after CCI injury or sham surgery. Results: When administered at 10 mg/kg, but not 2.5 or 5 mg/kg, memantine preserved cortical tissue and reduced neuronal degeneration 1 day after injury, and attenuated loss of synaptophysin immunoreactivity in the hippocampus 7 days after injury. No effects of 10 mg/kg memantine were observed on histopathology at 21 and 90 days after CCI injury or sham surgery, or on vestibulomotor function and spatial memory acquisition assessed during any of the testing periods. However, 10 mg/kg memantine resulted in trends for improved search strategy in the MWM memory retention probe trial. Conclusions: Administration of memantine at a clinically-relevant delay after moderate-severe CCI injury has beneficial effects on acute outcomes, while more significant improvement on subacute and chronic outcomes may require repeated drug administration or its combination with another therapy. Show more
Keywords: Excitotoxicity, glutamate, hippocampus, NMDA, traumatic brain injury
DOI: 10.3233/RNN-190909
Citation: Restorative Neurology and Neuroscience, vol. 37, no. 3, pp. 245-263, 2019
Authors: Nagaraja, Nandakumar | Wang, Wei-en | Duara, Ranjan | DeKosky, Steven T. | Vaillancourt, David
Article Type: Research Article
Abstract: Background: Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer’s disease (AD). Objective: To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD. Methods: Patients with a clinical diagnosis of AD and neuropathological confirmation of AD+/-CAA in the National Alzheimer’s Coordinating Center database were included in the study. The volumes of temporal lobe structures were calculated on T1-weighted imaging (T1-MRI) using automated FreeSurfer software, from images acquired on average 5 years prior to death. Multivariate regression analysis was performed to compare brain volumes in four CAA groups. The …hippocampal volume on T1-MRI was correlated with Clinical Dementia Rating sum of boxes (CDRsb) score, apolipoprotein E (APOE) genotype, and hippocampal atrophy at autopsy. Results: The study included 231 patients with no (n = 45), mild (n = 70), moderate (n = 67), and severe (n = 49) CAA. Among the four CAA groups, patients with severe CAA had a smaller mean left hippocampal volume (p = 0.023) but this was not significant when adjusted for APOE ɛ4 (p = 0.07). The left hippocampal volume on MRI correlated significantly with the hippocampal atrophy grading on neuropathology (p = 0.0003). Among patients with severe CAA, the left hippocampal volume on T1-MRI: (a) decreased with an increase in the number of APOE ɛ4 alleles (p = 0.04); but (b) had no evidence of correlation with CDRsb score (p = 0.57). Conclusion: Severe CAA was associated with smaller left hippocampal volume on T1-MRI up to five years prior to death among patients with neuropathologically confirmed AD. This relationship was dependent on APOE ɛ4 genotype. Show more
Keywords: Alzheimer’s disease, trophy, cerebral amyloid angiopathy, hippocampus
DOI: 10.3233/JAD-220624
Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 495-507, 2023
Authors: Shea, Yat-Fung | Barker, Warren | Greig-Gusto, Maria T. | Loewenstein, David A. | DeKosky, Steven T. | Duara, Ranjan
Article Type: Research Article
Abstract: Background: The impact of amyloid positron emission tomography (Aβ-PET) in a “real-world” memory disorders clinic remains poorly studied. Objective: We studied the impact of Aβ-PET in diagnosis and management in the memory clinic and factors making the most impact in diagnosis and management. Methods: We studied 102 patients who had presented at a memory disorders clinic (the Wien Center for Alzheimer’s Disease and Memory Disorders, Miami Beach, FL) and had a diagnostic work-up for cognitive complaints, including Aβ-PET scans. Results: Following Aβ-PET, changes were made in diagnosis (37.3%), in specific treatments for Alzheimer’s disease (26.5%) and in psychiatric treatments (25.5%). …The agreement between diagnosis pre-Aβ-PET versus post-Aβ-PET diagnosis was only fair, with a Cohen’s kappa of 0.23 (95% CI 0–0.42). Patients with MRI findings suggestive of AD (medial temporal and/or parietal atrophy) were more frequently amyloid positive than amyloid negative (66.2% versus 33.8%, p = 0.04). Among patients with atypical clinical features for AD, but with MRI findings suggestive of AD, an amyloid negative PET scan had a greater impact than an amyloid positive PET scan on diagnosis (84.2% versus 17.1%, p < 0.001), management (84.2% versus 40%, p < 0.01) and discussion of results and advice on lifestyle (73.7% versus 22.9%, p < 0.001). Conclusions: We conclude that MRI features suggestive of AD predict a positive amyloid PET scan. However, among those with MRI features suggestive of AD but with atypical clinical features of AD, the clinical impact on diagnosis and management is greater for an amyloid negative than an amyloid positive Aβ-PET scans. Show more
Keywords: Alzheimer’s disease, amyloid imaging, diagnosis, management, memory clinic, positron emission tomography
DOI: 10.3233/JAD-180683
Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1599-1608, 2018
Authors: Shea, Yat-Fung | Barker, Warren | Greig-Gusto, Maria T. | Loewenstein, David A. | Duara, Ranjan | DeKosky, Steven T.
Article Type: Research Article
Abstract: Background: Patients with cognitive impairment or dementias of uncertain etiology are frequently referred to a memory disorders specialty clinic. The impact of and role for amyloid PET imaging (Aβ -PET) may be most appropriate in this clinical setting. Objective: The primary objective of this study was to perform a systematic review and meta-analysis of the impact of Aβ -PET on etiological diagnosis and clinical management in the memory clinic setting. Methods: A search of the literature on the impact of Aβ -PET in the memory clinic setting between 1 January 2004 and 12 February 2018 was conducted. Meta-analysis using a …random effects model was performed to determine the pooled estimate of the impact of Aβ -PET in the changes of diagnoses and changes in management plan. Results: After rigorous review, results from 13 studies were extracted, involving 1,489 patients. Meta-analysis revealed a pooled effect of change in diagnoses of 35.2% (95% CI 24.6–47.5). Sub-analyses showed that the pooled effect in change in diagnoses if Aβ -PET was used under the appropriate use criteria (AUC) or non-AUC criteria were 47.8% (95% CI 25.9–70.5) and 29.6% (95% CI: 21.5–39.3), respectively. The pooled effect of a change of diagnosis from Alzheimer’s disease (AD) to non-AD and from non-AD to AD were 22.7% (95% CI: 17.1–29.5) and 25.6% (95% CI: 17.6–35.8), respectively. The pooled effect leading to a change of management was 59.6% (95% CI 39.4–77.0). Conclusions: Aβ -PET has a highly significant impact on both changes in diagnosis and management among patients being seen at a specialty memory clinic. Show more
Keywords: Alzheimer’s disease, amyloid imaging, diagnosis, management, memory clinic, positron emission tomography
DOI: 10.3233/JAD-180239
Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 323-335, 2018
Authors: Ikonomovic, Milos D. | Mufson, Elliott J. | Wuu, Joanne | Cochran, Elizabeth J. | Bennett, David A. | DeKosky, Steven T.
Article Type: Research Article
Abstract: Several recent studies indicate that activity of cholinergic enzymes in the cortex of people with mild cognitive impairment (MCI) and early Alzheimer's disease (AD) are preserved. We correlated levels of hippocampal choline acetyltransferase (ChAT) activity with the extent of AD lesions in subjects from the Religious Order Study, including cases with no cognitive impairment (NCI), MCI, and with mild to moderate AD. Hippocampal ChAT activity levels were also determined in a group of end-stage AD patients who were enrolled in the University of Pittsburgh Alzheimer's Disease Research Center. MCI subjects were characterized with increased hippocampal ChAT activity. This elevation was …no longer present in mild AD cases, which were not different from NCI subjects. Severe AD cases showed markedly depleted hippocampal ChAT levels. In NCI, MCI, and mild-moderate AD, there was a positive correlation between hippocampal ChAT activity levels and progression of neuritic plaque pathology in entorhinal cortex and hippocampus. A significant elevation of hippocampal ChAT in the MCI group was found selectively in the limbic (i.e., entorhinal-hippocampal, III/IV) Braak stages. We hypothesize that cholinergic changes in the hippocampus of MCI subjects reflect a compensatory response to the progressive denervation of the hippocampus by lost entorhinal cortex input. Moreover, the present findings suggest that the short-term memory loss observed in MCI is not caused by cholinergic deficits; it more likely relates to disrupted entorhinal-hippocampal connectivity. Show more
DOI: 10.3233/JAD-2003-5106
Citation: Journal of Alzheimer's Disease, vol. 5, no. 1, pp. 39-48, 2003
Authors: Shojaie, Mehdi | Tabarestani, Solale | Cabrerizo, Mercedes | DeKosky, Steven T. | Vaillancourt, David E. | Loewenstein, David | Duara, Ranjan | Adjouadi, Malek
Article Type: Research Article
Abstract: Background: Machine learning is a promising tool for biomarker-based diagnosis of Alzheimer’s disease (AD). Performing multimodal feature selection and studying the interaction between biological and clinical AD can help to improve the performance of the diagnosis models. Objective: This study aims to formulate a feature ranking metric based on the mutual information index to assess the relevance and redundancy of regional biomarkers and improve the AD classification accuracy. Methods: From the Alzheimer’s Disease Neuroimaging Initiative (ADNI), 722 participants with three modalities, including florbetapir-PET, flortaucipir-PET, and MRI, were studied. The multivariate mutual information metric was utilized to capture the redundancy and …complementarity of the predictors and develop a feature ranking approach. This was followed by evaluating the capability of single-modal and multimodal biomarkers in predicting the cognitive stage. Results: Although amyloid-β deposition is an earlier event in the disease trajectory, tau PET with feature selection yielded a higher early-stage classification F1-score (65.4%) compared to amyloid-β PET (63.3%) and MRI (63.2%). The SVC multimodal scenario with feature selection improved the F1-score to 70.0% and 71.8% for the early and late-stage, respectively. When age and risk factors were included, the scores improved by 2 to 4%. The Amyloid-Tau-Neurodegeneration [AT(N)] framework helped to interpret the classification results for different biomarker categories. Conclusion: The results underscore the utility of a novel feature selection approach to reduce the dimensionality of multimodal datasets and enhance model performance. The AT(N) biomarker framework can help to explore the misclassified cases by revealing the relationship between neuropathological biomarkers and cognition. Show more
Keywords: Alzheimer’s disease, amyloid-β, classification, feature selection, information theory, machine-learning, multimodal imaging, tau
DOI: 10.3233/JAD-210064
Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1497-1514, 2021
Authors: Koch, Manja | Costanzo, Simona | Fitzpatrick, Annette L. | Lopez, Oscar L. | DeKosky, Steven | Kuller, Lewis H. | Price, Julie | Mackey, Rachel H. | Jensen, Majken K. | Mukamal, Kenneth J.
Article Type: Research Article
Abstract: Background: Light to moderate alcohol consumption has been variably associated with lower or higher risk of dementia, but effects on Alzheimer’s disease pathology are less clear. Objective: We determined whether late-life alcohol consumption was associated with Alzheimer’s disease pathology among older adults. Methods: We assessed the associations of alcohol consumption self-reported in 2000–2002 with brain amyloid-β deposition on PET scans, and white matter lesion and hippocampal volume on MRIs measured 7–9 years later in 189 participants of the Ginkgo Evaluation of Memory Study (age 75–87 years at baseline) who were free of clinical dementia, using multivariable-adjusted and inverse probability-weighted robust …linear regression models. Results: Alcohol consumption was not statistically significantly associated with amyloid-β deposition (standardized uptake value ratio difference per drink: –0.013 [95% CI: –0.027, 0.002]). Both non-drinkers and participants consuming ≥1 drink(s)/week had higher white matter lesion volume (% intracranial volume) than did the reference group of those consuming <1 drink/week (differences: 0.25 % [95% CI: 0.01, 0.50]; 0.26 % [95% CI: 0.02, 0.50]). The association of alcohol consumption and hippocampal volume was modified by age (p = 0.02). Among participants younger than 77 years, participants consuming 1–7 drinks/week had larger hippocampal volume compared with participants consuming <1 drink/week. Conclusions: Alcohol consumption was not statistically significantly associated with amyloid-β deposition 7–9 years later. Non-drinking and greater alcohol consumption were associated with higher white matter lesion volume compared with drinking <1 drink/week. Moderate drinking was associated with higher hippocampal volume in younger individuals. Given the selective nature of this population and adverse health effects of excessive alcohol consumption, these findings warrant further investigation, but cannot be translated into clinical recommendations. Show more
Keywords: Alcohol, brain amyloid-β, epidemiology, hippocampal volume, white matter lesions
DOI: 10.3233/JAD-190834
Citation: Journal of Alzheimer's Disease, vol. 74, no. 2, pp. 509-519, 2020
Authors: Loewenstein, David A. | Curiel, Rosie E. | DeKosky, Steven | Rosselli, Monica | Bauer, Russell | Grieg-Custo, Maria | Penate, Ailyn | Li, Chunfei | Lizagarra, Gabriel | Golde, Todd | Adjouadi, Malek | Duara, Ranjan
Article Type: Research Article
Abstract: Background: The rise in incidence of Alzheimer’s disease (AD) has led to efforts to advance early detection of the disease during its preclinical stages. To achieve this, the field needs to develop more sensitive cognitive tests that relate to biological markers of disease pathology. Failure to recover from proactive interference (frPSI) is one such cognitive marker that is associated with volumetric reductions in the hippocampus, precuneus, and other AD-prone regions, and to amyloid load in the brain. Objective: The current study attempted to replicate and extend our previous findings that frPSI is a sensitive marker of early AD, and related …to a unique pattern of volumetric loss in AD prone areas. Methods: Three different memory measures were examined relative to volumetric loss and cortical thickness among 45 participants with amnestic mild cognitive impairment. Results: frPSI was uniquely associated with reduced volumes in the hippocampus (r = 0.50) precuneus (r = 0.41), and other AD prone regions, replicating previous findings. Strong associations between frPSI and lower entorhinal cortex volumes and cortical thickness (r≥0.60) and precuneus (r = 0.50) were also observed. Conclusion: Unique and strong associations between volumetric reductions and frPSI as observed by Loewenstein and colleagues were replicated. Together with cortical thickness findings, these results indicate that frPSI is worthy of further study as a sensitive and early cognitive marker of AD. Show more
Keywords: Cortical thickness, LASSI-L, mild cognitive impairment, MRI volume, proactive semantic interference
DOI: 10.3233/JAD-170276
Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 131-139, 2017
Authors: Wang, Xingbin | Lopez, Oscar L. | Sweet, Robert A. | Becker, James T. | DeKosky, Steven T. | Barmada, Mahmud M. | Demirci, F. Yesim | Kamboh, M. Ilyas
Article Type: Research Article
Abstract: There is a strong genetic basis for late-onset Alzheimer's disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer's Disease Research Center. Patients were classified as “rapid progressors” if the Mini-Mental State Examination (MMSE) changed ≥3 points in 12 months and “slow progressors” if the …MMSE changed ≤2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between single nucleotide polymorphisms (SNPs) and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p = 0.94) or APOE*2 (p = 0.33) with AD progression, we found multiple nominally significant associations (p < 0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2, and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ, and ADAM19) at p < 1E-05. Our data suggest that short-term clinical disease progression in AD has a genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies. Show more
Keywords: Alzheimer's disease progression, genome-wide association studies, late-onset Alzheimer's disease, Mini-Mental State Examination
DOI: 10.3233/JAD-140729
Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 649-655, 2015
Authors: Choi, Seong Hye | Olabarrieta, Mikel | Lopez, Oscar L. | Maruca, Victoria | DeKosky, Steven T. | Hamilton, Ronald L. | Becker, James T. | for the Alzheimer's Disease Research Center
Article Type: Research Article
Abstract: Up to 60% of the patients with Alzheimer's disease (AD) can have cortical or brainstem Lewy bodies (LB), and extrapyramidal signs (EPS) have been found to be associated with LB in AD patients. However, the relationship between EPS and brain volumes has not been studied in the LB variant of AD using structural magnetic resonance imaging (MRI). The purpose of this study was to determine the relationship between patterns of brain atrophy and clinical EPS in patients with pathologically confirmed AD. We compared gray matter structure using voxel-based morphometry in 29 Definite AD cases, 16 (55%) of whom also had …LBs identified with α-synuclein immunohistochemistry. Multivariate models analyzed brain volume at a voxel level accounting for subject group, Mini-Mental State Examination (MMSE), EPS, total brain volume, and the time from MRI scan to death. There was no significant difference in gray matter volume in the Definite AD patients as a function of LB. There was a significant association between gray matter volumes and the MMSE in AD patients, both with and without LBs. There was a significant correlation between gray matter volume and EPS only in the group of AD patients with LBs, and not in those with pure AD. These findings suggest that that the etiology of EPS in patients with the LB variant of AD is associated with neuronal loss in the nigrostriatal tracts. By contrast, the source of the EPS in AD alone appears to be less well localized. Show more
Keywords: Alzheimer's disease, extrapyramidal signs, imaging, Lewy bodies, magnetic resonance imaging, voxel-based morphometry
DOI: 10.3233/JAD-2012-121108
Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 1043-1049, 2012
