Authors: Grassi, Massimiliano | Perna, Giampaolo | Caldirola, Daniela | Schruers, Koen | Duara, Ranjan | Loewenstein, David A.
Article Type: Research Article
Abstract: Background: Available therapies for Alzheimer’s disease (AD) can only alleviate and delay the advance of symptoms, with the greatest impact eventually achieved when provided at an early stage. Thus, early identification of which subjects at high risk, e.g., with MCI, will later develop AD is of key importance. Currently available machine learning algorithms achieve only limited predictive accuracy or they are based on expensive and hard-to-collect information. Objective: The current study aims to develop an algorithm for a 3-year prediction of conversion to AD in MCI and PreMCI subjects based only on non-invasively and effectively collectable predictors. Methods: A dataset …of 123 MCI/PreMCI subjects was used to train different machine learning techniques. Baseline information regarding sociodemographic characteristics, clinical and neuropsychological test scores, cardiovascular risk indexes, and a visual rating scale for brain atrophy was used to extract 36 predictors. Leave-pair-out-cross-validation was employed as validation strategy and a recursive feature elimination procedure was applied to identify a relevant subset of predictors. Results: 16 predictors were selected from all domains excluding sociodemographic information. The best model resulted a support vector machine with radial-basis function kernel (whole sample: AUC = 0.962, best balanced accuracy = 0.913; MCI sub-group alone: AUC = 0.914, best balanced accuracy = 0.874). Conclusions: Our algorithm shows very high cross-validated performances that outperform the vast majority of the currently available algorithms, and all those which use only non-invasive and effectively assessable predictors. Further testing and optimization in independent samples will warrant its application in both clinical practice and clinical trials. Show more
Keywords: Alzheimer’s disease, clinical prediction rule, machine learning, mild cognitive impairment, personalized medicine
DOI: 10.3233/JAD-170547
Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1555-1573, 2018
Authors: Mowrey, Wenzhu B. | Lipton, Richard B. | Katz, Mindy J. | Ramratan, Wendy S. | Loewenstein, David A. | Zimmerman, Molly E. | Buschke, Herman
Article Type: Correction
DOI: 10.3233/JAD-179003
Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 951-952, 2017
Authors: Czaja, Sara J. | Loewenstein, David A. | Sabbag, Samir A. | Curiel, Rosie E. | Crocco, Elizabeth | Harvey, Philip D.
Article Type: Research Article
Abstract: Background: Recent findings indicate that impairments in functional performance do occur among individuals diagnosed with mild cognitive impairment (MCI). Most assessment strategies for everyday competence are associated with challenges with reliability, are typically in paper and pencil format, or require in-person administration by a trained professional. Objective: This paper reports on a novel technology-based assessment battery of everyday competence that includes ecologically valid simulations of daily activities important to independence. Methods: The sample included 85 non-cognitively impaired older adults aged 65+ and 62 older adults diagnosed with amnestic MCI (aMCI). Participants completed standard measures of cognitive abilities and the computerized …battery of everyday tasks, which included simulations of a doctor’s visit; and medication and financial management tasks. Results: The older adults with aMCI performed significantly poorer on all three tasks in the everyday task battery. Performance on these measures were also moderately correlated with standard measures of cognitive abilities and showed good test-retest reliability. Conclusions: The results show that it is feasible to use a technology-based assessment battery of everyday tasks with both non-cognitively impaired older adults and older adults with MCI. The use of this type of battery can overcome many of the logistic constraints associated with current functional assessment protocols. Show more
Keywords: Assessment, cognition, everyday competence, mild cognitive impairment, technology
DOI: 10.3233/JAD-161183
Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1229-1238, 2017
Authors: Liu, Che | Lee, Sang H. | Loewenstein, David A. | Galvin, James E. | Levin, Bonnie E. | McKinney, Alexander | Alperin, Noam
Article Type: Research Article
Abstract: Background: Lower cerebral blood flow (CBF) and excessive brain atrophy are linked to Alzheimer’s disease (AD). It is still undetermined whether reduced CBF precedes or follows brain tissue loss. Objective: We compared total CBF (tCBF), global cerebral perfusion (GCP), and volumes of AD-prone regions between cognitively normal (CN) and early amnestic mild cognitive impairment (aMCI) and tested their associations with cognitive performance to assess their predictive value for differentiation between CN and early aMCI. Methods: A total of 74 participants (mean age 69.9±6.2 years, 47 females) were classified into two groups: 50 CN and 24 aMCI, of whom 88% were …early aMCI. tCBF, GCP, and global and regional brain volumetry were measured using phase-contrast and T1-weighted MRI. Neuropsychological tests tapping global cognition and four cognitive domains (memory, executive function, language, and visuospatial) were administered. Comparisons and associations were investigated using analyses of covariance (ANCOVA) and linear regression analyses, respectively. Results: Women had significantly higher GCP than men. Both, tCBF and GCP were significantly reduced in aMCI compared with CN, while differences in volumes of cerebral gray matter, white matter, and AD-prone regions were not significant. tCBF and GCP were significantly associated with global cognition (standardized beta (stβ) = 0.324 and stβ= 0.326) and with memory scores (stβ≥0.297 and stβ≥0.264) across all participants. Associations of tCBF and GCP with memory scores were also significant in CN (stβ= 0.327 and stβ= 0.284) and in aMCI (stβ= 0.627 and stβ= 0.485). Conclusion: Reduced tCBF and GCP are sensitive biomarkers of early aMCI that likely precede brain tissue loss. Show more
Keywords: Amnestic mild cognitive impairment, cerebral blood flow, cerebral perfusion, global cognition, memory, phase-contrast MRI
DOI: 10.3233/JAD-220734
Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1313-1322, 2023
Authors: Crocco, Elizabeth | Curiel-Cid, Rosie E. | Kitaigorodsky, Marcela | González-Jiménez, Christian J. | Zheng, Diane | Duara, Ranjan | Loewenstein, David A.
Article Type: Research Article
Abstract: Background: The Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) is an increasingly utilized cognitive stress test designed to identify early cognitive changes associated with incipient neurodegenerative disease. Objective: To examine previously derived cut-points for cognitively unimpaired older adults that were suggestive of performance impairment on multiple subscales of the LASSI-L. These cut-points were applied to a new sample of older adults who were cognitive healthy controls (HC: n = 26) and those on the Alzheimer’s disease (AD) continuum from early stage mild cognitive impairment (EMCI: n = 28), late stage MCI (LMCI: n = 18) to mild AD (AD: n = 27). …Methods: All participants were administered the LASSI-L. All cognitively impaired participants were PET amyloid positive which likely reflects underlying AD neuropathology, while cognitively normal counterparts were deemed to have amyloid negative scans. Results: There was a monotonic relationship between the number of deficits on LASSI-L subscales and independent classification of study groups with greater severity of cognitive impairment. Importantly, taken together, impairment on maximum learning ability and measures of proactive semantic interference (both reflected by cued recall and intrusion errors) correctly classified 74.1% of EMCI, 94.4% of LMCI, and 96.3% of AD. Only 7.7% of HC were incorrectly classified as having impairments. Conclusion: A modest number of LASSI-L subscales taking approximately 8 minutes to administer, had excellent discriminative ability using established cut-offs among individuals with presumptive stages of AD. This has potential implications for both clinical practice and clinical research settings targeting AD during early prodromal stages. Show more
Keywords: Amyloid, biomarkers, cognitive screening, intrusion errors, mild cognitive impairment, neuroimaging, preclinical Alzheimer’s disease, semantic interference, structural MRI
DOI: 10.3233/JAD-200790
Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 789-799, 2020
Authors: Curiel, Rosie E. | Crocco, Elizabeth | Rosado, Marian | Duara, Ranjan | Greig, Maria T. | Raffo, Arlene | Loewenstein, David A.
Article Type: Research Article
Abstract: Background: Semantic memory interference has been found to be a predictive cognitive marker of incipient AD. This is relevant given that developing assessment paradigms to identify subtle cognitive and functional deficits is a priority in preclinical Alzheimer’s disease research. Objective: To examine the utility of a novel computerized paired associate test in distinguishing between mild cognitive impairment (MCI) and cognitively normal (CN) groups of older adults residing in the community. Methods: Participants that were CN (n = 64) or MCI (n = 34) were administered the Miami Test of Semantic Interference and Learning (MITSI-L). This novel instrument is a brief, computerized paired …associate test that measured the strength of memory binding of semantically related word pairs and introduced a proactive semantic interference condition which required participants to make different associations between semantically similar targets. A series of ANOVAs explored differences on MITSI-L performance. Logistic regression and receiver operator curves (ROC) analyses were employed to further determine discriminative validity. Results: MCI participants had lower scores on all indices relative to CN elders. A composite of two subscores correctly classified 85.3% of MCI and 84.4% of CN participants. Area under the ROC was higher relative to the MMSE, immediate memory for passages, and several subtests of a sensitive memory measure, the LASSI-L. Conclusions: The MITSI-L is a computerized test that can successfully differentiate MCI from CN participants. Area under the ROC curve exceeded that of global mental status and other memory measures. The effectiveness of the MITSI-L in detecting MCI, and its brief administration and portability render it worthy of further research. Show more
Keywords: Alzheimer’s disease, computerized tests, memory, mild cognitive impairment, MITSI-L
DOI: 10.3233/JAD-160370
Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 793-799, 2016
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: 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: Mowrey, Wenzhu B. | Lipton, Richard B. | Katz, Mindy J. | Ramratan, Wendy S. | Loewenstein, David A. | Zimmerman, Molly E. | Buschke, Herman
Article Type: Research Article
Abstract: Background: The Memory Binding Test (MBT) demonstrated good cross-sectional discriminative validity and predicted incident aMCI. Objective: To assess whether the MBT predicts incident dementia better than a conventional list learning test in a longitudinal community-based study. Methods: As a sub-study in the Einstein Aging Study, 309 participants age≥70 initially free of dementia were administered the MBT and followed annually for incident dementia for up to 13 years. Based on previous work, poor memory binding was defined using an optimal empirical cut-score of≤17 on the binding measure of the MBT, Total Items in the Paired condition (TIP). Cox proportional hazards models …were used to assess predictive validity adjusting for covariates. We compared the predictive validity of MBT TIP to that of the free and cued selective reminding test free recall score (FCSRT-FR; cut-score:≤24) and the single list recall measure of the MBT, Cued Recalled from List 1 (CR-L1; cut-score:≤12). Results: Thirty-five of 309 participants developed incident dementia. When assessing each test alone, the hazard ratio (HR) for dementia was significant for MBT TIP (HR = 8.58, 95% CI: (3.58, 20.58), p < 0.0001), FCSRT-FR (HR = 4.19, 95% CI: (1.94, 9.04), p = 0.0003) and MBT CR-L1 (HR = 2.91, 95% CI: (1.37, 6.18), p = 0.006). MBT TIP remained a significant predictor of dementia (p = 0.0002) when adjusting for FCSRT-FR or CR-L1. Conclusions: Older adults with poor memory binding as measured by the MBT TIP were at increased risk for incident dementia. This measure outperforms conventional episodic memory measures of free and cued recall, supporting the memory binding hypothesis. Show more
Keywords: Aging, Alzheimer’s disease, cognition, dementia, longitudinal studies, memory, survival analysis
DOI: 10.3233/JAD-170714
Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 293-304, 2018
Authors: Li, Chunfei | Loewenstein, David A. | Duara, Ranjan | Cabrerizo, Mercedes | Barker, Warren | Adjouadi, Malek | for the Alzheimer’s Disease Neuroimaging Initiative
Article Type: Research Article
Abstract: Background: Both amyloid (Aβ) load and APOE4 allele are associated with neurodegenerative changes in Alzheimer’s disease (AD) prone regions and with risk for cognitive impairment. Objective: To evaluate the unique and independent contribution of APOE4 allele status (E4+∖E4–), Aβ status (Amy+∖Amy–), and combined APOE4 and Aβ status on regional cortical thickness (CoTh) and cognition among participants diagnosed as cognitively normal (CN, n = 251), early mild cognitive impairment (EMCI, n = 207), late mild cognitive impairment (LMCI, n = 196), and mild AD (n = 162) from the ADNI. Methods: A series of two-way ANCOVAs with post-hoc Tukey HSD tests, controlling independently for Aβ …and APOE4 status and age were examined. Results: Among LMCI and AD participants, cortical thinning was widespread in association with Amy+ status, whereas in association with E4+ status only in the inferior temporal and medial orbito-frontal regions. Among CN and EMCI participants, E4+ status, but not Amy+ status, was independently associated with increased CoTh, especially in limbic regions [e.g., in the entorhinal cortex, CoTh was 0.123 mm greater (p = 0.002) among E4+ than E4–participants]. Among CN and EMCI, both E4+ and Amy+ status were independently associated with cognitive impairment, which was greatest among those with combined E4 + and Amy+ status. Conclusion: Decreased CoTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4 + status is associated with increased CoTh, in medial and inferior temporal regions, although cognitive impairment at this state is independently associated with Amy+ and E4 + status. These findings imply a unique pathophysiological mechanism for E4 + status in AD and its progression. Show more
Keywords: ADNI, Alzheimer’s disease, amyloid, APOE, cortical thinning, memory, mild cognitive impairment
DOI: 10.3233/JAD-170286
Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1269-1282, 2017