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ELEVATED BLOOD HOMOCYSTEINE AND RISK OF ALZHEIMER’S DEMENTIA: AN UPDATED SYSTEMATIC REVIEW AND META-ANALYSIS BASED ON PROSPECTIVE STUDIES

M. Zuin, C. Cervellati, G. Brombo, A. Trentini, L. Roncon, G. Zuliani

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Objective: To investigate whether high serum homocysteine (Hcy) levels is associated with the risk of developing Alzheimer’s disease (AD) by performing a meta-analysis based on updated published data. Methods: We conducted a comprehensive research using Medline (Pubmed), Scopus, Web of Science and EMBASE databases to identify all prospective studies published any time to July 7, 2020 evaluating the association between elevated Hcy levels and AD risk. Results: From an initial screening of 269 published papers, 9 prospective investigations conducted on a total of 7474 subjects with mean follow-up of 9.5 years (range: 3.7-10) were included in the meta-analysis. Eight seventy-five of these subjects converted to AD. Hcy was significantly higher in these individuals (HRadjusted:1.48, 95% CI:1.23-1.76, I2=65.6%, p<0.0001) compared with who did not convert to AD. There was a significant publication bias (Egger’s test, t=6.39, p=0.0003) and this was overcome by the trim and fill method, which allowed to calculate a bias-corrected imputed risk estimate of HRadjusted:1.20, 95% CI:1.01-1.44, Q value=41.92. Conclusions: The present meta-analysis found that having higher Hcy increases the risk of AD in the elderly and this finding is consistent with the widely suggested role of this non-proteinogenic α-amino acid in AD neurodegeneration.

CITATION:
M. Zuin ; C. Cervellati ; G. Brombo ; A. Trentini ; L. Roncon ; G. Zuliani (2021): Elevated Blood Homocysteine and Risk of Alzheimer’s Dementia: An Updated Systematic Review and Meta-Analysis Based on Prospective Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.7

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JPAD Volume 8, N°02 - 2021

 

NUTRITION-BASED APPROACHES IN CLINICAL TRIALS TARGETING COGNITIVE FUNCTION: HIGHLIGHTS OF THE CTAD 2020

K.V. Giudici

J Prev Alz Dis 2021;2(8):118-122

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CITATION:
K.V. Giudici (2021): Nutrition-Based Approaches in Clinical Trials Targeting Cognitive Function: Highlights of the CTAD 2020. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.6

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APPLICATION OF DIGITAL COGNITIVE BIOMARKERS FOR ALZHEIMER’S DISEASE: IDENTIFYING COGNITIVE PROCESS CHANGES AND IMPENDING COGNITIVE DECLINE

J.R. Bock, J. Hara, D. Fortier, M.D. Lee, R.C. Petersen, W.R. Shankle, The Alzheimer’s Disease Neuroimaging Initiative

J Prev Alz Dis 2021;2(8):123-126

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Background: Recent Alzheimer’s disease (AD) trials have faced significant challenges to enroll pre-symptomatic or early stage AD subjects with biomarker positivity, minimal or no cognitive impairment, and likelihood to decline cognitively during a short trial period. Our previous study showed that digital cognitive biomarkers (DCB), generated by a hierarchical Bayesian cognitive process (HBCP) model, were able to distinguish groups of cognitively normal individuals with impending cognitive decline from those without. We generated DCBs using only baseline Auditory Verbal Learning Test’s wordlist memory (WLM) item response data from the Mayo Clinic Alzheimer’s Disease Patient Registry. Objectives: To replicate our previous findings, using baseline ADAS-Cog WLM item response data from the Alzheimer’s Disease Neuroimaging Initiative, and compare DCBs to traditional approaches for scoring word-list memory tests. Design: Classified decliner subjects (n = 61) as those who developed amnestic MCI or AD dementia within 3 years of normal baseline assessment and non-decliner (n = 442) as those who did not. Measures: Evaluated the relative value of DCBs compared to traditional measures, using three analytic approaches to group differences: 1) logistic regression of summary scores per ADAS-Cog WLM task; 2) Bayesian modeling of summary scores; and 3) HBCP modeling to generate DCBs from item-level responses. Results: The HBCP model produced posterior distributions of group differences, of which Bayes factor assessment identified three DCBs with notable group differences: Immediate Retrieval from Durable Storage, (BFds = 11.8, strong evidence); One-Shot Learning, (BFds = 4.5, moderate evidence); and Partial Learning (BFds = 2.9, weak evidence). In contrast, logistic regression of summary scores did not significantly discriminate between groups, and the Bayes factor assessment of modeled summary scores provided moderate evidence that the groups were equivalent (BFsd = 3.4, 3.1, 2.9, and 1.4, respectively). Conclusions: This study demonstrated DCBs’ ability to distinguish , at baseline, between impending cognitive decline and non-decline groups where individuals in both groups were classified as cognitively normal. This validated findings from our previous study, demonstrating DCBs’ advantages over traditional approaches. This study warrants further refinement of the HBCP DCBs to predict impending cognitive decline in individuals and other factors associated with AD, such as physical biomarker load.

CITATION:
J.R. Bock ; J. Hara ; D. Fortier ; M.D. Lee ; R.C. Petersen ; W.R. Shankle ; The Alzheimer’s Disease Neuroimaging Initiative (2020): Application of Digital Cognitive Biomarkers for Alzheimer’s Disease: Identifying Cognitive Process Changes and Impending Cognitive Decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.63

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DIGITAL SCREENING FOR COGNITIVE IMPAIRMENT – A PROOF OF CONCEPT STUDY

V. Bloniecki, G. Hagman, M. Ryden, M. Kivipelto

J Prev Alz Dis 2021;2(8):127-134

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Background: Due to an ageing demographic and rapid increase of cognitive impairment and dementia, combined with potential disease-modifying drugs and other interventions in the pipeline, there is a need for the development of accurate, accessible and efficient cognitive screening instruments, focused on early-stage detection of neurodegenerative disorders. Objective: In this proof of concept report, we examine the validity of a newly developed digital cognitive test, the Geras Solutions Cognitive Test (GCST) and compare its accuracy against the Montreal Cognitive Assessment (MoCA). Methods: 106 patients, referred to the memory clinic, Karolinska University Hospital, due to memory complaints were included. All patients were assessed for presence of neurodegenerative disorder in accordance with standard investigative procedures. 66% were diagnosed with subjective cognitive impairment (SCI), 25% with mild cognitive impairment (MCI) and 9% fulfilled criteria for dementia. All patients were administered both MoCA and GSCT. Descriptive statistics and specificity, sensitivity and ROC curves were established for both test. Results: Mean score differed significantly between all diagnostic subgroups for both GSCT and MoCA (p<0.05). GSCT total test time differed significantly between all diagnostic subgroups (p<0.05). Overall, MoCA showed a sensitivity of 0.88 and specificity of 0.54 at a cut-off of <=26 while GSCT displayed 0.91 and 0.55 in sensitivity and specificity respectively at a cut-off of <=45. Conclusion: This report suggests that GSCT is a viable cognitive screening instrument for both MCI and dementia.

CITATION:
V. Bloniecki ; G. Hagman ; M. Ryden ; M. Kivipelto (2021): Digital Screening for Cognitive Impairment – A Proof of Concept Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.2

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A NOVEL COMPUTERIZED COGNITIVE STRESS TEST TO DETECT MILD COGNITIVE IMPAIRMENT

R.E. Curiel Cid, E.A. Crocco, M. Kitaigorodsky, L. Beaufils, P.A. Peña, G. Grau, U. Visser, D.A. Loewenstein

J Prev Alz Dis 2021;2(8):135-141

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BACKGROUND: The Loewenstein Acevedo Scales of Semantic Interference and Learning (LASSI-L) is a novel and increasingly employed instrument that has outperformed widely used cognitive measures as an early correlate of elevated brain amyloid and neurodegeneration in prodromal Alzheimer’s Disease (AD). The LASSI-L has distinguished those with amnestic mild cognitive impairment (aMCI) and high amyloid load from aMCI attributable to other non-AD conditions. The authors designed and implemented a web-based brief computerized version of the instrument, the LASSI-BC, to improve standardized administration, facilitate scoring accuracy, real-time data entry, and increase the accessibility of the measure. Objective: The psychometric properties and clinical utility of the brief computerized version of the LASSI-L was evaluated, together with its ability to differentiate older adults who are cognitively normal (CN) from those with amnestic Mild Cognitive Impairment (aMCI). Methods: After undergoing a comprehensive uniform clinical and neuropsychological evaluation using traditional measures, older adults were classified as cognitively normal or diagnosed with aMCI. All participants were administered the LASSI-BC, a computerized version of the LASSI-L. Test-retest and discriminant validity was assessed for each LASSI-BC subscale. Results: LASSI-BC subscales demonstrated high test-retest reliability, and discriminant validity was attained. Conclusions: The LASSI-BC, a brief computerized version of the LASSI-L is a valid and useful cognitive tool for the detection of aMCI among older adults.

CITATION:
R.E. Curiel Cid ; E.A. Crocco ; M. Kitaigorodsky ; L. Beaufils ; P.A. Peña ; G. Grau ; U. Visser ; D.A. Loewenstein (2021): A Novel Computerized Cognitive Stress Test to Detect Mild Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.1

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A WEB-BASED MULTIDOMAIN LIFESTYLE INTERVENTION FOR OLDER ADULTS: THE EMIND RANDOMIZED CONTROLLED TRIAL

P. de Souto Barreto, K. Pothier, G. Soriano, M. Lussier, L. Bherer, S. Guyonnet, A. Piau, P.-J. Ousset, B. Vellas

J Prev Alz Dis 2021;2(8):142-150

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Importance/Objective: To describe the feasibility and acceptability of a 6-month web-based multidomain lifestyle training intervention for community-dwelling older people and to test the effects of the intervention on both function- and lifestyle-related outcomes. Design: 6-month, parallel-group, randomized controlled trial (RCT). Setting: Toulouse area, South-West, France. Participants: Community-dwelling men and women, ≥ 65 years-old, presenting subjective memory complaint, without dementia. Intervention: The web-based multidomain intervention group (MIG) received a tablet to access the multidomain platform and a wrist-worn accelerometer measuring step counts; the control group (CG) received only the wrist-worn accelerometer. The multidomain platform was composed of nutritional advices, personalized exercise training, and cognitive training. Main outcomes and measures: Feasibility, defined as the proportion of people connecting to ≥75% of the prescribed sessions, and acceptability, investigated through content analysis from recorded semi-structured interviews. Secondary outcomes included clinical (eg, cognitive function, mobility, health-related quality of life (HRQOL)) and lifestyle (eg, step count, food intake) measurements. Results: Among the 120 subjects (74.2 ±5.6 years-old; 57.5% women), 109 completed the study (n=54, MIG; n=55, CG). 58 MIG subjects connected to the multidomain platform at least once; among them, adherers of ≥75% of sessions varied across multidomain components: 37 people (63.8% of 58 participants) for cognitive training, 35 (60.3%) for nutrition, and three (5.2%) for exercise; these three persons adhered to all multidomain components. Participants considered study procedures and multidomain content in a positive way; the most cited weaknesses were related to exercise: too easy, repetitive, and slow progression. Compared to controls, the intervention had a positive effect on HRQOL; no significant effects were observed across the other clinical and lifestyle outcomes. Conclusions and Relevance: Providing multidomain lifestyle training through a web-platform is feasible and well-accepted, but the training should be challenging enough and adequately progress according to participants’ capabilities to increase adherence. Recommendations for a larger on-line multidomain lifestyle training RCT are provided.

CITATION:
P. de Souto Barreto ; K. Pothier ; G. Soriano ; M. Lussier ; L. Bherer ; S. Guyonnet ; A. Piau ; P.-J. Ousset ; B. Vellas (2020): A Web-Based Multidomain Lifestyle Intervention for Older Adults: The eMIND Randomized Controlled Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.70

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PSYCHOMETRIC PROPERTIES OF THE CLINICAL DEMENTIA RATING – SUM OF BOXES AND OTHER COGNITIVE AND FUNCTIONAL OUTCOMES IN A PRODROMAL ALZHEIMER’S DISEASE POPULATION

F. McDougall, C. Edgar, M. Mertes, P.Delmar, P. Fontoura, D. Abi-Saab, C.J. Lansdall, M. Boada, R. Doody

J Prev Alz Dis 2021;2(8):151-160

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BACKGROUND: The Clinical Dementia Rating–Sum of Boxes (CDR-SB) has been proposed as a primary outcome for use in prodromal AD trials. However, the psychometric properties of this, and of other commonly used measures, have not been well-established in this patient population. OBJECTIVE: To describe the psychometric properties of commonly used efficacy measures in a clinical trial of prodromal AD. SETTING: Data were gathered as part of a two-year clinical trial. PARTICIPANTS: Patients had biomarker confirmed prodromal AD. MEASUREMENTS: Clinical Dementia Rating (CDR), Functional Activities Questionnaire (FAQ), Alzheimer’s Disease Assessment Scale – Cognition Subscale 11 and 13 (ADAS-Cog), Mini Mental State Exam (MMSE), and Free and Cued Selective Reminding Test (FCSRT-IR [words]). Assessments were conducted at least every 24 weeks. RESULTS: For the CDR-SB, test-retest reliability was good (intra-class correlation coefficient [ICC]=0.83); internal consistency was 0.65 at baseline but above 0.8 at later assessments. Relationships between the CDR-SB and other measures were as expected (higher correlations with more closely related constructs), and the CDR-SB differentiated between patients with different severities of dementia (-2.9 points difference between CDR-Global Score 0.5 and 1, P<.0001). Floor and ceiling effects on the CDR-SB total score were minimal; however, at baseline there were ceiling effects in the personal care domain. Further detail is provided on the psychometric properties of ADAS-Cog, MMSE, FCSRT-IR and FAQ in this population. CONCLUSION: The psychometric properties of the CDR-SB are adequate in prodromal AD and continued use is warranted in clinical trials. However, there remains scope for improvement in the assessment of functional constructs and development of novel measures should continue.

CITATION:
F. McDougall ; C. Edgar ; M. Mertes ; P.Delmar ; P. Fontoura ; D. Abi-Saab ; C.J. Lansdall ; M. Boada ; R. Doody (2020): Psychometric Properties of the Clinical Dementia Rating – Sum of Boxes and other Cognitive and Functional Outcomes in a Prodromal Alzheimer’s Disease Population. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.73

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EXECUTIVE FUNCTION PREDICTS THE VALIDITY OF SUBJECTIVE MEMORY COMPLAINTS IN OLDER ADULTS BEYOND DEMOGRAPHIC, EMOTIONAL, AND CLINICAL FACTORS

R.-Y. Chao, T.-F. Chen, Y.-L. Chang

J Prev Alz Dis 2021;2(8):161-168

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Background: Although evidence suggests that subjective memory complaints (SMCs) could be a risk factor for dementia, the relationship between SMCs and objective memory performance remains controversial. Old adults with or without mild cognitive impairment (MCI) may represent a highly heterogeneous group, based partly on the demonstrated variability in the level of executive function among those individuals. It is reasonable to speculate that the accuracy of the memory-monitoring ability could be affected by the level of executive function in old adults. Objective: This study investigated the effects of executive function level on the consistency between SMCs and objective memory performance while simultaneously considering demographic and clinical variables in nondemented older adults. Setting: Participants were recruited from both the memory clinics and local communities. Participants: Participants comprised 65 cognitively normal (CN) older adults and 54 patients with MCI. Measurements: Discrepancy scores between subjective memory evaluation and objective memory performance were calculated to determine the degree and directionality of the concordance between subjective and objective measures. Demographic, emotional, genetic, and clinical information as well as several executive function measurements were collected. Results: The CN and MCI groups exhibited similar degrees of SMC; however, the patients with MCI were more likely to overestimate their objective memory ability, whereas the CN adults were more likely to underestimate their objective memory ability. The results also revealed that symptoms of depression, group membership, and the executive function level together predicted the discrepancy between the subjective and objective measures of memory function; however, the executive function level retained its unique predictive ability even after the symptoms of depression, group membership, and other factors were controlled for. Conclusion: Although both noncognitive and cognitive factors were necessary for consideration, the level of executive function may play a unique role in understanding the equivocal relationship of the concurrence between subjective complaints and objective function measures. Through a comprehensive evaluation, high-risk individuals (i.e., CN individuals heightened self-awareness of memory changes) may possibly be identified or provided with the necessary intervention during stages at which objective cognitive impairment remains clinically unapparent.

CITATION:
R.-Y. Chao ; T.-F. Chen ; Y.-L. Chang (2020): Executive Function Predicts the Validity of Subjective Memory Complaints in Older Adults beyond Demographic, Emotional, and Clinical Factors. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.61

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MENTAL COMPONENT SCORE (MCS) FROM HEALTH-RELATED QUALITY OF LIFE PREDICTS INCIDENCE OF DEMENTIA IN U.S. MALES

X. Ding, E.L. Abner, F.A. Schmitt, J. Crowley, P. Goodman, R.J. Kryscio

J Prev Alz Dis 2021;2(8):169-174

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Background: The Medical Outcomes Study Questionnaire Short Form 36 health survey (SF-36) measures health-related quality of life (HRQoL) from the individual’s point of view and is an indicator of overall health status. Objective: To examine whether HRQoL shows differential changes over time prior to dementia onset and investigate whether HRQoL predicts incidence of dementia. Design: Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) trial, which recruited 7,547 non-demented men between 2002 and 2009. A subset of 2,746 PREADViSE participants who completed up to five SF-36 assessments at annual visits was included in the current analysis Setting: Secondary data analysis of PREADViSE data. Participants: A subset of 2,746 PREADViSE participants who completed up to five SF-36 assessments at annual visits was included in the current analysis. Measurements: Two summary T scores were generated for analysis: physical component score (PCS) and mental component score (MCS), each with a mean of 50 (standard deviation of 10); higher scores are better. Linear mixed models (LMM) were applied to determine if mean component scores varied over time or by eventual dementia status. Cox proportional hazards regression was used to determine if the baseline component scores were associated with dementia incidence, adjusting for baseline age, race, APOE-4 carrier status, sleep apnea, and self-reported memory complaint at baseline. Results: The mean baseline MCS score for participants who later developed dementia (mean± SD: 53.9±9.5) was significantly lower than for those participants who did not develop dementia during the study (mean±SD: 56.4±6.5; p = 0.005). Mean PCS scores at baseline (dementia: 49.3±7.9 vs. non-dementia: 49.8±7.8) were not significantly different (p = 0.5) but LMM analysis showed a significant time effect. For MCS, the indicator for eventual dementia diagnosis was significantly associated with poorer scores after adjusting for baseline age, race, and memory complaint. Adjusted for other baseline risk factors, the Cox model showed that a 10-unit increase in MCS was associated with a 44% decrease in the hazard of a future dementia diagnosis (95% CI: 32%-55%). Conclusion: The SF-36 MCS summary score may serve as a predictor for future dementia and could be prognostic in longitudinal dementia research.

CITATION:
X. Ding ; E.L. Abner ; F.A. Schmitt ; J. Crowley ; P. Goodman ; R.J. Kryscio (2020): Mental Component Score (MCS) from Health-Related Quality of Life Predicts Incidence of Dementia in U.S. Males. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.50

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CHINESE VERSION OF THE BAYLOR PROFOUND MENTAL STATUS EXAMINATION: A BRIEF STAGING MEASURE FOR PATIENTS WITH SEVERE ALZHEIMER’S DISEASE

X. Fu, W. Yu, M. Ke, X. Wang, J. Zhang, T. Luo, P.J. Massman, R.S. Doody, Y. Lü

J Prev Alz Dis 2021;2(8):175-180

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BACKGROUND: A specialized instrument for assessing the cognition of patients with severe Alzheimer’s disease (AD) is needed in China. Objectives: To validate the Chinese version of the Baylor Profound Mental Status Examination (BPMSE-Ch). Design: The BPMSE is a simplified scale which has proved to be a reliable and valid tool for evaluating patients with moderate to severe AD, it is worthwhile to extend the use of it to Chinese patients with AD. Setting: Patients were assessed from the Memory Clinic Outpatient. Participants: All participants were diagnosed as having probable AD by assessment. Measurements: The BPMSE was translated into Chinese and back translated. The BPMSE-Ch was administered to 102 AD patients with a Mini-Mental State Examination (MMSE) score below 17. We assessed the internal consistency, reliability, and construct validity between the BPMSE-Ch and MMSE, Severe Impairment Battery (SIB), Global Deterioration Scale (GDS-1), Geriatric Depression Scale(GDS-2), Instrumental Activities of Daily Living (IADL), Physical Self-Maintenance Scale (PSMS), Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR). Results: The BPMSE-Ch showed good internal consistency (α = 0.87); inter-rater and test-retest reliability were both excellent, ranging from 0.91 to 0.99. The construct validity of the measure was also supported by significant correlations with MMSE, SIB. Moreover, as expected, the BMPSE-Ch had a lower floor effect than the MMSE, but a ceiling effect existed for patients with MMSE scores above 11. Conclusions: The BPMSE-Ch is a reliable and valid tool for evaluating cognitive function in Chinese patients with severe AD.

CITATION:
X. Fu ; W. Yu ; M. Ke ; X. Wang ; J. Zhang ; T. Luo ; P.J. Massman ; R.S. Doody ; Y. Lü (2020): Chinese Version of the Baylor Profound Mental Status Examination: A Brief Staging Measure for Patients with Severe Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.72

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AMNESTIC MILD COGNITIVE IMPAIRMENT IS CHARACTERIZED BY THE INABILITY TO RECOVER FROM PROACTIVE SEMANTIC INTERFERENCE ACROSS MULTIPLE LEARNING TRIALS

D.A. Loewenstein, R.E. Curiel Cid, M. Kitaigorodsky, E.A. Crocco, D.D. Zheng, K.L. Gorman

J Prev Alz Dis 2021;2(8):181-187

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Background: Difficulties in inhibition and self-monitoring are early features of incipient Alzheimer’s disease and may manifest as susceptibility to proactive semantic interference. However, due to limitations of traditional memory assessment paradigms, recovery from interference effects following repeated learning opportunities has not been explored. Objective: This study employed a novel computerized list learning test consisting of repeated learning trials to assess recovery from proactive and retroactive semantic interference. Design: The design was cross-sectional. Setting: Participants were recruited from the community as part of a longitudinal study on normal and abnormal aging. Participants: The sample consisted of 46 cognitively normal individuals and 30 participants with amnestic mild cognitive impairment. Measurements: Participants were administered the Cognitive Stress Test and traditional neuropsychological measures. Step-wise logistic regression was applied to determine which Cognitive Stress Test measures best discriminated between diagnostic groups. This was followed by receiver operating characteristic analyses. Results: Cued A3 recall, Cued B3 recall and Cued B2 intrusions were all independent predictors of diagnostic status. The overall predictive utility of the model yielded 75.9% sensitivity, 91.1% specificity, and an overall correct classification rate of 85.1%. When these variables were jointly entered into receiver operating characteristic analyses, the area under the curve was .923 (p<.001). Conclusions: This novel paradigm’s use of repeated learning trials offers a unique opportunity to assess recovery from proactive and retroactive semantic interference. Participants with mild cognitive impairment exhibited a continued failure to recover from proactive interference that could not be explained by mere learning deficits.

CITATION:
D.A. Loewenstein ; R.E. Curiel Cid ; M. Kitaigorodsky ; E.A. Crocco ; D.D. Zheng ; K.L. Gorman (2021): Amnestic Mild Cognitive Impairment is Characterized by the Inability to Recover from Proactive Semantic Interference across Multiple Learning Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.3

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SUGAR IN BEVERAGE AND THE RISK OF INCIDENT DEMENTIA, ALZHEIMER’S DISEASE AND STROKE: A PROSPECTIVE COHORT STUDY

H. Miao, K. Chen, X. Yan, F. Chen

J Prev Alz Dis 2021;2(8):188-193

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Background: This study aimed to investigate the association between sugar in beverage and dementia, Alzheimer Disease (AD) dementia and stroke. Methods: This prospective cohort study were based on the US community-based Framingham Heart Study (FHS). Sugar in beverage was assessed between 1991 and 1995 (5th exam). Surveillance for incident events including dementia and stroke commenced at examination 9 through 2014 and continued for 15-20 years. Results: At baseline, a total of 1865 (63%) subjects consumed no sugar in beverage, whereas 525 (18%) subjects consumed it in 1-7 servings/week and 593 (29%) in over 7 servings/week. Over an average follow-up of 19 years in 1384 participants, there were 275 dementia events of which 73 were AD dementia. And 103 of 1831 participants occurred stroke during the follow-up nearly 16 years. After multivariate adjustments, individuals with the highest intakes of sugar in beverage had a higher risk of all dementia, AD dementia and stroke relative to individuals with no intakes, with HRs of 2.80(95%CI 2.24-3.50) for all dementia, 2.55(95%CI 1.55-4.18) for AD dementia, and 2.11(95%CI 1.48-3.00) for stroke. And the same results were shown in the subgroup for individuals with median intakes of sugar in beverage. Conclusion: Higher consumption of sugar in beverage was associated with an increased risk of all dementia, AD dementia and stroke.

CITATION:
H. Miao ; K. Chen ; X. Yan ; F. Chen (2020): Sugar in Beverage and the Risk of Incident Dementia, Alzheimer’s disease and Stroke: A Prospective Cohort Study . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.62

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DOES TEA DRINKING PROMOTE HEALTH OF OLDER ADULTS: EVIDENCE FROM THE CHINA HEALTH AND NUTRITION SURVEY

J. Wang, Q. Wei, X. Wan

J Prev Alz Dis 2021;2(8):194-198

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Objective: This study selects the health indicators of older adults to analyze the impact of tea drinking on health. Design: This is a panel data. Setting: This study uses data from China Health and Nutrition Survey (CHNS), which covers nine provinces and ten waves, between 1997 and 2015. Participants: a total of 706 old adults are consistently surveyed in six surveys on issues such as health and nutrition. Measurements: Health of old adults is assessed by self-reported health (SRH), tea drinking is 0-1 dummy variable, and also analyze with the frequency of tea drinking. This study uses ordered probit model to analyze the influence of tea drinking on SRH. Results: Findings reveal a significant negative correlation between tea drinking and SRH of older adults. It is shows that the significant positive correlation exists between the tea drinking frequency and SRH, but the quadratic term of tea frequency shows the significant negative correlation. It means drinking tea benefits older adults in terms of improved health, but excessive consumption of tea is not healthy for them. The heterogeneity analyses reveal that there are no significant geographic, tea-drinking pattern or gender differences in the conclusion that tea drinking is good for older adults’ health. Conclusion: In this study, we find correlation between tea drinking and SRH of older adults, and tea drinking is beneficial toward the improvement of SRH, but drinking tea in excess is not good for older adults’ health.

CITATION:
J. Wang ; Q. Wei ; X. Wan (2020): Does Tea Drinking Promote Health of Older Adults: Evidence from the China Health and Nutrition Survey. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.67

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LONGITUDINAL COURSE OF AGITATION AND AGGRESSION IN PATIENTS WITH ALZHEIMER’S DISEASE IN A COHORT STUDY: METHODS, BASELINE AND LONGITUDINAL RESULTS OF THE A3C STUDY

A. De Mauleon, J. Delrieu, C. Cantet, B. Vellas, S. Andrieu, P.B. Rosenberg, C.G. Lyketsos, M. Soto Martin

J Prev Alz Dis 2021;2(8):199-209

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BACKGROUND: To present methodology, baseline results and longitudinal course of the Agitation and Aggression in patients with Alzheimer’s Disease Cohort (A3C) study. Objectives: The central objective of A3C was to study the course, over 12 months of clinically significant Agitation and Aggression symptoms based on validated measures, and to assess relationships between symptoms and clinical significance based on global ratings. Design: A3C is a longitudinal, prospective, multicenter observational cohort study performed at eight memory clinics in France, and their associated long-term care facilities. Setting: Clinical visits were scheduled at baseline, monthly during the first 3 months, at 6 months, at 9 months and at 12 months. The first three months intended to simulate a classic randomized control trial 12-week treatment design. Participants: Alzheimer’s Disease patients with clinically significant Agitation and Aggression symptoms lived at home or in long-term care facilities. Measurements: Clinically significant Agitation and Aggression symptoms were rated on Neuropsychiatric Inventory (NPI), NPI-Clinician rating (NPI-C) Agitation and Aggression domains, and Cohen Mansfield Agitation Inventory. Global rating of agitation over time was based on the modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change. International Psychogeriatric Association “Provisional Diagnostic Criteria for Agitation”, socio-demographics, non-pharmacological approaches, psychotropic medication use, resource utilization, quality of life, cognitive and physical status were assessed. Results: A3C enrolled 262 AD patients with a mean age of 82.4 years (SD ±7.2 years), 58.4% women, 69.9% at home. At baseline, mean MMSE score was 10.0 (SD±8.0), Cohen Mansfield Agitation Inventory score was 62.0 (SD±15.8) and NPI-C Agitation and Aggression clinician severity score was 15.8 (SD±10.8). According to the International Psychogeriatric Association agitation definition, more than 70% of participants showed excessive motor activity (n=199, 76.3%) and/or a verbal aggression (n=199, 76.3%) while 115 (44.1%) displayed physical aggression. The change of the CMAI score and the NPI-C Agitation and Aggression at 1-year follow-up period was respectively -11.36 (Standard Error (SE)=1.32; p<0.001) and -6.72 (SE=0.77; p<0.001). Conclusion: Little is known about the longitudinal course of clinically significant agitation symptoms in Alzheimer’s Disease about the variability in different outcome measures over time, or the definition of a clinically meaningful improvement. A3C may provide useful data to optimize future clinical trials and guide treatment development for Agitation and Aggression in Alzheimer’s Disease.

CITATION:
A. De Mauleon ; J. Delrieu ; C. Cantet ; B. Vellas ; S. Andrieu ; P.B. Rosenberg ; C.G. Lyketsos ; M. Soto Martin (2020): Longitudinal Course of Agitation and Aggression in Patients with Alzheimer’s Disease in a Cohort study: Methods, Baseline and Longitudinal Results of the A3C Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.66

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COST-EFFECTIVENESS OF DEMENTIA PREVENTION INTERVENTIONS

I. McRae, L. Zheng, S. Bourke, N. Cherbuin, K.J. Anstey

J Prev Alz Dis 2021;2(8):210-217

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Background: Assessment of cost-effectiveness of interventions to address modifiable risk factors associated with dementia requires estimates of long-term impacts of these interventions which are rarely directly available and must be estimated using a range of assumptions. OBJECTIVES: To test the cost-effectiveness of dementia prevention measures using a methodology which transparently addresses the many assumptions required to use data from short-term studies, and which readily incorporates sensitivity analyses. DESIGN: We explore an approach to estimating cost-effective prices which uses aggregate data including estimated lifetime costs of dementia, both financial and quality of life, and incorporates a range of assumptions regarding sustainability of short- term gains and other parameters. SETTING: The approach is addressed in the context of the theoretical reduction in a range of risk factors, and in the context of a specific small-scale trial of an internet-based intervention augmented with diet and physical activity consultations. MEASUREMENTS: The principal outcomes were prices per unit of interventions at which interventions were cost-effective or cost-saving. RESULTS: Taking a societal perspective, a notional intervention reducing a range of dementia risk-factors by 5% was cost-effective at $A460 per person with higher risk groups at $2,148 per person. The on-line program costing $825 per person was cost-effective at $1,850 per person even if program effect diminished by 75% over time. CONCLUSIONS: Interventions to address risk factors for dementia are likely to be cost-effective if appropriately designed, but confirmation of this conclusion requires longer term follow-up of trials to measure the impact and sustainability of short-term gains.

CITATION:
I. McRae ; L. Zheng ; S. Bourke ; N. Cherbuin ; K.J. Anstey (2020): Cost-Effectiveness of Dementia Prevention Interventions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.71

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AMYLOID AND APOE STATUS OF SCREENED SUBJECTS IN THE ELENBECESTAT MISSIONAD PHASE 3 PROGRAM

C. Roberts, J. Kaplow, M. Giroux, S. Krause, M. Kanekiyo

J Prev Alz Dis 2021;2(8):218-223

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BACKGROUND/OBJECTIVES: Elenbecestat, an oral BACE-1 inhibitor that has been shown to reduce Aβ levels in cerebrospinal fluid, was investigated in two global phase 3 studies in early AD. Here we report on differences observed in characteristics of APOE ε4 and amyloid positive subjects in the large screening cohort. DESIGN: Screening was performed in 5 sequential tiers over a maximum of 80 days, as part of placebo controlled, double blind phase 3 studies. SETTING: Subjects were evaluated at sites in 7 regions (29 countries). PARTICIPANTS: Overall, 9758 subjects were screened. INTERVENTION: All screened subjects that were eligible received either placebo or 50 mg QID elenbecestat post randomisation. MEASUREMENTS: Gender, disease staging, APOE ε4 status, amyloid status, amyloid positron emission tomography (PET) standard uptake value ratio (SUVr) and amyloid PET Centiloid (CL) values were determined for screened subjects; by country and region. RESULTS: In this program, 44% of subjects were APOE ε4 positive. Frequency of females was similar in both APOE ε4 positive and negative groups. However, early mild AD subjects were slightly higher in the APOE ε4 positive group compared with the APOE ε4 negative group. 56% of subjects were amyloid positive. The mean age in the amyloid positive group was slightly higher than the amyloid negative group. The gender distribution was similar between amyloid groups. A lower number of mild cognitive impairment was observed in the amyloid positive group along with a higher number of early mild AD. APOE ε4 positive subjects were higher in amyloid positive group compared to the amyloid negative group. China had the lowest APOE ε4 and amyloid positivity rates with Western Europe and Oceania performing best. Subjects received florbetapir, florbetaben or flutemetamol amyloid PET tracer. Amyloid negative and positive subjects CL values were normally distributed around their respective means of 1.5 CL and 83 CL. However, there was an appreciable overlap in the 20-40 CL range. CONCLUSIONS: In this large cohort of cognitively impaired subjects, subject demographics characteristics were comparable regardless of APOE genotype or amyloid positivity. APOE ε4 positivity and amyloid positivity varied by country and by geographical region.

CITATION:
C. Roberts ; J. Kaplow ; M. Giroux ; S. Krause ; M. Kanekiyo (2021): Amyloid and APOE Status of Screened Subjects in the Elenbecestat MissionAD Phase 3 Program. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.4

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MOLECULAR SUBTYPING OF MILD COGNITIVE IMPAIRMENT BASED ON GENETIC POLYMORPHISM AND GENE EXPRESSION

H.-T. Li, S.-X. Yuan, J.-S. Wu, X.-Z. Zhang, Y. Liu, X. Sun, For the Alzheimer’s Disease Neuroimaging Initiative

J Prev Alz Dis 2021;2(8):224-233

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Background: Alzheimer’s Disease (AD) is a neurodegenerative brain disease in the elderly. Recent studies have revealed the heterogeneous nature of AD. Mild Cognitive Impairment (MCI) is the prodromal stage of AD. Objectives: In this study, we identified subtypes of MCI based on genetic polymorphism and gene expression. Methods: We utilized the two types of omics data, namely genetic polymorphism and gene expression profiling, derived from 125 MCI patients’ peripheral blood samples from the ADNI-1 dataset. Similarity network fusion (SNF) algorithm was implemented to cluster MCI patient subtypes. And 185 MCI patients in ADNI-2 were utilized to evaluate the effectiveness of this method. Two MCI subtypes were identified by implementing the SNF algorithm. Results: We used Kaplan-Meier analysis and log-rank testing for the conversion from MCI to AD between two subtypes, and p-value is 4.58×10-3. In addition, we compared patients among two MCI subtypes by the following factors: the changes in Alzheimer’s Disease cognitive scales and MRI image; significantly enriched pathways based on differentially expressed genes. This study proved that MCI is a heterogeneous disease by concluding that AD development in two MCI subtypes is significantly different. Conclusions: MCI patients with different molecular characteristics have different risks converting to AD. In addition to evaluating statistics, genetic polymorphism and gene expression profiling from MCI patients’ peripheral blood are non-invasiveness and cost-effectiveness markers to identify MCI subtypes for clinical application.

CITATION:
H.-T. Li ; S.-X. Yuan ; J.-S. Wu ; X.-Z. Zhang ; Y. Liu ; X. Sun ; and For the Alzheimer’s Disease Neuroimaging Initiative (2020): Molecular Subtyping of Mild Cognitive Impairment based on Genetic Polymorphism and Gene Expression. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.65

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OVERTREATING ALZHEIMER’S DISEASE

M. Canevelli, N. Vanacore, A. Blasimme, G. Bruno, M. Cesari

J Prev Alz Dis 2021;2(8):234-236

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The management of frailty in older persons is not easy, implying interventions beyond the simple prescription of medications. Biological complexity, multimorbidity, polypharmacy, and social issues often hamper the possibility to directly translate the evidence coming from research into clinical practice. Frailty indeed represents the most relevant cause of the “evidence-based medicine issue” influencing clinical decisions in geriatric care. Today, patients with Alzheimer’s disease (AD) are much older and frailer than some decades ago. They also tend to have more drugs prescribed. In parallel, research on AD has evolved over the years, hypothesizing that anticipating the interventions to the earliest stages of the disease may provide beneficial effects (to date, still lacking). In this article, we argue that, by focusing exclusively on “the disease” and pushing to anticipate its detection (sometimes even before the appareance of its clinical manifestations) may overshadow the person’s values and priorities. Research should be developed for better integrating the concept of aging and frailty in the design of clinical trials in order to provide results that can be implemented in real life. On the other hand, clinicians should be less prone to the easy (but unsupported by evidence) pharmacological prescription.

CITATION:
M. Canevelli ; N. Vanacore ; A. Blasimme ; G. Bruno ; M. Cesari (2020): Overtreating Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.74

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