Association of Lipidomics Signatures in Blood with Clinical Progression in Preclinical and Prodromal Alzheimer’s Disease

Background: Lipidomics may provide insight into biochemical processes driving Alzheimer’s disease (AD) pathogenesis and ensuing clinical trajectories. Objective: To identify a peripheral lipidomics signature associated with AD pathology and investigate its potential to predict clinical progression. Methods: We used Bayesian elastic net regression to select plasma lipid classes associated with the CSF pTau/Aβ42 ratio as a biomarker of AD pathology in preclinical and prodromal AD cases from the ADNI cohort. Consensus clustering of the selected lipid classes was used to identify lipidomic endophenotypes and study their association with clinical progression. Results: In the APOE4-adjusted model, ether-glycerophospholipids, lyso-glycerophospholipids, free-fatty acids, cholesterol esters, and complex sphingolipids were found to be associated with the CSF pTau/Aβ 42 ratio. We found an optimal number of five lipidomic endophenotypes in the prodromal and preclinical cases, respectively. In the prodromal cases, these clusters differed with respect to the risk of clinical progression as measured by clinical dementia rating score conversion. Conclusion: Lipid alterations can be captured at the earliest phases of AD. A lipidomic signature in blood may provide a dynamic overview of an individual’s metabolic status and may support identifying different risks of clinical progression.

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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

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2020.73 ◽

2020 ◽

pp. 1-10

Author(s):

F. McDougall ◽

C. Edgar ◽

M. Mertes ◽

P. Delmar ◽

P. Fontoura ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trial ◽

Psychometric Properties ◽

Disease Assessment ◽

Clinical Dementia Rating ◽

Prodromal Ad ◽

Ceiling Effects ◽

Prodromal Alzheimer’S Disease ◽

Selective Reminding Test

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.

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Plasma sex hormone-binding globulin predicts neurodegeneration and clinical progression in prodromal Alzheimer's disease

10.21203/rs.2.18945/v1 ◽

2019 ◽

Author(s):

Wei Xu ◽

Bing-Jie Su ◽

Xue-Ning Shen ◽

Yan-Lin Bi ◽

Chen-Chen Tan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Metabolism ◽

Sex Hormone ◽

Sex Hormone Binding Globulin ◽

Hormone Binding ◽

Clinical Progression ◽

Cross Sectional ◽

Prodromal Ad ◽

Prodromal Alzheimer’S Disease

Abstract Background: Sex hormone-binding globulin (SHBG) in plasma has been found to be significantly elevated in subjects with AD. We aimed to investigate whether plasma SHBG was associated with AD biomarkers and could predict neurodegeneration and clinical progression in prodromal AD.Methods: The study tested the cross-sectional relationship between plasma SHBG and CSF AD biomarkers in 707 non-demented adults. Next, the longitudinal influences of plasma SHBG at baseline on dynamic changes of CSF Aβ42, hippocampus volume, brain metabolism, and cognition were explored in 448 non-demented adults from the Alzheimer’s disease Neuroimaging Initiative (ADNI). Finally, the influence of plasma SHBG on the risk of incident AD was explored. Results: This study included 707 participants (mean [SD] age, 62.5 [10.5] years, 416 [58.8%] female) from CABLE and 448 from ADNI-1 (mean [SD] age, 74.8 [7.2] years, 166 [37.5%] female). A positive correlation was found for SHBG levels in plasma and CSF (p = 2.12 × 10 -10, r = 0.44). Cross-sectional analyses indicated that individuals with higher plasma SHBG had lower levels of CSF Aβ42 (p < 0.005), after adjusting for age, gender, education, APOE4 allele, and cognitive scores. The longitudinal data showed that higher levels of plasma SHBG contribute to accelerated CSF Aβ42 decrease (p < 0.0005), brain metabolism decline (p < 0.05), hippocampus atrophy (p < 0.01), cognitive decline (p < 0.01), and higher risk of AD dementia (p < 0.05).Conclusions: Plasma SHBG is associated with CSF Aβ42 levels and could predict neurodegeneration and clinical progression in prodromal AD. This finding indicates plasma SHBG is a potentially useful, early biomarker for AD.

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Clinical progression of moderate-to-severe Alzheimer's disease and caregiver burden: a 12-month multicenter prospective observational study

International Psychogeriatrics ◽

10.1017/s104161021000150x ◽

2010 ◽

Vol 22 (8) ◽

pp. 1265-1279 ◽

Cited By ~ 27

Author(s):

Luis Agüera-Ortiz ◽

Ana Frank-García ◽

Pedro Gil ◽

Alfonso Moreno

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Observational Study ◽

Caregiver Burden ◽

Major Influence ◽

Functional Impairments ◽

Clinical Progression ◽

Clinical Dementia Rating ◽

Cross Sectional ◽

Use Of Resources

ABSTRACTBackground: Prospective studies on the clinical progression of Alzheimer's disease (AD) and its relationship to caregiver burden are needed to improve illness management and use of resources.Methods: This national, multicenter, observational study evaluated 1235 moderate to severe AD patients under routine care in Spain. Baseline cross-sectional sociodemographic and clinical data, and changes from baseline to month 12 of various neuropsychological tests and clinical ratings, including Blessed Dementia Scale, Mini-mental State Examination (MMSE), Hughes Clinical Dementia Rating sum-of-boxes (CDR-SB), Clinical Global Impression of Change (CGIC) and Zarit Caregiver Burden scales, were recorded and comprehensively analyzed.Results: Baseline data were in accordance with characteristics consistently reported to influence AD risk regarding anthropometrics, sociocultural features and comorbidities. Significant progressive functional impairments (i.e. in routine activities and essential daily tasks) and cognitive (i.e. MMSE and CDR-SB) impairments were found at month 12. However, patients' behavior and caregivers' burden improved slightly, but significantly, corroborating the major influence of behavioral symptoms on caregivers' distress. Caregivers showed significantly lower burden with patients with higher levels of education and, to a lesser extent, when patients received AD-specific medication. Physicians accurately detected AD clinical evolution as their CGIC ratings significantly correlated with all tests.Conclusions: These findings reinforce previous AD knowledge and add data on the clinical course of advanced stages of AD. Caregiver burden depended more on patients' behavioral alterations than on their functional or cognitive declines; and it was diminished by their patients having higher levels of education and being treated with AD-specific medications. Research into unexplored factors that might reduce caregiver burden, ultimately benefiting both patients and caregivers, is encouraged.

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Plasma sex hormone-binding globulin predicts neurodegeneration and clinical progression in prodromal Alzheimer's disease

Aging ◽

10.18632/aging.103497 ◽

2020 ◽

Vol 12 (14) ◽

pp. 14528-14541

Author(s):

Wei Xu ◽

Bing-Jie Su ◽

Xue-Ning Shen ◽

Yan-Lin Bi ◽

Chen-Chen Tan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sex Hormone ◽

Sex Hormone Binding Globulin ◽

Hormone Binding ◽

Clinical Progression ◽

Prodromal Alzheimer’S Disease

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Cognitive Training and Brain Stimulation in Prodromal Alzheimer's Disease

Case Medical Research ◽

10.31525/ct1-nct04265378 ◽

2020 ◽

Author(s):

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Training ◽

Brain Stimulation ◽

Prodromal Alzheimer’S Disease

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Elucidating the risk factors for progression from amyloid-negative amnestic mild cognitive impairment to dementia

Current Alzheimer Research ◽

10.2174/1567205017666201130094259 ◽

2020 ◽

Vol 17 ◽

Author(s):

Hyung-Ji Kim ◽

Jae-Hong Lee ◽

E-nae Cheong ◽

Sung-Eun Chung ◽

Sungyang Jo ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Amnestic Mild Cognitive Impairment ◽

Amyloid Pet ◽

Clinical Progression ◽

Amnestic Mci

Background: Amyloid PET allows for the assessment of amyloid β status in the brain, distinguishing true Alzheimer’s disease from Alzheimer’s disease-mimicking conditions. Around 15–20% of patients with clinically probable Alzheimer’s disease have been found to have no significant Alzheimer’s pathology on amyloid PET. However, a limited number of studies had been conducted this subpopulation in terms of clinical progression. Objective: We investigated the risk factors that could affect the progression to dementia in patients with amyloid-negative amnestic mild cognitive impairment (MCI). Methods: This study was a single-institutional, retrospective cohort study of patients over the age of 50 with amyloidnegative amnestic MCI who visited the memory clinic of Asan Medical Center with a follow-up period of more than 36 months. All participants underwent brain magnetic resonance imaging (MRI), detailed neuropsychological testing, and fluorine-18[F18]-florbetaben amyloid PET. Results: During the follow-up period, 39 of 107 patients progressed to dementia from amnestic MCI. In comparison with the stationary group, the progressed group had a more severe impairment in verbal and visual episodic memory function and hippocampal atrophy, which showed an Alzheimer’s disease-like pattern despite the lack of evidence for significant Alzheimer’s disease pathology. Voxel-based morphometric MRI analysis revealed that the progressed group had a reduced gray matter volume in the bilateral cerebellar cortices, right temporal cortex, and bilateral insular cortices. Conclusion: Considering the lack of evidence of amyloid pathology, clinical progression of these subpopulation may be caused by other neuropathologies such as TDP-43, abnormal tau or alpha synuclein that lead to neurodegeneration independent of amyloid-driven pathway. Further prospective studies incorporating biomarkers of Alzheimer’s diseasemimicking dementia are warranted.

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On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

Clinical Trials ◽

10.1177/17407745211034497 ◽

2021 ◽

pp. 174077452110344

Author(s):

Michelle M Nuño ◽

Joshua D Grill ◽

Daniel L Gillen ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Cerebrospinal Fluid ◽

Phosphorylated Tau ◽

Inclusion Criteria ◽

Eligibility Criteria ◽

Total Tau ◽

Prodromal Alzheimer’S Disease ◽

Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

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Event-related potential and EEG oscillatory predictors of verbal memory in mild cognitive impairment

Brain Communications ◽

10.1093/braincomms/fcaa213 ◽

2020 ◽

Vol 2 (2) ◽

Author(s):

Jiangyi Xia ◽

Ali Mazaheri ◽

Katrien Segaert ◽

David P Salmon ◽

Danielle Harvey ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Verbal Memory ◽

Verbal Learning ◽

Event Related Potential ◽

Single Trial ◽

Prodromal Alzheimer’S Disease ◽

Alpha Beta

Abstract Reliable biomarkers of memory decline are critical for the early detection of Alzheimer’s disease. Previous work has found three EEG measures, namely the event-related brain potential P600, suppression of oscillatory activity in the alpha frequency range (∼10 Hz) and cross-frequency coupling between low theta/high delta and alpha/beta activity, each of which correlates strongly with verbal learning and memory abilities in healthy elderly and patients with mild cognitive impairment or prodromal Alzheimer’s disease. In the present study, we address the question of whether event-related or oscillatory measures, or a combination thereof, best predict the decline of verbal memory in mild cognitive impairment and Alzheimer’s disease. Single-trial correlation analyses show that despite a similarity in their time courses and sensitivities to word repetition, the P600 and the alpha suppression components are minimally correlated with each other on a trial-by-trial basis (generally |rs| < 0.10). This suggests that they are unlikely to stem from the same neural mechanism. Furthermore, event-related brain potentials constructed from bandpass filtered (delta, theta, alpha, beta or gamma bands) single-trial data indicate that only delta band activity (1–4 Hz) is strongly correlated (r = 0.94, P < 0.001) with the canonical P600 repetition effect; event-related potentials in higher frequency bands are not. Importantly, stepwise multiple regression analyses reveal that the three event-related brain potential/oscillatory measures are complementary in predicting California Verbal Learning Test scores (overall R2’s in 0.45–0.63 range). The present study highlights the importance of combining EEG event-related potential and oscillatory measures to better characterize the multiple mechanisms of memory failure in individuals with mild cognitive impairment or prodromal Alzheimer’s disease.

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