Association of Retinal Changes With Alzheimer Disease Neuroimaging Biomarkers in Cognitively Normal Individuals

ObjectiveTo determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals.MethodsCross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar β-amyloid (Aβ) with PET using the [11C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers.ResultsAccelerated changes in CSF Aβ1-42 (Aβ42) occurred at 48.28 years of age and in Aβ42/Aβ40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aβ42 and Aβ42/Aβ40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other.ConclusionsOur findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.

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Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease

Neurology ◽

10.1212/wnl.0000000000003916 ◽

2017 ◽

Vol 88 (19) ◽

pp. 1814-1821 ◽

Cited By ~ 28

Author(s):

Kok Pin Ng ◽

Tharick A. Pascoal ◽

Sulantha Mathotaarachchi ◽

Chang-Oh Chung ◽

Andréa L. Benedet ◽

...

Keyword(s):

Alzheimer Disease ◽

Neuropsychiatric Symptoms ◽

Posterior Cingulate Cortex ◽

Metabolic Dysfunction ◽

Tau Pathology ◽

Sleep Behavior ◽

Cognitively Normal ◽

Preclinical Ad ◽

Normal Individuals ◽

Metabolic Dysfunctions

Objective:To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD).Methods:We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET.Results:Individuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction.Conclusions:The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.

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Is comprehensiveness critical? Comparing short and long format cognitive assessments in preclinical Alzheimer disease

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00894-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Jason Hassenstab ◽

Jessica Nicosia ◽

Megan LaRose ◽

Andrew J. Aschenbrenner ◽

Brian A. Gordon ◽

...

Keyword(s):

Alzheimer Disease ◽

Multiple Regression ◽

Cortical Thickness ◽

Symptom Onset ◽

Alternative Assessment ◽

Amyloid Pet ◽

Cognitively Normal ◽

Long Form ◽

Neuroimaging Biomarkers ◽

Tau Pet

Abstract Background Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a “sampling” of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers. Methods Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal older adults (n = 6230) from the National Alzheimer’s Coordinating Center (NACC) cohort who had, on average, 2.3 ± 1.2 annual assessments. Multiple regression models in a separate sample (n = 416) from the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) compared the sensitivity of the MoCA and long-form measures to neuroimaging biomarkers including amyloid PET, tau PET, and cortical thickness. Results Hazard ratios suggested that both the MoCA and the long-form measures are similarly and modestly efficacious in predicting symptomatic conversion, although model comparison analyses indicated that the long-form measures slightly outperformed the MoCA (HRs > 1.57). AUC analyses indicated no difference between the measures in predicting conversion (DeLong’s test, Z = 1.48, p = 0.13). Sensitivity to AD neuroimaging biomarkers was similar for the two measures though there were only modest associations with tau PET (rs = − 0.13, ps < 0.02) and cortical thickness in cognitively normal participants (rs = 0.15–0.16, ps < 0.007). Conclusions Both test formats showed weak associations with symptom onset, AUC analyses indicated low diagnostic accuracy, and biomarker correlations were modest in cognitively normal participants. Alternative assessment approaches are needed to improve how clinicians and researchers monitor cognitive changes and disease progression prior to symptom onset.

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Neuroimaging biomarkers and impaired olfaction in cognitively normal individuals

Annals of Neurology ◽

10.1002/ana.24960 ◽

2017 ◽

Vol 81 (6) ◽

pp. 871-882 ◽

Cited By ~ 24

Author(s):

Maria Vassilaki ◽

Teresa J. Christianson ◽

Michelle M. Mielke ◽

Yonas E. Geda ◽

Walter K. Kremers ◽

...

Keyword(s):

Cognitively Normal ◽

Normal Individuals ◽

Neuroimaging Biomarkers

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Cerebrospinal Fluid Hypocretin and Nightmares in Dementia Syndromes

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000509585 ◽

2021 ◽

pp. 19-25

Author(s):

Lynn Marie Trotti ◽

Donald L. Bliwise ◽

Glenda L. Keating ◽

David B. Rye ◽

William T. Hu

Keyword(s):

Cerebrospinal Fluid ◽

Alzheimer Disease ◽

Cholinesterase Inhibitor ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Cognitively Normal ◽

Dementia Patients ◽

Sleep Questionnaires ◽

Sleep Alterations ◽

Normal Controls

Background/Aims: Hypocretin promotes wakefulness and modulates REM sleep. Alterations in the hypocretin system are increasingly implicated in dementia. We evaluated relationships among hypocretin, dementia biomarkers, and sleep symptoms in elderly participants, most of whom had dementia. Methods: One-hundred twenty-six adults (mean age 66.2 ± 8.4 years) were recruited from the Emory Cognitive Clinic. Diagnoses were Alzheimer disease (AD; n = 60), frontotemporal dementia (FTD; n = 21), and dementia with Lewy bodies (DLB; n = 20). We also included cognitively normal controls (n = 25). Participants and/or caregivers completed sleep questionnaires and lumbar puncture was performed for cerebrospinal fluid (CSF) assessments. Results: Except for sleepiness (worst in DLB) and nocturia (worse in DLB and FTD) sleep symptoms did not differ by diagnosis. CSF hypocretin concentrations were available for 87 participants and normal in 70, intermediate in 16, and low in 1. Hypocretin levels did not differ by diagnosis. Hypocretin levels correlated with CSF total τ levels only in men (r = 0.34; p = 0.02). Lower hypocretin levels were related to frequency of nightmares (203.9 ± 29.8 pg/mL in those with frequent nightmares vs. 240.4 ± 46.1 pg/mL in those without; p = 0.05) and vivid dreams (209.1 ± 28.3 vs. 239.5 ± 47.8 pg/mL; p = 0.014). Cholinesterase inhibitor use was not associated with nightmares or vivid dreaming. Conclusion: Hypocretin levels did not distinguish between dementia syndromes. Disturbing dreams in dementia patients may be related to lower hypocretin concentrations in CSF.

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Lower functional hippocampal redundancy in mild cognitive impairment

Translational Psychiatry ◽

10.1038/s41398-020-01166-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Stephanie Langella ◽

◽

Muhammad Usman Sadiq ◽

Peter J. Mucha ◽

Kelly S. Giovanello ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Decline ◽

Resting State ◽

Memory Performance ◽

Potential Mechanism ◽

Network Efficiency ◽

Cognitively Normal ◽

Normal Individuals ◽

The Relationship

AbstractWith an increasing prevalence of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in response to an aging population, it is critical to identify and understand neuroprotective mechanisms against cognitive decline. One potential mechanism is redundancy: the existence of duplicate elements within a system that provide alternative functionality in case of failure. As the hippocampus is one of the earliest sites affected by AD pathology, we hypothesized that functional hippocampal redundancy is protective against cognitive decline. We compared hippocampal functional redundancy derived from resting-state functional MRI networks in cognitively normal older adults, with individuals with early and late MCI, as well as the relationship between redundancy and cognition. Posterior hippocampal redundancy was reduced between cognitively normal and MCI groups, plateauing across early and late MCI. Higher hippocampal redundancy was related to better memory performance only for cognitively normal individuals. Critically, functional hippocampal redundancy did not come at the expense of network efficiency. Our results provide support that hippocampal redundancy protects against cognitive decline in aging.

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An overview of psychological and social factors in Charles Bonnet syndrome

Therapeutic Advances in Ophthalmology ◽

10.1177/25158414211034715 ◽

2021 ◽

Vol 13 ◽

pp. 251584142110347

Author(s):

Lee Jones ◽

Lara Ditzel-Finn ◽

Jamie Enoch ◽

Mariya Moosajee

Keyword(s):

Emotional Response ◽

Causal Mechanism ◽

Visual Hallucinations ◽

Cognitively Normal ◽

Charles Bonnet Syndrome ◽

Raising Awareness ◽

Normal Individuals ◽

The Social ◽

Recent Developments ◽

Insight Into

Charles Bonnet syndrome (CBS) is a condition where cognitively normal individuals with sight impairment experience simple and/or complex visual hallucinations. The exact pathogenesis of CBS is unknown; however, deafferentation is often recognised as a causal mechanism. Studies have provided insight into the multifaceted impact of CBS on wellbeing. Onset of CBS may cause distress among those believing visual hallucinations are indicative of a neurological condition. Hallucinatory content is often congruent with the emotional response. For example, hallucinations of a macabre nature typically result in a fearful response. Visual hallucinations may be highly disruptive, causing everyday tasks to become challenging. Clinical management relies on forewarning and pre-emptive questioning. Yet, knowledge and awareness of CBS is typically low. In this review, we provide a summary of the social and psychological implications of CBS and explore recent developments aimed at raising awareness and improving patient management.

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