Amyloid discordance analysis in cognitively normal monozygotic twins demonstrates that the memory domain is affected first in preclinical AD

Abstract Decline in driving skills begins in preclinical AD, when an older adult remains cognitively normal, but the underlying disease process has begun. Preclinical AD is detectable among cognitively normal individuals using molecular biomarkers: positron emission tomography (PET) imaging and cerebrospinal fluid (CSF). The aim of this prospective, longitudinal study is to determine whether naturalistic driving behavior using in-vehicle dataloggers can distinguish older adults with (n=36) and without preclinical AD (n=134). Driving data was calculated as mean/month for several variables (number of trips/day, trip length, trip time, speeding, and hard-braking) for participants followed between one to 46 months. Using stepwise logistic regression, the area under the receiver operating curve (AUC) and 95% confidence interval for these five variables was 0.73 (0.63-0.79) in distinguishing those with and without preclinical AD via amyloid imaging. When age, gender, race, and education were added, the model improved: 0.80 (0.72-0.88). Finally, when apolipoprotein ε4 allele (APOε4), obtained via blood or saliva, was added to the model, accuracy improved: 0.84 (0.77-0.89). Similar results were found using CSF biomarker tau/Aβ42: AUCs (95% CI) were 0.68 (0.58-0.79) for driving variables alone, 0.77 (0.69-0.86) for driving variables and demographics, and 0.87 (0.80-0.94) driving variables, demographics, and apolipoprotein ε4 allele. These promising findings suggest that naturalistic driving behavior can predict those with and without preclinical AD. The AUC is further improved with demographics and APOε4, an easily obtainable genetic biomarker. This model may be used in clinical/research settings as a screen or adjunct for diagnostics and prognostics purposes.

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"Preclinical" AD revisited: Neuropathology of cognitively normal older adults

Neurology ◽

10.1212/wnl.55.3.370 ◽

2000 ◽

Vol 55 (3) ◽

pp. 370-376 ◽

Cited By ~ 200

Author(s):

F. A. Schmitt ◽

D. G. Davis ◽

D. R. Wekstein ◽

C. D. Smith ◽

J. W. Ashford ◽

...

Keyword(s):

Older Adults ◽

Cognitively Normal ◽

Preclinical Ad

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A Naturalistic Study of Driving Behavior in Older Adults and Preclinical Alzheimer Disease: A Pilot Study

Journal of Applied Gerontology ◽

10.1177/0733464817690679 ◽

2017 ◽

Vol 38 (2) ◽

pp. 277-289 ◽

Cited By ~ 8

Author(s):

Ganesh M. Babulal ◽

Sarah H. Stout ◽

Tammie L. S. Benzinger ◽

Brian R. Ott ◽

David B. Carr ◽

...

Keyword(s):

Older Adults ◽

Sample Size ◽

Small Sample Size ◽

Driving Behavior ◽

Driving Performance ◽

Small Sample ◽

Clinical Consequence ◽

Cognitively Normal ◽

Preclinical Ad ◽

One Year

A clinical consequence of symptomatic Alzheimer’s disease (AD) is impaired driving performance. However, decline in driving performance may begin in the preclinical stage of AD. We used a naturalistic driving methodology to examine differences in driving behavior over one year in a small sample of cognitively normal older adults with ( n = 10) and without ( n = 10) preclinical AD. As expected with a small sample size, there were no statistically significant differences between the two groups, but older adults with preclinical AD drove less often, were less likely to drive at night, and had fewer aggressive behaviors such as hard braking, speeding, and sudden acceleration. The sample size required to power a larger study to determine differences was calculated.

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Evidence for Reduced Autobiographical Memory Episodic Specificity in Cognitively Normal Middle-Aged and Older Individuals at Increased Risk for Alzheimer’s Disease Dementia

Journal of the International Neuropsychological Society ◽

10.1017/s1355617718000577 ◽

2018 ◽

Vol 24 (10) ◽

pp. 1073-1083 ◽

Cited By ~ 14

Author(s):

Matthew D. Grilli ◽

Aubrey A. Wank ◽

John J. Bercel ◽

Lee Ryan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Older Individuals ◽

Autobiographical Memories ◽

Middle Aged ◽

Cognitively Normal ◽

Preclinical Ad ◽

Increased Risk ◽

And Gender

AbstractObjectives: Alzheimer’s disease (AD) typically eludes clinical detection for years, if not decades. The identification of subtle cognitive decline associated with preclinical AD would not only advance understanding of the disease, but also provide clinical targets to assess preventative and early intervention treatments. Disrupted retrieval of detailed episodic autobiographical memories may be a sensitive indicator of subtle cognitive decline, because this type of memory taxes a core neural network affected by preclinical AD neuropathology. Methods: To begin to address this idea, we assessed the episodic specificity of autobiographical memories retrieved by cognitively normal middle-aged and older individuals who are carriers of the apolipoprotein E ε4 allele – a population at increased risk for subtle cognitive decline related to neuropathological risk factors for AD. We compared the ε4 carriers to non-carriers of ε4 similar in age, education, and gender. Results: The ε4 carriers did not perform worse than the non-carriers on a comprehensive battery of neuropsychological tests. In contrast, as a group, the ε4 carriers generated autobiographical memories that were reduced in “internal” or episodic details relative to non-carriers. Conclusions: These findings support the notion that reduced autobiographical episodic detail generation may be a marker of subtle cognitive decline associated with AD. (JINS, 2018, 24, 1073–1183)

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Arterial spin labeled cerebral perfusion in cognitively normal monozygotic twins

Journal of the Neurological Sciences ◽

10.1016/j.jns.2017.08.2264 ◽

2017 ◽

Vol 381 ◽

pp. 804

Author(s):

C.Y. Lee ◽

M. Ten Kate ◽

J. Kuijer ◽

F. Barkhof

Keyword(s):

Cerebral Perfusion ◽

Monozygotic Twins ◽

Cognitively Normal

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Cognitively normal women with Alzheimer’s disease proteinopathy show relative preservation of memory but not of hippocampal volume

Alzheimer s Research & Therapy ◽

10.1186/s13195-019-0565-1 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Jessica Z. K. Caldwell ◽

Jeffrey L. Cummings ◽

Sarah J. Banks ◽

Sebastian Palmqvist ◽

Oskar Hansson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Verbal Memory ◽

Interactive Effect ◽

Hippocampal Volume ◽

Word Recall ◽

Subjective Cognitive Decline ◽

Cognitively Normal ◽

Sex Diagnosis ◽

Preclinical Ad

Abstract Background We examined interactive effects of sex, diagnosis, and cerebrospinal fluid (CSF) amyloid beta/phosphorylated tau ratio (Aβ/P-tau) on verbal memory and hippocampal volumes. Methods We assessed 682 participants (350 women) from BioFINDER (250 cognitively normal [CN]; and 432 symptomatic: 186 subjective cognitive decline [SCD], 246 mild cognitive impairment [MCI]). General linear models evaluated effects of Alzheimer’s disease (AD) proteinopathy (CSF Aß/p-tau ratio), diagnosis, and sex on verbal memory (ADAS-cog 10-word recall), semantic fluency (animal naming fluency), visuospatial skills (cube copy), processing speed/attention functions (Symbol Digit Modalities Test and Trail Making Part A), and hippocampal volumes. Results Amyloid-positive (Aβ/P-tau+) CN women (women with preclinical AD) showed memory equivalent to amyloid-negative (Aβ/P-tau−) CN women. In contrast, Aβ/P-tau+ CN men (men with preclinical AD) showed poorer memory than Aβ/P-tau− CN men. Symptomatic groups showed no sex differences in effect of AD proteinopathy on memory. There was no interactive effect of sex, diagnosis, and Aβ/P-tau on other measures of cognition or on hippocampal volume. Conclusions CN women show relatively preserved verbal memory, but not general cognitive reserve or preserved hippocampal volume in the presence of Aβ/P-tau+. Results have implications for diagnosing AD in women, and for clinical trials.

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Sequence of Alzheimer disease biomarker changes in cognitively normal adults

Neurology ◽

10.1212/wnl.0000000000010747 ◽

2020 ◽

Vol 95 (23) ◽

pp. e3104-e3116

Author(s):

Jingqin Luo ◽

Folasade Agboola ◽

Elizabeth Grant ◽

Colin L. Masters ◽

Marilyn S. Albert ◽

...

Keyword(s):

Alzheimer Disease ◽

Change Point ◽

Standardized Uptake Value ◽

Brain Structures ◽

Hippocampal Volume ◽

Cognitive Outcomes ◽

Cross Sectional ◽

Cognitively Normal ◽

Preclinical Ad ◽

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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Association of anxiety with subcortical amyloidosis in cognitively normal older adults

Molecular Psychiatry ◽

10.1038/s41380-018-0214-2 ◽

2018 ◽

Vol 25 (10) ◽

pp. 2599-2607 ◽

Cited By ~ 6

Author(s):

Bernard J. Hanseeuw ◽

Victoria Jonas ◽

Jonathan Jackson ◽

Rebecca A. Betensky ◽

Dorene M. Rentz ◽

...

Keyword(s):

Neuropsychiatric Symptoms ◽

Depression Scale ◽

Amyloid Β ◽

Staging System ◽

Older Individuals ◽

Cognitively Normal ◽

Preclinical Ad ◽

Positron Emission ◽

Subcortical Regions

Abstract Late-life anxiety has been associated with increased progression from normal cognition to amnestic MCI, suggesting that anxiety may be a neuropsychiatric symptom of Alzheimer’s disease (AD) pathological changes and a possible marker of anatomical progression in preclinical AD. This study examined whether cortical or subcortical amyloidosis, indicating earlier or later stages of preclinical AD, was associated with greater self-reported anxiety among 118 cognitively normal volunteers, aged 65–90 years, and whether this association was stronger in APOEε4 carriers. Participants underwent Pittsburgh Compound B Positron Emission Tomography (PiB-PET) to assess fibrillar amyloid-β burden in cortical and subcortical regions, and measurement of anxiety using the Hospital Anxiety and Depression Scale-anxiety subscale. Higher PiB-PET measures in the subcortex (striatum, amygdala, and thalamus), but not in the cortex, were associated with greater anxiety, adjusting for demographics, cognition, and depression. Findings were similar using a cortico-striatal staging system and continuous PET measurements. Anxiety was highest in APOEε4 carriers with subcortical amyloidosis. This work supports in vivo staging of amyloid-β deposition in both cortical and subcortical regions as a promising approach to the study of neuropsychiatric symptoms such as anxiety in cognitively normal older individuals. Elevated anxiety symptoms in combination with high-risk biological factors such as APOEε4 and subcortical amyloid-β may identify participants closest to MCI for secondary prevention trials.

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