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

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.

Download Full-text

Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET

Neurology ◽

10.1212/wnl.0000000000012775 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012775

Author(s):

Suzanne Schindler ◽

Yan Li ◽

Virginia D. Buckles ◽

Brian Andrew Gordon ◽

Tammie L.S. Benzinger ◽

...

Keyword(s):

Alzheimer Disease ◽

Symptom Onset ◽

Standardized Uptake Value ◽

Tipping Point ◽

Pet Scan ◽

Amyloid Pet ◽

Amyloid Burden ◽

Cognitively Normal ◽

Amyloid Accumulation ◽

Dementia Syndrome

Objective:To predict when cognitively normal individuals with brain amyloidosis will develop symptoms of Alzheimer disease (AD).Methods:Brain amyloid burden was measured by amyloid PET with Pittsburgh compound B. The mean cortical standardized uptake value ratio (SUVR) was transformed into a timescale using longitudinal data.Results:Amyloid accumulation was evaluated in 236 individuals who underwent more than one amyloid PET scan. The average age was 66.5 ± 9.2 years and twelve individuals (5%) had cognitive impairment at their baseline amyloid PET scan. A tipping point in amyloid accumulation was identified at a low level of amyloid burden (SUVR 1.2), after which nearly all individuals accumulated amyloid at a relatively consistent rate until reaching a high level of amyloid burden (SUVR 3.0). The average time between levels of amyloid burden was used to estimate the age at which an individual reached SUVR 1.2. Longitudinal clinical diagnoses for 180 individuals were aligned by the estimated age at SUVR 1.2. In the twenty-two individuals who progressed from cognitively normal to a typical AD dementia syndrome, the estimated age at which an individual reached SUVR 1.2 predicted the age at symptom onset (R2=0.54, p<0.0001, root mean square error (RMSE) 4.5 years); the model was more accurate after exclusion of three likely misdiagnoses (R2=0.84, p<0.0001, RMSE of 2.8 years).Conclusions:The age of symptom onset in sporadic AD is strongly correlated with the age that an individual reaches a tipping point in amyloid accumulation.

Download Full-text

Topographic Distribution of Amyloid-β, Tau, and Atrophy in Patients With Behavioral/Dysexecutive Alzheimer Disease

Neurology ◽

10.1212/wnl.0000000000011081 ◽

2020 ◽

Vol 96 (1) ◽

pp. e81-e92

Author(s):

Joseph Therriault ◽

Tharick A. Pascoal ◽

Melissa Savard ◽

Andrea L. Benedet ◽

Mira Chamoun ◽

...

Keyword(s):

Alzheimer Disease ◽

Clinical Symptoms ◽

Characteristic Curve ◽

Tertiary Care ◽

Amyloid Β ◽

Executive Dysfunction ◽

Anterior Cingulate ◽

Amyloid Pet ◽

Clinical Criteria ◽

Tau Pet

ObjectiveTo determine the associations between amyloid-PET, tau-PET, and atrophy with the behavioral/dysexecutive presentation of Alzheimer disease (AD), how these differ from amnestic AD, and how they correlate to clinical symptoms.MethodsWe assessed 15 patients with behavioral/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 patients with disease severity– and age-matched amnestic AD and a group of 131 cognitively unimpaired (CU) elderly individuals. All participants were evaluated with amyloid-PET with [18F]AZD4694, tau-PET with [18F]MK6240, MRI, and neuropsychological testing.ResultsVoxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioral/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate, and frontal insular cortices in contrast to amnestic AD. No differences were observed in the distribution of amyloid-PET or atrophy as determined by voxel-based morphometry. Voxelwise area under the receiver operating characteristic curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate, and frontal insular cortices were best able to differentiate between behavioral/dysexecutive and amnestic AD (area under the curve 0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction.ConclusionsOur results provide evidence of frontal cortical involvement of tau pathology in behavioral/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome.

Download Full-text

Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease

Neurology ◽

10.1212/wnl.0000000000006075 ◽

2018 ◽

Vol 91 (9) ◽

pp. e859-e866 ◽

Cited By ~ 58

Author(s):

Andrew J. Aschenbrenner ◽

Brian A. Gordon ◽

Tammie L.S. Benzinger ◽

John C. Morris ◽

Jason J. Hassenstab

Keyword(s):

Alzheimer Disease ◽

Executive Functioning ◽

Episodic Memory ◽

Cognitive Decline ◽

Hippocampal Volume ◽

Cognitive Change ◽

Pet Scan ◽

Cognitive Domain ◽

Amyloid Pet ◽

Tau Pet

ObjectiveTo examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline.MethodsA total of 152 middle-aged and older adult participants with at least 2 clinical and cognitive assessments, a Clinical Dementia Rating score of 0 or 0.5, and a flortaucipir (18F-AV-1451) tau PET scan, a florbetapir (18F-AV-45) amyloid PET scan, and a structural MRI scan were recruited from the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Cognition was assessed with standard measures reflecting episodic memory, executive functioning, semantic fluency, and processing speed.ResultsResults from retrospective longitudinal analyses showed that each biomarker had a univariate association with the global cognitive composite; however, when each marker was analyzed in a single statistical model, only tau was a significant predictor of global cognitive decline. There was an interaction between tau and amyloid such that tau-related cognitive decline was worse in individuals with high amyloid. There was also an interaction with hippocampal volume indicating that individuals with high levels of all 3 pathologies exhibited the greatest declines in cognition. Additional analyses within each cognitive domain indicated that tau had the largest negative influence on tests of episodic memory and executive functioning.ConclusionsTogether, these results suggest that increasing levels of tau most consistently relate to declines in cognition preceding biomarker collection. These findings support models of Alzheimer disease (AD) staging that suggest that elevated β-amyloid alone may be insufficient to produce cognitive change in individuals at risk for AD and support the use of multiple biomarkers to stage AD progression.

Download Full-text

Association of blood-based transcriptional risk scores with biomarkers for Alzheimer disease

Neurology Genetics ◽

10.1212/nxg.0000000000000517 ◽

2020 ◽

Vol 6 (6) ◽

pp. e517

Author(s):

Young Ho Park ◽

Angela Hodges ◽

Andrew Simmons ◽

Simon Lovestone ◽

Michael W. Weiner ◽

...

Keyword(s):

Alzheimer Disease ◽

Cortical Thickness ◽

Hippocampal Volume ◽

Risk Scores ◽

Functional Genes ◽

Class Iii ◽

Herpes Simplex Virus 1 ◽

Neuroimaging Biomarkers ◽

Simplex Virus

ObjectiveTo determine whether transcriptional risk scores (TRSs), a summation of polarized expression levels of functional genes, reflect the risk of Alzheimer disease (AD).MethodsBlood transcriptome data were from Caucasian participants, which included AD, mild cognitive impairment, and cognitively normal controls (CN) in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 661) and AddNeuroMed (n = 674) cohorts. To calculate TRSs, we selected functional genes that were expressed under the control of the AD risk loci and were identified as being responsible for AD by using Bayesian colocalization and mendelian randomization methods. Regression was used to investigate the association of the TRS with diagnosis (AD vs CN) and MRI biomarkers (entorhinal thickness and hippocampal volume). Regression was also used to evaluate whether expression of each functional gene was associated with AD diagnosis.ResultsThe TRS was significantly associated with AD diagnosis, hippocampal volume, and entorhinal cortical thickness in the ADNI. The association of the TRS with AD diagnosis and entorhinal cortical thickness was also replicated in AddNeuroMed. Among functional genes identified to calculate the TRS, CD33 and PILRA were significantly upregulated, and TRAPPC6A was significantly downregulated in patients with AD compared with CN, all of which were identified in the ADNI and replicated in AddNeuroMed.ConclusionsThe blood-based TRS is significantly associated with AD diagnosis and neuroimaging biomarkers. In blood, CD33 and PILRA were known to be associated with uptake of β-amyloid and herpes simplex virus 1 infection, respectively, both of which may play a role in the pathogenesis of AD.Classification of evidenceThe study is rated Class III because of the case control design and the risk of spectrum bias.

Download Full-text

Olfactory testing does not predict β-amyloid, MRI measures of neurodegeneration or vascular pathology in the British 1946 birth cohort

Journal of Neurology ◽

10.1007/s00415-020-10004-4 ◽

2020 ◽

Vol 267 (11) ◽

pp. 3329-3336

Author(s):

Sarah M. Buchanan ◽

Thomas D. Parker ◽

Christopher A. Lane ◽

Ashvini Keshavan ◽

Sarah E. Keuss ◽

...

Keyword(s):

White Matter ◽

Birth Cohort ◽

Entorhinal Cortex ◽

Cortical Thickness ◽

White Matter Hyperintensity ◽

Amyloid Pet ◽

Brain Health ◽

Cognitively Normal ◽

Olfactory Identification ◽

Β Amyloid

Abstract Objective To explore the value of olfactory identification deficits as a predictor of cerebral β-amyloid status and other markers of brain health in cognitively normal adults aged ~ 70 years. Methods Cross-sectional observational cohort study. 389 largely healthy and cognitively normal older adults were recruited from the MRC National Survey of Health and Development (1946 British Birth cohort) and investigated for olfactory identification deficits, as measured by the University of Pennsylvania Smell Identification Test. Outcome measures were imaging markers of brain health derived from 3 T MRI scanning (cortical thickness, entorhinal cortex thickness, white matter hyperintensity volumes); 18F florbetapir amyloid-PET scanning; and cognitive testing results. Participants were assessed at a single centre between March 2015 and January 2018. Results Mean (± SD) age was 70.6 (± 0.7) years, 50.8% were female. 64.5% had hyposmia and 2.6% anosmia. Olfaction showed no association with β-amyloid status, hippocampal volume, entorhinal cortex thickness, AD signature cortical thickness, white matter hyperintensity volume, or cognition. Conclusion and relevance In the early 70s, olfactory function is not a reliable predictor of a range of imaging and cognitive measures of preclinical AD. Olfactory identification deficits are not likely to be a useful means of identifying asymptomatic amyloidosis. Further studies are required to assess if change in olfaction may be a proximity marker for the development of cognitive impairment.

Download Full-text

THE ASSOCIATION BETWEEN PERSONALITY AND TAU PET DEPOSITION IN COGNITIVELY NORMAL OLDER ADULTS: FINDINGS FROM THE KNIGHT ALZHEIMER DISEASE RESEARCH CENTER

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.2572 ◽

2017 ◽

Vol 13 (7) ◽

pp. P145-P146

Author(s):

Stephanie A. Schultz ◽

Brian A. Gordon ◽

Shruti Mishra ◽

John C. Morris ◽

Janet M. Duchek ◽

...

Keyword(s):

Older Adults ◽

Alzheimer Disease ◽

Research Center ◽

Cognitively Normal ◽

Disease Research ◽

Tau Pet

Download Full-text

Tau-PET and in vivo Braak-staging as prognostic markers of future cognitive decline in cognitively normal to demented individuals

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00880-x ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Davina Biel ◽

Matthias Brendel ◽

Anna Rubinski ◽

Katharina Buerger ◽

Daniel Janowitz ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Decline ◽

Prognostic Markers ◽

Patient Specific ◽

Amyloid Pet ◽

Braak Stage ◽

Cognitively Normal ◽

Braak Staging ◽

Pet Tracer ◽

Tau Pet

Abstract Background To systematically examine the clinical utility of tau-PET and Braak-staging as prognostic markers of future cognitive decline in older adults with and without cognitive impairment. Methods In this longitudinal study, we included 396 cognitively normal to dementia subjects with 18F-Florbetapir/18F-Florbetaben-amyloid-PET, 18F-Flortaucipir-tau-PET and ~ 2-year cognitive follow-up. Annual change rates in global cognition (i.e., MMSE, ADAS13) and episodic memory were calculated via linear-mixed models. We determined global amyloid-PET (Centiloid) plus global and Braak-stage-specific tau-PET SUVRs, which were stratified as positive(+)/negative(−) at pre-established cut-offs, classifying subjects as Braak0/BraakI+/BraakI–IV+/BraakI–VI+/Braakatypical+. In bootstrapped linear regression, we assessed the predictive accuracy of global tau-PET SUVRs vs. Centiloid on subsequent cognitive decline. To test for independent tau vs. amyloid effects, analyses were further controlled for the contrary PET-tracer. Using ANCOVAs, we tested whether more advanced Braak-stage predicted accelerated future cognitive decline. All models were controlled for age, sex, education, diagnosis, and baseline cognition. Lastly, we determined Braak-stage-specific conversion risk to mild cognitive impairment (MCI) or dementia. Results Baseline global tau-PET SUVRs explained more variance (partial R2) in future cognitive decline than Centiloid across all cognitive tests (Cohen’s d ~ 2, all tests p < 0.001) and diagnostic groups. Associations between tau-PET and cognitive decline remained consistent when controlling for Centiloid, while associations between amyloid-PET and cognitive decline were non-significant when controlling for tau-PET. More advanced Braak-stage was associated with gradually worsening future cognitive decline, independent of Centiloid or diagnostic group (p < 0.001), and elevated conversion risk to MCI/dementia. Conclusion Tau-PET and Braak-staging are highly predictive markers of future cognitive decline and may be promising single-modality estimates for prognostication of patient-specific progression risk in clinical settings.

Download Full-text

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

JAMA Ophthalmology ◽

10.1001/jamaophthalmol.2021.0320 ◽

2021 ◽

Author(s):

Min Soo Byun ◽

Sung Wook Park ◽

Jun Ho Lee ◽

Dahyun Yi ◽

So Yeon Jeon ◽

...

Keyword(s):

Alzheimer Disease ◽

Cognitively Normal ◽

Normal Individuals ◽

Neuroimaging Biomarkers

Download Full-text

The implications of different approaches to define AT(N) in Alzheimer disease

Neurology ◽

10.1212/wnl.0000000000009485 ◽

2020 ◽

Vol 94 (21) ◽

pp. e2233-e2244 ◽

Cited By ~ 4

Author(s):

Niklas Mattsson-Carlgren ◽

Antoine Leuzy ◽

Shorena Janelidze ◽

Sebastian Palmqvist ◽

Erik Stomrud ◽

...

Keyword(s):

Alzheimer Disease ◽

Cognitive Decline ◽

Clinical Stage ◽

Hippocampal Volume ◽

Cognitively Impaired ◽

Amyloid Pet ◽

Prognostic Information ◽

Neurofilament Light ◽

Amyloid Aβ ◽

Tau Pet

ObjectiveTo compare different β-amyloid (Aβ), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies.MethodsA total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disease [AD] dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU and 144 CI [138 MCI and 6 AD dementia]). Biomarkers for A were CSF Aβ42 and amyloid-PET ([18F]flutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET ([18F]flortaucipir); and for (N), hippocampal volume, temporal cortical thickness, and CSF neurofilament light (NfL). Binarization of biomarkers was achieved using cutoffs defined in other cohorts. The relationship between different AT(N) combinations and cognitive trajectories (longitudinal Mini-Mental State Examination scores) was examined using linear mixed modeling and coefficient of variation.ResultsAmong CU participants, A−T−(N)− or A+T−(N)− variants were most common. However, more T+ cases were seen using p-tau than tau PET. Among CI participants, A+T+(N)+ was more common; however, more (N)+ cases were seen for MRI measures relative to CSF NfL. Tau PET best predicted longitudinal cognitive decline in CI and p-tau in CU participants. Among CI participants, continuous T (especially tau PET) and (N) measures improved the prediction of cognitive decline compared to binary measures.ConclusionsOur findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.

Download Full-text