To determine whether a digital clock-drawing test, DCTclock, improves upon standard cognitive assessments for discriminating diagnostic groups and for detecting biomarker evidence of amyloid and tau ...pathology in clinically normal older adults (CN).
Participants from the Harvard Aging Brain Study and the PET laboratory at Massachusetts General Hospital were recruited to undergo the DCTclock, standard neuropsychological assessments including the Preclinical Alzheimer Cognitive Composite (PACC), and amyloid/tau PET imaging. Receiver operating curve analyses were used to assess diagnostic and biomarker discriminability. Logistic regression and partial correlations were used to assess DCTclock performance in relation to PACC and PET biomarkers.
A total of 300 participants were studied. Among the 264 CN participants, 143 had amyloid and tau PET imaging (Clinical Dementia Rating CDR 0, Mini-Mental State Examination MMSE 28.9 ± 1.2). An additional 36 participants with a diagnosis of mild cognitive impairment or early Alzheimer dementia (CDR 0.5, MMSE 25.2 ± 3.9) were added to assess diagnostic discriminability. DCTclock showed excellent discrimination between diagnostic groups (area under the receiver operating characteristic curve 0.86). Among CN participants with biomarkers, the DCTclock summary score and spatial reasoning subscores were associated with greater amyloid and tau burden and showed better discrimination (Cohen d = 0.76) between Aβ± groups than the PACC (d = 0.30).
DCTclock discriminates between diagnostic groups and improves upon traditional cognitive tests for detecting biomarkers of amyloid and tau pathology in CN older adults. The validation of such digitized measures has the potential of providing an efficient tool for detecting early cognitive changes along the AD trajectory.
This study provides Class II evidence that DCTclock results were associated with amyloid and tau burden in CN older adults.
Neuroimaging studies of autosomal dominant Alzheimer's disease (ADAD) enable characterization of the trajectories of cerebral amyloid-β (Aβ) and tau accumulation in the decades prior to clinical ...symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD.
Fourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2-3 sessions of Aβ (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2-4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers.
Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aβ accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers.
Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aβ burden and neocortical tau accumulation in ADAD.
Objective
The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences ...might associate with cognitive trajectories.
Methods
Participants were 343 clinically normal individuals (women, 58%; 73.8 8.5 years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 7.3 years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined 18F‐Flortaucipir (FTP)‐positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP‐signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*Aβ‐PET positive / negative (+ / −) and sex*apolipoprotein ε4 (APOEε4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex‐differentiated tau ROIs and cognitive decline.
Results
Women showed significantly higher FTP‐signals than men across multiple regions of the cortical mantle (p < 0.007). β‐amyloid (Aβ)‐moderated sex differences in tau signal were localized to medial and inferio‐lateral temporal regions (p < 0.007); Aβ + women exhibited greater FTP‐signal than other groups. APOEε4‐moderated sex differences in FTP‐signal were only found in the lateral occipital lobe. Women with higher FTP‐signals in composite ROI exhibited faster cognitive decline than men (p = 0.04).
Interpretation
Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and Aβ were predominantly localized in the temporal lobe, however, sex differences in extra‐temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020;88:921–932
We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, ...and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline.
= 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample (
= 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging (
= 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5.
Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI 0.21-0.25,
< 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI 0.59-0.77,
< 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden (
= -0.20, 95% CI -0.38 - -0.01,
= 0.049) and tau deposition in the entorhinal cortex (
= -0.38, 95% CI -0.54 - -0.19,
< 0.001) and inferior-temporal lobe (
= -0.23, 95% CI -0.41 - -0.02,
= 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI 0.84-0.98), which was better than baseline C3 (
< 0.001) and baseline PACC-5 scores (
= 0.02).
While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.
Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive ...symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective.
The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator.
Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored.
Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012).
Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.
Background
Network hyperexcitability has emerged as an important contributor to cognitive dysfunction and clinical progression in Alzheimer’s disease (AD), with work in animal AD models supporting a ...mechanistic, feed‐forward link between neuronal hyperexcitability and amyloid and tau pathology. Seizures are a quintessential manifestation of network hyperexcitability in AD. AD is associated with a 2‐3‐fold increased risk of developing epilepsy, and epilepsy in AD is most often a focal, unilateral temporal lobe epilepsy. We hypothesized that if network hyperexcitability is mechanistically linked to AD pathology, then focal unitemporal hyperexcitability in individuals with AD and epilepsy would be associated with increased deposition of tau and/or amyloid within the epileptogenic hemisphere.
Method
We studied eight individuals with early clinical stages of AD who developed focal epilepsy early in the course of AD. All individuals underwent overnight scalp EEG, 3T structural brain MRI, and PET imaging with 11C‐PiB and 18F‐MK‐6240. We performed region‐of‐interest based imaging analyses and calculated asymmetry indices (AI) as: 200 * (Ipsilateral ‐ Contralateral) / (Ipsilateral + Contralateral), where ipsilateral and contralateral are relative to the epileptogenic hemisphere.
Result
Tau deposition was asymmetrically increased within the epileptogenic hemisphere. Individuals with a higher global tau burden showed asymmetrically increased tau in the lateral temporal lobe, medial and lateral parietal lobes, and frontal lobes of the epileptogenic hemisphere, while those with a lower global tau burden demonstrated a highly focal, discrete tau accumulation within the lateral temporal lobe. Amyloid deposition was also increased within the epileptogenic hemisphere, particularly in the lateral temporal, medial and lateral parietal, and frontal regions, though the magnitude of amyloid AI was lower than that of tau AI. We also found increased cortical atrophy in the lateral temporal and lateral parietal regions of the epileptogenic hemisphere.
Conclusion
Our study reveals a spatial association between focal epilepsy and asymmetries in tau and amyloid deposition and cortical atrophy in early clinical stages of AD. While historically, individuals with AD and epilepsy have been excluded from most studies in AD, our findings demonstrate that studying these individuals can provide unique insights on mechanisms that underlie the clinical and pathologic heterogeneity of AD.
Background
Previous work has shown that neuropsychiatric symptoms (NPS) such as depression in older adults are associated with cognitive decline and brain pathology related to Alzheimer’s disease ...(AD), but the constellation of NPS driving these associations is unclear. Traditionally, depressive symptoms have been assessed with the Geriatric Depression Scale (GDS), but newer NPS assessments, such as the Mild Behavioral Impairment‐Checklist (MBI‐C), have shown promise for identification of specific early features of symptomology. Here we examined the two affective domains of the MBI‐C in cognitively unimpaired older adults with moderate‐to‐severe depressive symptoms and non‐depressed older adults, and the association between these domains and neuroimaging biomarkers of AD.
Method
21 clinically normal (CN) older adults who met DSM5 criteria for major depression (MDD) (73.0±4.3 y.o., 62% female) and 25 non‐depressed older adults from related observational studies at our site (70.8±3.7 y.o., 64% female) underwent a clinical battery that included the GDS and MBI‐C self‐report domains focused on decreased interest‐motivation‐drive and increased dysphoria‐anhedonia‐anxiety (Range for each domain: 0–18). Participants completed neuroimaging consisting of MRI, amyloid‐(C11‐PiB)‐PET, and tau‐(F18‐FTP)‐PET. We focused analyses on neocortical amyloid and regional tau and atrophy in the amygdala and hippocampus. A Pearson correlation was used to assess the association between GDS total score and MBI‐C component scores. Linear regressions adjusted for age were used to investigate relationships between MBI‐C domains and ATN biomarkers.
Result
GDS total score was correlated with both MBI‐C domains across all participants (Fig.1, p<0.01). In participants with MDD, the MBI‐C decreased interest‐motivation‐drive domain was associated with elevated FTP in the amygdala and hippocampus, while the increased dysphoria‐anhedonia‐anxiety domain was not significantly related to PET signal (Table 2, Fig.2). MBI‐C domains were not related to PET signal or atrophy in non‐depressed control participants.
Conclusion
Preliminary findings with the MBI‐C suggest that the decreased interest‐motivation‐drive domain may be associated with tau pathology in older adults with moderate‐to‐severe depression. Additional work needs to be done in a larger depressed cohort to further understand the associations between specific depressive phenotypes and AD pathology.
Background
Clinically normal females exhibit greater 18F‐flortaucipir (FTP) PET signal than males in both temporal and neocortices. It remains unclear whether sex differences in neocortical regions ...are primarily explained by technical variability issues. We aimed to investigate the contribution of signal spillover/off‐target skull binding to sex differences in FTP‐PET. Next, we explored partial volume effects (PVE) by simulating sex differences in smoothed FTP‐PET signal. Discerning sex differences in tau signal versus noise is pivotal to understanding sex differences in the pathology of Alzheimer’s disease and associated tauopathies.
Method
343 clinically normal (female=58%; meanSD=73.88.5 years) (female=38%; meanSD=76.97.3 years) participants from the Harvard Aging Brain Study and the Alzheimer’s Disease Neuroimaging Initiative underwent cross‐sectional FTP‐PET (standardized uptake value ratios SUVrs). For skull analyses, we created skull ROIs based on signal 12mm from the outer perimeter of voxels in FreeSurfer‐defined tau ROIs. Linear regression models estimated the main effects of sex across cortical tau ROIs while correcting for local skull binding. We simulated PVE by convolving group‐level SUVr means in each ROI with 6mm Gaussian kernels, and then compared the sexes with linear regression models post‐smoothing.
Result
Widespread sex differences in skull binding were observed (Table 1). Covarying for skull binding ameliorated weaker sex differences in cortical FTP signal but did not impact the largest effects. Sex differences in PVE were observed in both female and male directions; no clear sex‐related biases in PVE were found to impact cortical tau sex differences except for the rostral middle frontal region (Figure 1).
Conclusion
Our findings suggest that sex differences in FTP‐PET are not solely attributed to skull ‘clouding’ or PVE, but rather support hypotheses of female‐related tau vulnerability. Nevertheless, as only two potential confounds were investigated, and gross morphology/volumetric issues remain a key concern, further investigation is needed to fully elucidate this phenomenon. Investigations of sex differences in longitudinal tau accumulation (a few preliminary reports already suggest faster rates in females) will add further support to the argument that noise properties inherent in FTP‐PET do not significantly contribute to sex differences in cortical tau signal.
Abstract
Background
Using a digital pen to record performance on neuropsychological tasks allows for the capture of much more subtle and nuanced aspects of cognitive performance. Previous research ...showed that lower DCTClock summary score was associated with greater entorhinal tau in clinically‐normal older adults (CN) (Rentz, AAIC 2019). Additionally, spatial reasoning was related to elevated entorhinal tau, inferior temporal tau, and neocortical amyloid. Given the observed cognitive heterogeneity in early stages of AD, we explored the relationship between different aspects of digital clock performance and amyloid and tau pathology across the cortical surface.
Method
CN from the Harvard Aging Brain Study completed both a spontaneous (COM) and copy (COP) clock drawing test using a digital pen. We used a summary score (DCTScore) and four main composite scores (drawing efficiency, simple motor, information processing and spatial reasoning) calculated by Digital Cognition Technologies. Participants also underwent
11
CPiB‐PET (n = 112) and
18
FT807‐PET (n = 116) acquisition within one year of cognitive testing. We utilized a vertex‐wise analysis with a cluster‐wise multiple comparison correction (minimum cluster extent=100mm
2
) and a threshold of ‐log(p)>2 to analyze relationships with clock scores across the vertices, adjusting for age, sex, and education.
Result
Lower DCTScore strongly correlated with greater amyloid signal in the frontal lobe, with some significant clusters also observed within the lateral temporal and inferior parietal cortices (Figure 1). Lower DCTScore also related to elevated tau signal in the right lateral temporal and inferior parietal lobes. Tau was most strongly associated with COM spatial reasoning score in the right lateral temporal lobe (Figure 2), reflecting known functional associations with this region; this was not reflected with COP spatial reasoning scores.
Conclusion
In clinically‐normal older adults, lower scores on clock drawing were associated with greater cortical amyloid and tau. Lower spatial reasoning scores were related to tauopathy, but only in spontaneous clock drawing, supporting the notion that more complex cognitive tasks are compromised earlier in the clinical continuum. More fine‐grained measurements of cognition using digital tasks in relation to neuroimaging markers has the potential to improve our understanding of the pathogenesis of early AD.
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