Jason Hassenstab

Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study

BACKGROUND New research criteria for preclinical Alzheimers disease have been proposed, which include stages for cognitively normal individuals with abnormal amyloid markers (stage 1), abnormal amyloid and neuronal injury markers (stage 2), or abnormal amyloid and neuronal injury markers and subtle cognitive changes (stage 3). We aimed to investigate the prevalence and long-term outcome of preclinical Alzheimers disease according to these criteria. METHODS Participants were cognitively normal (clinical dementia rating [CDR]=0) community-dwelling volunteers aged at least 65 years who were enrolled between 1998 and 2011 at the Washington University School of Medicine (MO, USA). CSF amyloid-β1-42 and tau concentrations and a memory composite score were used to classify participants as normal (both markers normal), preclinical Alzheimers disease stage 1-3, or suspected non-Alzheimer pathophysiology (SNAP, abnormal injury marker without abnormal amyloid marker). The primary outcome was the proportion of participants in each preclinical AD stage. Secondary outcomes included progression to CDR at least 0·5, symptomatic Alzheimers disease (score of at least 0·5 for memory and at least one other domain and cognitive impairments deemed to be due to Alzheimers disease), and mortality. We undertook survival analyses using subdistribution and standard Cox hazards models and linear mixed models. FINDINGS Of 311 participants, 129 (41%) were classed as normal, 47 (15%) as stage 1, 36 (12%) as stage 2, 13 (4%) as stage 3, 72 (23%) as SNAP, and 14 (5%) remained unclassified. The 5-year progression rate to CDR at least 0·5, symptomatic Alzheimers disease was 2% for participants classed as normal, 11% for stage 1, 26% for stage 2, 56% for stage 3, and 5% for SNAP. Compared with individuals classed as normal, participants with preclinical Alzheimers disease had an increased risk of death after adjusting for covariates (hazard ratio 6·2, 95% CI 1·1-35·0; p=0·040). INTERPRETATION Preclinical Alzheimers disease is common in cognitively normal elderly people and is associated with future cognitive decline and mortality. Thus, preclinical Alzheimers disease could be an important target for therapeutic intervention. FUNDING National Institute of Aging of the National Institutes of Health (P01-AG003991, P50-AG05681, P01-AG02676), Internationale Stichting Alzheimer Onderzoek, the Center for Translational Molecular Medicine project LeARN, the EU/EFPIA Innovative Medicines Initiative Joint Undertaking, and the Charles and Joanne Knight Alzheimer Research Initiative.

Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease

PET imaging of pathological tau correlates more closely with Alzheimer’s disease–related cognitive impairment than does imaging of β-amyloid. A window into Alzheimer’s disease Alzheimer’s disease is pathologically defined by the accumulation of β-amyloid (Aβ) plaques and tau tangles. The cognitive and pathological correlates of Aβ deposition have been well studied owing to the availability of PET imaging ligands. Using newly available tau imaging agents, Brier et al. now explore relationships among tau pathology and Aβ with PET imaging, cerebrospinal fluid measures of disease, and cognition. Overall, tau imaging provided a more robust predictor of disease status than did Aβ imaging. Thus, whereas Aβ imaging provides a good marker for early disease state, tau imaging is a more robust predictor of disease progression. Alzheimer’s disease (AD) is characterized by two molecular pathologies: cerebral β-amyloidosis in the form of β-amyloid (Aβ) plaques and tauopathy in the form of neurofibrillary tangles, neuritic plaques, and neuropil threads. Until recently, only Aβ could be studied in humans using positron emission tomography (PET) imaging owing to a lack of tau PET imaging agents. Clinical pathological studies have linked tau pathology closely to the onset and progression of cognitive symptoms in patients with AD. We report PET imaging of tau and Aβ in a cohort of cognitively normal older adults and those with mild AD. Multivariate analyses identified unique disease-related stereotypical spatial patterns (topographies) for deposition of tau and Aβ. These PET imaging tau and Aβ topographies were spatially distinct but correlated with disease progression. Cerebrospinal fluid measures of tau, often used to stage preclinical AD, correlated with tau deposition in the temporal lobe. Tau deposition in the temporal lobe more closely tracked dementia status and was a better predictor of cognitive performance than Aβ deposition in any region of the brain. These data support models of AD where tau pathology closely tracks changes in brain function that are responsible for the onset of early symptoms in AD.

Functional connectivity and graph theory in preclinical Alzheimer’s disease

Alzheimers disease (AD) has a long preclinical phase in which amyloid and tau cerebral pathology accumulate without producing cognitive symptoms. Resting state functional connectivity magnetic resonance imaging has demonstrated that brain networks degrade during symptomatic AD. It is unclear to what extent these degradations exist before symptomatic onset. In this study, we investigated graph theory metrics of functional integration (path length), functional segregation (clustering coefficient), and functional distinctness (modularity) as a function of disease severity. Further, we assessed whether these graph metrics were affected in cognitively normal participants with cerebrospinal fluid evidence of preclinical AD. Clustering coefficient and modularity, but not path length, were reduced in AD. Cognitively normal participants who harbored AD biomarker pathology also showed reduced values in these graph measures, demonstrating brain changes similar to, but smaller than, symptomatic AD. Only modularity was significantly affected by age. We also demonstrate that AD has a particular effect on hub-like regions in the brain. We conclude that AD causes large-scale disconnection that is present before onset of symptoms.

Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later

Objectives: We compared the ability of molecular biomarkers for Alzheimer disease (AD), including amyloid imaging and CSF biomarkers (Aβ42, tau, ptau181, tau/Aβ42, ptau181/Aβ42), to predict time to incident cognitive impairment among cognitively normal adults aged 45 to 88 years and followed for up to 7.5 years. Methods: Longitudinal data from Knight Alzheimers Disease Research Center participants (N = 201) followed for a mean of 3.70 years (SD = 1.46 years) were used. Participants with amyloid imaging and CSF collection within 1 year of a clinical assessment indicating normal cognition were eligible. Cox proportional hazards models tested whether the individual biomarkers were related to time to incident cognitive impairment. “Expanded” models were developed using the biomarkers and participant demographic variables. The predictive values of the models were compared. Results: Abnormal levels of all biomarkers were associated with faster time to cognitive impairment, and some participants with abnormal biomarker levels remained cognitively normal for up to 6.6 years. No differences in predictive value were found between the individual biomarkers (p > 0.074), nor did we find differences between the expanded biomarker models (p > 0.312). Each expanded model better predicted incident cognitive impairment than the model containing the biomarker alone (p < 0.005). Conclusions: Our results indicate that all AD biomarkers studied here predicted incident cognitive impairment, and support the hypothesis that biomarkers signal underlying AD pathology at least several years before the appearance of dementia symptoms.

Neuropsychological changes in asymptomatic persons with Alzheimer disease neuropathology

Objective: To determine whether asymptomatic persons with Alzheimer disease (AD) neuropathologic change differ in the trajectory of their cognitive performance compared to asymptomatic persons without AD neuropathologic change. Methods: Longitudinal performance on standard neuropsychological tests was examined in participants who died within 2 years of their last cognitive assessment and who were never diagnosed with mild cognitive impairment or dementia (Clinical Dementia Rating global score of 0 at all assessments). Using cognitive and neuropathologic data collected between 2005 and 2013 from the 34 National Institute on Aging–sponsored Alzheimers Disease Centers, cognitive trajectories were compared for persons with and without evidence of AD neuropathologic change. We evaluated rates of decline in 4 domains (episodic memory, language, attention/working memory, executive function). The significance of the differences (β) in rates of decline was tested using linear regression, adjusting for age, education, sex, and other neuropathologic lesions. Results: Participants who had low to high levels of AD neuropathologic change (n = 131) showed a greater rate of decline on the attention/working memory domain score (β = −0.11; 95% confidence interval = −0.19, −0.02; p = 0.02) when compared to 80 participants who died without evidence of AD neuropathologic change. Conclusions: Clinically normal individuals who come to autopsy with AD neuropathologic change exhibit subtle evidence of declining cognitive trajectories for attention/working memory.

The adverse effects of reduced cerebral perfusion on cognition and brain structure in older adults with cardiovascular disease

It is well established that aging and vascular processes interact to disrupt cerebral hemodynamics in older adults. However, the independent effects of cerebral perfusion on neurocognitive function among older adults remain poorly understood. We examined the associations among cerebral perfusion, cognitive function, and brain structure in older adults with varying degrees of vascular disease using perfusion magnetic resonance imaging (MRI) arterial spin labeling (ASL).

Cognitive Interference From Food Cues in Weight Loss Maintainers, Normal Weight, and Obese Individuals

Much attention has been paid to the behavioral characteristics of successful weight loss maintenance, but less is known about the cognitive processes that underlie this process. The purpose of this study was to investigate cognitive interference from food‐related cues in long‐term weight loss maintainers (WLM; N = 15) as compared with normal weight (NW; N = 19) and obese (OB; N = 14) controls. A Food Stroop paradigm was used to determine whether successful WLM differed from controls in both the speed and accuracy of color naming words for low‐calorie and high‐calorie foods. A significant group × condition interaction for reaction time was observed (P = 0.04). In post hoc analyses, no significant differences in reaction time across the three groups were observed for the low‐calorie foods (P = 0.66). However, for the high‐calorie foods, WLM showed a significantly slower reaction time than the NW (0.04) and OB (0.009) groups (885 ± 17.6, 834 ± 15.8, 816 ± 18.3 ms, respectively). No significant group differences were seen for number of correct trials in 45 s (P = 0.12). The differential interference among WLM did not appear to generalize to other types of distracters (i.e., nonfood). Overall, findings from this study suggest that WLM differ from OB and NW controls in their cognitive responses to high‐calorie food cues. Future research is needed to better understand why this bias exists and whether and how interventions can change cognitive processes to better facilitate long‐term weight control.

The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model

The Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimers disease in autosomal dominant Alzheimers disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN‐TU now plans to add new drugs to the platform, designated as the Next Generation (NexGen) prevention trial.

Absence of practice effects in preclinical Alzheimer's disease.

OBJECTIVE To describe how practice effects influence cognitive trajectories and determine if a reduction in practice effects is a potential marker of Stage-III preclinical Alzheimers disease (AD). METHOD Participants included 263 older adults who were cognitively normal at baseline (i.e., had a Clinical Dementia Rating [CDR] of 0; Morris, 1993) and returned for an average of 9.5 annual visits. Participants completed standard tests of episodic memory, visuospatial ability, semantic memory, and executive function. Progressors (n = 66) converted to CDR > 0 with a diagnosis of symptomatic AD after a minimum of 3 visits and stable participants (n = 197) never progressed to CDR > 0. Practice effects, defined as the slope of performance across Visits 1-3, were compared between groups and used within subjects to predict risk of conversion. Change-point models that accounted for retest were contrasted with linear models that ignored retest. RESULTS The stable group showed practice effects on episodic-memory measures (β = 0.14, SE = .02, p < .0001) but the progressor group did not (β = 0.03, SE = .03, p = .343). Across all participants, practice effects on episodic-memory tests were associated with a decreased risk of progression to AD as indicated by the subdistribution hazards model (SHR; Fine & Gray, 1999); SHR = .110, 95% CI [.032, .384], p = .001). Finally, use of change-point models dramatically altered rate-of-change estimates compared with models that ignored practice. CONCLUSION Our results indicate that preclinical AD is marked by a reduction in practice effects in episodic memory and that the magnitude of gain from retesting is inversely related to progression risk. Assessment of practice effects may be a face-valid indicator of Stage-III preclinical AD.

Cortical thickness of the cognitive control network in obesity and successful weight loss maintenance: A preliminary MRI study

Cortical thickness of the cognitive control network was contrasted between obese (OB), successful weight loss maintainers (SWLM), and lean individuals. OB individuals had significant thinning, most notably in the anterior cingulate and posterior parietal cortices. SWLM individuals exhibited trends towards thicker cortex than OB individuals, which may be important in future studies.