A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings.

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (n = 342), mild cognitive impairment (n = 118) or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid Alzheimer's disease biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5) as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test whether baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and mild cognitive impairment conversion rates of cognitively unimpaired participants and those with subjective cognitive decline. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy initially affected the medial temporal lobes, followed by further temporal regions and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological Alzheimer's disease biomarker levels, APOE ε4 carriership and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe, with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive Alzheimer's disease biomarkers and was associated with more generalized cognitive impairment. Limbic-predominant atrophy, in all participants and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of mild cognitive impairment conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, at both the subject and the group level, was excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for Alzheimer's disease in applied settings. The implementation of atrophy subtype- and stage-specific end points might increase the statistical power of pharmacological trials targeting early Alzheimer's disease.

Hoarding Symptoms in Late Life Depression are Associated With Greater Executive Dysfunction and Disability and Poorer Response to Depression Treatment.

OBJECTIVES: Late life depression (LLD) and hoarding disorder (HD) are common in older adults and characterized by executive dysfunction and disability. We aimed to determine the frequency of co-occurring HD in LLD and examine hoarding severity as an additional contributor to executive dysfunction, disability, and response to psychotherapy for LLD. DESIGN: Cross-sectional. SETTING: Outpatient psychiatry program. PARTICIPANTS: Eighty-three community-dwelling adults ages 65-90 with LLD. INTERVENTION: Problem-solving therapy. MEASUREMENTS: Measures of executive function, disability, depression, and hoarding severity were completed at post-treatment. Pearson's chi-squared tests evaluated group differences in rates of cognitive impairment, disability, and depression treatment response between participants with HD (LLD+HD) and LLD only. Separate linear regressions assessed associations between hoarding severity and executive function, disability, and psychotherapy response. Covariates included age, education, gender, and depression severity. RESULTS: 30.1% (25/83) of LLD participants met HD criteria. Relative to LLD, LLD+HD participants demonstrated greater impairment rates on measures of executive function (Letter-Number-Sequencing, X2(1)=4.0, p = 0.045; Stroop-Interference, X2(1) = 4.8, p = 0.028). Greater hoarding severity was associated with poorer executive functioning performance (Letter-Number-Sequencing (t[70] = -2.1, ß = -0.05, p = 0.044), Digit-Span (t[71] = -2.4, ß = -0.07, p = 0.019), Letter-Fluency (t[ 71] = -2.8, ß = -0.24, p = 0.006)). Rates of disability were significantly higher for LLD+HD (88.0%) than LLD (62.3%), (X2[1] = 5.41, p = 0.020) and higher hoarding severity was related to greater disability (t[72] = 2.97, ß = 0.13, p = 0.004). Depression treatment response rates were significantly lower for LLD+HD (24.0%) compared to LLD (48.3%), X2(1) = 4.26, p = 0.039, and HD status predicted psychotherapy response, t(67) = -2.15, ß = -15.6, p = 0.035. CONCLUSIONS: We found 30.1% co-occurrence of HD in LLD, which was accompanied by greater executive dysfunction, disability, and poorer response to depression treatment. Results underscore the need for increased screening of hoarding behaviors in LLD and tailored interventions for this LLD+HD group.

Relationship of Hoarding and Depression Symptoms in Older Adults.

Hoarding disorder (HD) is a debilitating neuropsychiatric condition that affects 2%-6% of the population and increases in incidence with age. Major depressive disorder (MDD) co-occurs with HD in approximately 50% of cases and leads to increased functional impairment and disability. However, only one study to date has examined the rate and trajectory of hoarding symptoms in older individuals with a lifetime history of MDD, including those with current active depression (late-life depression; LLD). We therefore sought to characterize this potentially distinct phenotype. We determined the incidence of HD in two separate cohorts of participants with LLD (n = 73) or lifetime history of MDD (n = 580) and examined the reliability and stability of hoarding symptoms using the Saving Inventory-Revised (SI-R) and Hoarding Rating Scale-Self Report (HRS), as well as the co-variance of hoarding and depression scores over time. HD was present in 12% to 33% of participants with MDD, with higher rates found in those with active depressive symptoms. Hoarding severity was stable across timepoints in both samples (all correlations >0.75), and fewer than 30% of participants in each sample experienced significant changes in severity between any two timepoints. Change in depression symptoms over time did not co-vary with change in hoarding symptoms. These findings indicate that hoarding is a more common comorbidity in LLD than previously suggested, and should be considered in screening and management of LLD. Future studies should further characterize the interaction of these conditions and their impact on outcomes, particularly functional impairment in this vulnerable population.

Anxiety in late-life depression is associated with poorer performance across multiple cognitive domains.

OBJECTIVE: Anxiety is a common comorbid feature of late-life depression (LLD) and is associated with poorer global cognitive functioning independent of depression severity. However, little is known about whether comorbid anxiety is associated with a domain-specific pattern of cognitive dysfunction. We therefore examined group differences (LLD with and without comorbid anxiety) in cognitive functioning performance across multiple domains. METHOD: Older adults with major depressive disorder (N = 228, ages 65-91) were evaluated for anxiety and depression severity, and cognitive functioning (learning, memory, language, processing speed, executive functioning, working memory, and visuospatial functioning). Ordinary least squares regression adjusting for age, sex, education, and concurrent depression severity examined anxiety group differences in performance on tests of cognitive functioning. RESULTS: Significant group differences emerged for confrontation naming and visuospatial functioning, as well as for verbal fluency, working memory, and inhibition with lower performance for LLD with comorbid anxiety compared to LLD only, controlling for depression severity. CONCLUSIONS: Performance patterns identified among older adults with LLD and comorbid anxiety resemble neuropsychological profiles typically seen in neurodegenerative diseases of aging. These findings have potential implications for etiological considerations in the interpretation of neuropsychological profiles.

Tau positron emission tomography in preclinical Alzheimer's disease.

Rates of tau accumulation in cognitively unimpaired older adults are subtle, with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid-ß-dependent. Thus, there is a need to evaluate the pattern and consistency of tau accumulation across multiple cognitively unimpaired cohorts and how these patterns relate to amyloid burden, in order to design optimal tau end points for clinical trials. Using three large cohorts of cognitively unimpaired older adults, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and companion study, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (n = 447), the Alzheimer's Disease Neuroimaging Initiative (n = 420) and the Harvard Aging Brain Study (n = 190), we attempted to identify regions with high rates of tau accumulation and estimate how these rates evolve over a continuous spectrum of baseline amyloid deposition. Optimal combinations of regions, tailored to multiple ranges of baseline amyloid burden as hypothetical clinical trial inclusion criteria, were tested and validated. The inferior temporal cortex, fusiform gyrus and middle temporal cortex had the largest effect sizes of accumulation in both longitudinal cohorts when considered individually. When tau regions of interest were combined to find composite weights to maximize the effect size of tau change over time, both longitudinal studies exhibited a similar pattern-inferior temporal cortex, almost exclusively, was optimal for participants with mildly elevated amyloid ß levels. For participants with highly elevated baseline amyloid ß levels, combined optimal composite weights were 53% inferior temporal cortex, 31% amygdala and 16% fusiform. At mildly elevated levels of baseline amyloid ß, a sample size of 200/group required a treatment effect of 0.40-0.45 (40-45% slowing of tau accumulation) to power an 18-month trial using the optimized composite. Neither a temporal lobe composite nor a global composite reached 80% power with 200/group with an effect size under 0.5. The focus of early tau accumulation on the medial temporal lobe has resulted from the observation that the entorhinal cortex is the initial site to show abnormal levels of tau with age. However, these abnormal levels do not appear to be the result of a high rate of accumulation in the short term, but possibly a more moderate rate occurring early with respect to age. While the entorhinal cortex plays a central role in the early appearance of tau, it may be the inferior temporal cortex that is the critical region for rapid tau accumulation in preclinical Alzheimer's disease.

Anxiety in late-life depression: Associations with brain volume, amyloid beta, white matter lesions, cognition, and functional ability.

OBJECTIVES: Late-life depression (LLD) is common and frequently co-occurs with neurodegenerative diseases of aging. Little is known about how heterogeneity within LLD relates to factors typically associated with neurodegeneration. Varying levels of anxiety are one source of heterogeneity in LLD. We examined associations between anxiety symptom severity and factors associated with neurodegeneration, including regional brain volumes, amyloid beta (Aß) deposition, white matter disease, cognitive dysfunction, and functional ability in LLD. PARTICIPANTS AND MEASUREMENTS: Older adults with major depression (N = 121, Ages 65-91) were evaluated for anxiety severity and the following: brain volume (orbitofrontal cortex [OFC], insula), cortical Aß standardized uptake value ratio (SUVR), white matter hyperintensity (WMH) volume, global cognition, and functional ability. Separate linear regression analyses adjusting for age, sex, and concurrent depression severity were conducted to examine associations between anxiety and each of these factors. A global regression analysis was then conducted to examine the relative associations of these variables with anxiety severity. RESULTS: Greater anxiety severity was associated with lower OFC volume (ß = -68.25, t = -2.18, p = .031) and greater cognitive dysfunction (ß = 0.23, t = 2.46, p = .016). Anxiety severity was not associated with insula volume, Aß SUVR, WMH, or functional ability. When examining the relative associations of cognitive functioning and OFC volume with anxiety in a global model, cognitive dysfunction (ß = 0.24, t = 2.62, p = .010), but not OFC volume, remained significantly associated with anxiety. CONCLUSIONS: Among multiple factors typically associated with neurodegeneration, cognitive dysfunction stands out as a key factor associated with anxiety severity in LLD which has implications for cognitive and psychiatric interventions.

Speech patterns during memory recall relates to early tau burden across adulthood.

INTRODUCTION: Early cognitive decline may manifest in subtle differences in speech. METHODS: We examined 238 cognitively unimpaired adults from the Framingham Heart Study (32-75 years) who completed amyloid and tau PET imaging. Speech patterns during delayed recall of a story memory task were quantified via five speech markers, and their associations with global amyloid status and regional tau signal were examined. RESULTS: Total utterance time, number of between-utterance pauses, speech rate, and percentage of unique words significantly correlated with delayed recall score although the shared variance was low (2%-15%). Delayed recall score was not significantly different between ß-amyoid-positive (Aß+) and -negative (Aß-) groups and was not associated with regional tau signal. However, longer and more between-utterance pauses, and slower speech rate were associated with increased tau signal across medial temporal and early neocortical regions. DISCUSSION: Subtle speech changes during memory recall may reflect cognitive impairment associated with early Alzheimer's disease pathology. HIGHLIGHTS: Speech during delayed memory recall relates to tau PET signal across adulthood. Delayed memory recall score was not associated with tau PET signal. Speech shows greater sensitivity to detecting subtle cognitive changes associated with early tau accumulation. Our cohort spans adulthood, while most PET imaging studies focus on older adults.

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.

INTRODUCTION: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification. HIGHLIGHTS: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

Natural cubic splines for the analysis of Alzheimer's clinical trials.

Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical-time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios.

Early stages of tau pathology and its associations with functional connectivity, atrophy and memory.

In Alzheimer's disease, post-mortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with Brodmann area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 amyloid-ß- cognitively unimpaired, 81 amyloid-ß+ cognitively unimpaired and 87 amyloid-ß+ individuals with mild cognitive impairment, who each underwent 18F-RO948 tau and 18F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and Brodmann area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, Brodmann area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, Brodmann area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease stage-specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.

Cognitive outcomes are differentially associated with depression severity trajectories during psychotherapy treatment for late life major depressive disorder.

OBJECTIVES: Late Life Depression (LLD) is associated with persistent cognitive dysfunction even after depression symptoms improve. The present study was designed to examine cognitive outcomes associated with the pattern of depression severity change during psychotherapy intervention for LLD. METHODS: 96 community-dwelling adults ages 65-91 with major depressive disorder completed 12 sessions of Problem-Solving Therapy at the University of California, San Francisco. Nonlinear trajectories of depression severity ratings using the Hamilton Depression Rating Scale were computed from multiple time points collected throughout the weekly psychotherapy intervention. Performance on measures of cognition (information processing speed, executive functioning, verbal learning, memory) was assessed at baseline and post-treatment. Linear mixed-effects models examined associations between nonlinear depression severity trajectories and post-treatment change in cognitive performance. RESULTS: Broadly, different patterns of depression change during treatment were associated with improved cognition post-treatment. Greater and more consistent interval improvements in depression ratings were differentially associated with improvements in aspects of verbal learning, memory, and executive function post-treatment, while no associations were found with information processing speed. CONCLUSIONS: The heterogeneity of depression trajectories associated with improved cognitive outcomes suggests that the temporal pattern of depression response may impact specific cognitive processes distinctly. Results suggest that use of nonlinear depression severity trajectories may help to elucidate complex associations between the time course of depression response and cognitive outcomes of psychotherapy in LLD. These findings have important implications for identifying treatment targets to enhance clinical and cognitive outcomes of psychotherapy in LLD.

Time between milestone events in the Alzheimer's disease amyloid cascade.

OBJECTIVE: Estimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimer's disease. METHODS: In a cohort of 335 older adults, ranging in cognitive functioning, we estimated the time of initial changes of Aß, tau, and decreases in cognition with respect to the time of Aß-positivity. RESULTS: Small effect sizes of change in CSF Aß42 and regional Aß PET were estimated to occur several decades before Aß-positivity. Increases in CSF tau occurred 7-8 years before Aß-positivity. Temporoparietal tau PET showed increases 4-5 years before Aß-positivity. Subtle cognitive dysfunction was observed 4-6 years before Aß-positivity. CONCLUSIONS: Increases in tau and cognitive dysfunction occur years before commonly used thresholds for Aß-positivity. Explicit estimates of the time for these events provide a clearer picture of the time-course of the amyloid cascade and identify potential windows for specific treatments.

A multicenter comparison of [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis.

PURPOSE: This study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer's disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neurodegenerative diseases. METHODS: A total of 1755 participants underwent tau PET using either [18F]flortaucipir (n = 975), [18F]RO948 (n = 493), or [18F]MK6240 (n = 287). SUVR values were calculated across four theory-driven ROIs and several tracer-specific data-driven (hierarchical clustering) regions of interest (ROIs). Diagnostic performance and cut-offs for ROIs were determined using receiver operating characteristic analyses and the Youden index, respectively. RESULTS: Comparable diagnostic performance (area under the receiver operating characteristic curve [AUC]) was observed between theory- and data-driven ROIs. The theory-defined temporal meta-ROI generally performed very well for all three tracers (AUCs: 0.926-0.996). An SUVR value of approximately 1.35 was a common threshold when using this ROI. CONCLUSION: The temporal meta-ROI can be used for differential diagnosis of dementia patients with [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET with high accuracy, and that using very similar cut-offs of around 1.35 SUVR. This ROI/SUVR cut-off can also be applied across tracers to define tau positivity.

Somatic and anxiety symptoms of depression are associated with disability in late life depression.

Objectives: To assess the relationships of somatic and anxiety symptoms of depression with functional disability in a sample of older adults with late life depression.Method: Data were analyzed from 78 older adults aged 65-88 with current major depression. Somatic and anxiety symptoms from the 24-item Hamilton Depression Rating Scale (HDRS) were summed to create variables measuring severity of these symptoms. Other symptoms of depression were also assessed using the remaining items of the HDRS. Current physical health burden was assessed using the Functional Comorbidity Index (FCI). Disability was measured with the Late Life Function and Disability Instrument (LLFDI) total limitation score. A linear regression analysis was performed to assess the association of somatic and anxiety symptoms with disability independent of other factors.Results: The model accounted for 26.6% of variance in disability, (F(6,51) = 3.1, p = .01). Somatic (B = -1.9, p = .004) and anxiety (B = -3.7, p = .04) symptoms of depression were significantly associated with disability. Other depressive symptoms and physical illness burden were not associated with disability.Discussion: In older adults with major depression, somatic and anxiety symptoms of depression are associated with disability. Identification and treatment to remission of these symptoms may improve functional outcomes among older depressed adults.

Depression Severity, but Not Cognitive Impairment or Frailty, is Associated with Disability in Late-Life Depression.

OBJECTIVES: Assess the relationship of cognitive impairment to disability, accounting for depression severity and frailty, among older adults with late-life depression (LLD). METHODS: Data were analyzed from 78 community-dwelling older adults with LLD and without dementia (age M = 71.9; SD = 6.1). Cognitive functioning was assessed using a comprehensive neuropsychological battery. Depression severity was measured using the 17-item Hamilton Depression Rating Scale (HDRS; cutoff ≥15). Frailty was assessed using several motor tests. The World Health Organization Disability Assessment Schedule (WHO-DAS) measured disability status. A linear regression analysis was performed to identify relationships of cognition, frailty and depression severity with disability. RESULTS: The average number of impaired cognitive tests was 2.0 (SD = 1.9), with 28.2% of participants showing no impaired scores. On average participants reported depression severity of 17.3 (SD = 3.6), and disability total score of 15.1 (SD = 6.9). The regression model accounted for 25.1% of the variance in disability, with only depression severity significantly predicting disability status. Burden of cognitive impairment and frailty were not predictive of disability in this sample. CONCLUSIONS: In this sample, only depression severity was associated with increased disability. CLINICAL IMPLICATIONS: These findings have implications for intervention in LLD, as depression severity may represent a more modifiable risk factor for disability.

Latent Classes of Cognitive Functioning Among Depressed Older Adults Without Dementia.

OBJECTIVE: Use latent class analysis (LCA) to identify patterns of cognitive functioning in a sample of older adults with clinical depression and without dementia and assess demographic, psychiatric, and neurobiological predictors of class membership. METHOD: Neuropsychological assessment data from 121 participants in the Alzheimer's Disease Neuroimaging Initiative-Depression project (ADNI-D) were analyzed, including measures of executive functioning, verbal and visual memory, visuospatial and language functioning, and processing speed. These data were analyzed using LCA, with predictors of class membership such as depression severity, depression and treatment history, amyloid burden, and APOE e4 allele also assessed. RESULTS: A two-class model of cognitive functioning best fit the data, with the Lower Cognitive Class (46.1% of the sample) performing approximately one standard deviation below the Higher Cognitive Class (53.9%) on most tests. When predictors of class membership were assessed, carrying an APOE e4 allele was significantly associated with membership in the Lower Cognitive Class. Demographic characteristics, age of depression onset, depression severity, history of psychopharmacological treatment for depression, and amyloid positivity did not predict class membership. CONCLUSION: LCA allows for identification of subgroups of cognitive functioning in a mostly cognitively intact late life depression (LLD) population. One subgroup, the Lower Cognitive Class, more likely to carry an APOE e4 allele, may be at a greater risk for subsequent cognitive decline, even though current performance on neuropsychological testing is within normal limits. These findings have implications for early identification of those at greatest risk, risk factors, and avenues for preventive intervention.

Accurate risk estimation of ß-amyloid positivity to identify prodromal Alzheimer's disease: Cross-validation study of practical algorithms.

INTRODUCTION: The aim was to create readily available algorithms that estimate the individual risk of ß-amyloid (Aß) positivity. METHODS: The algorithms were tested in BioFINDER (n = 391, subjective cognitive decline or mild cognitive impairment) and validated in Alzheimer's Disease Neuroimaging Initiative (n = 661, subjective cognitive decline or mild cognitive impairment). The examined predictors of Aß status were demographics; cognitive tests; white matter lesions; apolipoprotein E (APOE); and plasma Aß42/Aß40, tau, and neurofilament light. RESULTS: Aß status was accurately estimated in BioFINDER using age, 10-word delayed recall or Mini-Mental State Examination, and APOE (area under the receiver operating characteristics curve = 0.81 [0.77-0.85] to 0.83 [0.79-0.87]). When validated, the models performed almost identical in Alzheimer's Disease Neuroimaging Initiative (area under the receiver operating characteristics curve = 0.80-0.82) and within different age, subjective cognitive decline, and mild cognitive impairment populations. Plasma Aß42/Aß40 improved the models slightly. DISCUSSION: The algorithms are implemented on http://amyloidrisk.com where the individual probability of being Aß positive can be calculated. This is useful in the workup of prodromal Alzheimer's disease and can reduce the number needed to screen in Alzheimer's disease trials.

Predicting diagnosis and cognition with 18F-AV-1451 tau PET and structural MRI in Alzheimer's disease.

INTRODUCTION: The relative importance of structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) to predict diagnosis and cognition in Alzheimer's disease (AD) is unclear. METHODS: We tested 56 cognitively unimpaired controls (including 27 preclinical AD), 32 patients with prodromal AD, and 39 patients with AD dementia. Optimal classifiers were constructed using the least absolute shrinkage and selection operator with 18F-AV-1451 (tau) PET and structural MRI data (regional cortical thickness and subcortical volumes). RESULTS: 18F-AV-1451 in the amygdala, entorhinal cortex, parahippocampal gyrus, fusiform, and inferior parietal lobule had 93% diagnostic accuracy for AD (prodromal or dementia). The MRI classifier involved partly the same regions plus the hippocampus, with 83% accuracy, but did not improve upon the tau classifier. 18F-AV-1451 retention and MRI were independently associated with cognition. DISCUSSION: Optimized tau PET classifiers may diagnose AD with high accuracy, but both tau PET and structural brain MRI capture partly unique information relevant for the clinical deterioration in AD.

Serum tau and neurological outcome in cardiac arrest.

OBJECTIVE: To test serum tau as a predictor of neurological outcome after cardiac arrest. METHODS: We measured the neuronal protein tau in serum at 24, 48, and 72 hours after cardiac arrest in 689 patients in the prospective international Target Temperature Management trial. The main outcome was poor neurological outcome, defined as Cerebral Performance Categories 3-5 at 6 months. RESULTS: Increased tau was associated with poor outcome at 6 months after cardiac arrest (median = 38.5, interquartile range [IQR] = 5.7-245ng/l in poor vs median = 1.5, IQR = 0.7-2.4ng/l in good outcome, for tau at 72 hours, p < 0.0001). Tau improved prediction of poor outcome compared to using clinical information (p < 0.0001). Tau cutoffs had low false-positive rates (FPRs) for good outcome while retaining high sensitivity for poor outcome. For example, tau at 72 hours had FPR = 2% (95% CI = 1-4%) with sensitivity = 66% (95% CI = 61-70%). Tau had higher accuracy than serum neuron-specific enolase (NSE; the area under the receiver operating characteristic curve was 0.91 for tau vs 0.86 for NSE at 72 hours, p = 0.00024). During follow-up (up to 956 days), tau was significantly associated with overall survival. The accuracy in predicting outcome by serum tau was equally high for patients randomized to 33 °C and 36 °C targeted temperature after cardiac arrest. INTERPRETATION: Serum tau is a promising novel biomarker for prediction of neurological outcome in patients with cardiac arrest. It may be significantly better than serum NSE, which is recommended in guidelines and currently used in clinical practice in several countries to predict outcome after cardiac arrest. Ann Neurol 2017;82:665-675.

Chronic depressive symptomatology and CSF amyloid beta and tau levels in mild cognitive impairment.

OBJECTIVES: To investigate the association between chronic subsyndromal symptoms of depression (SSD), cerebrospinal fluid (CSF) biomarkers, and neuropsychological performance in individuals with mild cognitive impairment (MCI). METHODS: Participants included 238 older adults diagnosed with MCI from the Alzheimer's Disease Neuroimaging Initiative repository with cognitive and CSF amyloid beta (Aß1-42 ), total tau (t-tau), and phosphorylated tau (p-tau) data. The Neuropsychiatric Inventory identified individuals with chronic endorsement (SSD group N = 80) or no endorsement (non-SSD group N = 158) of depressive symptoms across timepoints. CSF biomarker and cognitive performance were evaluated with linear regression models adjusting for age, education, gender, APOE genotype, global cognitive status, and SSD group. RESULTS: As compared to the non-SSD group, the SSD group displayed lower CSF Aß1-42 levels (ß = -24.293, S.E. = 6.345, P < 0.001). No group differences were observed for CSF t-tau (P = 0.497) or p-tau levels (P = 0.392). Lower CSF Aß1-42 levels were associated with poorer performance on learning (ß = 0.041, S.E. = 0.018, P = 0.021) and memory (ß = -0.012, S.E. = 0.005, P = 0.031) measures, whereas higher CSF t-tau levels were associated with poorer performance on measures of global cognition (ß = 0.022, S.E = 0.008, P = 0.007) and language (ß = -0.010, S.E = 0.004, P = 0.019). SSD was independently associated with diminished global cognition, learning and memory, language, and executive function performance over and above the effects of CSF biomarkers (all P < 0.05). CONCLUSIONS: MCI participants with SSD displayed diminished CSF Aß1-42 levels but did not differ from non-SSD controls in CSF tau levels. Additionally, CSF biomarkers and SSD independently accounted for variance in cognitive performance, suggesting that these factors may uniquely confer cognitive risk in MCI.