Optimal blood tau species for the detection of Alzheimer's disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study.

Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer's disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD = 69, non-AD = 54) from the Boston University Alzheimer's disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195-205, 212-221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC = 89.8), p-tau231 (AUC = 83.4), and p-tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR < 1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (ORp-tau217 = 15.29, ORp-tau205 = 5.05 and ORp-tau231 = 3.86) and Braak staging (ORp-tau217 = 14.29, ORp-tau205 = 5.27 and ORp-tau231 = 4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease.

Ante-mortem plasma phosphorylated tau (181) predicts Alzheimer's disease neuropathology and regional tau at autopsy.

Blood-based biomarkers such as tau phosphorylated at threonine 181 (phosphorylated-tau181) represent an accessible, cost-effective and scalable approach for the in vivo detection of Alzheimer's disease pathophysiology. Plasma-pathological correlation studies are needed to validate plasma phosphorylated-tau181 as an accurate and reliable biomarker of Alzheimer's disease neuropathological changes. This plasma-to-autopsy correlation study included participants from the Boston University Alzheimer's Disease Research Center who had a plasma sample analysed for phosphorylated-tau181 between 2008 and 2018 and donated their brain for neuropathological examination. Plasma phosphorelated-tau181 was measured with single molecule array technology. Of 103 participants, 62 (60.2%) had autopsy-confirmed Alzheimer's disease. Average time between blood draw and death was 5.6 years (standard deviation = 3.1 years). Multivariable analyses showed higher plasma phosphorylated-tau181 concentrations were associated with increased odds for having autopsy-confirmed Alzheimer's disease [AUC = 0.82, OR = 1.07, 95% CI = 1.03-1.11, P < 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50-5.93, P < 0.01]. Higher plasma phosphorylated-tau181 levels were associated with increased odds for having a higher Braak stage (OR = 1.06, 95% CI = 1.02-1.09, P < 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03-1.06, P < 0.05). The association between plasma phosphorylated-tau181 and Alzheimer's disease was strongest in those who were demented at time of blood draw (OR = 1.25, 95%CI = 1.02-1.53), but an effect existed among the non-demented (OR = 1.05, 95% CI = 1.01-1.10). There was higher discrimination accuracy for Alzheimer's disease when blood draw occurred in years closer to death; however, higher plasma phosphorylated-tau181 levels were associated with Alzheimer's disease even when blood draw occurred >5 years from death. Ante-mortem plasma phosphorylated-tau181 concentrations were associated with Alzheimer's disease neuropathology and accurately differentiated brain donors with and without autopsy-confirmed Alzheimer's disease. These findings support plasma phosphorylated-tau181 as a scalable biomarker for the detection of Alzheimer's disease.

Plasma p-tau181 shows stronger network association to Alzheimer's disease dementia than neurofilament light and total tau.

INTRODUCTION: We examined the ability of plasma hyperphosphorylated tau (p-tau)181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL). METHODS: Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables. RESULTS: Plasma p-tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM. DISCUSSION: These results support plasma p-tau181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection.

Placebo Response in Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis.

OBJECTIVES: Chronic idiopathic constipation (CIC), like other functional gastrointestinal disorders, has been associated with a high placebo response rate. However, the placebo response in randomized controlled trials has not been described. METHODS: We conducted a search of the medical literature following the protocol outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement using MEDLINE, EMBASE and EMBASE Classic, Web of Science, and the Cochrane Central Register of Controlled Trials for all drugs used for the treatment of CIC. Two independent reviewers performed eligibility assessment and data extraction. The mean response rate was examined for the following 2 responder endpoints: (i) greater than or equal to 3 complete spontaneous bowel movements (CSBMs)/wk (≥3 CSBMs/wk responders) and (ii) mean increase of ≥1 CSBM/wk compared with baseline (increase in ≥1 CSBM/wk responders). RESULTS: A total of 23 placebo-controlled trials met our inclusion criteria and were included in this meta-analysis. The placebo response in CIC trials ranged from 4% to 44%. The magnitude of the placebo response was 13% (95% confidence interval 11%-16%) with the ≥3 CSBM/wk responder endpoint and 28% (95% confidence interval 21%-30%) with the increase of ≥1 in the CSBM responder endpoint. Higher baseline CSBM, older age, and trials with more male participants were significantly associated with a stronger placebo response for both the ≥3 CSBMs/wk endpoint and increase in the ≥1 CSBM/wk endpoint. Trial characteristics such as location (Europe vs Asia/United States) and laxative class (prokinetic vs secretagogue) revealed key differences in the placebo response for both endpoints. The placebo response was not significantly affected by the number of study visits, study duration, year of publication, number of drop outs, or likelihood of receiving active drug. DISCUSSION: The placebo response in CIC trials ranges from 4% to 44% depending on the endpoint. Modifying factors of the placebo response include multiple subject and trial characteristics.

Failure to detect an association between self-reported traumatic brain injury and Alzheimer's disease neuropathology and dementia.

INTRODUCTION: Recent research with neuropathologic or biomarker evidence of Alzheimer's disease (AD) casts doubt on traumatic brain injury (TBI) as a risk factor for AD. We leveraged the National Alzheimer's Coordinating Center to examine the association between self-reported TBI with loss of consciousness and AD neuropathologic changes, and with baseline and longitudinal clinical status. METHODS: The sample included 4761 autopsy participants (453 with remote TBI with loss of consciousness; 2822 with AD neuropathologic changes) from National Alzheimer's Coordinating Center. RESULTS: Self-reported TBI did not predict AD neuropathologic changes (P > .10). Reported TBI was not associated with baseline or change in dementia severity or cognitive function in participants with or without autopsy-confirmed AD. DISCUSSION: Self-reported TBI with loss of consciousness may not be an independent risk factor for clinical or pathological AD. Research that evaluates number and severity of TBIs is needed to clarify the neuropathological links between TBI and dementia documented in other large clinical databases.

Efficacy of Treatments for Opioid-Induced Constipation: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Opioid-induced constipation (OIC) is a common problem in patients on chronic opioid therapy for cancer-related and non-cancer-related pain. Approved treatments for OIC are methylnaltrexone, naloxone, naloxegol, alvimopan, naldemedine, and lubiprostone. Since a meta-analysis performed in 2014, 2 new agents have been approved by the Food and Drug Administration for treatment of OIC (naloxegol and naldemedine). METHODS: We conducted a search of the medical literature following the protocol outlined in the Cochrane Handbook for systematic review. We searched MEDLINE, EMBASE, EMBASE Classic, Web of Science, and the Cochrane Central Register of Controlled Trials until March 2017 to identify randomized controlled trials of peripheral µ-opioid-receptor antagonists (methylnaltrexone, naloxone, naloxegol, alvimopan, axelopran, or naldemedine), lubiprostone, or prucalopride. Response to therapy was extracted in a dichotomous assessment as an overall response to therapy. The effect of pharmacologic therapies was pooled and reported as a relative risk (RR) of failure to respond to the treatment drug, with 95% CIs. RESULTS: We included 27 placebo-controlled trials in our meta-analysis (23 trials evaluated µ-opioid-receptor antagonists, 3 trials evaluated lubiprostone, and 1 trial evaluated prucalopride). In these trials, 5390 patients received a drug and 3491 received a placebo. Overall, µ-opioid-receptor antagonists, lubiprostone, and prucalopride were superior to placebo for the treatment of OIC, with a RR of failure to respond to therapy of 0.70 (95% CI, 0.64-0.75) and an overall number needed to treat of 5 (95% CI, 4-7). When restricted to only Food and Drug Administration-approved medications for OIC, the RR of failure to respond to therapy was 0.69 (95% CI, 0.62-0.77), with a number needed to treat of 5 (95% CI, 4-7). Sensitivity analyses and meta-regression performed to account for heterogeneity showed that treatment was more likely to be effective in study populations taking higher doses of opiates at baseline or refractory to laxatives. Study duration and prespecified primary outcome did not affect the RR of failure. Participants who received µ-opioid-receptor antagonists were significantly more likely to have diarrhea, abdominal pain, nausea, or vomiting than patients who received placebo. CONCLUSIONS: In a systematic review and meta-analysis, we found µ-opioid-receptor antagonists to be safe and effective for the treatment of OIC. Prescription-strength laxatives (prucalopride, lubiprostone) are slightly better than placebo in reducing OIC.

Spared emotional perception in patients with Alzheimer's disease is associated with negative caregiver outcomes.

OBJECTIVES: Caregivers (CGs) for patients with Alzheimer's disease (AD) often experience negative mental health and relationship outcomes. Additionally, emotional perception abilities are often compromised in early AD; the relationships between these deficits and CG outcomes are unclear. The present study investigated the relationship between emotional perception abilities in AD participants and CG well-being. METHODS: Participants included 28 individuals with AD, their spousal CGs, and 30 older controls (OCs). Patients and controls completed the Montreal Cognitive Assessment and Advanced Clinical Solutions: Social Perception subtest. CGs completed questionnaires related to relationship satisfaction, burden, depression, and patient neuropsychiatric symptoms and activities of daily living. RESULTS: The patient group performed significantly worse than OCs on measures of cognition and emotional perception. Several significant relationships emerged between AD participant emotional perception and CG outcomes. Higher CG depression was associated with greater overall emotional perception abilities (r = .39, p = .041). Caregiver burden was positively correlated with AD participants' ability to label the emotional tones of voices (r = .47, p = .015). Relationship satisfaction was not significantly correlated with emotional perception. DISCUSSION: This study replicated earlier findings of impaired emotional perception abilities in AD participants. However, preserved abilities in emotional perception were associated greater CG depression and burden. Interestingly, the CGs satisfaction with the marital relationship did not appear to be influenced by changes in emotional perception. Higher emotional engagement among couples in which one spouse has cognitive impairment may contribute to increased negative interactions and in turn a greater sense of burden and depression, while leaving the marital relationship preserved.

The Aging Well through Interaction and Scientific Education (AgeWISE) Program.

OBJECTIVE: We conducted a randomized controlled trial of the Aging Well through Interaction and Scientific Education (AgeWISE) program, a 12-week manualized cognitive rehabilitation program designed to provide psychoeducation to older adults about the aging brain, lifestyle factors associated with successful brain aging, and strategies to compensate for age related cognitive decline. METHODS: Forty-nine cognitively intact participants ≥ 60 years old were randomly assigned to the AgeWISE program (n = 25) or a no-treatment control group (n = 24). Questionnaire data were collected prior to group assignment and post intervention. Two-factor repeated-measures analyses of covariance (ANCOVAs) were used to compare group outcomes. RESULTS: Upon completion, participants in the AgeWISE program reported increases in memory contentment and their sense of control in improving memory; no significant changes were observed in the control group. Surprisingly, participation in the group was not associated with significant changes in knowledge of memory aging, perception of memory ability, or greater use of strategies. CONCLUSIONS: The AgeWISE program was successfully implemented and increased participants' memory contentment and their sense of control in improving memory in advancing age. CLINICAL IMPLICATIONS: This study supports the use of AgeWISE to improve perspectives on healthy cognitive aging.

Utility of the Montreal Cognitive Assessment and Mini-Mental State Examination in predicting general intellectual abilities.

OBJECTIVE: To determine whether scores from 2 commonly used cognitive screening tests can help predict general intellectual functioning in older adults. BACKGROUND: Cutoff scores for determining cognitive impairment have been validated for both the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). However, less is known about how the 2 measures relate to general intellectual functioning as measured by the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV). METHODS: A sample of 186 older adults referred for neuropsychological assessment completed the MoCA, MMSE, and WAIS-IV. Regression equations determined how accurately the screening measures could predict the WAIS-IV Full Scale Intelligence Quotient (FSIQ). We also determined how predictive the MoCA and MMSE were when combined with 2 premorbid estimates of FSIQ: the Test of Premorbid Functioning (TOPF) (a reading test of phonetically irregular words) and a predicted TOPF score based on demographic variables. RESULTS: MoCA and MMSE both correlated moderately with WAIS-IV FSIQ. Hierarchical regression models containing the MoCA or MMSE combined with TOPF scores accounted for 58% and 49%, respectively, of the variance in obtained FSIQ. Both regression equations accurately estimated FSIQ to within 10 points in >75% of the sample. CONCLUSIONS: Both the MoCA and MMSE provide reasonable estimates of FSIQ. Prediction improves when these measures are combined with other estimates of FSIQ. We provide 4 equations designed to help clinicians interpret these screening measures.

Functional magnetic resonance imaging of semantic memory as a presymptomatic biomarker of Alzheimer's disease risk.

Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer's disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Comparison of semantic and episodic memory BOLD fMRI activation in predicting cognitive decline in older adults.

Previous studies suggest that task-activated functional magnetic resonance imaging (fMRI) can predict future cognitive decline among healthy older adults. The present fMRI study examined the relative sensitivity of semantic memory (SM) versus episodic memory (EM) activation tasks for predicting cognitive decline. Seventy-eight cognitively intact elders underwent neuropsychological testing at entry and after an 18-month interval, with participants classified as cognitively "Stable" or "Declining" based on ≥ 1.0 SD decline in performance. Baseline fMRI scanning involved SM (famous name discrimination) and EM (name recognition) tasks. SM and EM fMRI activation, along with Apolipoprotein E (APOE) ε4 status, served as predictors of cognitive outcome using a logistic regression analysis. Twenty-seven (34.6%) participants were classified as Declining and 51 (65.4%) as Stable. APOE ε4 status alone significantly predicted cognitive decline (R(2) = .106; C index = .642). Addition of SM activation significantly improved prediction accuracy (R(2) = .285; C index = .787), whereas the addition of EM did not (R(2) = .212; C index = .711). In combination with APOE status, SM task activation predicts future cognitive decline better than EM activation. These results have implications for use of fMRI in prevention clinical trials involving the identification of persons at-risk for age-associated memory loss and Alzheimer's disease.

Cross-sectional and longitudinal evaluation of plasma glial fibrillary acidic protein to detect and predict clinical syndromes of Alzheimer's disease.

Introduction: This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p-tau)181+231. Methods: Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross-sectional and longitudinal outcomes. Results: Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia. Discussion: Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD.

Decision rules for an abbreviated administration of the Test of Memory Malingering.

The present study investigated abbreviation methods for the Test of Memory Malingering (TOMM) in relation to traditional manual-based test cutoffs and independently derived more stringent cutoffs suggested by recent research (≤48 on Trial 2 or 3). Consecutively referred outpatient U.S. military veterans (n = 260) were seen for neuropsychological evaluation for mild traumatic brain injury or possible attention-deficit/hyperactivity disorder. Performance on TOMM Trial 1 was evaluated, including the total score and errors on the first 10 items (TOMMe10), to determine correspondence and redundancy with Trials 2 and 3. Using the traditional cutoff, valid performance on Trials 2 and 3 was predicted by zero errors on TOMMe10 and by Trial 1 scores greater than 41. Invalid performance was predicted by commission of more than three errors on TOMMe10 and by Trial 1 scores less than 34. For revised TOMM cutoffs, a Trial 1 score above 46 was predictive of a valid score, and a TOMMe10 score of three or more errors or a Trial 1 score below 36 was associated with invalid TOMM performance. Conditional abbreviation of the TOMM is feasible in a vast majority of cases without sacrificing information regarding performance validity. Decision trees are provided to facilitate administration of the three trials.

A longitudinal examination of plasma neurofilament light and total tau for the clinical detection and monitoring of Alzheimer's disease.

We examined baseline and longitudinal associations between plasma neurofilament light (NfL) and total tau (t-tau), and the clinical presentation of Alzheimer's disease (AD). A total of 579 participants (238, normal cognition [NC]; 185, mild cognitive impairment [MCI]; 156, AD dementia) had baseline blood draws; 82% had follow-up evaluations. Plasma samples were analyzed for NfL and t-tau using Simoa technology. Baseline plasma NfL was higher in AD dementia than MCI (standardized mean difference = 0.55, 95% CI: 0.37-0.73) and NC (standardized mean difference = 0.68, 95% CI: 0.49-0.88), corresponded to Clinical Dementia Rating scores (OR = 1.94, 95% CI: 1.35-2.79]), and correlated with all neuropsychological tests (r's = 0.13-0.42). Longitudinally, NfL did not predict diagnostic conversion but predicted decline on 3/10 neuropsychological tests. Baseline plasma t-tau was higher in AD dementia than NC with a small effect (standardized mean difference = 0.33, 95% CI: 0.10-0.57) but not MCI. t-tau did not statistically significant predict any longitudinal outcomes. Plasma NfL may be useful for the detection of AD dementia and monitoring of disease progression. In contrast, there was minimal evidence in support of plasma t-tau.

Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer's Coordinating Center Uniform Data Set.

BACKGROUND: Longitudinal investigations are needed to improve understanding of the contributions of cerebral small vessel disease to the clinical manifestation of Alzheimer's disease, particularly in the early disease stages. This study leveraged the National Alzheimer's Coordinating Center Uniform Data Set to longitudinally examine the association between white matter hyperintensities and neuropsychological, neuropsychiatric, and functional decline among participants with normal cognition. METHODS: The sample included 465 participants from the National Alzheimer's Coordinating Center Uniform Data Set who had quantitated volume of white matter hyperintensities from fluid-attenuated inversion recovery MRI, had normal cognition at the time of their MRI, and were administered the National Alzheimer's Coordinating Center Uniform Data Set neuropsychological test battery within 1 year of study evaluation and had at least two post-MRI time points of clinical data. Neuropsychiatric status was assessed by the Geriatric Depression Scale-15 and Neuropsychiatric Inventory-Questionnaire. Clinical Dementia Rating Sum of Boxes defined functional status. For participants subsequently diagnosed with mild cognitive impairment (MCI) or dementia, their impairment must have been attributed to Alzheimer's disease (AD) to evaluate the relationships between WMH and the clinical presentation of AD. RESULTS: Of the 465 participants, 56 converted to MCI or AD dementia (average follow-up = 5 years). Among the 465 participants, generalized estimating equations controlling for age, sex, race, education, APOE ε4, and total brain and hippocampal volume showed that higher baseline log-white matter hyperintensities predicted accelerated decline on the following neuropsychological tests in rank order of effect size: Trails B (p < 0.01), Digit Symbol Coding (p < 0.01), Logical Memory Immediate Recall (p = 0.02), Trail Making A (p < 0.01), and Semantic Fluency (p < 0.01). White matter hyperintensities predicted increases in Clinical Dementia Rating Sum of Boxes (p < 0.01) and Geriatric Depression Scale-15 scores (p = 0.01). Effect sizes were comparable to total brain and hippocampal volume. White matter hyperintensities did not predict diagnostic conversion. All effects also remained after including individuals with non-AD suspected etiologies for those who converted to MCI or dementia. CONCLUSIONS: In this baseline cognitively normal sample, greater white matter hyperintensities were associated with accelerated cognitive, neuropsychiatric, and functional decline independent of traditional risk factors and MRI biomarkers for Alzheimer's disease.

Neuropsychiatric Symptoms and the Diagnostic Stability of Mild Cognitive Impairment.

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate diagnosis between normal cognition (NC) and dementia, including Alzheimer's disease (AD) dementia. However, MCI is heterogeneous; many individuals subsequently revert to NC while others remain stable at MCI for several years. Identifying factors associated with this diagnostic instability could assist in defining clinical populations and determining cognitive prognoses. OBJECTIVE: The current study examined whether neuropsychiatric symptoms could partially account for the temporal instability in cognitive diagnoses. METHOD: The sample included 6,763 participants from the National Alzheimer's Coordinating Center Uniform Data Set. All participants had NC at baseline, completed at least two follow-up visits (mean duration: 5.5 years), and had no recent neurological conditions. Generalized linear models estimated by generalized estimating equations examined associations between changes in cognitive diagnoses and symptoms on the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS-15). RESULTS: 1,121 participants converted from NC to MCI; 324 reverted back to NC and 242 progressed to AD dementia. Higher symptoms on the GDS-15 and circumscribed symptom domains on the NPI-Q were associated with conversion from NC to MCI and a decreased likelihood of reversion from MCI to NC. Individuals with higher symptoms on NPI-Q Hyperactivity and Mood items were more likely to progress to AD dementia. DISCUSSION: The temporal instability of MCI can be partially explained by neuropsychiatric symptoms. Individuals with higher levels of specific symptoms are more likely to progress to AD dementia and less likely to revert to NC. Identification and treatment of these symptoms might support cognitive functioning in older adults.

A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology.

BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer's disease. Clinicopathological studies are needed to elucidate and confirm this possibility. OBJECTIVE: This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer's disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP. METHODS: The sample included 82 participants from the National Alzheimer's Coordinating Center's Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. RESULTS: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP-participants (ps < 0.04). CONCLUSIONS: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer's disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

Performance validity and processing speed in a VA Polytrauma sample.

OBJECTIVE: While recognition memory has been the primary tool for the assessment of performance validity in neuropsychological evaluations, some consideration has also been given to embedded measures from other cognitive domains, including processing speed. The present study evaluated the classification accuracy of several speed-based measures in a Veterans Affairs Medical Center Polytrauma sample. METHOD: The present sample consisted of 114 military veterans (Mean age = 35.5, SD = 9.4) referred for a suspected history of mild traumatic brain injury who were administered a full neuropsychological protocol that included several validity checks. Veterans were assigned to Valid (n = 80) or Invalid (n = 34) groups based on outcomes of performance validity measures (PVMs). RESULTS: Several processing speed measures yielded acceptable or excellent classification accuracy; sensitivity values ranged from 29 to 53% with specificity values above 90%. Efforts to identify an improved algorithm that would collapse across multiple processing speed PVMs were unsuccessful compared to classification based on single measures. CONCLUSIONS: Processing speed measures can serve as efficient performance validity assessment tools.

Obsessive-compulsive disorder has a reduced placebo (and antidepressant) response compared to other anxiety disorders: A meta-analysis.

BACKGROUND: Previous studies have indicated that obsessive-compulsive disorder (OCD) might have a reduced placebo response compared to other anxiety-related disorders including generalized anxiety disorder, panic disorder, post-traumatic stress disorder, and social anxiety disorder. No previous analysis has directly compared antidepressant and placebo responses between OCD and these conditions. METHOD: We analyzed pre-post change scores within drug and placebo groups as well as between-groups change scores (i.e., drug compared to placebo) for all FDA-approved antidepressants for the treatment of these five anxiety-related disorders. Antidepressants included duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. Random effects meta-analysis was used to examine all trials submitted to the FDA, plus additional post-approval trials available from manufacturer-sponsored clinical trial registers. Clinician-rated symptom inventories were the outcome measures for all conditions to facilitate comparisons across diagnoses. RESULTS: Fifty-six trials met inclusion criteria. OCD had significantly lower pre-post effect sizes (ps<0.003) for both placebo (Hedges' g=0.49) and antidepressants (g=0.84) compared to the other four conditions (gs between 0.70 and 1.10 for placebo and 1.11 and 1.40 for antidepressants). However, the drug-placebo effect sizes did not significantly differ across diagnoses (Q(4)=6.09, p=0.193, I2 =34.3% [95% CI: -7.0,59.7]), with gs between=0.26 and 0.39. CONCLUSIONS: Overall pre-post change scores were smaller for OCD compared to other anxiety disorders for both antidepressants and placebo, although drug-placebo effects sizes did not significantly differ across disorders. Theoretical and clinical implications for the understanding and treatment of OCD are discussed.