Wenzhu Mowrey

Classification of amyloid-positivity in controls: Comparison of visual read and quantitative approaches

UNLABELLED An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aβ) deposition. Use of amyloid PET for this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Aβ deposition from those in which Aβ deposition has begun. We previously reported the iterative outlier approach (IO) for the analysis of Pittsburgh Compound-B (PiB) PET data. Developments in amyloid imaging since the initial report of IO have led us to re-examine the generalizability of this method. IO was developed using full-dynamic atrophy-corrected PiB PET data obtained from a group of control subjects with a fairly distinct separation between PiB-positive [PiB(+)] and PiB-negative [PiB(-)] subjects. METHODS We tested the performance of IO using late-summed tissue ratio data with atrophy correction or with an automated template method without atrophy correction and tested the robustness of the method when applied to a cohort of older subjects in which separation between PiB(+) and PiB(-) subjects was not so distinct. RESULTS The IO method did not perform consistently across analyses and performed particularly poorly when separation was less clear. We found that a sparse k-means (SKM) cluster analysis approach performed significantly better; performing more consistently across methods and subject cohorts. We also compared SKM to a consensus visual read approach and found very good correspondence. CONCLUSION The visual read and SKM methods, applied together, may optimize the identification of early Aβ deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers.

Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study

BACKGROUND The biomarker model of Alzheimers disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimers disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed. METHODS For this prospective cohort study, carriers of autosomal dominant Alzheimers disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimers Disease Research Center every 1-2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using (11)C-Pittsburgh Compound-B PET, posterior cortical metabolism with (18)F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimers Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65-89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls). FINDINGS 16 people with mutations in PSEN1, PSEN2, or APP, aged 28-56 years, completed between two and eight assessments (a total of 83 assessments) over 2-11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6-11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline. INTERPRETATION Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimers disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimers disease-active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline-indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimers disease. FUNDING National Institutes of Health and Howard Hughes Medical Institute.

CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of infantile spasms.

Infantile spasms (IS) have poor outcomes and limited treatment options, including vigabatrin, a γ‐aminobutyric acid (GABA) aminotransferase inactivator. Vigabatrin has been associated with retinal toxicity. A high affinity vigabatrin analogue (CPP‐115; Catalyst Pharmaceutical Partners, Inc., Coral Gables, FL, U.S.A.) has shown lower risk of retinal toxicity. Here, we test the efficacy of CPP‐115 in reducing spasms and its tolerability in the multiple‐hit rat model of IS, in which daily vigabatrin reduced spasms for only one day, but was not well tolerated.

Relative 11C-PiB Delivery as a Proxy of Relative CBF: Quantitative Evaluation Using Single-Session 15O-Water and 11C-PiB PET

The primary goal of this study was to assess the suitability of 11C-Pittsburgh compound B (11C-PiB) blood–brain barrier delivery (K1) and relative delivery (R1) parameters as surrogate indices of cerebral blood flow (CBF), with a secondary goal of directly examining the extent to which simplified uptake measures of 11C-PiB retention (amyloid-β load) may be influenced by CBF, in a cohort of controls and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). Methods: Nineteen participants (6 controls, 5 AD, 8 MCI) underwent MR imaging, 15O-water PET, and 11C-PiB PET in a single session. Fourteen regions of interest (including cerebellar reference region) were defined on MR imaging and applied to dynamic coregistered PET to generate time–activity curves. Multiple analysis approaches provided regional 15O-water and 11C-PiB measures of delivery and 11C-PiB retention that included compartmental modeling distribution volume ratio (DVR), arterial- and reference-based Logan DVR, simplified reference tissue modeling 2 (SRTM2) DVR, and standardized uptake value ratios. Spearman correlation was performed among delivery measures (i.e., 15O-water K1 and 11C-PiB K1, relative K1 normalized to cerebellum [Rel-K1-Water and Rel-K1-PiB], and 11C-PiB SRTM2-R1) and between delivery measures and 11C-PiB retention, using the Bonferroni method for multiple-comparison correction. Results: Primary analysis showed positive correlations (ρ ≈0.2–0.5) between 15O-water K1 and 11C-PiB K1 that did not survive Bonferroni adjustment. Significant positive correlations were found between Rel-K1-Water and Rel-K1-PiB and between Rel-K1-Water and 11C-PiB SRTM2-R1 (ρ ≈0.5–0.8, P < 0.0036) across primary cortical regions. Secondary analysis showed few significant correlations between 11C-PiB retention and relative 11C-PiB delivery measures (but not 15O-water delivery measures) in primary cortical areas that arose only after accounting for cerebrospinal fluid dilution. Conclusion: 11C-PiB SRTM2-R1 is highly correlated with regional relative CBF, as measured by 15O-water K1 normalized to cerebellum, and cross-sectional 11C-PiB retention did not strongly depend on CBF across primary cortical regions. These results provide further support for potential dual-imaging assessments of regional brain status (i.e., amyloid-β load and relative CBF) through dynamic 11C-PiB imaging.

Memory Binding Test Distinguishes Amnestic Mild Cognitive Impairment and Dementia from Cognitively Normal Elderly

Objective We aimed to assess reliability and cross-sectional discriminative validity of the Memory Binding Test (MBT) to distinguish persons with amnestic cognitive impairment (aMCI) and dementia from cognitively normal elderly controls. Method The MBT was administered to 20 participants with dementia, 31 with aMCI and 246 controls, who received the first administration of the MBT from May 2003 to December 2007, as a substudy of the community-based Einstein Aging Study (age range: 70+). The optimal index resulted from comparing the partial area under the receiver operating characteristic curves (ROC AUC) of four major MBT indices for specificities ≥0.70. Optimal cut-score of the optimal index was selected by maximizing the sum of sensitivity and specificity. Age and education effects were assessed using stratified cut-scores and adjusted logistic regression. Reliability was computed as intraclass correlation between scores at baseline and 1-year follow-up for participants who remained cognitively normal. Results Total number of Items recalled in the Paired condition (TIP) was elected the optimal index. TIP cut-score was ⩽22 for differentiating aMCI alone (sensitivity = 0.74, specificity = 0.73) and aMCI and dementia combined (sensitivity = 0.84, specificity = 0.73) from controls. It was ⩽17 for differentiating dementia from aMCI and controls (sensitivity = 0.95, specificity = 0.87). Age and education adjustments did not materially improve discriminative validity. The reliability of TIP was 0.77. Conclusions MBT achieved moderate to good reliability. TIP had superior cross-sectional discriminative validity than the other MBT indices. We recommend using the empirical cut-score of TIP ⩽22 for discriminating aMCI and dementia and ⩽17 for discriminating dementia alone.

Scalp EEG Ictal gamma and beta activity during infantile spasms: Evidence of focality

We investigated temporal and spatial characteristics of ictal gamma and beta activity on scalp EEG during spasms in patients with West syndrome (WS) to evaluate potential focal cortical onset.

Two-stage screening for early dementia in primary care

ABSTRACT Objective: The objective was to compare two screening strategies for dementia in an urban primary care clinic, serving a low-education, minority community composed largely of Latino and African American patients. Method: Two hundred and fifty-seven patients underwent two-stage patient-based screening (PBS) and informant-based screening (IBS) followed by a diagnostic evaluation. In the first stage, PBS included brief tests of episodic memory (Memory Impairment Screen), semantic memory (Animal Fluency), and executive function (Reciting Months Backwards). For IBS, the first stage consisted of the short Informant Questionnaire on Cognitive Decline in the Elderly, administered to a family member or friend. Patients who screened positive in the first stage of either strategy underwent testing with the picture version of the Free and Cued Selective Reminding Test with Immediate Recall to identify memory impairment. Sensitivity, specificity, and positive and negative predictive values were computed for various cutoffs of each test and combination of tests. Dementia was diagnosed using Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition (DSM–IV) criteria without access to the screening test results. Results: We identified 66 patients (25.7%) with previously undiagnosed dementia. Sensitivity was the same (77%) for both strategies but specificity was higher for IBS than for PBS (92% versus 83%). IBS’s higher specificity makes it the preferred strategy if a knowledgeable informant is available. Conclusion: Unrecognized dementia is common in primary care. Case-finding can be improved using either PBS or IBS two-stage screening strategies.

Memory Binding Test Predicts Incident Amnestic Mild Cognitive Impairment

BACKGROUND The Memory Binding Test (MBT), previously known as Memory Capacity Test, has demonstrated discriminative validity for distinguishing persons with amnestic mild cognitive impairment (aMCI) and dementia from cognitively normal elderly. OBJECTIVE We aimed to assess the predictive validity of the MBT for incident aMCI. METHODS In a longitudinal, community-based study of adults aged 70+, we administered the MBT to 246 cognitively normal elderly adults at baseline and followed them annually. Based on previous work, a subtle reduction in memory binding at baseline was defined by a Total Items in the Paired (TIP) condition score of ≤22 on the MBT. Cox proportional hazards models were used to assess the predictive validity of the MBT for incident aMCI accounting for the effects of covariates. The hazard ratio of incident aMCI was also assessed for different prediction time windows ranging from 4 to 7 years of follow-up, separately. RESULTS Among 246 controls who were cognitively normal at baseline, 48 developed incident aMCI during follow-up. A baseline MBT reduction was associated with an increased risk for developing incident aMCI (hazard ratio (HR) = 2.44, 95% confidence interval: 1.30-4.56, p = 0.005). When varying the prediction window from 4-7 years, the MBT reduction remained significant for predicting incident aMCI (HR range: 2.33-3.12, p: 0.0007-0.04). CONCLUSION Persons with poor performance on the MBT are at significantly greater risk for developing incident aMCI. High hazard ratios up to seven years of follow-up suggest that the MBT is sensitive to early disease.

Spinal Fusion for Scoliosis in Rett Syndrome With an Emphasis on Respiratory Failure and Opioid Usage

Our objective was to characterize our experience with 8 patients with Rett syndrome undergoing scoliosis surgery in regard to rates of respiratory failure and rates of ventilator-acquired pneumonia in comparison to patients with neurologic scoliosis and adolescent idiopathic scoliosis. This study was a retrospective chart review of patients undergoing scoliosis surgery at a tertiary children’s hospital. Patients were divided into 3 groups: (1) adolescent idiopathic scoliosis, (2) neurologic scoliosis, and (3) Rett syndrome. There were 133 patients with adolescent idiopathic scoliosis, 48 patients with neurologic scoliosis, and 8 patients with Rett syndrome. We found that patients with Rett syndrome undergoing scoliosis surgery have higher rates of respiratory failure and longer ventilation times in the postoperative period when compared with both adolescent idiopathic scoliosis and neurologic scoliosis patients. There is insufficient evidence to suggest a difference in the incidence of ventilator-acquired pneumonia between the Rett syndrome and the neurologic scoliosis group. We believe our findings are the first in the literature to show a statistically significant difference between these 3 groups in regard to incidence of respiratory failure.

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

Preclinical studies have produced numerous drugs with antiseizure properties that currently are the standard of care. One third of the human population with epilepsy still continues to have seizures despite the ongoing discoveries. The recognized clinical gaps of care that need to be addressed are the identification of antiepileptogenic and disease‐modifying treatments, and treatments for refractory seizures or for seizures and epilepsies with limited or unsatisfactory treatments, such as early life epileptic encephalopathies. In this invited review, we provide a historical summary of the international efforts to reevaluate the strategies adopted in preclinical epilepsy therapy discovery studies. We discuss issues that may affect the quality, interpretation, and validation of preclinical studies and their translation to successful therapies for humans affected with epilepsy. These include the selection of animal models and the study design; research practices that affect rigor (such as appropriate use of statistics and reporting of study methods and results, their validation across models, labs, and preclinical‐clinical studies); the need to harmonize research methods and outcome assessment; and the importance of improving translation to clinically appropriate situations. The epilepsy research community is incrementally adopting collaborative research, including consortia or multicenter studies to meet these needs. Improving the infrastructure that can support these efforts will be instrumental in future success.