Peter D. Bulova

Imaging brain amyloid in nondemented young adults with Down syndrome using Pittsburgh compound B

Down syndrome (DS) is one of the most common causes of intellectual disability. Although DS accounts for only 15% of all individuals with intellectual disabilities, adults with DS account for approximately 60% of individuals with intellectual disabilities and Alzheimers disease. This is thought to be because of overproduction of the β‐amyloid (Aβ) protein due to trisomy for the Aβ precursor protein gene on chromosome 21. Pittsburgh compound B (PiB) is a noninvasive in vivo positron emission tomography tracer used to image amyloid deposition in living humans. Studies using PiB have shown an age‐dependent asymptomatic amyloid deposition in more than 20% of the cognitively normal elderly population. Presymptomatic carriers of presenilin (PS‐1) and Aβ precursor protein gene mutations who are destined to develop Alzheimers disease also show preclinical amyloid deposition. This report describes a pilot study involving the use of PiB in seven adults with DS (age: 20–44 years). Compared with objective cutoffs for amyloid positivity in older non‐DS cognitively normal control subjects, only two of the seven DS subjects (age: 38 and 44 years) showed increased PiB retention. The remaining five subjects aged between 20 and 35 years showed no detectable increase in PiB retention. Interestingly, the two subjects who showed elevated PiB retention showed a striatal‐predominant pattern similar to that previously reported for PS‐1 mutation carriers. These results demonstrate the feasibility of conducting PiB positron emission tomography scanning in this special population, and suggest a link between Aβ overproduction and early striatal deposition of fibrillar Aβ.

The effects of normal aging on amyloid-β deposition in nondemented adults with Down syndrome as imaged by carbon 11-labeled Pittsburgh compound B.

In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer‐like neuropathology.

Managing the care of adults with Down’s syndrome

#### Summary points #### Sources and selection criteria We based this narrative review on articles found by searching PubMed and the Cochrane Database of Systematic Reviews. We then applied snowball techniques to sources for the articles identified from both databases. Search terms first included “Down syndrome”, “preventive health care”, “epidemiology”, and “adults with Down syndrome”. We then searched specifically for articles dealing with comorbidities identified within that search. To date, few randomized controlled trials have involved adults with Down’s syndrome, and many studies that do exist used small sample sizes. We referenced many of these studies to ensure that our review was thorough and accurate. The information contained in this review results primarily from literature arising from observational studies and expert consensus, unless noted otherwise. Down’s syndrome results from increased genetic material on all or a portion of chromosome 21 and is characterized by intellectual disability and risk for comorbidities involving multiple organ systems.1 2 3 The survival of people with Down’s …

Longitudinal changes in amyloid positron emission tomography and volumetric magnetic resonance imaging in the nondemented Down syndrome population

Down syndrome (DS) arises from a triplication of chromosome 21, causing overproduction of the amyloid precursor protein and predisposes individuals to early Alzheimers disease (AD).

Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome

BACKGROUND The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimers disease (AD). OBJECTIVE The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. METHODS Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. RESULTS Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. CONCLUSIONS In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

Leisure Activity and Caregiver Involvement in Middle-Aged and Older Adults With Down Syndrome

The present study examined leisure activity and its association with caregiver involvement (i.e., residence and time spent with primary caregiver) in 62 middle-aged and older adults with Down syndrome (aged 30-53 years). Findings indicated that middle-aged and older adults with Down syndrome frequently participated in social and passive leisure activities, with low participation in physical and mentally stimulating leisure activities. Residence and time spent with primary caregiver were associated with participation in physical leisure activity. The findings suggest a need for support services aimed at increasing opportunities for participating in physical and mentally stimulating leisure activity by middle-aged and older adults with Down syndrome. These support services should partner with primary caregivers in order to best foster participation in physical leisure activity.

Going Beyond the Checklist with Hybrid Simulation

M ore and more we are seeing residents shying away from bedside procedures. They cite time, lack of experience, and perhaps the conviction that there are safer places, such as interventional radiology suites, to perform procedures such as lumbar punctures. Due to advances in technology, educators now have outstanding bench model simulators to train residents in a variety of commonly performed procedures. However, this does not mean educators can assume that passing a test using an evaluator/checklist approach in a sterile idealized simulation will translate to proficient performance in the true clinical setting. In this issue of JGIM, Dr. Mikael Henriksen and colleagues present an educational innovation that combines multiple facets of medical education. They asked, BHow do you assess competency in a standardized simulated setting in order to minimize patient risk, but assure the simulation is predictive of proficiency in a clinical setting? Is a checklist adequate for the assessor to rate competency? Is the real-world scenario recreated effectively enough in the lab to predict who can perform the procedure on a patient in typical circumstances?^ They set out to develop an assessment that measures technical skill, but takes into account Bextenuating circumstances^ unique to the setting—in this case, a safely, compassionately, and competently performed lumbar puncture. The authors used two distinct steps to develop their assessment innovation. They created a global rating scale (GRS) by first conducting a literature search for validated models, then combining that with a Delphi approach that involved interviewing both experts and novices in multiple specialties. They found important differences between novices and experts: for example, while novices focused on barriers to technical performance, experts focused more on the clinical environment, and while novices focused more narrowly on the ability to obtain spinal fluid, experts concentrated on factors such as pain control, patient positioning, and working with an assistant. In other words, experts focus on real-world complexities that have been implicated in lumbar puncture complications. Their new assessment tool, the LumPAT, is innovative in that it combines the clinical and environmental facets of the procedure. Instead of a checklist using ratings of Bcompleted^ or Bdid not complete^ (a validated method in multiple studies), a five-point scale was used, with ratings ranging from Bpoor^ to Bperfect.^ The authors incorporated simulated Blive^ patients to assess residents’ competency with real-world interactions and environmental factors. To assess technical aspects, the procedural simulator was strapped to the back of the simulated patent at the time of the actual intervention. Each session was graded, with 44 out of 55 points used as a pass/fail standard. There was good inter-rater reliability despite the five-point scale, which one might think would be more vulnerable to interpretation by the assessor. Other trials have also shown the inter-rater reliability to be higher with a GRS compared to a checklist. The hybrid model—combining a simulator with a human actor—adds realism to the simulation and integrates communication and technical skills, improving the experience even for those who have performed the procedure before. Combining a bench model simulator with a human actor was well described in a University of Toronto curricular innovation combining an arthrocentesis model with an actor. The Toronto study demonstrated that simulated patients add a new, important dimension to the procedure, even for those who have performed the procedure in the past. This suggests there is much to be said for stepping beyond mechanical simulation by adding a human component. To go one step farther, in Dr. Henriksen’s article in this issue, the authors take this Bhybrid method^ and incorporate it into the development of a new competency assessment tool. A novel portion of this lumbar puncture training innovation is a newly crafted GRS, which the authors found could be used to assess readiness for practice. The goal of the study was to differentiate between those with little but adequate experience and those with experience but lacking competence. The new 11-question tool combined multiple validated tools with Breal-world^ information gleaned from the interviews. The authors acknowledge limitations, including small sample size and testing at a single institution, but their study notably included physicians from neurology, internal medicine, and anesthesiology. Their model needs to Published online February 28, 2017

ALZHEIMER-LIKE PATHOPHYSIOLOGICAL CHANGES IN THE NON-DEMENTED DOWN SYNDROME POPULATION

the activity. In AD brain, GSK-3b is truncated at the C-terminus by over-activated calpain I, leading to an increase in its activity. However, the effect of truncation on its phosphorylation is unknown.Methods:We determined themolecular mechanism bywhich the truncation of GSK3b leads to increase in its activity by usingWestern blots, immunofluorescencent staining, subcellular fractionation, in vitro dephosphorylation, and co-immunoprecipitation. Results:We found that in AD brain and in cultured cells, theC-terminally truncatedGSK-3bwas less phosphorylated at Ser9 than the full-length enzyme. The truncated GSK-3b was observed more than the full-length in the nucleus in cultured cells and in AD brain. The truncated GSK-3b interacted with protein phosphatase 2A (PP2A) more strongly and was dephosphorylated by PP2A more efficiently than the full-lengthGSK-3b.Conclusions:TheC-terminal truncation of GSK-3b promotes its nuclear translocation and enhances its interaction with and dephosphorylation by PP2A. Thus, the truncation of GSK-3b may enhance its activity through Ser9 dephosphorylation by PP2A. These findings shed a new light onto the role of calpain-GSK-3b-PP2A in tau pathogenesis in AD.

Imaging brain amyloid in non-demented young adults with Down syndrome using PiB-PET

heimer’s disease (AD) (MCI-c) from those that remain stable (MCI-s). Longitudinal percentage volume changes (PVC) in hippocampal, parahippocampal and entorhinal cortex (ERC) and left/right asymmetry were compared to standard cross-sectional measures. Methods: Data on 58 MCI-c and 239 MCI-s subjects was acquired from the public ADNI consortium database. Multiple 1.5T scanners were used to obtain MP-RAGE scans at baseline, six-months and one-year. Hippocampal volume and parahippocampal/ERC thickness were measured using FreeSurfer and used to calculate PVC and asymmetry measuresbetweenbaseline&six-months, six-months&one-year and baseline & one-year. A mixed-model logistic regression analyses using a generalised linear approachwith randomeffects for centre and controlling for age and genderwas used to examine the extent towhich normalised volumes could predict group membership. Akaike information criterion (AIC) and Bayesian information criterion (BIC) were used to identify the best models which were then reported in terms of sensitivity, specificity and balanced accuracy. Results: Cross-sectional volumes at one-year were found to be the best model (Sensitivity 1⁄4 71%, Specificity 1⁄4 69%, Accuracy 1⁄4 70%) with both the left hippocampus (p<0.001) and right ERC (p1⁄4 0.05) significantly predicting conversion. The best longitudinal models from each group were PVCs between baseline and one-year (Sensitivity 1⁄4 64%, Specificity 1⁄4 67%, Accuracy 1⁄4 66%) with the left ERC as the most accurate predictor (p 1⁄4 0.001), and asymmetry changes between six-months and one-year (Sensitivity1⁄4 61%, Specificity1⁄4 64%, Accuracy1⁄4 62%). Combining cross-sectional volumes at baseline with PVC measures from baseline to six-months improved the ability to predict conversion (Sensitivity 1⁄4 70%, Specificity 1⁄4 72%, Accuracy 1⁄4 71%). Conclusions: Longitudinal PVC and asymmetry measures were not as accurate at predicting group membership as cross-sectional volumes. However, the ability to predict conversion was improved by combining longitudinal measures with cross-sectional volumes. Consistent with previous findings, we confirm that the left hippocampus and right ERC are the most accurate cross-sectional predictors of conversion, but PVCs of the left ERC are amore important longitudinalmarker of conversion.