Jessica Powell

Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain‐only donations and currently has banked more than 1600 brains. More than 430 whole‐body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimers disease, Parkinsons disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimers Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinsons Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinsons Research. The Program has made rapid autopsy a priority, with a 3.0‐hour median post‐mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant‐funded projects.

Florbetapir PET, FDG PET, and MRI in Down syndrome individuals with and without Alzheimer's dementia

Down syndrome (DS) is associated with amyloid b (Ab) deposition.

Age- and education-adjusted normative data for the Montreal Cognitive Assessment (MoCA) in older adults age 70–99

The original validation study for the Montreal Cognitive Assessment (MoCA) suggests a cutoff score of 26; however, this may be too stringent for older adults, particularly for those with less education. Given the rapidly increasing number of older adults and associated risk of dementia, this study aims to provide appropriate age- and education-adjusted norms for the MoCA. Data from 205 participants in an ongoing longevity study were used to derive normative data. Individuals were grouped based on age (70–79, 80–89, 90–99) and education level (≤12 Years, 13–15, ≥16 Years). There were significant differences between age and education groups with younger and more educated participants outperforming their counterparts. Forty-six percent of our sample scored below the suggested cutoff of 26. These normative data may provide a more accurate representation of MoCA performance in older adults for specific age and education stratifications.

Longitudinal EEG changes correlate with cognitive measure deterioration in Parkinson's disease

BACKGROUND QEEG could provide physiological biomarkers for changes over time in Parkinsons disease (PD) cognitive decline if they track with longitudinal neuropsychological performance. OBJECTIVE Our aim was to correlate longitudinal changes in frequency domain quantitative electroencephalography (QEEG) measures with change in neuropsychological performance testing in PD. METHODS 71 PD subjects, not demented at baseline, were studied from the Arizona Study of Aging and Neurodegenerative Disorders cohort. Baseline and follow-up digital EEG from PD subjects were analyzed for QEEG measures of background rhythm frequency and global relative power in delta (2.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), and beta (13-30 Hz) bands. Baseline and subsequent evaluation included Mini Mental Status Examination and five other neuropsychological tests that load on cognitive domains known to decline in PD. Pearson coefficient was used to assess correlations. Multiple linear regression modeling was used to assess the effect of variable combinations of QEEG and other measures, including age and PD duration. RESULTS Changes in delta bandpower showed the highest and most consistent pattern of correlations with longitudinal changes in neuropsychological testing. The highest correlation was between delta bandpower increase and decline in the Rey Auditory-Verbal Learning Test (-0.59:p < 0.001). Delta bandpower was also increased in the incident dementia group compared to non-dementia at followup. CONCLUSIONS 1) Longitudinal change in the QEEG frequency domain measure of delta bandpower correlated best with longitudinal neuropsychological performance change in PD; 2) These results constitute preliminary evidence that delta bandpower may be a suitable biomarker for evaluating PD cognitive deterioration longitudinally.

Added value and limitations of amyloid-PET imaging: review and analysis of selected cases of mild cognitive impairment and dementia

ABSTRACT Amyloid-positron emission tomography (PET) imaging of the brain detects elevated amyloid-beta (amyloid-β) neuritic plaques in vivo, which can be helpful in appropriately selected cases of mild cognitive impairment (MCI) and dementia, when Alzheimer’s disease remains a possible etiology, after a comprehensive clinical evaluation. We reviewed cases of cognitively impaired patients who underwent amyloid-PET imaging because of diagnostic uncertainty. Pre- and post-PET elements of diagnosis and management were first compared, to assess impact of scan results on clinical decision-making, and then an analysis of those decisions was undertaken in appropriate clinical situations, to delineate the added value and limitations of amyloid-PET imaging. The potential benefits and limitations of this diagnostic tool are important to understand in an era when the utility of such scans in clinical practice is evolving.

Neuropsychological Correlates of the Alzheimer's Questionnaire.

Informant-based assessments of cognition and function are commonly used to differentiate individuals with amnestic mild cognitive impairment (aMCI) and Alzheimers disease (AD) from those who are cognitively normal. However, determining the extent to which informant-based measures correlate to objective neuropsychological tests is important given the widespread use of neuropsychological tests in making clinical diagnoses of aMCI and AD. The aim of the current study is to determine how well the Alzheimers Questionnaire (AQ) correlates with objective neuropsychological tests. The study utilized data from 300 individuals participating in a brain and body donation program. Individuals diagnosed with aMCI (n = 83) and AD (n = 67) were matched on age, gender, and education to a control individual (n = 150). The average age for the entire sample was 83.52±6.51 years with an average education level of 14.57±2.55 years. Results showed that the AQ correlated strongly with the Mini-Mental State Exam (r =-0.71, p <  0.001) and the Mattis Dementia Rating Scale-2 (r =-0.72, p <  0.001), and moderate correlations were noted for the AQ with memory function (Rey Auditory Verbal Learning Test Delayed Recall, r =-0.61, p <  0.001) and executive function (Trails B, r = 0.53, p <  0.001). The findings of this study suggest that the AQ correlates well with several neuropsychological tests and lend further support to the validity of the AQ as a screening instrument for cognitive impairment.

Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer’s Disease: Results from a Double-Blind, Placebo-Controlled Trial

INTRODUCTION To date there is no cure for Alzheimers disease (AD). After amyloid beta immunotherapies have failed to meet primary endpoints of slowing cognitive decline in AD subjects, the inhibition of the beta-secretase BACE1 appears as a promising therapeutic approach. Pre-clinical data obtained in APP23 mice suggested that the anti-cancer drug thalidomide decreases brainBACE1 and Aβ levels. This prompted us to develop an NIH-supported Phase IIa clinical trial to test the potential of thalidomide for AD. We hypothesized that thalidomide can decrease or stabilize brain amyloid deposits, which would result in slower cognitive decline in drug- versus placebo-treated subjects. METHODS This was a 24-week, randomized, double-blind, placebo-controlled, parallel group study with escalating dose regimen of thalidomide with a target dose of 400mg daily in patients with mild to moderate AD. The primary outcome measures were tolerability and cognitive performance assessed by a battery of tests. RESULTS A total of 185 subjects have been pre-screened, out of which25 were randomized. Mean age of the sample at baseline was 73.64 (±7.20) years; mean education was 14.24 (±2.3) years; mean MMSE score was 21.00 (±5.32); and mean GDS score was 2.76 (±2.28).Among the 25 participants, 14 (56%) terminated early due to adverse events, dramatically decreasing the power of the study. In addition, those who completed the study (44%) never reached the estimated therapeutic dose of 400 mg/day thalidomide because of reported adverse events. The cognitive data showed no difference between the treated and placebo groups at the end of the trial. CONCLUSION This study demonstrates AD patients have poor tolerability for thalidomide, and are unable to reach a therapeutic dose felt to be sufficient to have effects on BACE1. Because of poor tolerability, this study failed to demonstrate a beneficial effect on cognition.

Early and Mild Phases of Primary Progressive Aphasia: A Case Series

BACKGROUND The early and mild phases of various neurodegenerative diseases, sometimes described as Mild Cognitive Impairment (MCI), has been characterized as the transitional state between normal cognition and dementia. It is described as having cognitive decline not severe enough to cause functional impairment. MCI has been divided into amnestic and non-amnestic subtypes with the amnestic subtype most commonly progressing to AD. The MCI phase of other dementias such as DLB has also been described. There are very few reports summarizing this early phase of Primary Progressive Aphasia. AIMS Our aim is to contribute to the clinical characterization of the early and mild phases of clinically suspect PPA in order to better describe the presenting features and neuropsychological profile. METHODS This is a cross-sectional case series abstracted from our memory disorders clinic. We retrospectively queried and analyzed the cases of 9 patients with a primary diagnosis of MCI and secondary diagnosis of progressive aphasia. Acquired (non-degenerative) aphasias (e.g. stroke, mass) were excluded. RESULTS Of the 9 cases, 5 were non-amnestic MCI and 4 were amnestic MCI, all with language as the primary domain. All eMCI cases were non-amnestic. Word finding difficulty was observed in 8 of the 9 cases and sentence repetition impairments in 8 of 8 tested. CONCLUSION PPA is a syndrome with an underlying progressive neurodegenerative etiology that results in dementia. PPA, like other neurodegenerative conditions, can transition through an early (i.e. MCI) phase prior to the dementia phase. The clinical description of this early stage of PPA is predominantly characterized by word finding difficulty on observation, sentence repetition impairment on neuropsychological testing, and a diagnosis of MCI or early MCI (eMCI) with language as the primary impaired domain ± an amnestic component.