Rebecca Bothwell

Learning proficiency on the Wisconsin Card Sorting Test in people with serious mental illness: What are the cognitive characteristics of good learners?

Although it is widely accepted that schizophrenia and other serious mental illnesses (SMI) are associated with neurocognitive difficulties, there is great variability in neurocognitive functioning across individuals. In recent years, a growing number of schizophrenia studies have utilized the concept of learning potential to explore individual variation in cognition. Learning potential refers to the ability to benefit from instruction and is measured by assessing test performance before and after training. The present study was intended to explore the cognitive characteristics associated with learning potential in people with serious mental illness. Sixty individuals with schizophrenia, bipolar or major (unipolar) depression completed a learning potential assessment using the Wisconsin Card Sorting Test (WCST) and a battery of standard cognitive measures. Based on established criteria for WCST learner subgroups, participants were categorized as high achievers, learners or non-retainers. There were several significant cognitive differences among the three learner subgroups. Most notably, individuals who were categorized as learners on the WCST showed significantly better verbal and working memory compared to non-retainers. Secondary analyses revealed that the three SMI diagnostic groups (depression, bipolar, schizophrenia) were similar in learning potential and did not differ on any of the standard cognitive measures. This study provides support for learning potential classification in schizophrenia as well as other serious mental illnesses, and indicates that learning potential may specifically be related to verbal and working memory abilities.

Safety of disclosing amyloid status in cognitively normal older adults

Disclosing amyloid status to cognitively normal individuals remains controversial given our lack of understanding the tests clinical significance and unknown psychological risk.

Platelet cytochrome oxidase and citrate synthase activities in APOE ε4 carrier and non-carrier Alzheimer's disease patients

A degradation product of APOE ε4-encoded apolipoprotein E protein targets mitochondria and inhibits cytochrome oxidase (COX), and autopsy brains from young adult APOE ε4 carriers show reduced COX activity. To further explore relationships between APOE alleles and COX, we measured platelet mitochondria COX activity in AD subjects with (n=8) and without (n=7) an APOE ε4 allele and found the mean COX activity, when normalized to sample total protein, was lower in the APOE ε4 carriers (p<0.05). Normalizing COX activity to citrate synthase (CS) activity eliminated this difference, but notably the mean CS activity was itself lower in the APOE ε4 carriers (p<0.05). COX and CS protein levels did not appear to cause the lower APOE ε4 carrier COX and CS Vmax activities. If confirmed in larger studies, these data could suggest mitochondria at least partly mediate the well-recognized association between APOE alleles and AD risk.

Tolerability and pharmacokinetics of oxaloacetate 100 mg capsules in Alzheimer's subjects.

Bioenergetics and bioenergetic-related functions are altered in Alzheimers disease (AD) subjects. These alterations represent therapeutic targets and provide an underlying rationale for modifying brain bioenergetics in AD-affected persons. Preclinical studies in cultured cells and mice found that administering oxaloacetate (OAA), a Krebs cycle and gluconeogenesis intermediate, enhanced bioenergetic fluxes and upregulated some brain bioenergetic infrastructure-related parameters. We therefore conducted a study to provide initial data on the tolerability and pharmacokinetics of OAA in AD subjects. Six AD subjects received OAA 100 mg capsules twice a day for one month. The intervention was well-tolerated. Blood level measurements following ingestion of a 100 mg OAA capsule showed modest increases in OAA concentrations, but pharmacokinetic analyses were complicated by relatively high amounts of endogenous OAA. We conclude that OAA 100 mg capsules twice per day for one month are safe in AD subjects but do not result in a consistent and clear increase in the OAA blood level, thus necessitating future clinical studies to evaluate higher doses.

Safety and Tolerability of R(+) Pramipexole in Mild-to-Moderate Alzheimer's Disease

Alzheimers disease (AD) is an aging-related, degenerative brain disease of adults. Most (∼95%) of AD occurs sporadically and is associated with early-appearing deficits in brain regional glucose uptake, changes in cerebrospinal fluid (CSF) AD-related proteins, regional brain atrophy, and oxidative stress damage. We treated mild-moderate AD individuals with R(+)-pramipexole-dihydrochloride (R(+)PPX), a neuroprotective, lipophilic-cation, free-radical scavenger that accumulates into brain and mitochondria. 19 subjects took R(+)PPX twice a day in increasing daily doses up to 300 mg/day under a physician-sponsor IND (60,948, JPB), IRB-approved protocol and quarterly external safety committee monitoring. 15 persons finished and contributed baseline and post-treatment serum, lumbar spinal fluid, brain 18F-2DG PET scans, and ADAS-Cog scores. ADAS-Cog scores did not change (n = 1), improved (n = 2), declined 1-3 points (n = 5), or declined 4-13 points (n = 8) over 6 months of R(+)PPX treatment. Serum PPX levels were not related to changes in ADAS-Cog scores. Fasting AM serum PPX levels at 6 months varied considerably across subjects and correlated strongly with CSF [PPX] (r = 0.97, p <  0.0001). CSF [PPX] was not related to CSF [Aβ(42)], [Tau], or [P-Tau]. Regional 18F-2DG measures of brain glucose uptake demonstrated a 3-6% decline during R(+)PPX treatment. 56 mild-moderate adverse events occurred, 26 probably/definitely related to R(+)PPX use, with 4 withdrawals. R(+)PPX was generally well-tolerated and entered brain extracellular space linearly. Further studies of R(+)PPX in AD should include a detailed pharmacokinetic study of peak and trough serum [PPX] variations among subjects prior to planning any larger studies that would be needed to determine efficacy in altering disease progression.

Handwriting with a preferred retinal locus for AMD with scotomas.

Purpose Individuals with macular scotomas from age-related macular degeneration frequently have difficulty writing legibly. The purpose of this study was to investigate the causes of this difficulty by documenting the location of the retinal image of the pen used for writing in relation to the scotoma and fixational preferred retinal locus (fPRL). Methods Subjects with macular scotomas from age-related macular degeneration and visually normal age-matched controls wrote words while observing their hand, pen, and text in a scanning laser ophthalmoscope. Scanning laser ophthalmoscope video images were analyzed to find the retinal positions of the subject’s scotoma, fixation area, and pen tip. Results Control subjects placed their fovea and scotoma subjects placed their fPRL on or very close to the pen tip for both cursive writing and printing. Scotoma subjects’ written text sloped downward at a greater angle than controls’. Text angle was negatively correlated with fPRL eccentricity, visual acuity, and the amount the scotoma obscured the writing guides. When printing, control subjects placed their fovea precisely in the center of printing box guides, whereas scotoma subjects exhibited highly dispersed placement of the fPRL. Conclusions The principal finding is that, because the retinal locations of the pen tip and the fPRL or fovea are coincident or very close, the fPRL and fovea are “monitoring” the pen tip and its location on the page. It is the PRL determined by asking subjects to fixate (i.e., the fPRL) that is used when handwriting, not a separate “handwriting” PRL. The poor handwriting performance of those with macular scotomas seems to be primarily caused by difficulty in placing letters in the appropriate location probably because of reduced visual acuity of the fPRL and scotoma obscuration of the area on which to write.

A Mitochondrial Biomarker-Based Study of S-Equol in Alzheimer’s Disease Subjects: Results of a Single-Arm, Pilot Trial

Reductions in bioenergetic fluxes, mitochondrial enzyme activities, and mitochondrial number are observed in Alzheimers disease (AD). Preclinical work indicates estrogen pathway signaling by either estrogen or selective β estrogen receptor (ERβ) agonists benefits these parameters. To assess whether an ERβ agonist could improve mitochondrial function in actual AD subjects, we administered S-equol (10 mg twice daily) to 15 women with AD and determined the platelet mitochondria cytochrome oxidase (COX) activity before initiating S-equol (lead-in), after two weeks of S-equol (active treatment), and two weeks after stopping S-equol (wash-out). Because the intra-individual variation of this enzyme across samples taken at different times was unknown we used a nonparametric, single-arm, dichotomous endpoint that classified subjects whose active treatment COX activity exceeded the average of their lead-in and wash-out measures as positive responders. Eleven positive responses were observed (p < 0.06). The implications of this finding on our null hypothesis (that S-equol does not influence platelet mitochondria COX activity) are discussed. To our knowledge, this is the first time a direct mitochondrial target engagement biomarker has been utilized in an AD clinical study.

Disclosure of amyloid imaging results in cognitively normal individuals

(acute care, home care, physician visits), placement in long-term care and survival. New cases of physician-diagnosed dementia were also identified. Descriptive statistics and Cox proportional hazard models were used to compare individuals with and without dementia on these outcomes, and patient level demographic and functional predictors, including the role of coexisting chronic conditions, were examined. Results:There was a two-fold increase in the number of community-dwelling older adults with physiciandiagnosed dementia over six years (40,251 in 2007 to 74,450 in 2012). Compared to older adults without a dementia diagnosis, those with dementia were more likely to be 85 years and older (36.9% versus 9.9%), female (60.9% versus 54.8%) and a higher number of coexisting chronic conditions. At the end of six years 73.9% of individuals with dementia had visited an emergency department (versus 66.7% no dementia); 58.8% had been admitted to acute care (versus 45.0% no dementia) and 32.2% had applied for long-term care placement (versus 5.5% no dementia) (p-values >0.01). Over the six-year period 15.3% of individuals with dementia were placed in long-term care and 45.9% died. Conclusions: Our findings suggest that community-dwelling older adults with physician-diagnosed dementia make frequent contact with the Ontario health care system. Results highlight that community supports, such as home care, are priority areas for future investments.

PLATELET AND LYMPHOCYTE MITOCHONDRIAL BIOMARKERS IN APOE ε4-CARRIER AD SUBJECTS

Note: SD1⁄4 Standard Deviation; QSMC1⁄4 Questionnaire for Subjective Memory Complaints (patient); CCI1⁄4 Charlson Comorbidity Index; CAMCOG-R1⁄4 Cambridge Cognitive Assessment-Revised total score; MMSE1⁄4 Mini Mental State Examination; SDFR1⁄4 Short Delay Free Recall from the California Verbal Learning Test; LDFR1⁄4 Long Delay Free Recall from the California Verbal Learning Test; BNT1⁄4 Boston Naming Test total score; TMT-A1⁄4 Trial Making TestForm A, score in seconds; TMT-B1⁄4 Trail Making TestForm B, score in seconds; IADL1⁄4 Instrumental Activities of Daily Living from the Lawton & Brody Index. Table 2 Descriptive parameters of cerebrospinal fluid (CSF) and nutritional biomarkers

TRIAL OF OXALOACETATE IN ALZHEIMER’S DISEASE (TOAD): INTERIM FDG PET ANALYSIS

Mild-to-Moderate AD Doneoezil Placebo 0.64 (0.24 to 1.04) 1.91 (1.08 to 2.76) 3.02 (1.30 to 4.76) 1.81 (0.37 to 3.03) Galantamine Placebo 0.62 (0.01 to 1.21) 2.83 (1.87 to 3.77) 2.18 (1.04 to 3.14) 1.26 (-0.27 to 2.69) Memantine Placebo 0.21 (-0.48 to 0.91) 1.68 (-0.81 to 4.17) -0.16 (-1.95 to 1.64) 3.08 (0.62 to 5.35) Rivastigmine Placebo 1.08 (0.63 to 1.53) 1.90 (0.74 to 3.07) 2.26 (0.61 to 3.95) 0.98 (-1.30 to 3.17) Memantine + AChEI Placebo 0.25 (-0.5 to 1.01) 2.28 (-0.27 to 4.86) -0.61 (-2.36 to 1.07) 0.30 (-5.39 to 6.00) Galantamine Doneoezil -0.02 (-0.63 to 0.57) 0.91 (-0.24 to 2.04) -0.84 (-2.72 to 0.97) -0.54 (-2.08 to 1.12) Memantine Doneoezil -0.43 (-1.13 to 0.28) -0.24 (-2.77 to 2.28) -3.18 (-5.61 to-0.71) 1.27 (-0.90 to 3.41) Rivastigmine Doneoezil 0.44 (-0.09 to 0.98) -0.01 (-1.30 to 1.28) -0.76 (-3.14 to 1.66) -0.83 (-3.07 to 1.58) Memantine + AChEI Doneoezil -0.39 (-1.18 to 0.41) 0.37 (-2.27 to 3.00) -3.62 (-6.00 to-1.25) -1.51 (-7.20 to 4.28) Memantine Galantamine -0.41 (-1.20 to 0.41) -1.15 (-3.78 to 1.50) -2.34 (-4.18 to-0.38) 1.81 (-0.83 to 4.33) Rivastigmine Galantamine 0.46 (-0.20 to 1.14) -0.93 (-2.31 to 0.48) 0.08 (-1.70 to 2.04) -0.28 (-2.65 to 2.10) Memantine + AChEl Galantamine -0.37 (-1.21 to 0.50) -0.54 (-3.04 to 1.98) -2.78 (-4.51 to-1.03) -0.96 (-6.72 to 4.82) Rivastigmine Memantine 0.87 (0.10 to 1.63) 0.22 (-2.49 to 2.94) 2.42 (0.29 to 4.60) -2.09 (-5.10 to 1.07) Memantine + AChEI Memantine 0.04 (-0.77 to 0.86) 0.61 (-2.95 to 4.17) -0.45 (-1.92 to 0.89) -2.77 (-8.82 to 3.36) Memantine + AChEI Rivastigmine -0.83 (-1.58 to -0.07) 0.38 (-2.19 to 2.97) -2.87 (-4.87 to-0.96) -0.68 (-5.90 to 4.56) Moderate-to-Severe AD Doneoezil Placebo 0.76 (-1.07 to 2.60) 1.01 (-0.87 to 2.74) -0.34 (-4.90 to 3.96) Galantamine Placebo Memantine Placebo 0.08 (-1.74 to 1.78) 3.02 (-9.30 to 15.46) 0.56 (-1.42 to 2.51) 3.00 (-0.50 to 6.68) Rivastigmine Placebo 0.10 (-2.85 to 3.09) -2.93 (-7.93 to 2.01) 3.08 (-1.22 to 7.29) Memantine + AChEI Placebo 1.23 (-1.22 to 3.80) 1.26 (-1.56 to 3.81) 3.05 (-5.67 to 11.55) Galantamine Doneoezil Memantine Doneoezil -0.69 (-3.14 to 1.65) -0.46 (-3.08 to 2.28) 3.34 (-2.14 to 9.27) Rivastigmine Donepezil -0.67 (-3.64 to 2.32) 2.07 (-1.81 to 5.95) Memantine + AChEI Doneoezil 0.46 (-1.54 to 2.60) 0.24 (-1.83 to 2.21) 3.39 (-4.01 to 10.79) Rivastigmine Galantamine Memantine Galantamine Memantine + AChEI Galantamine Rivastigmine Memantine 0.02 (-3.31 to 3.49) -5.95 (-19.33 to 7.28) 2.52 (-2.23 to 7.17) Memantine + AChEI Memantine 1.15 (-1.62 to 4.13) 0.70 (-2.75 to 3.94) 0.05 (-9.51 to 9.20) Memantine + AChEI Rivastigmine 1.13 (-2.34 to 4.72) -1.83 (-6.24. to 2.52)