Curtis Tatsuoka

Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.

Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimers disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimers disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimers disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimers disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimers disease phenotypes. These findings indicate that Alzheimers disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains.

Illness experience and reasons for nonadherence among individuals with bipolar disorder who are poorly adherent with medication

AIM Nonadherent individuals are the most likely to avoid participating in research studies, thus limiting potential opportunities to develop evidence-based approaches for adherence enhancement. This mixed-method analysis evaluated factors related to adherence among 20 poorly adherent community mental health clinic patients with bipolar disorder (BD). METHODS Illness experience was evaluated with qualitative interview. Quantitative assessments measured symptoms (Hamilton Depression Rating Scale, Young Mania Rating Scale, Brief Psychiatric Rating Scale), adherence behavior, and treatment attitudes. Poor adherence was defined as missing 30% or more of medication. RESULTS Minorities (80%), unmarried individuals (95%), and those with substance abuse (65%) predominated in this nonadherent group of patients with BD. Individuals were substantially depressed (mean Hamilton Depression Rating Scale, 19.2), had at least some manic symptoms (mean Young Mania Rating Scale, 13.6), and had moderate psychopathology (mean Brief Psychiatric Rating Scale, 41.2). Rates of missed medications were 41% to 43%. Forgetting to take medications was the top reason for nonadherence (55%), followed by side effects (20%). Disorganized home environments (30%), concern regarding having to take long-term medications (25%) or fear of side effects (25%), and insufficient information regarding BD (35%) were relatively common. Almost one third of patients had individuals in their core social network who specifically advised against medication. Access problems included difficulty paying for medications among more than half of patients. Interestingly, patients reported good relationships with their providers. CONCLUSIONS Forgetting to take medication and problems with side effects are primary drivers of nonadherence. Lack of medication routines, unsupportive social networks, insufficient illness knowledge, and treatment access problems may likewise affect overall adherence. Complementary quantitative and qualitative data collection can identify reasons for nonadherence and may inform specific clinical approaches to enhance adherence.

Diagnostic and prognostic value of human prion detection in cerebrospinal fluid

Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second‐generation real‐time quaking‐induced conversion (RT‐QuIC). The objective of this study was to investigate the diagnostic performance of the RT‐QuIC prion test in the broad phenotypic spectrum of prion diseases.

Age-specific periictal electroclinical features of generalized tonic-clonic seizures and potential risk of sudden unexpected death in epilepsy (SUDEP)

Generalized tonic-clonic seizure (GTCS) is the commonest seizure type associated with sudden unexpected death in epilepsy (SUDEP). This study examined the semiological and electroencephalographic differences (EEG) in the GTCSs of adults as compared with those of children. The rationale lies on epidemiological observations that have noted a tenfold higher incidence of SUDEP in adults. We analyzed the video-EEG data of 105 GTCS events in 61 consecutive patients (12 children, 23 seizure events and 49 adults, 82 seizure events) recruited from the Epilepsy Monitoring Unit. Semiological, EEG, and 3-channel EKG features were studied. Periictal seizure phase durations were analyzed including tonic, clonic, total seizure, postictal EEG suppression (PGES), and recovery phases. Heart rate variability (HRV) measures including RMSSD (root mean square successive difference of RR intervals), SDNN (standard deviation of NN intervals), and SDSD (standard deviation of differences) were analyzed (including low frequency/high frequency power ratios) during preictal baseline and ictal and postictal phases. Generalized estimating equations (GEEs) were used to find associations between electroclinical features. Separate subgroup analyses were carried out on adult and pediatric age groups as well as medication groups (no antiepileptic medication cessation versus unchanged or reduced medication) during admission. Major differences were seen in adult and pediatric seizures with total seizure duration, tonic phase, PGES, and recovery phases being significantly shorter in children (p<0.01). Generalized estimating equation analysis, using tonic phase duration as the dependent variable, found age to correlate significantly (p<0.001), and this remained significant during subgroup analysis (adults and children) such that each 0.12-second increase in tonic phase duration correlated with a 1-second increase in PGES duration. Postictal EEG suppression durations were on average 28s shorter in children. With cessation of medication, total seizure duration was significantly increased by a mean value of 8s in children and 11s in adults (p<0.05). Tonic phase duration also significantly increased with medication cessation, and although PGES durations increased, this was not significant. Root mean square successive difference was negatively correlated with PGES duration (longer PGES durations were associated with decreased vagally mediated heart rate variability; p<0.05) but not with tonic phase duration. This study clearly points out identifiable electroclinical differences between adult and pediatric GTCSs that may be relevant in explaining lower SUDEP risk in children. The findings suggest that some prolonged seizure phases and prolonged PGES duration may be electroclinical markers of SUDEP risk and merit further study.

Six-month outcomes of customized adherence enhancement (CAE) therapy in bipolar disorder

BACKGROUND There are few psychosocial interventions specifically focused on improved treatment adherence in people with bipolar disorder (BD). Customized adherence enhancement (CAE) is a needs-based, manualized approach intended to improve medication adherence in individuals with BD. This was a six-month prospective trial of a CAE among 43 medication non-adherent individuals with BD who were receiving treatment in a community mental health clinic (CMHC). METHODS CAE was flexibly administered in modules applied as indicated by an initial adherence vulnerabilities screening. Screening identified reasons for non-adherence and modules were then administered using pre-set criteria. CAE effects were evaluated at six-week, three-month, and six-month follow-up. The six-month follow-up was our primary time point of interest. The primary outcome was change from baseline in adherence using the Tablets Routine Questionnaire (TRQ) and pill counts. Secondary outcomes included change from baseline in BD symptoms [Hamilton Depression Rating Scale (HAM-D), Young Mania Rating Scale (YMRS), and Brief Psychiatric Rating Scale (BPRS)]. RESULTS Subjects completed 86% of scheduled sessions, with only two individuals (5%) not participating in any sessions. The number of dropouts at six months was 12 (28%). Mean baseline non-adherence by TRQ was 48% [standard error (SE) 4.8%] missed tablets within the previous week and 51% (4.1%) missed tablets within the previous month. At six-month follow-up, mean TRQ non-adherence improved to 25% (6.8%) missed tablets for the previous week (p = 0.002) and 21% (5.5%) for the previous month (p < 0.001). Symptoms improved, with a change in the baseline mean (SE) BPRS of 43.6 (1.8) versus an endpoint of 36.1 (2.3) (p = 0.001), and baseline mean (SE) HAM-D of 17.8 (1.1) versus an endpoint of 15.3 (1.6) (p = 0.044). CONCLUSION CAE was associated with improvements in adherence, symptoms, and functional status. Controlled trials are needed to confirm these preliminary findings.

Asenapine in the treatment of older adults with bipolar disorder

In spite of growing numbers of older people, there are few treatment studies on late‐life bipolar disorder (BD). This was a 12‐week prospective, open‐label trial to assess efficacy and tolerability of adjunct asenapine in non‐demented older adults (≥60 years) with sub‐optimal previous response to BD treatments.

Enhanced Exercise Therapy in Parkinson's disease: A comparative effectiveness trial

Objectives Exercise can improve motor function in people with Parkinson’s disease but depression reduces the motivation to participate in regular exercise. The aim of this study was to develop a novel Enhanced Exercise Therapy program that uses manual-driven guided exercise and peer-facilitated psychoeducation for individuals with Parkinson’s disease and depression. Design 24 week randomized controlled design. Methods Thirty individuals were randomized to Enhanced Exercise Therapy or self-guided therapy, and evaluated at baseline, 12-weeks and at 24-weeks. Enhanced Exercise Therapy included group exercise and group psychoeducation for 12 weeks. Between 13–24 weeks, individuals had access to the fitness facility but group sessions were not held. Self-guided therapy included written guidelines for a self-paced exercise program and psychoeducation. Primary outcome measures included the number of exercise sessions and International Physical Activity Questionnaire score. Secondary measures included resting heart rate, supine blood pressure, estimated VO2max and incidence of orthostatic hypotension. Results Twenty four individuals completed the study (80% retention) and both groups attended similar number of exercise sessions. There were no significant changes in cardiovascular fitness measures but there was a significant increase in the amount of physical activity in the Enhanced Exercise Therapy group and a decrease in the self-guided therapy group during the post-intervention period. Conclusions Enhanced exercise therapy appears to promote engagement in an exercise program and more physical activity, even after group sessions were concluded in individuals with Parkinson’s disease and depression.

Prospective Trial of Customized Adherence Enhancement Plus Long-Acting Injectable Antipsychotic Medication in Homeless or Recently Homeless Individuals With Schizophrenia or Schizoaffective Disorder

BACKGROUND Treatment nonadherence in people with schizophrenia is associated with relapse and homelessness. Building on the usefulness of long-acting medication and our work in psychosocial interventions to enhance adherence, we conducted a prospective uncontrolled trial of customized adherence enhancement (CAE) plus long-acting injectable antipsychotic (LAI) using haloperidol decanoate in 30 homeless or recently homeless individuals with DSM-IV-defined schizophrenia or schizoaffective disorder. METHOD Participants received monthly CAE and LAI (CAE-L) for 6 months. Primary outcomes were adherence, as measured by the Tablets Routine Questionnaire, and housing status. Secondary outcomes included psychiatric symptoms, functioning, side effects, and hospitalizations. The study was conducted from July 2010 to December 2012. RESULTS The mean age of participants was 41.8 years (SD = 8.6); they were mainly minorities (90%, n = 27 African-American) and mainly single/never married (70%, n = 21). Most (97%, n = 29) had past or current substance abuse and had been incarcerated (97%, n = 29). Ten individuals (33%) terminated the study prematurely. CAE-L was associated with good adherence to LAI (at 6 months, 76%) and dramatic improvement in oral medication adherence, which changed from missing 46% of medication at study enrollment to missing only 10% at study end (P = .03). There were significant improvements in psychiatric symptoms (P < .001) and functioning (P < .001). Akathisia was a major side effect with LAI. CONCLUSIONS While interpretation of findings must be tempered by the methodological limitations, CAE-L appears to be associated with improved adherence, symptoms, and functioning in homeless or recently homeless individuals with schizophrenia or schizoaffective disorder. Additional research is needed on effective and practical approaches to improving health outcomes for homeless people with serious mental illness. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01152697.

Modeling the heterogeneity in risk of progression to Alzheimer's disease across cognitive profiles in mild cognitive impairment.

IntroductionHeterogeneity in risk of conversion to Alzheimers disease (AD) among individualswith mild cognitive impairment (MCI) is well known. Novel statistical methods thatare based on partially ordered set (poset) models can be used to create modelsthat provide detailed and accurate information about performance with specificcognitive functions. This approach allows for the study of direct links betweenspecific cognitive functions and risk of conversion to AD from MCI. It also allowsfor further delineation of multi-domain amnestic MCI, in relation to specificnon-amnestic cognitive deficits, and the modeling of a range of episodic memoryfunctioning levels.MethodsFrom the Alzheimers Disease Neuroimaging Initiative (ADNI) study, conversion at24 months of 268 MCI subjects was analyzed. It was found that 101 of thosesubjects (37.7%) converted to AD within that time frame. Poset models were thenused to classify cognitive performance for MCI subjects. Respective observedconversion rates to AD were calculated for various cognitive subgroups, and byAPOE e4 allele status. These rates were then compared across subgroups.ResultsThe observed conversion rate for MCI subjects with a relatively lower functioningwith a high level of episodic memory at baseline was 61.2%. In MCI subjects whoadditionally also had relatively lower perceptual motor speed functioning and atleast one APOE e4 allele, the conversion rate was 84.2%. In contrast, the observedconversion rate was 9.8% for MCI subjects with a relatively higher episodic memoryfunctioning level and no APOE e4 allele. Relatively lower functioning withcognitive flexibility and perceptual motor speed by itself also appears to beassociated with higher conversion rates.ConclusionsAmong MCI subjects, specific baseline cognitive profiles that were derived throughposet modeling methods, are clearly associated with differential rates ofconversion to AD. More precise delineation of MCI by such cognitive functioningprofiles, including notions such as multidomain amnestic MCI, can help in gainingfurther insight into how heterogeneity arises in outcomes. Poset-based modelingmethods may be useful for providing more precise classification of cognitivesubgroups among MCI for imaging and genetics studies, and for developing moreefficient and focused cognitive test batteries.

Customized adherence enhancement for individuals with bipolar disorder receiving antipsychotic therapy

OBJECTIVE A three-month prospective trial of a psychosocial intervention--customized adherence enhancement (CAE)--was conducted with 43 medication-nonadherent individuals with bipolar disorder. METHODS CAE modules were administered as indicated by a screen that identifies reasons for nonadherence. The primary outcome was change in adherence to mood-stabilizing medications as measured by the Tablet Routines Questionnaire and pill counts. Secondary outcomes included change in symptoms, measured by the Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS), and Brief Psychiatric Rating Scale (BPRS). RESULTS Participants completed 76% of sessions. Dropout at three months was 13 (30%). Adherence improved from a baseline mean±SD of 34%±27% of tablets missed in the past month to only 10%±15% (p<.001). BPRS, HAM-D, andYMRS scores all indicated significant improvement at three-month follow-up (p<.05). CONCLUSIONS Although conclusions must be tempered by the uncontrolled design, CAE appeared to be well accepted and was associated with improvements in adherence, symptoms, and functioning.