Characterizing Clinical Progression in Cognitively Unimpaired Older Individuals with Brain Amyloid: Results from the A4 Study.

BACKGROUND: Clinical Dementia Rating (CDR) global (CDR-G) and sum of box scores (CDR-SB) are commonly used as primary outcome variables to measure progression or treatment effects in symptomatic Alzheimer disease (AD) clinical trials. OBJECTIVES: We sought to determine whether the CDR is sensitive to change in pre-symptomatic AD and whether there are specific CDR boxes that are dynamic during the multi-year Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) secondary prevention study. DESIGN: All participants entered the study with a CDR-G of 0. Box scores were examined individually and as composites of cognition (memory, orientation and judgment /problem solving) and function (community affairs and home/ hobbies). A progression in box score was tabulated only when the change occurred at two consecutive visits. SETTING: The A4 study took place at 67 sites in Australia, Canada, Japan and the United States. PARTICIPANTS: 1,147 individuals, ages 65-85, were randomized to either placebo (n= 583) or solanezumab (n= 564). All participants received a baseline flobetapir PET scan, an annual CDR, and cognitive testing every 6 months with the Primary Alzheimer Cognitive Composite (PACC) over the course of 240 weeks. MEASUREMENTS: Generalized estimating equations and generalized least square models were used to explore the modeled mean progression rate in the CDR-G, CDR-SB, individual CDR boxes, and CDR composite scores in the combined solanezumab and placebo groups. Models were refitted to explore the probability of CDR progression in centiloid tertiles of amyloid at baseline (< 46.1 CL, 46.1 to 77.2 CL, > 77.2 CL). All models included effects for age, education, APOEε4 carrier status, baseline amyloid with flobetapir PET, treatment, and time-by-treatment. RESULTS: There were no statistical differences between the placebo or solanezumab groups in CDR-G, CDR-SB, specific CDR boxes or CDR composite scores over the course of the trial. Changes in judgment/ problem solving were present at baseline and persisted over time, but progression on the CDR memory box and the CDR cognitive composite quickly predominated. Community affairs and home/ hobbies showed little progression. Personal care remained stable. The probability of cognitive and functional progression in CDR boxes began either at the intermediate or advanced amyloid level (46.1 to 77.2 CL, > 77.2 CL), while amyloid at the lowest level (< 46.1 CL) showed relatively little CDR progression. CONCLUSIONS: The findings suggest that the CDR memory box and the CDR cognitive composite progressed over 240 weeks and were associated with intermediate and advanced stages of amyloid at baseline. Functional changes in community affairs and home/hobbies were relatively stable. These finding suggest that specific CDR box score changes may help refine our measurement of expected treatment effects in future AD prevention trials.

Longitudinal Course of Agitation and Aggression in Patients with Alzheimer's Disease in a Cohort Study: Methods, Baseline and Longitudinal Results of the A3C Study.

BACKGROUND: To present methodology, baseline results and longitudinal course of the Agitation and Aggression in patients with Alzheimer's Disease Cohort (A3C) study. OBJECTIVES: The central objective of A3C was to study the course, over 12 months of clinically significant Agitation and Aggression symptoms based on validated measures, and to assess relationships between symptoms and clinical significance based on global ratings. DESIGN: A3C is a longitudinal, prospective, multicenter observational cohort study performed at eight memory clinics in France, and their associated long-term care facilities. SETTING: Clinical visits were scheduled at baseline, monthly during the first 3 months, at 6 months, at 9 months and at 12 months. The first three months intended to simulate a classic randomized control trial 12-week treatment design. PARTICIPANTS: Alzheimer's Disease patients with clinically significant Agitation and Aggression symptoms lived at home or in long-term care facilities. MEASUREMENTS: Clinically significant Agitation and Aggression symptoms were rated on Neuropsychiatric Inventory (NPI), NPI-Clinician rating (NPI-C) Agitation and Aggression domains, and Cohen Mansfield Agitation Inventory. Global rating of agitation over time was based on the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. International Psychogeriatric Association "Provisional Diagnostic Criteria for Agitation", socio-demographics, non-pharmacological approaches, psychotropic medication use, resource utilization, quality of life, cognitive and physical status were assessed. RESULTS: A3C enrolled 262 AD patients with a mean age of 82.4 years (SD ±7.2 years), 58.4% women, 69.9% at home. At baseline, mean MMSE score was 10.0 (SD±8.0), Cohen Mansfield Agitation Inventory score was 62.0 (SD±15.8) and NPI-C Agitation and Aggression clinician severity score was 15.8 (SD±10.8). According to the International Psychogeriatric Association agitation definition, more than 70% of participants showed excessive motor activity (n=199, 76.3%) and/or a verbal aggression (n=199, 76.3%) while 115 (44.1%) displayed physical aggression. The change of the CMAI score and the NPI-C Agitation and Aggression at 1-year follow-up period was respectively -11.36 (Standard Error (SE)=1.32; p<0.001) and -6.72 (SE=0.77; p<0.001). CONCLUSION: Little is known about the longitudinal course of clinically significant agitation symptoms in Alzheimer's Disease about the variability in different outcome measures over time, or the definition of a clinically meaningful improvement. A3C may provide useful data to optimize future clinical trials and guide treatment development for Agitation and Aggression in Alzheimer's Disease.

The role of STIM1 and SOCE in smooth muscle contractility.

Contraction is a central feature for skeletal, cardiac and smooth muscle; this unique feature is largely dependent on calcium (Ca2+) signaling and therefore maintenance of internal Ca2+ stores. Stromal interaction molecule 1 (STIM1) is a single-pass transmembrane protein that functions as a Ca2+ sensor for the activation store-operated calcium channels (SOCCs) on the plasma membrane in response to depleted internal sarco(endo)plasmic (S/ER) reticulum Ca2+ stores. STIM1 was initially characterized in non-excitable cells; however, evidence from both animal models and human mutations suggests a role for STIM1 in modulating Ca2+ homeostasis in excitable tissues as well. STIM1-dependent SOCE is particularly important in tissues undergoing sustained contraction, leading us to believe STIM1 may play a role in smooth muscle contraction. To date, the role of STIM1 in smooth muscle is unknown. In this review, we provide a brief overview of the role of STIM1-dependent SOCE in striated muscle and build off that knowledge to investigate whether STIM1 contributes to smooth muscle contractility. We conclude by discussing the translational implications of targeting STIM1 in the treatment of smooth muscle disorders.

Neuropsychiatric symptoms as risk factors for progression from CIND to dementia: the Cache County Study.

OBJECTIVES: To examine the association of neuropsychiatric symptom (NPS) severity with risk of transition to all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD). DESIGN: Survival analysis of time to dementia, AD, or VaD onset. SETTING: Population-based study. PARTICIPANTS: 230 participants diagnosed with cognitive impairment, no dementia (CIND) from the Cache County Study of Memory Health and Aging were followed for a mean of 3.3 years. MEASUREMENTS: The Neuropsychiatric Inventory (NPI) was used to quantify the presence, frequency, and severity of NPS. Chi-squared statistics, t-tests, and Cox proportional hazard ratios were used to assess associations. RESULTS: The conversion rate from CIND to all-cause dementia was 12% per year, with risk factors including an APOE ε4 allele, lower Mini-Mental State Examination, lower 3MS, and higher CDR sum-of-boxes. The presence of at least one NPS was a risk factor for all-cause dementia, as was the presence of NPS with mild severity. Nighttime behaviors were a risk factor for all-cause dementia and of AD, whereas hallucinations were a risk factor for VaD. CONCLUSIONS: These data confirm that NPS are risk factors for conversion from CIND to dementia. Of special interest is that even NPS of mild severity are a risk for all-cause dementia or AD.

The association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer's disease.

OBJECTIVE: The use of psychotropic medications in Alzheimer's disease (AD) has been associated with both deleterious and potentially beneficial outcomes. We examined the longitudinal association of psychotropic medication use with cognitive, functional, and neuropsychiatric symptom (NPS) trajectories among community-ascertained incident AD cases from the Cache County Dementia Progression Study. METHODS: A total of 230 participants were followed for a mean of 3.7 years. Persistency index (PI) was calculated for all antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (atypical and typical), and benzodiazepines as the proportion of observed time of medication exposure. Mixed-effects models were used to examine the association between PI for each medication class and Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-Sum), and Neuropsychiatric Inventory - Total (NPI-Total) trajectories, controlling for appropriate demographic and clinical covariates. RESULTS: At baseline, psychotropic medication use was associated with greater severity of dementia and poorer medical status. Higher PI for all medication classes was associated with a more rapid decline in MMSE. For antidepressant, SSRI, benzodiazepine, and typical antipsychotic use, a higher PI was associated with a more rapid increase in CDR-Sum. For SSRIs, antipsychotics, and typical antipsychotics, a higher PI was associated with more rapid increase in NPI-Total. CONCLUSIONS: Psychotropic medication use was associated with more rapid cognitive and functional decline in AD, and not with improved NPS. Clinicians may tend to prescribe psychotropic medications to AD patients at risk of poorer outcomes, but one cannot rule out the possibility of poorer outcomes being caused by psychotropic medications.

Effects of cardiovascular medications on rate of functional decline in Alzheimer disease.

BACKGROUND: Evidence suggests that cardiovascular medications, including statins and antihypertensive medications, may delay cognitive decline in patients with Alzheimer dementia (AD). We examined the association of cardiovascular medication use and rate of functional decline in a population-based cohort of individuals with incident AD. METHODS: In the Dementia Progression Study of the Cache County Study on Memory, Health, and Aging, 216 individuals with incident AD were identified and followed longitudinally with in-home visits for a mean of 3.0 years and 2.1 follow-up visits. The Clinical Dementia Rating (CDR) was completed at each follow-up. Medication use was inventoried during in-home visits. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) as the outcome and cardiovascular medication use as the major predictors. RESULTS: CDR-Sum increased an average of 1.69 points annually, indicating a steady decline in functioning. After adjustment for demographic variables and the baseline presence of cardiovascular conditions, use of statins (p = 0.03) and beta-blockers (p = 0.04) was associated with a slower annual rate of increase in CDR-Sum (slower rate of functional decline) of 0.75 and 0.68 points respectively, while diuretic use was associated with a faster rate of increase in CDR-Sum (p = 0.01; 0.96 points annually). Use of calcium-channel blockers, angiotensin-converting enzyme inhibitors, digoxin, or nitrates did not affect the rate of functional decline. CONCLUSIONS: In this population-based study of individuals with incident AD, use of statins and beta-blockers was associated with delay of functional decline. Further studies are needed to confirm these results and to determine whether treatment with these medications may help delay AD progression.

Vascular factors predict rate of progression in Alzheimer disease.

BACKGROUND: While there is considerable epidemiologic evidence that cardiovascular risk factors increase risk of incident Alzheimer disease (AD), few studies have examined their effect on progression after an established AD diagnosis. OBJECTIVE: To examine the effect of vascular factors, and potential age modification, on rate of progression in a longitudinal study of incident dementia. METHODS: A total of 135 individuals with incident AD, identified in a population-based sample of elderly persons in Cache County, UT, were followed with in-home visits for a mean of 3.0 years (range: 0.8 to 9.5) and 2.1 follow-up visits (range: 1 to 5). The Clinical Dementia Rating (CDR) Scale and Mini-Mental State Examination (MMSE) were administered at each visit. Baseline vascular factors were determined by interview and physical examination. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) or MMSE as the outcome, and vascular index or individual vascular factors as independent variables. RESULTS: Atrial fibrillation, systolic hypertension, and angina were associated with more rapid decline on both the CDR-Sum and MMSE, while history of coronary artery bypass graft surgery, diabetes, and antihypertensive medications were associated with a slower rate of decline. There was an age interaction such that systolic hypertension, angina, and myocardial infarction were associated with greater decline with increasing baseline age. CONCLUSION: Atrial fibrillation, hypertension, and angina were associated with a greater rate of decline and may represent modifiable risk factors for secondary prevention in Alzheimer disease. The attenuated decline for diabetes and coronary artery bypass graft surgery may be due to selective survival. Some of these effects appear to vary with age.

An open-label study of escitalopram (Lexapro) for the treatment of 'Depression of Alzheimer's disease' (dAD).

BACKGROUND: Depression is a frequent neuropsychiatric complication of Alzheimer's Disease. METHODS: This study investigated the safety and effectiveness of escitalopram (LEXAPRO) for depression in AD (dAD) as defined by the NIMH consensus criteria in an 8-week, open-label treatment study. CONCLUSION: Escitalopram was efficacious and safe for the treatment of dAD in this study. Larger, controlled studies are warranted to further assess the efficacy for mood and behavioral disturbances in this medically fragile population.

Nefazodone in the adjunctive therapy of schizophrenia: an open-label exploratory study.

Compared to conventional antipsychotic medications, atypical antipsychotic medications demonstrate greater central serotonin (5HT2) receptor antagonism than dopamine type 2 (D2) receptor antagonism. Nefazodone, an antidepressant medication, exhibits 5HT2 receptor antagonism; we therefore wondered if its addition to stable regimens of antipsychotic medication would increase antipsychotic efficacy, independently of a primary effect on mood, through the mechanism of augmented 5HT2 receptor antagonism. In a pilot investigation, we administered nefazodone (400 mg/d) for 6 weeks as an open-label adjunct to antipsychotic medication in 10 patients with chronic schizophrenia. The patients were moderately depressed at baseline but did not meet criteria for major depressive episode. The Brief Psychiatric Rating Scale (BPRS) and Montgomery-Asberg Depression Rating Scale scores showed statistically significant and clinically robust improvements with nefazodone treatment, which were maintained at follow-up evaluation 2 weeks after the end of nefazodone treatment. There were no adverse events. These results suggest that nefazodone may be a safe and effective adjunct to antipsychotic medications in schizophrenia and that augmentation of 5HT2 antagonism may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating depressive symptoms in schizophrenia.

Methylene blue adjuvant therapy of schizophrenia.

There is growing interest in the role of the nitric oxide (NO) pathway in idiopathic psychotic disorders such as schizophrenia. In this preliminary study, we examined the therapeutic efficacy of methylene blue (MB), a "downstream" inhibitor of one of NO's actions, administered orally as an adjuvant to conventional neuroleptic medications. Specifically, MB blocks NO's activation of soluble guanylyl cyclase. MB has previously been reported to have therapeutic effects in the treatment of psychosis and mania. Preclinical data also suggest that MB might possess antipsychotic potential. Participants in the current study were eight patients with schizophrenia who had incomplete responses to conventional antipsychotics (as evidenced by a Brief Psychiatric Rating Scale [BPRS] total score of 35 or more). These patients completed a 4-week open-label study with a 1 week "off", 2 week "on", and one final week "off" design. Measures of treatment efficacy were the BPRS, Schedule for the Assessment of Negative Symptoms, and Clinical Global Improvement Scale administered weekly. Final scores for each outcome measure item were based on the consensus of at least two trained raters present during each rating interview. A statistically significant, albeit modest, decrease in the severity of psychopathology was observed while the subjects were taking MB, and psychopathology significantly worsened when MB was discontinued. The results suggest a need for further study with MB or perhaps other NO-dependent guanylyl cyclase-inhibiting medications.

Smooth pursuit eye movements in the evaluation of famotidine adjunctive therapy of schizophrenia: a preliminary report.

Smooth pursuit eye movements (SPEM) are often abnormal in schizophrenic patients and have been proposed as a trait marker of the disorder. We explored the use of SPEM as an outcome measure in an open-label clinical trial of famotidine, an H-2 antagonist, in patients with schizophrenia; famotidine has been proposed as an adjunctive medication, particularly for negative symptoms. Prior studies using SPEM as an outcome measure have not found a significant effect with "typical" neuroleptic medication, and one study found greater SPEM dysfunction with clozapine treatment. In this study, 19 schizophrenic subjects were stabilized for at least 1 week on conventional neuroleptic medications and then administered oral famotidine, 100 mg daily, for an additional 3 weeks. SPEM and clinical measures were assessed. Whereas Brief Psychiatric Rating Scale (BPRS) and Schedule for Assessment of Negative Symptoms (SANS) scores decreased significantly with famotidine administration, there was no significant change in SPEM performance over the course of the study. Two subjects (11%) doubled their signal/noise ratio and maintained this increase after famotidine discontinuation, whereas three subjects (17%) approximately halved this ratio and returned to baseline after famotidine discontinuation. SPEM changes were not found to correlate significantly with changes in BPRS or SANS scores. These findings suggest that SPEM dysfunction reflects a "trait" rather than clinical "state" in schizophrenia, and changes in SPEM performance might not be expected always to parallel changes in clinical ratings.

Methylphenidate in depressed medically ill patients.

BACKGROUND: The purpose of the authors' study was to evaluate the efficacy of methylphenidate in the medically ill depressed patients and to examine the factors that appear to affect therapeutic response and side effects. METHOD: Hospital charts were reviewed for 29 patients who received trials of methylphenidate for treatment of depressive disorders while admitted to a medical/surgical unit. RESULTS: Of the 29 patients, 16 (55%) had moderate or marked improvement, all within 2 days of commencing treatment with the maximal dose. Of the 25 nondelirious patients, 16 (64%) had moderate or marked improvement, and the presence of delirium was significantly associated with decreased response. Therapeutic response was significantly correlated with maximum methylphenidate dose. Side effects were noted in 8 (28%) patients; most side effects were mild (tachycardia or agitation), and all reversed after the medication was discontinued. CONCLUSIONS: Methylphenidate provides a safe and effective alternative to tricyclic antidepressants in medically ill populations but appears to be less effective in the presence of delirium.

Perceptual-motor and attentional correlates of developmental dyscalculia.

From the patient population of a learning disorders clinic, a group of 72 "relative math underachievers" was selected for achievement test performance below grade level on mathematics but at or above grade level on reading, with a difference of at least 1.5 standard deviation between the two. A comparison group of 30 "relative reading underachievers" met the converse criteria. Neurological examination showed mixed laterality preference (right hand and foot but left eye) to be more prevalent among the math underachievers. The two groups were closely comparable on Wechsler intelligence quotient scores, although the "freedom from distractibility quotient" tended to be lower for the match group. The latter group also showed a lower mean achievement quotient on the Bender Visuomotor Gestalt Test. On a standard questionnaire derived from DSM-III criteria for attention deficit disorder, the math group showed higher scores for inattention, but not for hyperactivity, impulsivity, or poor peer relations. Both perceptual-motor and attentional deficits appear to characterize children who are specifically learning disabled for math.