Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease.

INTRODUCTION: The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported. METHODS: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors. Measures included the 3-Domain Composite Cognition Score (CCS-3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding. RESULTS: Verubecestat showed worsening on the CCS-3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency. DISCUSSION: In both studies, many measures showed treatment-associated cognitive worsening, whereas verbal fluency tasks showed improvement.

Efficacy and tolerability of rizatriptan in pediatric migraineurs: results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design.

BACKGROUND: Treatment options for children and adolescents with migraine are limited. This study evaluated rizatriptan for the acute treatment of migraine in children and adolescents. METHODS: Randomized, double-blind, placebo-controlled, parallel-group trial in migraineurs 6-17 years old with unsatisfactory response to nonsteroidal anti-inflammatory drugs or acetaminophen/paracetamol. The trial included a double-blind run-in with weight-based rizatriptan dosing (5 mg for < 40 kg, 10 mg for ≥ 40 kg). In the Stage 1 run-in, patients were randomized in a ratio of 20:1 placebo:rizatriptan and were instructed to treat within 30 minutes of a moderate/severe migraine. Patients with mild/no pain after 15 minutes of treatment (responders) took no further study medication, whereas patients with moderate/severe pain (non-responders) proceeded to take study medication in Stage 2. Non-responders who received placebo in Stage 1 were randomized 1:1 to rizatriptan:placebo, whereas non-responders who received rizatriptan in Stage 1 were allocated to placebo in Stage 2. The primary efficacy endpoint was pain freedom at 2 hours after Stage 2 dose in 12-17-year-olds. RESULTS: A higher proportion of 12-17-year-olds on rizatriptan had pain freedom at 2 hours compared with those on placebo: 87/284 (30.6%) versus 63/286 (22.0%), odds ratio = 1.55 [95% CI: 1.06 to 2.26], p = 0.025. Adverse events within 14 days of dose in 12-17-year-olds were similar for rizatriptan and placebo. The pattern of findings was similar in 6-17-year-olds. CONCLUSION: Rizatriptan demonstrated a statistically significant improvement over placebo in eliminating pain and was generally well tolerated in migraineurs aged 12-17 and 6-17 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01001234.

Pilot study on the effect of estrogen replacement therapy on brain dopamine transporter availability in healthy, postmenopausal women.

OBJECTIVE: Authors investigated the association between estrogen replacement therapy (ERT) and dopamine transporter (DAT) availability in women. METHODS: Thirteen postmenopausal women were administered ERT and underwent neuroimaging, using single-photon emission computed tomography (SPECT) and [99mTc]TRODAT-1, a radioligand that binds DAT. In this 6-week pilot study, subjects underwent SPECT before ERT, after 4 weeks of 0.625 mg/day of conjugated estrogens (CEE), and after an additional 2 weeks of 0.625 mg/day CEE plus 10 mg/day of medroxyprogesterone acetate. Specific uptake values (SUVs) of [99mTc]TRODAT-1 were calculated for the caudate and putamen. RESULTS: When compared with baseline values, [99mTc]TRODAT-1 binding demonstrated a modest, but statistically significant, increase in the left anterior putamen after 4 weeks of CEE. After the 6-week ERT intervention, both the left and right anterior putamen demonstrated an increase in SUVs. CONCLUSION: Short-term administration of ERT in postmenopausal women is associated with a modest increase in DAT in the putamen. These findings may further the understanding of how ERT is associated with improvement in Parkinson's disease and late-onset schizophrenia.

Relationship between clock-drawing and neuropsychological and functional status in elderly institutionalized patients with schizophrenia.

OBJECTIVE: The authors sought to examine the usefulness of the clock-drawing test (CDT) as a measure of general cognitive and adaptive functioning in elderly patients with schizophrenia. METHODS: CDT performance of elderly institutionalized patients with schizophrenia were contrasted with a comparison group, similar in age. Cognitive and functional status was examined using an expanded battery from the Consortium to Establish a Registry for Alzheimer's disease and the Psychogeriatric Dependency Rating Scale. RESULTS: Patients (N=21) performed more poorly overall on the CDT than the comparison group (N=21), with greater clock number and hand errors. Production of the clock's gestalt did not differ between groups. In patients, overall CDT performance and clock hand placement were significantly correlated with general cognitive functioning, memory, visuoconstruction, and word-list generation. CDT global and hand placement performances corresponded to patients' general orientation. CONCLUSIONS: Impaired CDT performance in elderly patients with schizophrenia is not attributable to normal aging. Also, the CDT uniquely relates to an array of cognitive abilities in this population, validating its multicognitive character and implicating multiple brain regions. The CDT's tolerability and brevity make it attractive for use in geriatric schizophrenia.

Memory-delineated subtypes of schizophrenia: relationship to clinical, neuroanatomical, and neurophysiological measures.

Memory performance was examined in patients with schizophrenia to determine whether subgroups conforming to cortical and subcortical dementias could be identified and, if so, whether subgroups differed on clinical, neuroanatomical, and neurophysiological measures. A cluster analysis of California Verbal Learning Test performance classified patients into 3 subgroups. Two groups exhibited memory deficits consistent with the cortical-subcortical distinction, whereas 1 group was unimpaired. Cortical patients tended to be male, and they had earlier illness onset, reduced temporal lobe gray matter, and hypometabolism. Subcortical patients had ventricular enlargement and more negative symptoms. Unimpaired patients had fewer negative symptoms and dorsal medial prefrontal hypermetabolism. The authors conclude that categorizing patients on the basis of memory deficits may yield neurobiologically meaningful disease subtypes.

Neuropsychological functioning in elderly patients with schizophrenia and Alzheimer's disease.

Cognitive functioning was compared in elderly patients with schizophrenia, elderly patients with probable Alzheimer's disease (AD), and matched healthy controls using a brief neuropsychological battery. Both schizophrenia and AD patients demonstrated marked impairment as compared to controls, with the profile of neuropsychological deficits in both disorders appearing remarkably similar. Only visual confrontation naming, verbal delayed recall, and rate of forgetting (i.e. savings score) significantly differentiated between the two patient groups, with AD patients showing poorer overall recall and more rapid forgetting of verbal information over delay. In addition, schizophrenia subjects showed a significantly greater deficit in visual confrontation naming than the AD group. The relationship of neuropsychological function and clinical symptoms of schizophrenia subjects was also examined. Results showed that word list learning, delayed recall, and rate of forgetting correlated most strongly with positive and negative symptoms. Recent neuropathological studies have indicated abnormalities in specific subfields of the hippocampal formation in schizophrenia that are also severely affected in AD. Though the specific histopathology of the two disorders differs, abnormalities in the common sites may underlie the common neuropsychological profile.