Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
Add more filters










Database
Language
Publication year range
1.
J Prev Alzheimers Dis ; 8(2): 151-160, 2021.
Article in English | MEDLINE | ID: mdl-33569561

ABSTRACT

BACKGROUND: The Clinical Dementia Rating-Sum of Boxes (CDR-SB) has been proposed as a primary outcome for use in prodromal AD trials. However, the psychometric properties of this, and of other commonly used measures, have not been well-established in this patient population. OBJECTIVE: To describe the psychometric properties of commonly used efficacy measures in a clinical trial of prodromal AD. SETTING: Data were gathered as part of a two-year clinical trial. PARTICIPANTS: Patients had biomarker confirmed prodromal AD. MEASUREMENTS: Clinical Dementia Rating (CDR), Functional Activities Questionnaire (FAQ), Alzheimer's Disease Assessment Scale - Cognition Subscale 11 and 13 (ADAS-Cog), Mini Mental State Exam (MMSE), and Free and Cued Selective Reminding Test (FCSRT-IR [words]). Assessments were conducted at least every 24 weeks. RESULTS: For the CDR-SB, test-retest reliability was good (intra-class correlation coefficient [ICC]=0.83); internal consistency was 0.65 at baseline but above 0.8 at later assessments. Relationships between the CDR-SB and other measures were as expected (higher correlations with more closely related constructs), and the CDR-SB differentiated between patients with different severities of dementia (-2.9 points difference between CDR-Global Score 0.5 and 1, P<.0001). Floor and ceiling effects on the CDR-SB total score were minimal; however, at baseline there were ceiling effects in the personal care domain. Further detail is provided on the psychometric properties of ADAS-Cog, MMSE, FCSRT-IR and FAQ in this population. CONCLUSION: The psychometric properties of the CDR-SB are adequate in prodromal AD and continued use is warranted in clinical trials. However, there remains scope for improvement in the assessment of functional constructs and development of novel measures should continue.


Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/psychology , Cognition/physiology , Mental Status and Dementia Tests , Psychometrics , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Neuropsychological Tests , Reproducibility of Results
2.
J Prev Alzheimers Dis ; 8(1): 3-6, 2021.
Article in English | MEDLINE | ID: mdl-33336218

ABSTRACT

Previous findings from the positron emission tomography (PET) substudy of the SCarlet RoAD and Marguerite RoAD open-label extension (OLE) showed gantenerumab doses up to 1200 mg every 4 weeks administered subcutaneously resulted in robust beta-amyloid (Aß) plaque removal over 24 months in people with prodromal-to-moderate Alzheimer's disease (AD). In this 36-month update, we demonstrate continued reduction, with mean (standard error) centiloid values at 36 months of -4.3 (7.5), 0.8 (6.7), and 4.7 (8.0) in the SCarlet RoAD (double-blind pooled placebo and active groups), Marguerite RoAD double-blind placebo, and Marguerite RoAD double-blind active groups respectively, representing a change of -57.0 (10.3), -90.3 (9.0), and -74.9 (10.5) centiloids respectively. These results demonstrate that prolonged gantenerumab treatment, at doses up to 1200 mg, reduces amyloid plaque levels below the amyloid positivity threshold. The ongoing GRADUATE Phase III trials will evaluate potential clinical benefits associated with gantenerumab-induced amyloid-lowering in people with early (prodromal-to-mild) AD.


Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/drug effects , Antibodies, Monoclonal, Humanized/administration & dosage , Brain/drug effects , Aged , Aged, 80 and over , Alzheimer Disease/diagnostic imaging , Amyloid beta-Peptides/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Brain/diagnostic imaging , Brain/metabolism , Double-Blind Method , Female , Humans , Male , Middle Aged , Positron-Emission Tomography
3.
Eur Neuropsychopharmacol ; 24(7): 1024-36, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24735806

ABSTRACT

Bitopertin is a glycine reuptake inhibitor postulated to improve N-methyl-d-aspartate receptor hypofunction by increasing synaptic glycine concentrations. This randomised, double-blind, placebo- and active-controlled phase II/III trial evaluated the efficacy and safety of bitopertin monotherapy over 4 weeks in patients with acute exacerbation of schizophrenia. Of 301 patients randomised, 299 received placebo (n=80), bitopertin 10mg (n=80) or 30mg (n=77), or olanzapine 15mg (n=62). The primary endpoint, change from baseline in mean Positive and Negative Syndrome Scale (PANSS) total score, showed non-statistically significant improvements with bitopertin 30mg and olanzapine vs. placebo: bitopertin 10mg (-11.7; standard error [SE], 1.89; p=0.945), bitopertin 30mg (-15.3; SE, 1.87; p=0.211), olanzapine (-14.9; SE, 2.13; p=0.295) and placebo (-11.9; SE, 1.90). The PANSS positive subscale score, a secondary endpoint, also showed improvement with bitopertin 30mg (p=0.030) whereas a trend was observed with olanzapine (p=0.072) vs. placebo. Although not statistically significant, bitopertin 30mg and olanzapine reduced overall illness severity (Clinical Global Impression-Severity Scale; p=0.098 and p=0.126, respectively). More patients receiving bitopertin 30mg (51.3%) or olanzapine (52.5%) than placebo (32.9%) were ready for hospital discharge at Week 4 (bitopertin, p=0.014; olanzapine, p=0.024). In summary, this study failed due to lack of statistical separation of either bitopertin or olanzapine (active control) from placebo on the primary endpoint. Of interest, improved positive symptoms and readiness for hospital discharge were associated with both bitopertin and olanzapine treatment. Bitopertin was safe and well tolerated in this study.


Subject(s)
Antipsychotic Agents/therapeutic use , Piperazines/therapeutic use , Schizophrenia/drug therapy , Sulfones/therapeutic use , Adult , Benzodiazepines/therapeutic use , Double-Blind Method , Female , Humans , Male , Middle Aged , Olanzapine , Treatment Outcome
4.
Biol Psychiatry ; 47(5): 450-62, 2000 Mar 01.
Article in English | MEDLINE | ID: mdl-10704956

ABSTRACT

BACKGROUND: The amino acid glycine, modulates neurotransmission via actions at GLY-A receptor and GLY-B receptor. The latter are coagonist sites associated with N-Methyl-D-Aspartate (NMDA) glutamate receptors. The central bioavailability of peripherally administered glycine has not been adequately characterized in humans. METHODS: Healthy human subjects were administered either oral D-cycloserine (50 mg or placebo) and intravenous glycine (saline, 100 mg/kg or 200 mg/kg) in random order over 4 test days under double-blind conditions. Cerebrospinal fluid was collected by lumbar puncture performed on the first test day was analyzed to determine amino acid levels. The acoustic startle response was measured on the second test day. RESULTS: Intravenous glycine dose-dependently increased both serum and CSF glycine and serine levels. Neither glycine nor DCS produced any significant effects on behavior, cognition or the acoustic startle response. Neither IV glycine nor DCS were associated with any toxicity. CONCLUSIONS: Thus, peripheral glycine administration raised CSF glycine levels without producing any clear central nervous system effects. Glycine and D-cycloserine did not worsen cognitive test performance and did not induce behavioral symptoms on their own. The possibility that glycine and D-cycloserine enhanced cognitive test performance cannot be excluded given the psychometric limitations of the test battery.


Subject(s)
Amino Acids/blood , Amino Acids/cerebrospinal fluid , Antimetabolites/pharmacology , Cycloserine/pharmacology , Glycine/pharmacology , Acoustic Stimulation , Administration, Oral , Adult , Antimetabolites/administration & dosage , Biological Availability , Cycloserine/administration & dosage , Dose-Response Relationship, Drug , Double-Blind Method , Female , Glycine/administration & dosage , Glycine/blood , Glycine/cerebrospinal fluid , Humans , Injections, Intravenous , Male , Middle Aged , Neuropsychological Tests , Psychiatric Status Rating Scales , Receptors, Glycine/drug effects , Receptors, N-Methyl-D-Aspartate/drug effects , Reflex, Startle/drug effects , Serine/blood , Serine/cerebrospinal fluid
5.
Biol Psychiatry ; 47(2): 137-43, 2000 Jan 15.
Article in English | MEDLINE | ID: mdl-10664830

ABSTRACT

BACKGROUND: The demands of the Wisconsin Card Sorting Test (WCST) change with experience. This report contains two studies designed to examine N-methyl-D-aspartate (NMDA) receptor contributions to the executive components of WCST performance. These aspects of WCST performance figure more prominently in the initial completion of this task than in subsequent task repetitions in healthy populations. METHODS: In the first study, healthy subjects (n = 15) completed the WCST on two occasions separated by 1 week. In the second study, healthy subjects (n = 22) completed two test days spaced by approximately 1 week, during which, they completed the WCST and other assessments after administration of the NMDA antagonist ketamine (intravenous bolus 0.26 mg/kg followed by infusion of 0.65 mg/kg/hour) or matched placebo. RESULTS: In the first study, subjects reduced the number of total and perseverative errors with a single repetition of the WCST. In the second study, ketamine significantly increased the number of total errors and the number and percent of perseverative errors on the first, but not the second test day. Similarly, it reduced the number of category criteria met on the first, but not second test day. Ketamine also increased distractibility, impaired recall, produced psychosis, altered perception, and had effects resembling the negative symptoms of schizophrenia. However, only WCST performance showed order dependency. CONCLUSIONS: This order dependency further implicates NMDA receptors in executive cognitive functions associated with the frontal cortex.


Subject(s)
Anesthetics, Dissociative/adverse effects , Cognition Disorders/chemically induced , Ketamine/adverse effects , Learning/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Adult , Arousal/drug effects , Cognition Disorders/diagnosis , Female , Humans , Male , Neuropsychological Tests , Psychomotor Performance/drug effects
6.
Psychopharmacology (Berl) ; 145(2): 193-204, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10463321

ABSTRACT

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with prominent psychoactive effects in humans. This study evaluated whether the oral administration of haloperidol 5 mg would block the effects of an intravenous ketamine infusion (bolus of 0.26 mg/kg followed by 0.65 mg/kg per hour). Twenty healthy subjects completed 4 test days involving the oral administration of haloperidol or matched placebo 2 h prior to the intravenous infusion of ketamine or saline. Ketamine produced cognitive, behavioral, neuroendocrine, and physiologic effects in the healthy subjects that were similar to previous reports. Haloperidol pretreatment reduced impairments in executive cognitive functions produced by ketamine as measured by proverb interpretations and the Wisconsin Card Sorting Test. However, it failed to block the capacity of ketamine to produce psychosis, perceptual changes, negative symptoms, or euphoria in healthy subjects. These data outline an important, but functionally delineated modulation of ketamine effects by dopamine2 receptors and other sites of haloperidol action.


Subject(s)
Anesthetics, Dissociative/pharmacology , Antipsychotic Agents/pharmacology , Cognition/drug effects , Haloperidol/pharmacology , Ketamine/pharmacology , Adult , Double-Blind Method , Drug Interactions , Female , Humans , Hydrocortisone/blood , Male , Prolactin/blood , Receptors, N-Methyl-D-Aspartate/drug effects , Sleep Stages/drug effects
7.
Psychopharmacology (Berl) ; 135(3): 213-29, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9498724

ABSTRACT

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.


Subject(s)
Anesthetics, Intravenous/pharmacology , Anti-Anxiety Agents/pharmacology , Ketamine/pharmacology , Lorazepam/pharmacology , Mental Processes/drug effects , Adult , Anesthetics, Intravenous/adverse effects , Anesthetics, Intravenous/pharmacokinetics , Anti-Anxiety Agents/adverse effects , Anti-Anxiety Agents/pharmacokinetics , Arousal/drug effects , Attention/drug effects , Cognition/drug effects , Double-Blind Method , Drug Interactions , Female , Hormones/blood , Humans , Ketamine/adverse effects , Ketamine/pharmacokinetics , Learning/drug effects , Lorazepam/adverse effects , Lorazepam/pharmacokinetics , Male , Memory/drug effects , Psychiatric Status Rating Scales
SELECTION OF CITATIONS
SEARCH DETAIL
...