piperidines and Down-Syndrome

People with Down syndrome are vulnerable to developing dementia at an earlier age than the general population. Alzheimer's disease and cognitive decline in people with Down syndrome can place a significant burden on both the person with Down syndrome and their family and carers. Various pharmacological interventions, including donepezil, galantamine, memantine and rivastigmine, appear to have some effect in treating cognitive decline in people without Down syndrome, but their effectiveness for those with Down syndrome remains unclear.. To assess the effectiveness of anti-dementia pharmacological interventions and nutritional supplements for treating cognitive decline in people with Down syndrome.. In January 2015, we searched CENTRAL, ALOIS (the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group), Ovid MEDLINE, Embase, PsycINFO, seven other databases, and two trials registers. In addition, we checked the references of relevant reviews and studies and contacted study authors, other researchers and relevant drug manufacturers to identify additional studies.. Randomised controlled trials (RCTs) of anti-dementia pharmacological interventions or nutritional supplements for adults (aged 18 years and older) with Down syndrome, in which treatment was administered and compared with either placebo or no treatment.. Two review authors independently assessed the risk of bias of included trials and extracted the relevant data. Review authors contacted study authors to obtain missing information where necessary.. Only nine studies (427 participants) met the inclusion criteria for this review. Four of these (192 participants) assessed the effectiveness of donepezil, two (139 participants) assessed memantine, one (21 participants) assessed simvastatin, one study (35 participants) assessed antioxidants, and one study (40 participants) assessed acetyl-L-carnitine.Five studies focused on adults aged 45 to 55 years, while the remaining four studies focused on adults aged 20 to 29 years. Seven studies were conducted in either the USA or UK, one between Norway and the UK, and one in Japan. Follow-up periods in studies ranged from four weeks to two years. The reviewers judged all included studies to be at low or unclear risk of bias.Analyses indicate that for participants who received donepezil, scores in measures of cognitive functioning (standardised mean difference (SMD) 0.52, 95% confidence interval (CI) -0.27 to 1.13) and measures of behaviour (SMD 0.42, 95% CI -0.06 to 0.89) were similar to those who received placebo. However, participants who received donepezil were significantly more likely to experience an adverse event (odds ratio (OR) 0.32, 95% CI 0.16 to 0.62). The quality of this body of evidence was low. None of the included donepezil studies reported data for carer stress, institutional/home care, or death.For participants who received memantine, scores in measures of cognitive functioning (SMD 0.05, 95% CI -0.43 to 0.52), behaviour (SMD -0.17, 95% CI -0.46 to 0.11), and occurrence of adverse events (OR 0.45, 95% CI 0.18 to 1.17) were similar to those who received placebo. The quality of this body of evidence was low. None of the included memantine studies reported data for carer stress, institutional/home care, or death.Due to insufficient data, it was possible to provide a narrative account only of the outcomes for simvastatin, antioxidants, and acetyl-L-carnitine. Results from one pilot study suggest that participants who received simvastatin may have shown a slight improvement in cognitive measures.. Due to the low quality of the body of evidence in this review, it is difficult to draw conclusions about the effectiveness of any pharmacological intervention for cognitive decline in people with Down syndrome.

Topics: Acetylcarnitine; Adult; Antioxidants; Cognition; Cognition Disorders; Donepezil; Down Syndrome; Humans; Indans; Memantine; Middle Aged; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Simvastatin

At present, there may be over 210,000 people with Down syndrome (DS) over the age of 55 in the United States (US) who have significant needs for augmented services due to circumstances related to ordinary and/or pathological aging. From 1979 through 2003, the birth prevalence of DS rose from 9.0 to 11.8 (31.1%) per 10,000 live births in 10 representative US regions. This increase, largely due to women conceiving after age 35, portends an ever-growing population of people with DS who may be subject to pathogenic aging. Whereas Trisomy 21 is one of the most widespread genetic causes of intellectual disability (ID), it still is one of the least understood of all genetic ID syndromes. While longevity in people with DS has improved appreciably in as modest a period as 30 years, age-specific risk for mortality still is considerably increased compared both with other people with ID or with the typically developing population. The penetrance of the phenotype is widely distributed, even though a consistent genotype is assumed in 95% of the cases. Some, but not all body systems, exhibit signs of premature or accelerated aging. This may be due to both genetic and epigenetic inheritance. We now know that the long-term outcome for people with DS is not as ominous as once contemplated; a number of people with DS are living into their late 60s and 70s with few if any major signs of pathogenic aging. Alzheimer's disease (AD), a devastating disease that robs a person of their memory, abilities and personality, is particularly common in elder adults with DS, but is not a certainty as originally thought, some 20% to 30% of elder adults with DS might never show any, or at most mild signs of AD. DS has been called a mature well-understood syndrome, not in need of further research or science funding. We are only beginning to understand how epigenetics affects the phenotype and it may be feasible in the future to alter the phenotype through epigenetic interventions. This chapter is divided into two sections. The first section will review typical and atypical aging patterns in somatic issues in elder adults with DS; the second section will review the multifaceted relationship between AD and DS.

Topics: Adult; Aging; Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Dementia; Donepezil; Down Syndrome; Female; Humans; Incidence; Indans; Intellectual Disability; Male; Metabolic Syndrome; Middle Aged; Nootropic Agents; Oxidative Stress; Peptide Fragments; Phenotype; Piperidines; Prevalence; Telomere Shortening; Treatment Outcome; United States

This review describes on comprehensive care for persons with Down syndrome especially in adulthood. Down syndrome is probably believed too special and therefore many clinicians seems to hesitate to attend them or scare to give wrong treatment. Quite a few psychiatrists make diagnoses of psychiatric diseases instead of behavior problems due to environmental effects and give inappropriate and/or unnecessary medication. Special care is needed on (1) muscle hypotonia, (2) characteristic mental development and developmental retardation, and (3) various complications. Complications are not too special and treatment is similar to common diseases. Persons with Down syndrome have many excellences, but maltreatment and/or environment without normalization may lead them psychiatric disorders.

Topics: Adolescent; Adult; Aged; Alzheimer Disease; Child; Comprehensive Health Care; Continuity of Patient Care; Counseling; Donepezil; Down Syndrome; Female; Humans; Indans; Male; Middle Aged; Piperidines; Psychomotor Disorders; Young Adult

Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome [DS]. Acetylcholine is a chemical found in the brain that has an important role in memory, attention, reason and language. Donepezil a reversible inhibitor of acetylcholinesterase, which is thought to maintain levels of acetylcholine, and is reported to have some benefits for people with AD in the general population. It is important to note that people with DS tend to present with AD at a much younger age than the normal population as well as having subtle differences in physiology (e.g. metabolism and heart rate) and may therefore have different requirements from the general population.. To determine the effectiveness and safety of donepezil for people with DS who develop AD.. CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, BIOSIS, SCI, SSCI and the NRR were searched up to October 2008. We contacted the manufacturers of donepezil as well as experts in the field, to ask about reports of unpublished or ongoing trials.. Randomised controlled trials of participants with DS and AD in which treatment with donepezil was administered compared with a placebo group.. Data were extracted from the published reports of the one relevant study identified.. The one study included in this review is a small (n=30) randomised controlled trial lasting 24 weeks. It was followed-up by an open label study with a crossover design.No significant differences were found on any four validated outcomes including global functioning and three measures of cognitive abilities and behavioural problems. 6 out of 16 carers (37%) of participants on donepezil and 2 out of 15 (13%) on placebo reported improvement. No data were available for day to day skills, institutionalisation, reduction in carers' stress or economic outcomes. Half the intervention group and 20% of the placebo group reported adverse events; two participants left because of adverse events.. To date there is only one small randomised controlled study on the effect of donepezil. This shows, at best, a modest, non statistically significant trend in favour of people with Down syndrome and Alzheimer's dementia who are able to tolerate donepezil (this drug is currently only dispensed in relatively large doses and is contraindicated for those with cardiac and respiratory problems).This study does not provide good evidence on which to base practice. Findings in an open-label follow up to this study suggest possible benefit in some individuals. Further, larger randomised controlled studies with longer-term follow up are required.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Down Syndrome; Humans; Indans; Piperidines; Randomized Controlled Trials as Topic

This review discusses the laboratory and clinical research supporting the rationale for the efficacy of donepezil (Aricept USA) in enhancing cognition in autism, Alzheimer disease, Down syndrome, traumatic brain injury, Attention Deficit Hyperactivity Disorder (ADHD), and schizophrenia. While preliminary animal models have shown effective, human studies exclusive of Alzheimer disease are sparse. Although attention and memory are unlikely a sole operation of the cholinergic system, evidence indicates a promising direction for further examination of this hypothesis in autism. Studies that examine changes in operationally defined behaviors and reliable and valid measure of changes in attention and memory are needed.

Topics: Alzheimer Disease; Animals; Attention; Attention Deficit Disorder with Hyperactivity; Autistic Disorder; Brain Injuries; Donepezil; Down Syndrome; Humans; Indans; Learning Disabilities; Memory Disorders; Mental Recall; Nootropic Agents; Piperidines; Schizophrenia; Treatment Outcome

The management of dementia in Alzheimer's disease has dramatically changed since the development of anti-dementia drugs. However, there is limited information available regarding the bio-medical aspects of the differing drugs; particularly relating to adults with intellectual disability. Indeed the information available for the intellectual disabled population is limited to adults with Down syndrome. This review highlights the important pharmacological and clinical aspects of donepezil, rivastigmine, galantamine and memantine and supports the view that such drugs play an important part in the management of dementia in adults with intellectual disability. Future clinical and research issues are discussed.

Topics: Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Donepezil; Down Syndrome; Galantamine; Humans; Indans; Memantine; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine

Down syndrome (DS) patients share certain neuropathological features with Alzheimer disease patients. A randomized, double-blind, placebo-controlled study was performed to investigate the efficacy and safety of donepezil, an Alzheimer disease drug, for DS patients.. Twenty-one DS patients with severe cognitive impairment were assigned to take donepezil (3 mg daily) or a placebo for 24 weeks, and evaluated for activities in daily lives by concisely modified International Classification of Functioning, Disability and Health (ICF) scaling system.. ICF scores significantly increased without any adverse effects in the donepezil group in comparison to those in the placebo control. Among the individual functions tested, there was a dramatic improvement in the global mental functions and in specific mental functions.. Donepezil may effectively and safely improve overall functioning of DS patients with severe cognitive impairment.

Topics: Activities of Daily Living; Adult; Cognition Disorders; Donepezil; Double-Blind Method; Down Syndrome; Female; Humans; Indans; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Quality of Life; Treatment Outcome

The objective of this 10-week, randomized, double-blind, placebo-controlled multicenter study was to assess the efficacy and safety of donepezil for the treatment of cognitive dysfunction exhibited by children with Down syndrome (DS). Intervention comprised donepezil (2.5-10 mg/day) in children (aged 10-17 years) with DS of mild-to-moderate severity. The primary measures were the Vineland-II Adaptive Behavior Scales (VABS-II) Parent/Caregiver Rating Form (PCRF) the sum of nine subdomain standardized scores and standard safety measures. Secondary measures included the VABS-II/PCRF scores on the following domains and their respective individual subdomains: Communication (receptive, expressive, and written); Daily Living Skills (personal, domestic, and community); Socialization (interpersonal relationships, play and leisure time, and coping skills), and scores on the Test of Verbal Expression and Reasoning, a subject-performance-based measure of expressive language. At baseline, 129 participants were assigned treatment with donepezil or placebo. During the double-blind phase, VABS II/PCRF sum of the nine subdomain standardized scores, called v-scores, improved significantly from baseline in both groups (P < 0.0001), with no significant between-group differences. This trial failed to demonstrate any benefit for donepezil versus placebo in children and adolescents with DS, although donepezil appeared to be well tolerated.

Topics: Adolescent; Behavior; Caregivers; Child; Cholinesterase Inhibitors; Cognition Disorders; Diarrhea; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Down Syndrome; Drug Tolerance; Female; Humans; Indans; Learning; Male; Neuropsychological Tests; Piperidines; Severity of Illness Index; Vomiting

The objective of our study was to assess the efficacy and safety of donepezil in young adults with Down syndrome (DS) but no evidence of Alzheimer disease (AD). A 12-week, randomized, double-blind, placebo-controlled study with a 12-week, open-label extension was conducted. The intervention consisted of donepezil (5-10 mg/day) in young adults (aged 18-35 years) with DS, but no AD. The primary measure was the Severe Impairment Battery (SIB) test and secondary measures were the Vineland Adaptive Behavior Scales (VABS), the Rivermead Behavioral Memory Test for Children, and the Clinical Evaluation of Language Fundamentals, Third Edition. At baseline, 123 subjects were randomly assigned treatment with donepezil or placebo. During the double-blind phase, SIB scores improved significantly from baseline in both groups, with no significant between-group differences. During the open-label phase, SIB scores in the original donepezil group remained stable; the original placebo group showed an improvement similar to that seen in the double-blind phase. VABS scores improved for donepezil, but not placebo, during the double-blind phase (observed cases, P = 0.03; last observation carried forward, P = 0.07). Post hoc responder analyses were significant for donepezil using three of five response definitions (P < or = 0.045). Adverse event rates were comparable to AD studies. In this first large-scale, multicenter trial of a pharmacological agent for DS, donepezil appears safe. Efficacy interpretation was limited for the primary measure due to apparent learning/practice and ceiling effects. Outcomes in post hoc analyses suggested efficacy in some, but not all subjects, consistent with phenotypic variability of DS. Additional studies are required to confirm potential benefits of donepezil in this population.

Topics: Adult; Demography; Donepezil; Double-Blind Method; Down Syndrome; Female; Humans; Indans; Learning; Male; Nootropic Agents; Piperidines; Treatment Outcome; Young Adult

There is growing evidence to support the use of early central cholinergic enhancement to improve cognitive functioning in individuals with Down syndrome (DS). This report summarizes preliminary safety and cognitive efficacy data for seven children (8-13 years) with DS who participated in a 22-week, open-label trial of donepezil hydrochloride. Donepezil was dosed once daily at 2.5 mg and, based on tolerability, increased to 5 mg/day. Safety assessments were conducted at Week 1 (baseline), Week 8 (2.5 mg donepezil), Week 16 (5 mg) and Week 22 (after the donepezil had been discontinued). Measures of cognitive function were administered at each visit, encompassing the following domains: memory; attention; mood; and adaptive functioning. Donepezil was well tolerated at the 2.5 and 5 mg doses. The side effects were mild, transient, and consistent with the adverse events noted with cholinesterase inhibitors. Some children showed improvement on measures of memory (NEPSY Memory for Names and Narrative Memory) and sustained attention to tasks (Conners' Parent Rating Scales), although increased irritability and/or assertiveness were noted in some patients. Overall, this clinical report series adds to our initial findings of language gains in children with DS treated with donepezil. It also supports the need for larger, double-blind studies of the safety and efficacy of donepezil and other cholinesterase inhibitors for children with DS.

Topics: Adolescent; Child; Cholinesterase Inhibitors; Cognition; Donepezil; Down Syndrome; Drug Administration Schedule; Female; Humans; Indans; Male; Piperidines; Treatment Outcome

Topics: Adolescent; Adult; Donepezil; Down Syndrome; Humans; Indans; Male; Nootropic Agents; Piperidines

Topics: Adolescent; Child; Cholinesterase Inhibitors; Donepezil; Down Syndrome; Female; Humans; Indans; Language; Male; Nootropic Agents; Pilot Projects; Piperidines; Time Factors; Treatment Outcome; Verbal Behavior

At present, there is no proven pharmacologic treatment for cognitive or language impairments in Down syndrome (DS). Cholinergic deficits have been documented in DS and linked to cognitive deficits. This study is a 24-week open-label clinical trial of donepezil hydrochloride for the treatment of language deficits in adults with DS. To our knowledge, this is the first prospective study to evaluate systematically the effects of donepezil, a cholinesterase inhibitor, on specific language domains in DS. The main finding that emerged was an improvement in expressive language performance following donepezil therapy. Despite the multiple methodological limitations, the results raise important questions regarding the role of the cholinergic system in language function and the specific effect of cholinergic therapy in the treatment of language impairment in DS. The results support the need for large-scale controlled studies of the effects of donepezil treatment on language and on other cognitive domains in DS.

Topics: Adult; Appetite; Cholinesterase Inhibitors; Diarrhea; Donepezil; Dose-Response Relationship, Drug; Down Syndrome; Female; Follow-Up Studies; Humans; Hypotension; Indans; Language Disorders; Language Tests; Male; Muscle Cramp; Nausea; Piperidines; Treatment Outcome

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Down Syndrome; Humans; Indans; Long-Term Care; Middle Aged; Neuropsychological Tests; Piperidines

Our goal in this study was to determine whether donepezil, an acetylcholinesterase inhibitor, would improve cognitive functioning in 19 subjects with Down syndrome and no dementia. They were assigned to either a donepezil or placebo group. Cognitive functioning and caregiver ratings were measured at baseline, 4 weeks, and 12 weeks. With the exception of one area (language), no improvement was noted in any of the cognitive subtests, behavioral scores, or caregiver ratings. Subjects in the donepezil group showed an improvement in language scores compared to subjects in the placebo group. The results suggest that donepezil may improve language performance in subjects with Down syndrome and no dementia, but further studies need to be done on a larger group to confirm this result.

Topics: Adolescent; Adult; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Down Syndrome; Drug Administration Schedule; Female; Humans; Indans; Language Development Disorders; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Treatment Outcome

Individuals with Down syndrome who develop Alzheimer disease may show an improvement in cognitive functioning after treatment with acetylcholinesterase inhibitors.. To determine whether individuals with Down syndrome and Alzheimer disease will show improvement after institution of donepezil treatment.. A nonrandomized controlled trial using donepezil in a pilot study format.. Academic medical center.. Convenience sample of 6 treated patients with Down syndrome and 9 closely matched historical control subjects.. Oral administration of donepezil for a 5-month period.. The Down Syndrome Dementia Scale.. Significant improvement in dementia scores for the treated group during a 3- to 5-month period (P =.03).. Acetylcholinesterase inhibitors may be helpful in reversing the symptoms of dementia during early and middle stages of cognitive decline. These findings support the rationale for a more extensive study of the efficacy of acetylcholinesterase inhibitors in Down syndrome dementia.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Down Syndrome; Drug Administration Schedule; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Pilot Projects; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

Donepezil Hydrochloride (Aricept) is a selective anticholinesterase inhibitor developed for the treatment of Alzheimer's disease (AD). This study investigated the safety and efficacy of the drug to treat Down syndrome (DS) adults with mild to moderate AD.. This was a 24-week, double blind, placebo controlled, parallel-group trial. Patients were randomized to receive placebo or donepezil (5 mg per day during the first four weeks, and then 10 mg per day thereafter). Primary efficacy was measured using the Dementia Scale for Mentally Retarded Persons (DMR), and secondary efficacy was measured using the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI) and by the Adaptive Behavior Scale (ABS).. A total of 30 DS patients with AD entered the study of which 27 were included in the subsequent data analysis. The donepezil group had non-statistically significant reduction in deterioration in DMR, SIB, and ABS mean scores relative to the placebo group. However NPI scores showed less improvement in the donepezil group when compared to the placebo group. Fifty percent of subjects in the donepezil group showed improvement in mean DMR scores at the end point compared to baseline, when compared to 31% on placebo. There were no life threatening adverse effects associated with treating adults with DS with donepezil. A number of side-effects did occur including diarrhoea, insomnia, fatigue, and nausea.. Donepezil Hydrochloride administered once a day appears to be generally well tolerated and safe in DS adults who have AD. There is some possible efficacy in the treatment of symptoms of mild to moderate Alzheimer's disease in this population, although the sample size of this study was too small for statistical significance. It is recommended that donepezil, with the appropriate precautions, should be considered for the treatment of AD in adults with DS as deemed by a specialist.

Topics: Adult; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Comorbidity; Donepezil; Double-Blind Method; Down Syndrome; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Pilot Projects; Piperidines; Treatment Outcome

Topics: Adaptation, Psychological; Adult; Cholinesterase Inhibitors; Dementia; Donepezil; Down Syndrome; Drug Administration Schedule; Female; Humans; Indans; Intelligence Tests; Male; Middle Aged; Piperidines; Treatment Outcome

Topics: Adult; Arthritis, Psoriatic; Down Syndrome; Female; Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines

Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Alterations of this system contribute to the pathogenesis of several neurological and neurodevelopmental disorders. However, the involvement of the endocannabinoid system in the pathogenesis of Down syndrome has not been explored before. We used the best-characterized preclinical model of Down syndrome, the segmentally trisomic Ts65Dn model. In male Ts65Dn mice, cannabinoid type-1 receptor (CB1R) expression was enhanced and its function increased in hippocampal excitatory terminals. Knockdown of CB1R in the hippocampus of male Ts65Dn mice restored hippocampal-dependent memory. Concomitant with this result, pharmacological inhibition of CB1R restored memory deficits, hippocampal synaptic plasticity and adult neurogenesis in the subgranular zone of the dentate gyrus. Notably, the blockade of CB1R also normalized hippocampal-dependent memory in female Ts65Dn mice. To further investigate the mechanisms involved, we used a second transgenic mouse model overexpressing a single gene candidate for Down syndrome cognitive phenotypes, the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). CB1R pharmacological blockade similarly improved cognitive performance, synaptic plasticity and neurogenesis in transgenic male Dyrk1A mice. Our results identify CB1R as a novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.

Topics: Animals; Brain; Cannabinoid Receptor Antagonists; Cognition; Cognitive Dysfunction; Disease Models, Animal; Down Syndrome; Female; Male; Mice; Mice, Transgenic; Neurogenesis; Phenotype; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

A 14-year-old boy with Down syndrome (DS) showed a gradual decline in his daily activities and feeding capacities, and a marked deterioration triggered by a streptococcal infection was observed at the age of 15 years. He became bedridden, accompanied by sleep disturbance, sustained upward gaze, and generalized rigidity. Magnetic resonance imaging showed unremarkable findings, but antiglutamate receptor autoantibodies were positive in his cerebrospinal fluid. Treatment with thiamine infusion and steroid pulse therapy showed little effect, but gross motor dysfunction and appetite loss were ameliorated by the administration of l-DOPA and serotonin reuptake inhibitors. Thereafter, autistic behaviors predominated, including loss of social interaction, oral tendency, water phobia, and aggressiveness. Initiation of donepezil, an acetylcholinesterase inhibitor, resulted in the disappearance of these symptoms and total recovery of the patient to his previous psychosocial levels. We hypothesize that the acute regression in adolescence represents a process closely related to the defects of serotonergic and cholinergic systems that are innate to DS brains and not just a nonspecific comorbidity of depression or limbic encephalitis.

Topics: Adolescent; Brain; Disease Progression; Donepezil; Down Syndrome; Electroencephalography; Humans; Indans; Male; Nootropic Agents; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS.

Topics: Animals; Anti-Anxiety Agents; Benzodioxoles; CA1 Region, Hippocampal; Disease Models, Animal; Down Syndrome; Drug Evaluation, Preclinical; Endocannabinoids; Male; Maze Learning; Memory, Short-Term; Mice, Transgenic; Monoacylglycerol Lipases; Motor Activity; Piperidines; Recognition, Psychology

Although antagonists to GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) have been widely considered to be neuroprotective under certain pathological conditions, their immediate and lasting impacts on synaptic, circuit, and cognitive functions are poorly understood. In hippocampal slices, we found that the GluN2B-selective antagonist Ro25-6981 (Ro25) reduced synaptic NMDAR responses and consequently neuronal output in a subpopulation of GABAergic interneurons, but not pyramidal neurons. Consistent with these effects, Ro25 reduced GABAergic responses in pyramidal neurons and hence could affect circuit functions by altering the excitation/inhibition balance in the brain. In slices from Ts65Dn mice, a Down syndrome model with excess inhibition and cognitive impairment, acutely applied Ro25-rescued long-term potentiation (LTP) and gamma oscillation deficits, whereas prolonged dosing induced persistent rescue of LTP. In contrast, Ro25 did not impact LTP in wild-type (wt) mice but reduced gamma oscillations both acutely and following prolonged treatment. Although acute Ro25 treatment impaired memory performance in wt mice, memory deficits in Ts65Dn mice were unchanged. Thus, GluN2B-NMDARs contribute to the excitation/inhibition balance via impacts on interneurons, and blocking GluN2B-NMDARs can alter functions that depend on this balance, including synaptic plasticity, gamma oscillations, and memory. That prolonged GluN2B antagonism leads to persistent changes in synaptic and circuit functions, and that the influence of GluN2B antagonism differs between wt and disease model mice, provide critical insight into the therapeutic potential and possible liabilities of GluN2B antagonists.

Topics: Action Potentials; Animals; Brain Waves; Down Syndrome; Excitatory Postsynaptic Potentials; GABAergic Neurons; Hippocampus; Interneurons; Long-Term Potentiation; Male; Maze Learning; Memory; Mice; Mice, Neurologic Mutants; Neuronal Plasticity; Phenols; Piperidines; Pyramidal Cells; Receptors, N-Methyl-D-Aspartate

The Ts65Dn mouse displays several phenotypic abnormalities that parallel characteristics found in Down syndrome. One important characteristic associated with Down syndrome is an increased incidence of early-onset Alzheimer's disease. Since Alzheimer's disease is characterized largely by progressive memory loss, it is of interest to study working memory in the Ts65Dn mouse. Previous research in our lab using a titrating, delayed matching-to-position schedule of reinforcement has demonstrated that young, adult male Ts65Dn mice do not display a working memory deficit when compared to age-matched littermate controls. However, there have been no studies examining the working memory of these mice as they age. Due to the correlation between Down syndrome and Alzheimer's disease, and as part of a larger effort to further characterize the phenotype of the Ts65Dn mouse, the purpose of this study was to determine whether aged Ts65Dn mice possess a working memory deficit when compared to age-matched littermate controls. In order to study working memory, two groups of mice were trained under a titrating, delayed matching-to-position schedule of reinforcement. The first group was trained beginning at 3 months of age, and the second group began training at 15 months of age. Both groups were studied to 24 months of age. Initially, both groups of Ts65Dn mice performed at a lower level of accuracy than the control mice; however, this difference disappeared with further practice. The results from these lifespan studies indicate that the aged Ts65Dn mouse does not possess a working memory deficit when compared to age-matched controls.

Topics: Aging; Animals; Antidepressive Agents; Central Nervous System Stimulants; Cognition; Conditioning, Operant; Dextroamphetamine; Donepezil; Dose-Response Relationship, Drug; Down Syndrome; Indans; Longitudinal Studies; Male; Memantine; Memory, Short-Term; Mice; Mice, Neurologic Mutants; Nootropic Agents; Piperidines; Psychomotor Performance; Rolipram

Topics: Adolescent; Child; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition; Donepezil; Dose-Response Relationship, Drug; Down Syndrome; Drug Tolerance; Humans; Indans; Multicenter Studies as Topic; Neuropsychological Tests; Piperidines; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome

Topics: Adenoidectomy; Anesthetics, Intravenous; Anticoagulants; Antihypertensive Agents; Bosentan; Child; Down Syndrome; Elective Surgical Procedures; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Intubation, Intratracheal; Piperazines; Piperidines; Propofol; Purines; Remifentanil; Severity of Illness Index; Sildenafil Citrate; Sleep Apnea, Obstructive; Sulfonamides; Sulfones; Tonsillectomy; Treatment Outcome; Vasodilator Agents; Warfarin

The most commonly used model of Down syndrome, the Ts65Dn (TS) mouse, is trisomic for most of the region of MMU16 that is homologous to HSA21. This mouse shares many phenotypic characteristics with people with Down syndrome including behavioral and cognitive alterations. The objective of this study was to analyze the ability of two drugs that improve cognition in different experimental models, the acetylcholinesterase inhibitor donepezil and the non-competitive GABA(A) antagonist pentylenetetrazole (PTZ), to improve the cognitive deficits found in TS mice. The drugs were administered p.o. to TS and CO mice for 8 weeks and a behavioral characterization was performed. Sensorimotor abilities, including vision, hearing, strength and motor coordination, as well as locomotor activity in the home cage, were not modified by any chronic treatment in TS and CO mice. TS mice showed altered equilibrium in the aluminium rod, and this effect was larger under PTZ treatment. This result may indicate a potential adverse effect of PTZ in Ts65Dn mice. Learning and memory were evaluated in TS and CO mice after both treatments in the Morris water maze. Donepezil administration did not modify learning and memory in animals of any genotype. On the other hand, PTZ administration rescued TS performance in the Morris water maze.

Topics: Acetylcholine; Animals; Brain; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Disease Models, Animal; Donepezil; Down Syndrome; Drug Administration Schedule; GABA Antagonists; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Indans; Male; Maze Learning; Memory Disorders; Mice; Mice, Neurologic Mutants; Neural Inhibition; Pentylenetetrazole; Piperidines; Receptors, GABA-A; Treatment Outcome; Trisomy

Adults with Down syndrome (DS) develop progressive cognitive impairment resembling the cognitive profile of Alzheimer's disease (AD). Although the specific neurobiological correlates of cognitive deficits in DS are still not completely understood, it has been proposed that cholinergic dysfunction may contribute to some of these deficits in DS who develop AD. A recently devised test of motor cortex excitability, the short latency afferent inhibition (SAI), has been proven to be helpful in exploring some cholinergic circuits of the human brain. The authors used this test to assess the involvement of the cholinergic transmission in the DS.. We evaluated the SAI in 12 patients with DS and in 15 healthy subjects.. SAI was significantly reduced in DS patients when compared with the controls; the values correlated with the patient's age and the score on Dementia Scale for Down Syndrome. SAI was increased after administration of a single dose of donezepil in a subgroup of 5 patients.. Our findings suggest that, with respect to this putative marker of central cholinergic activity, dementia in aging DS shares pathophysiological similarities to AD in the general population.. This technique may help to clarify the pathophysiological basis of cognitive dysfunction in DS and may represent an additional tool for the diagnosis of Alzheimer-type dementia in subjects with DS.

Topics: Adult; Alzheimer Disease; Brain; Cholinesterase Inhibitors; Donepezil; Down Syndrome; Female; Humans; Indans; Male; Middle Aged; Neural Inhibition; Piperidines; Transcranial Magnetic Stimulation

To report 2 cases of patients with Down syndrome and severe cognitive impairment who gained dramatic improvements in quality of life (QOL) upon donepezil treatment.. Case 1. A 38-year-old woman with Down syndrome, diagnosed with secondary progressive dementia when her mental state had deteriorated rapidly after graduation from junior high school, started donepezil treatment. The loading dose was 3 mg/day and was increased to 5 mg/day for maintenance. One month after the dose was increased, adverse effects such as soft stool and urinary incontinence appeared. These adverse effects disappeared when the dose was decreased again to 3 mg/day. Her QOL improved dramatically with this minimal dose. She recovered verbal and written communication skills that she had lost for the past 21 years. Case 2. A 22-year-old man with Down syndrome, who had been diagnosed as having severe mental retardation, was put on donepezil therapy. Both loading and maintenance doses were 3 mg/day. His QOL had also dramatically improved, with some recovery in verbal communication. Transient agitation/violence and transient muscle weakness appeared during the first few months of treatment.. Patients with Down syndrome may be more sensitive to donepezil therapy than others and may benefit from this medicine, although they may also have adverse effects more frequently.. Donepezil may be a useful medicine for some patients with Down syndrome with severe cognitive impairment or mental retardation if the adverse effects are manageable.

Topics: Adult; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Down Syndrome; Female; Humans; Indans; Intellectual Disability; Male; Piperidines; Quality of Life

Topics: Dementia; Donepezil; Down Syndrome; Humans; Indans; Nootropic Agents; Piperidines

Topics: Adult; Cholinesterase Inhibitors; Dementia; Donepezil; Down Syndrome; Humans; Indans; Neuropsychological Tests; Pilot Projects; Piperidines; Treatment Outcome

Topics: Adult; Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia; Donepezil; Down Syndrome; Female; Humans; Indans; Male; Middle Aged; Piperidines; Research Design; Sample Size

Topics: Adult; Age Factors; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Down Syndrome; Female; Humans; Indans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales

Topics: Adult; Age Factors; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Comorbidity; Donepezil; Dose-Response Relationship, Drug; Down Syndrome; Drug Administration Schedule; Humans; Indans; Middle Aged; Piperidines; Treatment Outcome

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Comorbidity; Donepezil; Down Syndrome; Female; Humans; Indans; Male; Middle Aged; Piperidines; Urinary Incontinence

We describe the use of remifentanil in three infants with complex medical issues (hepatic failure, cyanotic heart disease and renal compromise). The short duration of opioid effect even after a long period of drug infusion (18 h) suggests this drug may be useful in some infants. Continued study is warranted.

Topics: Analgesics, Opioid; Down Syndrome; Ductus Arteriosus, Patent; Endocardial Cushion Defects; Heart Failure; Hemodynamics; Humans; Infant; Infant, Newborn; Infant, Premature; Intubation, Intratracheal; Kidney Diseases; Liver Failure; Male; Piperidines; Remifentanil; Rubinstein-Taybi Syndrome

Cisapride was used to treat gastro-oesophageal reflux in seven children with neurodevelopmental disorders and in 15 children who were neurologically normal. 24-hour lower-oesophageal pH monitoring was carried out before and after treatment. The neurologically normal group had a statistically significant decrease after treatment in percentage time pH less than 4, but children with neurological abnormalities did not have a comparable improvement in reflux scores.

Topics: Acetylcholine; Brain Damage, Chronic; Cerebral Palsy; Child; Child, Preschool; Cisapride; Down Syndrome; Gastric Acidity Determination; Gastroesophageal Reflux; Humans; Infant; Myenteric Plexus; Piperidines; Serotonin Antagonists

We measured the binding of the vesicular acetylcholine transport blocker [3H]vesamicol (2-[4-phenylpiperidino] cyclohexanol; AH-5183) to autopsied frontal cortex and amygdala of patients from 4 disorders having a marked brain cholinergic reduction, namely Alzheimer's disease, Parkinson's disease with dementia, dominantly inherited olivopontocerebellar atrophy and Down's syndrome. Although mean activity of the specific cholinergic marker enzyme choline acetyltransferase (ChAT) was markedly reduced by about 60% in frontal cortex in the 4 patient groups and by 80% or greater in amygdala of the Alzheimer's and Down's syndrome patients, [3H]vesamicol binding density was, on average, either normal or only slightly reduced as compared with the controls. This discrepancy suggests that in human brain [3H]vesamicol binding is either not preferentially localized to cholinergic nerve endings or, in these cholinergic deficiency syndromes, a substantial proportion of the vesamicol binding sites persist on cholinergic nerve terminals despite loss of ChAT activity.

Topics: Acetylcholine; Adult; Aged; Alzheimer Disease; Amygdala; Autonomic Nervous System Diseases; Brain Chemistry; Cerebral Cortex; Choline O-Acetyltransferase; Down Syndrome; Humans; Middle Aged; Neuromuscular Depolarizing Agents; Olivopontocerebellar Atrophies; Parasympathetic Nervous System; Parkinson Disease; Piperidines

Topics: Adult; Amines; Down Syndrome; Female; Histamine; Humans; Intestines; Male; Neomycin; Octopamine; Phenelzine; Piperidines; Sulfathiazoles; Tryptamines; Tyramine