RESUMEN
In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer's disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aß, with higher levels of Aß40 promoting a more 'aggressive' form of CAA, and higher levels of Aß42(3) favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Amiloide/metabolismo , Vasos Sanguíneos/metabolismo , Síndrome de Down/genética , Síndrome de Down/patología , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteínas E/genética , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/patología , Femenino , Duplicación de Gen , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Placa Amiloide/genética , Placa Amiloide/patologíaRESUMEN
BACKGROUND: Prevalence of Alzheimer's disease in people with Down's syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimer's disease. Evidence to support treatment with Alzheimer's drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Down's syndrome. METHODS: In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Down's syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Down's syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898. FINDINGS: We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of -4·1 (95% CI -13·1 to 4·8) in DAMES scores, -8·5 (-20·1 to 3·1) in ABS I scores, and 2·0 (-7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77). INTERPRETATION: There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Down's syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimer's disease are not necessarily effective in this group of patients. FUNDING: Lundbeck.
Asunto(s)
Demencia/tratamiento farmacológico , Síndrome de Down/complicaciones , Memantina/uso terapéutico , Adulto , Enfermedad de Alzheimer/tratamiento farmacológico , Cognición/efectos de los fármacos , Demencia/etiología , Método Doble Ciego , Síndrome de Down/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , N-Metilaspartato/antagonistas & inhibidoresRESUMEN
It is poorly understood why people with Down syndrome (DS) are at extremely high-risk of developing Alzheimer's disease (AD) compared to the general population. One explanation may be related to their extra copy of risk factors modulated by chromosome 21. Myo-inositol (mI), whose transporter gene is located on chromosome 21, has been associated with dementia in the non-DS population; however, nobody has contrasted brain mI in DS with (DS+) and without (DS-) dementia to other non-DS groups. Our primary aim was to compare the hippocampal concentration of mI ([mI]) and other brain metabolites such as N-acetylaspartate (NAA; a proxy measure of neuronal density and mitochondrial function) in DS+, DS-, and age-matched healthy controls using proton Magnetic Resonance Spectroscopy (((1))H-MRS). We compared hippocampal [mI] and other metabolites in 35 individuals with genetically-confirmed DS [DS+ (n=17, age=53±6) and DS- (n=18, age=47±8)] to age-matched healthy controls (n=13, age=51±10) adjusting for proportion of the MRS voxel occupied by cerebrospinal spinal fluid, and gray/white matter. DS+ had a significantly higher [mI] than both DS- and healthy controls. In contrast neither DS+ nor DS- differed significantly from controls in [NAA] (although NAA in DS+ was significantly lower than DS-). Our secondary aim of comparing brain metabolites in DS+ and DS- to Alzheimer's disease (AD; n=39; age=77±5) revealed that the DS+ group had significantly elevated [mI] compared to AD or DS-. [mI] may modify risk for dementia in this vulnerable population.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Química Encefálica/genética , Síndrome de Down/metabolismo , Hipocampo/química , Anciano , Enfermedad de Alzheimer/complicaciones , Ácido Aspártico/análogos & derivados , Ácido Aspártico/análisis , Estudios de Casos y Controles , Demencia/etiología , Demencia/metabolismo , Síndrome de Down/complicaciones , Síndrome de Down/genética , Femenino , Hipocampo/metabolismo , Humanos , Inositol/análisis , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
TDP-43 immunoreactive (TDP-43-ir) pathological changes were investigated in the temporal cortex and hippocampus of 11 patients with autosomal dominant familial forms of Alzheimer's disease (FAD), 169 patients with sporadic AD [85 with early onset disease (EOAD) (i.e before 65 years of age), and 84 with late onset after this age (LOAD)], 50 individuals with Down's Syndrome (DS) and 5 patients with primary hippocampal sclerosis (HS). TDP-43-ir pathological changes were present, overall, in 34/180 of AD cases. They were present in 1/11 (9%) FAD, and 9/85 (10%) EOAD patients but were significantly more common (p = 0.003) in LOAD where 24/84 (29%) patients showed such changes. There were no demographic differences, other than onset age, between AD patients with or without TDP-43-ir pathological changes. Double immunolabelling indicated that these TDP-43-ir inclusions were frequently ubiquitinated, but were only rarely AT8 (tau) immunoreactive. Only 3 elderly DS individuals and 4/5 cases of primary HS showed similar changes. Overall, 21.7% of AD cases and 6% DS cases showed hippocampal sclerosis (HS). However, only 9% FAD cases and 16% EOAD cases showed HS, but 29% LOAD cases showed HS. The proportion of EOAD cases with both TDP-43 pathology and HS tended to be greater than those in LOAD, where nearly half of all the cases with TDP-43 pathology did not show HS. The presence of TDP-43-ir changes in AD and DS may therefore be a secondary phenomenon, relating more to ageing than to AD itself. Nevertheless, a challenge to such an interpretation comes from the finding in AD of a strong relationship between TDP-43 pathology and cognitive phenotype. Patients with TDP-43 pathology were significantly more likely to present with an amnestic syndrome than those without (p < 0.0001), in keeping with pathological changes in medial temporal lobe structures. HS was also associated more commonly with an amnestic presentation (p < 0.005), but this association disappeared when TDP-43-positive cases were excluded from the analysis. TDP-43 may, after all, be integral to the pathology of AD, and to some extent determine the clinical phenotype present.
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Envejecimiento/patología , Enfermedad de Alzheimer/patología , Proteínas de Unión al ADN/metabolismo , Síndrome de Down/patología , Hipocampo/patología , Fenotipo , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Apolipoproteínas E/genética , Autopsia , Cognición , Estudios de Cohortes , Síndrome de Down/metabolismo , Femenino , Genotipo , Hipocampo/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Esclerosis , Proteínas tau/metabolismoRESUMEN
Amyloid beta (Aß) is thought to play a critical role in the pathogenesis of Alzheimer's disease (AD). Prion-like Aß polymorphs, or "strains", can have varying pathogenicity and may underlie the phenotypic heterogeneity of the disease. In order to develop effective AD therapies, it is critical to identify the strains of Aß that might arise prior to the onset of clinical symptoms and understand how they may change with progressing disease. Down syndrome (DS), as the most common genetic cause of AD, presents promising opportunities to compare such features between early and advanced AD. In this work, we evaluate the neuropathology and Aß strain profile in the post-mortem brain tissues of 210 DS, AD, and control individuals. We assayed the levels of various Aß and tau species and used conformation-sensitive fluorescent probes to detect differences in Aß strains among individuals and populations. We found that these cohorts have some common but also some distinct strains from one another, with the most heterogeneous populations of Aß emerging in subjects with high levels of AD pathology. The emergence of distinct strains in DS at these later stages of disease suggests that the confluence of aging, pathology, and other DS-linked factors may favor conditions that generate strains that are unique from sporadic AD.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Síndrome de Down/metabolismo , Proteínas tau/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND/AIMS: Most people with Down syndrome (DS) develop Alzheimer's disease (AD). The extended tau haplotype has been linked to AD. In this study, we examined the haplotype's effect on the age of onset of AD in DS. METHODS: People with DS were assessed for dementia. Genotyping was performed for the extended tau haplotype, APOE and a polymorphism in APP, attt(5-8). RESULTS: Haplotype frequencies vary between those developing AD before 45 and those developing dementia after this age (p = 0.03). H1/H2 individuals are more likely to develop dementia before 45 than H1/H1 individuals (OR = 3, 95% CI = 1.01-8.91). CONCLUSION: Even in a condition driven by excess amyloid pathology, factors affecting tau are also important and should be considered as potential treatment targets.
Asunto(s)
Enfermedad de Alzheimer/genética , Síndrome de Down/genética , Proteínas tau/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Síndrome de Down/epidemiología , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenAsunto(s)
Enfermedad de Alzheimer/sangre , Síndrome de Down/sangre , Índices de Eritrocitos , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Síndrome de Down/complicaciones , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Adulto JovenRESUMEN
While post mortem studies have identified the major cell types and functional systems affected in Alzheimer's disease (AD) the initial sites and molecular characteristics of pathology are still unclear. Because individuals with Down syndrome (DS) (trisomy 21) develop the full pathological changes of AD in a predictable way by the time they reach middle to late age, a study of the brains of such persons at different ages makes an ideal 'model system' in which the sites of earliest onset of pathology can be detected and the subsequent progression of changes be monitored. In the present study we have examined the brains of 56 individuals with DS ranging from new-born to 76 years for the presence of amyloid and tau pathology in key cortical and subcortical regions. Amyloid pathology was found to commence in the late teens to twenties as a deposition of diffuse plaques initially within the temporal neocortex, quickly involving other neocortical regions but only reaching subcortical regions and cerebellum by the late forties. Cerebral amyloid angiopathy did not regularly commence until after 45-50 years of age. Tau pathology usually commenced after 35 years of age, initially involving not only entorhinal areas and hippocampus but also subcortical regions such as locus caeruleus (LC) and dorsal raphe nucleus (DRN). Later, tau pathology spread throughout the neocortex reaching occipital lobes in most instances by mid-50 years of age. Such a pattern of spread is consistent with that seen in typical AD. We found no evidence that tau pathology might commence within the brain in DS before amyloid deposition had occurred, but there was limited data that suggests tau pathology in LC or DRN might predate that in entorhinal areas and hippocampus or at least be coincident.
Asunto(s)
Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Encéfalo/patología , Síndrome de Down/patología , Placa Amiloide/patología , Adolescente , Adulto , Edad de Inicio , Anciano , Enfermedad de Alzheimer/complicaciones , Niño , Preescolar , Progresión de la Enfermedad , Síndrome de Down/complicaciones , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Adulto Joven , Proteínas tau/metabolismoRESUMEN
Dementia in Alzheimer's disease (DAD) is more common in adults with Down syndrome (DS), with characteristically an earlier onset. The treatment of DAD is not too dissimilar in the general population and in people with intellectual disabilities. However, the underlying intellectual disability can make the management of DAD more challenging in older adults with DS. This literature review aimed to look at the management of DAD in people with DS. The management of dementia is holistic. This includes treating reversible factors, aiming to slow the cognitive decline, psychological therapies, ensuring that the environment is appropriate, and use of psychotropic medication when necessary to manage behavioral problems, psychotic symptoms, depressive symptoms, and sleep difficulty. Antidementia medications have a role to play but remain limited. The management of DAD in the DS population can be at times challenging, but good clinical practice should involve accurate diagnosis of dementia, treating any reversible additional factors, consideration of psychological and behavioral management, use of antidementia medication, and a multidisciplinary team approach.
RESUMEN
Individuals with Down's syndrome (DS) are living longer and many will survive into their fifth or sixth decade of life. Among the DS population, the prevalence of dementia in Alzheimer's disease increases from 9.4% in age group 30-39 years to 54.5% age group 60-69 years. The psychopathology of dementia in Alzheimer's disease is similar to that seen in the general population although differences are apparent due to the underlying intellectual disability in DS and on the reliance on collateral information from informants. The diagnostic workup follows accepted practice although neuropsychological tests and neuroimaging will only be adjuncts to the clinical assessment; such investigations have limited diagnostic value. Presently, research is focused on identifying genetic and biological measures of Alzheimer's disease in DS.
Asunto(s)
Demencia/complicaciones , Demencia/diagnóstico , Síndrome de Down/complicaciones , Adulto , Anciano , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND: Down's syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimer's disease (DAD) compared with the general population. Recent collaborative genome-wide association studies of large case control data sets of individuals with and without Alzhemier's disease (AD) have revealed new risk variants for dementia, as well as confirming previously identified risk variants. In this study, nine AD-derived SNPs, near or within the CR1 (rs3818361), BIN1 (rs744373), CD2AP (rs9349407), EPHA1 (rs11767557), CLU (rs1532278), MS4A6A/4A (rs610932), PICALM (rs561655), ABCA7 (rs3764650) and CD33 (rs3865444) genes were genotyped in 295 individuals with DS. RESULTS: There were no significant associations between these nine GWAS-derived SNPs and DAD in British Caucasian individuals with DS. Interestingly the CR1 rs3818361 variant appeared to be associated with mortality in our cohort, particularly in the subjects without dementia. To our knowledge, this is the first time that this variant has been implicated as a determinant of mortality and the finding warrants further investigation in other cohorts with DS. CONCLUSIONS: This study shows negative associations of nine AD-derived SNPs with DAD in DS. This may be due to the modest size of our cohort, which may indicate that our study is insufficiently powered to pick up such associations. We cannot conclusively exclude a role for these SNPs in DAD in DS. Clearly, efforts to investigate genetic variants with small effects on disease risk require a much larger cohort of individuals with DS. In fact, we hypothesize that a sample size of 4465 individuals with DS would be needed to determine the role in DAD in DS of the nine AD-derived SNPs investigated in this study. We therefore recommend that all national and international clinics with access to individuals with DS should contribute DNA samples to form DS consortia.
Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Transportadoras de Casetes de Unión a ATP/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Clusterina/genética , Proteínas del Citoesqueleto/genética , Demencia/genética , Síndrome de Down/genética , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Proteínas de la Membrana/genética , Proteínas de Ensamble de Clatrina Monoméricas/genética , Proteínas Nucleares/genética , Vigilancia de la Población/métodos , Estudios Prospectivos , Receptor EphA1/genética , Receptores de Complemento 3b/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
BACKGROUND: The Strengths and Difficulties Questionnaire (SDQ) has been widely used to screen typically developing children for mental health problems; in recent years it has also been used with children with intellectual disabilities. The present study investigated the possible use of the SDQ to screen adults with Down syndrome (DS). METHOD: Only four items on the SDQ were changed slightly to remove references to children. Parents or carers completed the SDQ and all 125 adults with DS (aged 18-43 years) were assessed for mental health problems by a psychiatrist. RESULTS: Twenty-eight adults were diagnosed with a psychiatric condition. Parents and carers found the SDQ easy to complete and liked the inclusion of positive behaviours. The SDQ did discriminate significantly between those with and without a diagnosis, however the sensitivity and specificity were insufficient. Exploratory and Confirmatory Factor Analyses showed a four factor model (pro-social behaviour, emotional difficulties, hyperactivity and conduct disorders) to be the best solution. This structure was similar to previous research findings of three factors of pro-social behaviour, internalising disorders and externalising disorders. CONCLUSION: Construct validity and reliability suggest that the SDQ has potential for use with adults with DS and possibly those with other intellectual disabilities. The SDQ is user friendly for parents and carers, and did highlight behavioural and mental health needs, suggesting that it would be worthwhile to develop the SDQ specifically for adults with intellectual disability.
Asunto(s)
Síndrome de Down/psicología , Trastornos Mentales/diagnóstico , Trastornos Mentales/psicología , Encuestas y Cuestionarios/normas , Adolescente , Adulto , Síntomas Afectivos/diagnóstico , Síntomas Afectivos/psicología , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/psicología , Femenino , Humanos , Hipercinesia/diagnóstico , Hipercinesia/psicología , Masculino , Salud Mental , Curva ROC , Reproducibilidad de los Resultados , Conducta Social , Adulto JovenRESUMEN
BACKGROUND: Down syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimer's disease (DAD) compared with the general population. Many studies have investigated genetic susceptibility to AD in the general population, resulting in a number of potential candidate genes that may influence the development of DAD. The majority of these variants, however, have not been investigated in subjects with DS. AIM: The aim of this study was to determine whether genetic variants previously associated with AD in the general population, were also associated with DAD in individuals with DS. METHODS: Genotyping of 43 SNPs within 28 genes was undertaken in 187 individuals with Down syndrome with and without dementia of Alzheimer's disease, using the SNPlex platform. RESULTS: Significant associations of SNPs in five genes with DAD in DS were found, namely APOE, SORL1, BACE1, RUNX1 and ALDH18A1. As expected, the most strongly associated SNP was the APOE É4 rs429358 variant (HR=2.47 [1.58, 3.87], p=7.52×10(-5)), although variants within the more recently implicated SORL1 and RUNX1 genes were also strongly associated with DAD in DS (HR=0.54 [0.37, 0.80], p=0.002 and HR=1.61 [1.15, 2.26], p=0.006 respectively). CONCLUSIONS: Our study demonstrates that a number of variants previously associated with AD in the general population are also associated with DAD in DS. To enable us to determine whether these variants, as well as other more recently revealed AD susceptibility variants, truly contribute to the development of DAD in DS, further multi-centre collaborative studies comprising large number of individuals with DS are needed.
Asunto(s)
Aldehído Deshidrogenasa/genética , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Apolipoproteína E4/genética , Ácido Aspártico Endopeptidasas/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Síndrome de Down/genética , Variación Genética/genética , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/genética , Adulto , Anciano , Familia de Aldehído Deshidrogenasa 1 , Enfermedad de Alzheimer/metabolismo , Estudios de Cohortes , Demencia/genética , Demencia/metabolismo , Síndrome de Down/metabolismo , Femenino , Estudios de Seguimiento , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Retinal-DeshidrogenasaRESUMEN
People with Down syndrome (DS) develop Alzheimer's disease (AD) with an early age of onset. A tetranucleotide repeat, attt(5-8), in intron 7 of the amyloid precursor protein has been associated with the age of onset of AD in DS in a preliminary study. The authors examine the impact of this polymorphism in a larger cohort of individuals with DS. Adults with DS were genotyped for attt(5-8) and APOE. The results were analysed with respect to the age of onset of dementia. The presence of three copies of the six-repeat allele resulted in onset of dementia seven years earlier than in the presence of other genotypes. Further study is essential to elucidate the mechanism by which this polymorphism functions, with an exciting opportunity to identify novel treatment targets relevant for people with DS and AD.
RESUMEN
OBJECTIVE: No definitive peripheral biological marker has yet been found to correlate with Alzheimer's disease (AD). This study investigated the role of macrocytosis as a marker which could significantly improve our understanding of AD in the Down's syndrome (DS) population. METHODS: This study investigated the possible association between raised mean corpuscular volume (MCV) and AD in 150 adults with DS over a five year study period. RESULTS: A raised MCV is common in the DS population. A statistically significant association between a further elevated MCV and clinically diagnosed AD in adults with DS was found. CONCLUSIONS: The findings suggest that further research into the association between macrocytosis and DS could improve our understanding of the underlying biological mechanisms of AD. The measurement of MCV should be undertaken in all DS individuals with a diagnosis of possible or definite dementia. A significant raised MCV (above 97fl for males and 99fl for females) may further improve the clinical diagnosis. A single MCV measurement, however, cannot be recommended as a diagnostic test for AD in adults with DS.
RESUMEN
BACKGROUND: 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. METHOD: 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). RESULTS: 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. CONCLUSION: 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.