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1.
Chromosome Res ; 26(1-2): 93-111, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29460123

RESUMO

Alu elements are a highly successful family of primate-specific retrotransposons that have fundamentally shaped primate evolution, including the evolution of our own species. Alus play critical roles in the formation of neurological networks and the epigenetic regulation of biochemical processes throughout the central nervous system (CNS), and thus are hypothesized to have contributed to the origin of human cognition. Despite the benefits that Alus provide, deleterious Alu activity is associated with a number of neurological and neurodegenerative disorders. In particular, neurological networks are potentially vulnerable to the epigenetic dysregulation of Alu elements operating across the suite of nuclear-encoded mitochondrial genes that are critical for both mitochondrial and CNS function. Here, we highlight the beneficial neurological aspects of Alu elements as well as their potential to cause disease by disrupting key cellular processes across the CNS. We identify at least 37 neurological and neurodegenerative disorders wherein deleterious Alu activity has been implicated as a contributing factor for the manifestation of disease, and for many of these disorders, this activity is operating on genes that are essential for proper mitochondrial function. We conclude that the epigenetic dysregulation of Alu elements can ultimately disrupt mitochondrial homeostasis within the CNS. This mechanism is a plausible source for the incipient neuronal stress that is consistently observed across a spectrum of sporadic neurological and neurodegenerative disorders.


Assuntos
Elementos Alu/fisiologia , Evolução Biológica , Encéfalo/fisiologia , Doenças do Sistema Nervoso/genética , Genoma Humano , Humanos , Neurogênese , Retroelementos
2.
Alzheimers Dement ; 13(7): 828-838, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28242298

RESUMO

It is hypothesized that retrotransposons have played a fundamental role in primate evolution and that enhanced neurologic retrotransposon activity in humans may underlie the origin of higher cognitive function. As a potential consequence of this enhanced activity, it is likely that neurons are susceptible to deleterious retrotransposon pathways that can disrupt mitochondrial function. An example is observed in the TOMM40 gene, encoding a ß-barrel protein critical for mitochondrial preprotein transport. Primate-specific Alu retrotransposons have repeatedly inserted into TOMM40 introns, and at least one variant associated with late-onset Alzheimer's disease originated from an Alu insertion event. We provide evidence of enriched Alu content in mitochondrial genes and postulate that Alus can disrupt mitochondrial populations in neurons, thereby setting the stage for progressive neurologic dysfunction. This Alu neurodegeneration hypothesis is compatible with decades of research and offers a plausible mechanism for the disruption of neuronal mitochondrial homeostasis, ultimately cascading into neurodegenerative disease.


Assuntos
Elementos Alu , Mitocôndrias/genética , Doenças Neurodegenerativas/fisiopatologia , Primatas , Animais , Humanos , Íntrons , Proteínas de Membrana Transportadoras/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial
3.
Alzheimers Dement ; 13(12): 1380-1388, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28624335

RESUMO

INTRODUCTION: The study investigated the role of neuropathologies in the relationship between TOMM40 '523 genotype and late-life cognitive decline. METHODS: Participants were community-dwelling older persons who had annual cognitive assessments and brain autopsies after death. Genotyping used DNA from peripheral blood or postmortem brain tissue. Linear mixed models assessed the extent to which the association of '523 genotype with cognitive decline is attributable to neuropathologies. RESULTS: Relative to ε3/ε3 homozygotes with '523-S/VL or '523-VL/VL genotype, both '523-L carriers and ε3/ε3 homozygotes with '523-S/S genotype had faster cognitive decline. The association of '523-L with cognitive decline was attenuated and no longer significant after controlling for Alzheimer's and other neuropathologies. By contrast, the association of '523-S/S was unchanged. DISCUSSION: There are two distinct TOMM40 '523 signals in relation to late-life cognitive decline. One signal primarily acts through AD and other common neuropathologies, whereas the other operates through a different mechanism.


Assuntos
Encéfalo/patologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Predisposição Genética para Doença/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo Genético/genética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Estudos de Coortes , Diagnóstico , Feminino , Genótipo , Humanos , Masculino , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Testes Neuropsicológicos
4.
Alzheimers Dement ; 10(6): 592-601.e2, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25260913

RESUMO

BACKGROUND: Several studies have demonstrated a lower apolipoprotein E4 (APOE ε4) allele frequency in African-Americans, but yet an increased age-related prevalence of AD. An algorithm for prevention clinical trials incorporating TOMM40'523 (Translocase of Outer Mitochondria Membrane) and APOE depends on accurate TOMM40'523-APOE haplotypes. METHODS: We have compared the APOE and TOMM40'523 phased haplotype frequencies of a 9.5 kb TOMM40/APOE genomic region in West African, Caucasian, and African-American cohorts. RESULTS: African-American haplotype frequency scans of poly-T lengths connected in phase with either APOE ε4 or APOE ε3 differ from both West Africans and Caucasians and represent admixture of several distinct West African and Caucasian haplotypes. A new West African TOMM40'523 haplotype, with APOE ε4 connected to a short TOMM40'523 allele, is observed in African-Americans but not Caucasians. CONCLUSION: These data have therapeutic implications for the age of onset risk algorithm estimates and the design of a prevention trial for African-Americans or other mixed ethnic populations.


Assuntos
Apolipoproteínas E/genética , População Negra/genética , Proteínas de Membrana Transportadoras/genética , População Branca/genética , África Ocidental , Estudos de Coortes , Feminino , Frequência do Gene , Haplótipos , Humanos , Masculino , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Poli T/genética , Estados Unidos
5.
Nat Genet ; 37(1): 84-9, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15608640

RESUMO

Interindividual variability in drug response, ranging from no therapeutic benefit to life-threatening adverse reactions, is influenced by variation in genes that control the absorption, distribution, metabolism and excretion of drugs. We genotyped 904 single-nucleotide polymorphisms (SNPs) from 55 such genes in two population samples (European and Japanese) and identified a set of tagging SNPs that represents the common variation in these genes, both known and unknown. Extensive empirical evaluations, including a direct assessment of association with candidate functional SNPs in a new, larger population sample, validated the performance of these tagging SNPs and confirmed their utility for linkage-disequilibrium mapping in pharmacogenetics. The analyses also suggest that rare variation is not amenable to tagging strategies.


Assuntos
Preparações Farmacêuticas/metabolismo , Farmacocinética , Polimorfismo de Nucleotídeo Único , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos
6.
Alzheimers Dement ; 9(2): 132-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23333464

RESUMO

A number of recent studies have not replicated the association of the translocase of the outer mitochondrial membrane pore subunit (TOMM40) rs10524523 polymorphism, which is in linkage disequilibrium with apolipoprotein E (APOE), with age of onset of Alzheimer's disease (AD). This perspective describes the differences between these later studies and the original experiments. We highlight the necessity for using standardized and informative assessment tools and processes when determining the age of development of AD or AD symptoms, and also stress that this clinical phenotype is best measured reliably in prospective studies during which subjects are monitored over time. This is true when assessing potential biomarkers for age of onset and when assessing the therapeutic potential of medicines that may delay the onset or progression of this disease.


Assuntos
Idade de Início , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Ensaios Clínicos como Assunto/normas , Proteínas de Membrana Transportadoras/genética , Genótipo , Humanos , Desequilíbrio de Ligação , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Fenótipo , Polimorfismo de Nucleotídeo Único
7.
J Alzheimers Dis ; 95(4): 1697-1707, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37718796

RESUMO

BACKGROUND: TOMM40 '523 has been associated with cognitive performance and risk for developing Alzheimer's disease independent of the effect of APOE genotype. Few studies have considered the longitudinal effect of this genotype on change in cognition over time. OBJECTIVE: Our objective was to evaluate the relationship between TOMM40 genotype status and change in cognitive performance in the TOMMORROW study, which was designed to prospectively evaluate an algorithm that includes TOMM40 '523 for genetic risk for conversion to mild cognitive impairment. METHODS: We used latent growth curve models to estimate the effect of TOMM40 allele carrier (short, very long) status on the intercept and slope of change in cognitive performance in four broad cognitive domains (attention, memory, executive function, and language) and a combined overall cognitive score over 30 months. RESULTS: TOMM40 very long allele carriers had significantly lower baseline performance for the combined overall cognitive function score (B = -0.088, p = 0.034) and for the executive function domain score (B = -0.143, p = 0.013). Slopes for TOMM40 very long carriers had significantly greater increases over time for the executive function domain score only. In sensitivity analyses, the results for executive function were observed in participants who remained clinically stable, but not in those who progressed clinically over the study duration. CONCLUSIONS: Our results add to the growing body of evidence that TOMM40, in the absence of APOEɛ4, may contribute to cognitive changes with aging and dementia and support the view that mitochondrial function is an important contributor to Alzheimer's disease risk.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Homozigoto , Doença de Alzheimer/genética , Função Executiva , Genótipo , Disfunção Cognitiva/genética , Cognição , Apolipoproteínas E/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial
8.
Alzheimers Dement ; 8(6): 490-5, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23102119

RESUMO

BACKGROUND: TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21-29 T residues) poly-T variants within intron 6 of TOMM40, whereas APOE e3 can be associated with either a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer's disease onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline. METHODS: An APOE e4-enriched cohort of 639 cognitively normal individuals aged 21 to 97 years with known TOMM40 genotype underwent longitudinal neuropsychological testing every 2 years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross-sectional and longitudinal effects of age on the Auditory Verbal Learning Test Long-Term Memory score by APOE, TOMM40, and the interaction between the two. RESULTS: There were significant effects overall for both TOMM40 (linear effect, P = .04; quadratic effect, P = .03) and APOE (linear effect, P = .06; quadratic effect, P = .008), with no significant interaction (P = .63). In a piecewise model, there was a significant TOMM40 effect before age 60 years (P = .009), characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect, and a significant APOE effect after age 60 years (P = .006), characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect. CONCLUSION: Both TOMM40 and APOE significantly influence age-related memory performance, but they appear to do so independently of each other.


Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Proteínas de Membrana Transportadoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Testes Neuropsicológicos , Adulto Jovem
9.
Alzheimers Dement ; 8(5): 381-8, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22863908

RESUMO

INTRODUCTION: A highly polymorphic T homopolymer was recently found to be associated with late-onset Alzheimer's disease risk and age of onset. OBJECTIVE: To explore the effects of the polymorphic polyT tract (rs10524523, referred as '523') on cognitive performance in cognitively healthy elderly individuals. METHODS: One hundred eighty-one participants were recruited from local independent-living retirement communities. Informed consent was obtained, and participants completed demographic questionnaires, a conventional paper-and-pencil neuropsychological battery, and the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB). Saliva samples were collected for determination of the TOMM40 '523' (S, L, VL) and the apolipoprotein E (APOE) (ɛ2, 3, 4) genotypes. From the initial sample of 181 individuals, 127 were eligible for the association analysis. Participants were divided into three groups based on '523' genotypes (S/S, S/L-S/VL, and L/L-L/VL-VL/VL). Generalized linear models were used to evaluate the association between the '523' genotypes and neuropsychological test performance. Analyses were adjusted for age, sex, education, depression, and APOE ɛ4 status. A planned subanalysis was undertaken to evaluate the association between '523' genotypes and test performance in a sample restricted to APOE ɛ3 homozygotes. RESULTS: The S homozygotes performed better, although not significantly, than the S/L-S/VL and the VL/L-L/VL-VL/VL genotype groups on measures associated with memory (CANTAB Paired Associates Learning, Verbal Recognition Memory free recall) and executive function (CANTAB measures of Intra-Extra Dimensional Set Shift). Follow-up analysis of APOE ɛ3 homozygotes only showed that the S/S group performed significantly better than the S/VL group on measures of episodic memory (CANTAB Paired Associates Learning and Verbal Recognition Memory free recall), attention (CANTAB Rapid Visual Information Processing latency), and executive function (Digit Symbol Substitution). The S/S group performed marginally better than the VL/VL group on Intra-Extra Dimensional Set Shift. None of the associations remained significant after applying a Bonferroni correction for multiple testing. CONCLUSIONS: Results suggest important APOE-independent associations between the TOMM40 '523' polymorphism and specific cognitive domains of memory and executive control that are preferentially affected in early-stage Alzheimer's disease.


Assuntos
Envelhecimento/genética , Transtornos Cognitivos/genética , Predisposição Genética para Doença/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo Genético/genética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Testes Neuropsicológicos
10.
Proc Natl Acad Sci U S A ; 105(4): 1343-6, 2008 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-18212130

RESUMO

Convergent evidence has revealed an association between insulin resistance and Alzheimer's disease (AD), and the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, an insulin sensitizer and mitochondrial activator, improves cognition in patients with early or mild-to-moderate AD. Apolipoprotein (apo) E4, a major genetic risk factor for AD, exerts neuropathological effects through multiple pathways, including impairment of dendritic spine structure and mitochondrial function. Here we show that rosiglitazone significantly increased dendritic spine density in a dose-dependent manner in cultured primary cortical rat neurons. This effect was abolished by the PPAR-gamma-specific antagonist, GW9662, suggesting that rosiglitazone exerts this effect by activating the PPAR-gamma pathway. Furthermore, the C-terminal-truncated fragment of apoE4 significantly decreased dendritic spine density. Rosiglitazone rescued this detrimental effect. Thus, rosiglitazone might improve cognition in AD patients by increasing dendritic spine density.


Assuntos
Apolipoproteína E4/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Dendritos/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Neurônios/metabolismo , Tiazolidinedionas/farmacologia , Animais , Animais Recém-Nascidos , Apolipoproteína E4/biossíntese , Contagem de Células , Células Cultivadas , Córtex Cerebral/patologia , Neurônios/patologia , Ratos , Rosiglitazona
11.
Alzheimers Dement ; 7(4): 456-65, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21784354

RESUMO

OBJECTIVE: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late-onset Alzheimer's disease (LOAD), with APOE epsilon 4 (APOE ε4) having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the translocase of the outer mitochondrial membrane (TOMM40) gene, has been shown to influence age of onset in LOAD, with very long (VL) poly-T length associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain and cognitive changes suggestive of presymptomatic LOAD may be associated with this TOMM40 polymorphism. METHODS: Among healthy APOE ε3 homozygous adults (N = 117; mean age, 55 years), we compared those who were homozygous for VL/VL (n = 35) TOMM40 poly-T lengths (who were presumably at higher risk) with those homozygous for short (S/S; n = 38) poly-T lengths, as well as those with heterozygous (S/VL; n = 44) poly-T length polymorphisms, on measures of learning and memory and on structural brain imaging. RESULTS: The VL/VL group showed lower performance than the S/S TOMM40 group on primacy retrieval from a verbal list learning task, a finding which is also seen in early Alzheimer's disease. A dose-dependent increase in the VL TOMM40 polymorphism (from no VL alleles, to S/VL heterozygous, to VL/VL homozygous) was associated with decreasing gray matter volume in the ventral posterior cingulate and medial ventral precuneus, a region of the brain affected early in LOAD. CONCLUSIONS: These findings among APOE ε3/ε3 late middle-aged adults suggest that a subgroup with VL TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes.


Assuntos
Apolipoproteína E3/genética , Encéfalo/patologia , Transtornos Cognitivos/genética , Proteínas de Membrana Transportadoras/genética , Poli T/genética , Fatores Etários , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Análise de Variância , Transtornos Cognitivos/etiologia , Feminino , Frequência do Gene , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
12.
Front Neurosci ; 15: 666958, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220427

RESUMO

Alzheimer's disease is a quintessential 'unmet medical need', accounting for ∼65% of progressive cognitive impairment among the elderly, and 700,000 deaths in the United States in 2020. In 2019, the cost of caring for Alzheimer's sufferers was $244B, not including the emotional and physical toll on caregivers. In spite of this dismal reality, no treatments are available that reduce the risk of developing AD or that offer prolonged mitiagation of its most devestating symptoms. This review summarizes key aspects of the biology and genetics of Alzheimer's disease, and we describe how pioglitazone improves many of the patholophysiological determinants of AD. We also summarize the results of pre-clinical experiments, longitudinal observational studies, and clinical trials. The results of animal testing suggest that pioglitazone can be corrective as well as protective, and that its efficacy is enhanced in a time- and dose-dependent manner, but the dose-effect relations are not monotonic or sigmoid. Longitudinal cohort studies suggests that it delays the onset of dementia in individuals with pre-existing type 2 diabetes mellitus, which small scale, unblinded pilot studies seem to confirm. However, the results of placebo-controlled, blinded clinical trials have not borne this out, and we discuss possible explanations for these discrepancies.

13.
Lancet Neurol ; 20(7): 537-547, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34146512

RESUMO

BACKGROUND: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. METHODS: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65-83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. FINDINGS: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85-12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45-1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. INTERPRETATION: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. FUNDING: Takeda and Zinfandel.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Pioglitazona/uso terapêutico , Medição de Risco/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Biomarcadores Farmacológicos , Disfunção Cognitiva/metabolismo , Método Duplo-Cego , Feminino , Humanos , Masculino , Pioglitazona/metabolismo , Prognóstico , Fatores de Risco , Resultado do Tratamento
14.
Epilepsia ; 51(9): 1906-9, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20345936

RESUMO

Temporal lobe epilepsy (TLE) is not a unitary electroclinical imaging syndrome. We asked if seizures arising from the parahippocampal-inferior temporal (PIT) region differ from those associated with hippocampal sclerosis (HS). The electroclinical features of 22 patients with HS and 14 patients with lesions in the PIT region who underwent epilepsy surgery and were seizure free for at least 2 years postoperatively were analyzed retrospectively. Patients with PIT lesions had a higher frequency of hypermotor and bilateral features and a lower frequency of behavioral arrest at the onset of seizure compared to cases with HS, suggesting that TLE originating in the PIT area can mimic frontal lobe epilepsy or contralateral mesial TLE.


Assuntos
Epilepsia do Lobo Frontal/patologia , Epilepsia do Lobo Temporal/diagnóstico , Epilepsia do Lobo Temporal/patologia , Hipocampo/patologia , Giro Para-Hipocampal/patologia , Adolescente , Adulto , Criança , Diagnóstico Diferencial , Eletroencefalografia , Epilepsia do Lobo Frontal/diagnóstico , Epilepsia do Lobo Frontal/fisiopatologia , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , Lobo Frontal/patologia , Lobo Frontal/fisiopatologia , Lateralidade Funcional , Hipocampo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Giro Para-Hipocampal/fisiopatologia , Esclerose , Lobo Temporal/patologia , Lobo Temporal/fisiopatologia , Gravação de Videoteipe
15.
Dement Geriatr Cogn Disord ; 30(2): 131-46, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20733306

RESUMO

BACKGROUND/AIMS: A phase II study of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer's disease (AD) detected a treatment benefit to cognition in apolipoprotein E(APOE)-ε4-negative subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR. METHODS: This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (ε4-positive, ε4-negative), subjects were randomized (2:2:2:1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+). RESULTS: At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-ε4-negative subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%). CONCLUSION: No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-ε4-negative or other analysis populations. The safety and tolerability of RSG XR was consistent with its known pharmacology.


Assuntos
Doença de Alzheimer , Tiazolidinedionas , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Apolipoproteínas E/genética , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Donepezila , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Edema/induzido quimicamente , Feminino , Genótipo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Indanos/administração & dosagem , Indanos/efeitos adversos , Testes de Inteligência , Entrevista Psicológica , Masculino , Pessoa de Meia-Idade , Nasofaringite/induzido quimicamente , PPAR gama/agonistas , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Rosiglitazona , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/efeitos adversos , Resultado do Tratamento
16.
Alzheimers Dement ; 6(2): 125-31, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20298972

RESUMO

This perspective article provides an opportunity to explain a new genetic finding for late-onset Alzheimer's disease (LOAD). It is specifically written for physicians and scientists who are interested in LOAD, but it may be relevant to those interested in identifying susceptibility variants for other complex diseases. The significant finding discussed here is that a variable-length, deoxythymidine homopolymer (poly-T) within intron 6 of the TOMM40 gene is associated with the age of onset of LOAD [Roses AD, Lutz MW, Amrine-Madsen H, Saunders AM, Crenshaw DG, Sundseth SS, et al. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J 2009 December 22;[Epublication ahead of print]. This result was obtained with a phylogenetic study of the genetic polymorphisms that reside within the linkage disequilibrium (LD) block that contains the TOMM40, APOE, and APOC1 genes from patients with LOAD and age-matched subjects without disease. Although the data will have diagnostic, prognostic, and therapeutic strategy implications, this perspective is meant to place the inheritance pattern for this "complex" human disease into context, and to highlight the potential utility of applying phylogenetic tools to the study of the genetics of complex diseases.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Proteínas de Membrana Transportadoras/genética , Idade de Início , Doença de Alzheimer/epidemiologia , Apolipoproteína C-I/genética , Apolipoproteínas E/genética , Mapeamento Cromossômico , Análise Mutacional de DNA , Testes Genéticos , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Biologia Molecular , Filogenia , Polimorfismo Genético/genética , Valor Preditivo dos Testes , Prognóstico
17.
Neurol Genet ; 6(2): e406, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32185242

RESUMO

OBJECTIVE: As structural variations may underpin susceptibility to complex neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), the objective of this study was to investigate a structural variant (SV) within sequestosome 1 (SQSTM1). METHODS: A candidate insertion/deletion variant within intron 5 of the SQSTM1 gene was identified using a previously established SV evaluation algorithm and chosen according to its subsequent theoretical effect on gene expression. The variant was systematically assessed through PCR, polyacrylamide gel fractionation, Sanger sequencing, and reverse transcriptase PCR. RESULTS: A reliable and robust assay confirmed the polymorphic nature of this variant and that the variant may influence SQSTM1 transcript levels. In a North American cohort of patients with familial ALS (fALS) and sporadic ALS (sALS) (n = 403) and age-matched healthy controls (n = 562), we subsequently showed that the SQSTM1 variant is associated with fALS (p = 0.0036), particularly in familial superoxide dismutase 1 mutation positive patients (p = 0.0005), but not with patients with sALS (p = 0.97). CONCLUSIONS: This disease association highlights the importance and implications of further investigation into SVs that may provide new targets for cohort stratification and therapeutic development.

18.
Neurol Genet ; 6(4): e470, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32754644

RESUMO

OBJECTIVE: To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 (SOD1) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease. METHODS: Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with SOD1 was identified according to its theoretical effect on gene expression. An 12-18 poly-T repeat (rs573116164) within the 3' untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 (SCAF4), a gene that is adjacent to SOD1, was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection. RESULTS: In a North American cohort of predominantly SOD1 fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T SCAF4 allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9-11.2; p = 4.0e-11), but also within non-SOD1 cases (n = 27; OR 5.3; 95% CI 1.9-14.5; p = 0.0014). This finding suggests genetically SOD1-independent effects of SCAF4 on fALS susceptibility. Furthermore, carriage of an 18T allele was associated with a 26-month reduction in survival time (95% CI 6.6-40.8; p = 0.014), but did not affect age at onset of disease. CONCLUSIONS: The findings in this fALS cohort suggest that rs573116164 could have SOD1-independent and broader relevance in ALS, warranting further investigation in other fALS and sporadic ALS cohorts, as well as studies of functional effects of the 18T variant on gene expression.

19.
Alzheimers Dement (N Y) ; 5: 661-670, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31720367

RESUMO

INTRODUCTION: Alzheimer's disease (AD) is a continuum with neuropathologies manifesting years before clinical symptoms; thus, AD research is attempting to identify more disease-modifying approaches to test treatments administered before full disease expression. Designing such trials in cognitively normal elderly individuals poses unique challenges. METHODS: The TOMMORROW study was a phase 3 double-blind, parallel-group study designed to support qualification of a novel genetic biomarker risk assignment algorithm (BRAA) and to assess efficacy and safety of low-dose pioglitazone to delay onset of mild cognitive impairment due to AD. Eligible participants were stratified based on the BRAA (using TOMM40 rs 10524523 genotype, Apolipoprotein E genotype, and age), with high-risk individuals receiving low-dose pioglitazone or placebo and low-risk individuals receiving placebo. The primary endpoint was time to the event of mild cognitive impairment due to AD. The primary objectives were to compare the primary endpoint between high- and low-risk placebo groups (for BRAA qualification) and between high-risk pioglitazone and high-risk placebo groups (for pioglitazone efficacy). Approximately 300 individuals were also asked to participate in a volumetric magnetic resonance imaging substudy at selected sites. RESULTS: The focus of this paper is on the design of the study; study results will be presented in a separate paper. DISCUSSION: The design of the TOMMORROW study addressed many key challenges to conducting a dual-objective phase 3 pivotal AD clinical trial in presymptomatic individuals. Experiences from planning and executing the TOMMORROW study may benefit future AD prevention/delay-of-onset trials.

20.
J Alzheimers Dis ; 14(1): 27-41, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18525125

RESUMO

MicroRNAs have essential functional roles in brain development and neuronal specification but their roles in neurodegenerative diseases such as Alzheimer's disease (AD) is unknown. Using a sensitive qRT-PCR platform we identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Encéfalo/patologia , Marcadores Genéticos/genética , MicroRNAs/líquido cefalorraquidiano , MicroRNAs/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Amiloide/metabolismo , Biomarcadores/líquido cefalorraquidiano , Linhagem Celular Tumoral , Cerebelo/patologia , Feminino , Lobo Frontal/patologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Hipocampo/patologia , Humanos , Imunidade Inata/fisiologia , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Neurônios/fisiologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
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