RESUMO
BACKGROUND AND PURPOSE: MR imaging has been widely used for the noninvasive evaluation of MS. Although clinical MR imaging sequences are highly effective in showing focal macroscopic tissue abnormalities in the brains of patients with MS, they are not specific to myelin and correlate poorly with disability. We investigated direct imaging of myelin using a 2D adiabatic inversion recovery ultrashort TE sequence to determine its value in assessing disability in MS. MATERIALS AND METHODS: The 2D inversion recovery ultrashort TE sequence was evaluated in 14 healthy volunteers and 31 patients with MS. MPRAGE and T2-FLAIR images were acquired for comparison. Advanced Normalization Tools were used to correlate inversion recovery ultrashort TE, MPRAGE, and T2-FLAIR images with disability assessed by the Expanded Disability Status Scale. RESULTS: Weak correlations were observed between normal-appearing white matter volume (R = -0.03, P = .88), lesion load (R = 0.22, P = .24), and age (R = 0.14, P = .44), and disability. The MPRAGE signal in normal-appearing white matter showed a weak correlation with age (R = -0.10, P = .49) and disability (R = -0.19, P = .31). The T2-FLAIR signal in normal-appearing white matter showed a weak correlation with age (R = 0.01, P = .93) and disability (R = 0.13, P = .49). The inversion recovery ultrashort TE signal was significantly negatively correlated with age (R = -0.38, P = .009) and disability (R = -0.44; P = .01). CONCLUSIONS: Direct imaging of myelin correlates with disability in patients with MS better than indirect imaging of long-T2 water in WM using conventional clinical sequences.
Assuntos
Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/patologia , Adulto , Idoso , Envelhecimento/patologia , Avaliação da Deficiência , Feminino , Voluntários Saudáveis , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Substância Branca/diagnóstico por imagemRESUMO
BACKGROUND: In Huntington disease (HD), substantial striatal atrophy precedes clinical motor symptoms. Accordingly, neuroprotection should prevent major cell loss before such symptoms arise. To evaluate neuroprotection, biomarkers such as MRI measures are needed. This requires first establishing the best imaging approach. METHODS: Using a cross-sectional design, we acquired T1-weighted and diffusion-weighted scans in 39 preclinical (pre-HD) individuals and 25 age-matched controls. T1-weighted scans were analyzed with gross whole-brain segmentation and voxel-based morphometry. Analysis of diffusion-weighted scans used skeleton-based tractography. For all imaging measures, we compared pre-HD and control groups and within the pre-HD group we examined correlations with estimated years to clinical onset. RESULTS: Pre-HD individuals had lower gross gray matter (GM) and white matter (WM) volume. Voxel-wise analysis demonstrated local GM volume loss, most notably in regions consistent with basal ganglia-thalamocortical pathways. By contrast, pre-HD individuals showed widespread reductions in WM integrity, probably due to a loss of axonal barriers. Both GM and WM imaging measures correlated with estimated years to onset. CONCLUSIONS: Using automated, observer-independent methods, we found that GM loss in pre-HD was regionally specific, while WM deterioration was much more general and probably the result of demyelination rather then axonal degeneration. These findings provide important information about the nature, relative staging, and topographic specificity of brain changes in pre-HD and suggest that combining GM and WM imaging may be the best biomarker approach. The empirically derived group difference images from this study are provided as regions-of-interest masks for improved sensitivity in future longitudinal studies.
Assuntos
Encéfalo/patologia , Doença de Huntington/patologia , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Amielínicas/patologia , Adulto , Mapeamento Encefálico , Distribuição de Qui-Quadrado , Estudos Transversais , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To investigate the regional pattern of white matter and cerebellar changes, as well as subcortical and cortical changes, in Huntington disease (HD) using morphometric analyses of structural MRI. METHODS: Fifteen individuals with HD and 22 controls were studied; groups were similar in age and education. Primary analyses defined six subcortical regions, the gray and white matter of primary cortical lobes and cerebellum, and abnormal signal in the cerebral white matter. RESULTS: As expected, basal ganglia and cerebral cortical gray matter volumes were significantly smaller in HD. The HD group also demonstrated significant cerebral white matter loss and an increase in the amount of abnormal signal in the white matter; occipital white matter appeared more affected than other cerebral white matter regions. Cortical gray and white matter measures were significantly related to caudate volume. Cerebellar gray and white matter volumes were both smaller in HD. CONCLUSIONS: The cerebellum and the integrity of cerebral white matter may play a more significant role in the symptomatology of HD than previously thought. Furthermore, changes in cortical gray and cerebral white matter were related to caudate atrophy, supporting a similar mechanism of degeneration.
Assuntos
Cerebelo/patologia , Córtex Cerebral/patologia , Doença de Huntington/patologia , Bainha de Mielina/patologia , Adulto , Atrofia , Núcleo Caudado/patologia , Diencéfalo/patologia , Diagnóstico Precoce , Feminino , Humanos , Doença de Huntington/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Degeneração Neural , Núcleo Accumbens/patologia , Tamanho do Órgão , Índice de Gravidade de Doença , Substância Negra/patologia , Tálamo/patologiaRESUMO
BACKGROUND: The APOE epsilon4 allele has emerged as a major genetic factor for Alzheimer disease (AD), and its presence has been associated with an increase in beta-amyloid senile plaques (SPs) and neuritic plaques (NPs). Whether it affects neurofibrillary tangle (NFT) accumulation or cholinergic losses in AD remains controversial. In contrast, the epsilon2 allele has been reported to decrease the risk for AD. However, its effect on neuropathologic and neurochemical markers of disease is unclear. OBJECTIVE: To investigate the relationship between APOE genotype and both pathologic severity and cholinergic dysfunction in AD. METHODS: In an autopsy series of 296 patients with AD, APOE genotype was determined in blood or postmortem brain tissue. NPs and NFTs were counted in the midfrontal (MF), inferior parietal (IP), and superior temporal (ST) cortices and the hippocampus. Choline acetyltransferase (ChAT) activity was assessed in the MF, IP, and ST cortices. RESULTS: Compared with patients with no epsilon4 alleles, epsilon4 carriers (patients with either one or two epsilon4 alleles) did not differ significantly with regard to any pathologic or neurochemical measures, except for increased ST NPs. However, when cases were stratified into three groups according to the number of epsilon4 alleles, patients with two epsilon4 alleles had significantly more NPs and NFTs in all neocortical regions than those with either one or no epsilon4 alleles. The association of the epsilon4/4 genotype with neocortical pathologic severity remained significant even after adjusting for age at onset or age at death. In contrast, there were no significant group differences with regard to neocortical ChAT activity. When pathologic and neurochemical measures were compared between patients with the epsilon2 allele and those without, a strong relationship emerged between the epsilon2 allele and decreased NPs in all neocortical regions. CONCLUSIONS: The epsilon4 allele does not predict cholinergic decline in AD. Although the presence of a single epsilon4 allele appears to have no effect, the presence of two epsilon4 alleles is an important determinant of both NP and NFT accumulation. A putative protective role for the epsilon2 allele in AD may be mediated by reduced plaque burden.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/fisiologia , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Apolipoproteína E2 , Apolipoproteína E4 , Apolipoproteínas E/genética , Encéfalo/enzimologia , Encéfalo/patologia , California/epidemiologia , Colina O-Acetiltransferase/análise , Estudos de Coortes , Feminino , Seguimentos , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/análise , Emaranhados Neurofibrilares/genética , Placa Amiloide/genética , Método Simples-CegoRESUMO
OBJECTIVE: To determine the relation of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) to the development and evolution of Alzheimer disease (AD). METHODS: An autopsy series of 102 patients with dementia and pathologically confirmed AD and 29 normal control subjects (NCs) was studied. AD cases were stratified according to their last Mini-Mental State Examination (MMSE) before death as mild, moderate, severe, or very severe. NPs and NFTs were enumerated in the midfrontal (MF), inferior parietal (IP), superior temporal (ST), hippocampal (Hip), or entorhinal cortices using thioflavin-S preparations. RESULTS: Most (87%) of the NCs had allocortical NFTs, whereas only a minority (37%) displayed neocortical NPs, and even fewer (19%) showed Hip NPs. In contrast, none of the NCs exhibited neocortical NFTs, except one case with a single ST tangle. However, neocortical NFTs were not detected in even 10% of the patients with AD and, in particular, were absent in nearly 50% of those with mild disease at death. Thus, their sensitivity as a marker of AD was lower than that of NPs, which, conversely, were found in all patients with AD. Comparing NCs and patients with mild AD, significant differences were found for numbers of NPs only. Across the AD groups, in contrast, although NP and NFT density increased with dementia severity, significant differences consistently emerged for NFTs alone. CONCLUSIONS: Deterioration in Alzheimer disease appears to be driven by neuritic plaques and neurofibrillary tangles at different stages of the disease. The significant increase in neuritic plaques, but not neurofibrillary tangles, in patients with even mild Alzheimer disease at death compared with normal control subjects suggests that only neuritic plaques are associated with the earliest symptoms of Alzheimer disease.
Assuntos
Doença de Alzheimer/patologia , Emaranhados Neurofibrilares , Placa Amiloide , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Encéfalo/patologia , California/epidemiologia , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
OBJECTIVE: To compare the clinical and pathologic features of plaque only Alzheimer disease (POAD) with plaque and tangle Alzheimer disease (PTAD). METHODS: An autopsy series of 16 patients with POAD and 32 subjects with PTAD on whom extensive antemortem neuropsychological testing was available. Plaques, tangles, and cerebral amyloid angiopathy were examined in the neocortex and hippocampus using thioflavin S staining. In addition, immunocytochemical analysis with AT8 for phosphorylated tau was performed. Midfrontal (MF) synaptic density, MF choline acetyltransferase (ChAT) activity, and apolipoprotein E genotyping were also assessed. RESULTS: Initial neuropsychological test scores and rates of cognitive decline on the Mini-Mental State Examination and Blessed Information-Memory-Concentration were similar between the two groups. However, compared to PTAD, POAD patients tended to deteriorate more slowly on the Mattis Dementia Rating Scale. Furthermore, they were somewhat less impaired on all these measures at last examination. There was an older age at onset and death, and a trend toward a shorter disease duration, in POAD compared to PTAD patients. POAD subjects, by definition, had no neocortical neurofibrillary tangles (NFT) (Braak stages IV or less). In addition, they also had fewer hippocampal NFT, fewer neuritic plaques, and higher mean MF ChAT activity than PTAD subjects. On the other hand, the two groups did not differ significantly in brain weight or MF synaptic density. Although lacking overt tangle formation, the POAD group displayed abnormal phosphorylated tau immunoreactivity in neocortical pyramidal neurons. CONCLUSIONS: Dementing syndromes virtually indistinguishable from each other can, and do, develop in the presence or absence of neocortical NFT. Patients without neocortical NFT are, on average, older at disease onset and death, and show a trend toward a shorter disease duration with somewhat slower deterioration. Although neocortical NFT per se are not obligatory for the development of clinical dementia, more subtle neocortical cytoskeletal tau pathology may contribute to cognitive decline in these subjects.
Assuntos
Doença de Alzheimer/patologia , Neocórtex/patologia , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteínas E/genética , California , Colina O-Acetiltransferase/análise , Progressão da Doença , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Neocórtex/metabolismo , Testes Neuropsicológicos/estatística & dados numéricos , Tamanho do Órgão , Isoformas de Proteínas/genética , Sinaptofisina/análiseRESUMO
OBJECTIVE: To determine the rate and correlates of weight change in a large, well characterised sample of patients with Huntington's disease followed at 44 sites by the Huntington Study Group. PARTICIPANTS AND METHODS: Weight change was assessed in 927 adults with a definite diagnosis of Huntington's disease who were followed prospectively for (mean (SD)) 3.4 (1.4) years. The unified Huntington's disease rating scale was used to assess weight, motor dysfunction (including chorea and dystonia), depressive symptoms, and functional decline. RESULTS: Random effects modelling determined that patients gained an average of 0.11 (1.7) kg/year and their chorea scores increased by 0.36 (0.78) points/year. There were significant but weak relations between weight loss and increasingly severe chorea (r = -0.13), worse baseline motor performance (r = -0.12), less severe baseline depressed mood (r = 0.14), and poorer baseline independence ratings (r = 0.07). Patients who were within 0 to 2 years of symptom onset at the time of the baseline visit gained more weight than those with longer disease duration. CONCLUSIONS: Weight loss following symptom onset is not a consistent feature of Huntington's disease. The mechanisms contributing to weight change in this condition are unclear and probably multifactorial. Future studies examining asymptomatic carriers of the mutation could be helpful in identifying incipience of low body weight and may be better suited for identifying clinical correlates of weight loss than studies in symptomatic patients.
Assuntos
Doença de Huntington/fisiopatologia , Redução de Peso/fisiologia , Coreia/diagnóstico , Coreia/etiologia , Cromossomos Humanos Par 4/genética , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Disartria/diagnóstico , Disartria/etiologia , Distonia/diagnóstico , Distonia/etiologia , Metabolismo Energético , Feminino , Humanos , Proteína Huntingtina , Doença de Huntington/complicações , Doença de Huntington/genética , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso , Proteínas Nucleares , Proteínas/genética , Transtornos Psicomotores/diagnóstico , Transtornos Psicomotores/etiologia , Repetições de Trinucleotídeos/genéticaRESUMO
OBJECTIVE: To determine whether AD neurofibrillary pathology influences clinical diagnostic accuracy in dementia with Lewy bodies (DLB). BACKGROUND: Pathologic diagnosis of DLB mandates Lewy bodies but also allows for AD pathology in the form of plaques and tangles. Because clinical diagnostic accuracy of DLB remains low, the authors questioned whether the severity of AD pathology in the form of tangles might affect the clinician's ability to correctly diagnose DLB in life. DESIGN/METHODS: Ninety-eight subjects with autopsy-proven DLB who had been evaluated annually at the University of California San Diego AD Research Center were identified. The clinical diagnosis used was the last diagnosis before death. Pathologic diagnosis of DLB was made according to Consensus guidelines, and Braak staging was used to assess the degree of neurofibrillary AD pathology. The clinical characteristics of subjects with DLB with low vs high Braak stages were compared and the clinical diagnostic accuracy for subjects stratified according to Braak stage was determined. RESULTS: Only 27% of the subjects with DLB demonstrated both visual hallucinations and spontaneous extrapyramidal signs (EPS). The low Braak stage (0 to 2, n = 24) subjects had a higher frequency of visual hallucinations (65%) than did subjects with DLB with higher (3 to 6, n = 66) Braak stages (33%, p = 0.008), and showed a slightly greater but not significant degree of EPS. Although clinical diagnostic accuracy for DLB was relatively low (49%), it was higher for subjects with low (75%) compared to high (39%) Braak stages (p = 0.0039). CONCLUSIONS: The degree of concomitant AD tangle pathology has an important influence on the clinical characteristics and, therefore, the clinical diagnostic accuracy of DLB.
Assuntos
Doença de Alzheimer/diagnóstico , Doença por Corpos de Lewy/diagnóstico , Emaranhados Neurofibrilares , Placa Amiloide , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Doenças dos Gânglios da Base/etiologia , Encéfalo/patologia , Estudos de Coortes , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Alucinações , Humanos , Corpos de Lewy/química , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Coloração e Rotulagem/métodosRESUMO
Dementia has the potential to become a major public health concern during this century due to increasing life expectancy and growth in the ageing population. The commonest types of dementia include Alzheimer's disease (AD), vascular dementia (VaD), and dementia with cerebrovascular components. Galantamine is the only acetylcholinesterase inhibitor that exhibits a dual mechanism of action--inhibition of acetylcholinesterase and nicotinic receptor modulation. Clinical studies demonstrate the efficacy and safety of galantamine in patients with AD, VaD, and AD with cerebrovascular components. Galantamine shows beneficial effects on cognition, global function, activities of daily living and behaviour. Adverse events observed with galantamine use are generally mild to moderate in severity, transient and gastrointestinal in nature. The dose of galantamine should be escalated to 16 and 24 mg/day at four-week intervals to achieve maximal tolerability. Because of its unique mechanism of action, galantamine may have potential benefits over conventional enzyme-inhibiting agents.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Demência Vascular/tratamento farmacológico , Galantamina/uso terapêutico , HumanosRESUMO
The independent and relative contributions of motor, cognitive, and behavioural deficits to functional decline in patients with Huntington's disease are examined. Twenty two patients with Huntington's disease were assessed with rating scales for motor dysfunction, cognitive measures of executive functions, and behavioural measures of apathy, executive dysfunction, and disinhibition. Their functional status was assessed with informant based and clinician based ratings of activities of daily living (ADL). A composite apathy/executive dysfunction behavioural index was strongly related to decline in ADL independently and after controlling for motor and cognitive deficits. These results suggest that behavioural dysfunction contributes to functional decline in patients with Huntington's disease and may impede their ability to utilise motor or cognitive skills that remain available in the early stages of the disease.
Assuntos
Sintomas Comportamentais/diagnóstico , Sintomas Comportamentais/fisiopatologia , Doença de Huntington/fisiopatologia , Atividades Cotidianas , Sintomas Comportamentais/etiologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Progressão da Doença , Feminino , Humanos , Doença de Huntington/complicações , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Análise de RegressãoRESUMO
OBJECTIVE: To update the 1994 practice parameter for the diagnosis of dementia in the elderly. BACKGROUND: The AAN previously published a practice parameter on dementia in 1994. New research and clinical developments warrant an update of some aspects of diagnosis. METHODS: Studies published in English from 1985 through 1999 were identified that addressed four questions: 1) Are the current criteria for the diagnosis of dementia reliable? 2) Are the current diagnostic criteria able to establish a diagnosis for the prevalent dementias in the elderly? 3) Do laboratory tests improve the accuracy of the clinical diagnosis of dementing illness? 4) What comorbidities should be evaluated in elderly patients undergoing an initial assessment for dementia? RECOMMENDATIONS: Based on evidence in the literature, the following recommendations are made. 1) The DSM-III-R definition of dementia is reliable and should be used (Guideline). 2) The National Institute of Neurologic, Communicative Disorders and Stroke--AD and Related Disorders Association (NINCDS-ADRDA) or the Diagnostic and Statistical Manual, 3rd edition, revised (DSM-IIIR) diagnostic criteria for AD and clinical criteria for Creutzfeldt--Jakob disease (CJD) have sufficient reliability and validity and should be used (Guideline). Diagnostic criteria for vascular dementia, dementia with Lewy bodies, and frontotemporal dementia may be of use in clinical practice (Option) but have imperfect reliability and validity. 3) Structural neuroimaging with either a noncontrast CT or MR scan in the initial evaluation of patients with dementia is appropriate. Because of insufficient data on validity, no other imaging procedure is recommended (Guideline). There are currently no genetic markers recommended for routine diagnostic purposes (Guideline). The CSF 14-3-3 protein is useful for confirming or rejecting the diagnosis of CJD (Guideline). 4) Screening for depression, B(12) deficiency, and hypothyroidism should be performed (Guideline). Screening for syphilis in patients with dementia is not justified unless clinical suspicion for neurosyphilis is present (Guideline). CONCLUSIONS: Diagnostic criteria for dementia have improved since the 1994 practice parameter. Further research is needed to improve clinical definitions of dementia and its subtypes, as well as to determine the utility of various instruments of neuroimaging, biomarkers, and genetic testing in increasing diagnostic accuracy.
Assuntos
Demência/diagnóstico , HumanosRESUMO
OBJECTIVE: To determine the timing of cholinergic loss and reduction of synapses in AD. BACKGROUND: Decrements in neocortical synapses and cholinergic function occur in AD and correlate with cognitive decline. However, how early in the disease process these changes appear remains unclear. METHODS: An autopsy series of 89 demented patients with pathologically confirmed AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria) and 18 normal control subjects (NC). The AD cases were stratified according to their last Mini-Mental State Examination (MMSE) score prior to death as mild (MMSE = 20; n = 14), moderate (MMSE = 10 to 19; n = 20), severe (MMSE = 1 to 9; n = 29), and very severe (MMSE = 0; n = 26). Midfrontal (MF) synapse density was assessed by dot-immunobinding assay for synaptophysin (Syn), and MF choline acetyltransferase (ChAT) activity was determined using standard protocols. RESULTS: Compared with those in NC, neither Syn nor ChAT was appreciably reduced in patients with mild AD at death. Decline of ChAT was significant only in AD patients who died in the late stages of the disease and was maximal in those who had more severely deteriorated. In contrast, decline of Syn was significant and almost maximal in patients in intermediate or moderate stages. Consequently, the last MMSE score prior to death correlated more strongly with ChAT than Syn when the AD cohort included more impaired patients (r = 0.46 versus 0.40). The reverse occurred when only less impaired patients (MMSE = 10) were included in the analyses (r = 0.28 versus 0.64). There was only a modest correlation between Syn and ChAT activity. CONCLUSIONS: The results imply an asynchronous pattern of decline of synapses and cholinergic activity, with Syn loss preceding ChAT decrements. However, neither MF synapse reduction nor cholinergic dysfunction appears to be an early event in AD.
Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Fibras Colinérgicas/patologia , Sinapses/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Escalas de Graduação PsiquiátricaRESUMO
We sought to delineate differences between alpha7 nicotinic acetylcholine receptor (nAChR) levels in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and age matched controls, as well as the correlations between alpha7 or non-alpha7 nAChR levels and synaptophysin (Syn) or choline acetyltransferase (ChAT) in DLB. Mean bungarotoxin (Bgt) binding was 2.7 - 1.1 for controls, 2.4 +/- 1.0 for AD and 1.4 +/- 0.5 for DLB. There were significant decreases in Bgt binding for the DLB group compared to either controls or AD. Mean epibatidine (Epi) binding was 14.8 +/- 3.2 for controls, 6.3 +/- 3.2 for AD and 7.1 +/- 2.4 fmoles/mg protein for DLB. Epi binding in both the AD and DLB groups was significantly lower than in the controls. Although Syn loss correlated with the decrease in Epi binding in both diseases, declining ChAT levels correlated with Epi binding only in DLB. These data demonstrate a different pattern of nAChR loss in AD and DLB that may, in part, explain some of the differences in the two phenotypes.
Assuntos
Doença de Alzheimer/metabolismo , Doença por Corpos de Lewy/metabolismo , Receptores Nicotínicos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Bungarotoxinas/metabolismo , Bungarotoxinas/farmacologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Colina O-Acetiltransferase/metabolismo , Humanos , Radioisótopos do Iodo , Doença por Corpos de Lewy/patologia , Neurônios/química , Neurônios/enzimologia , Neurônios/patologia , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacologia , Piridinas/metabolismo , Piridinas/farmacologia , Ensaio Radioligante , Receptores Nicotínicos/análise , Trítio , Receptor Nicotínico de Acetilcolina alfa7RESUMO
BACKGROUND: Diagnostic criteria for dementia with Lewy bodies (DLB) are still evolving. No data exist on prospective differentiation of DLB and Alzheimer disease (AD). OBJECTIVE: To examine the clinician's diagnostic accuracy for DLB and analyze factors contributing to false-positive DLB diagnoses. METHODS: A prospective series of 10 patients with clinically diagnosed DLB who came to autopsy was compared with 32 autopsy-confirmed cases of DLB (27 Lewy body variant, 5 diffuse Lewy body disease) and 20 autopsy-confirmed cases of AD (matched on age, sex, education, and initial Mini-Mental State Examination score) with regard to distinguishing and/or confounding clinical features. RESULTS: The clinical diagnostic accuracy for DLB was 50%, with 5 of the 10 patients clinically presumed to have DLB confirmed at autopsy. Of the 5 misdiagnosed cases, 4 had AD and 1 had progressive supranuclear palsy. The misdiagnosed DLB cases who had pure AD had fewer hallucinations (25%) than those with Lewy body variant (63%) or diffuse Lewy body disease (100%) (P = .048); however, an equal amount of spontaneous (in the absence of neuroleptics) extrapyramidal signs was found. There were no differences among groups with regard to daily fluctuations in cognition or falls. Compared with the AD control group, the misdiagnosed DLB cases with pure AD showed significantly more spontaneous extrapyramidal signs (P< or =.02). CONCLUSIONS: The clinician's diagnostic accuracy for DLB was poor. Early spontaneous extrapyramidal signs in AD were associated with false-positive clinical diagnoses of DLB. The distinction between DLB and AD may be improved by greater emphasis on hallucinations.
Assuntos
Doença de Alzheimer/diagnóstico , Doença por Corpos de Lewy/diagnóstico , Entrevista Psiquiátrica Padronizada , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Diagnóstico Diferencial , Reações Falso-Positivas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Competência Profissional , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: To investigate the relationship between apolipoprotein E (APOE) genotype and both cholinergic dysfunction and synapse loss in AD. BACKGROUND: A reduction in neocortical synapses and marked losses in the cholinergic system occur in AD. It has been suggested that the number of APOE epsilon4 alleles is inversely related to choline acetyltransferase (ChAT) activity, thereby influencing cholinergic function. Whether APOE genotype may influence neocortical synapse loss remains unclear. METHODS: An autopsy series of 182 patients with AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria) and 16 normal controls (NC). APOE genotype was determined in blood samples or in postmortem brain tissue. Midfrontal synapse counts (AU/microg) were quantified by a dot-immunobinding assay for synaptophysin (Syn). Midfrontal ChAT activity (nmol/h/100 mg) was assessed using standard assays. RESULTS: Mean midfrontal ChAT activity and Syn were both significantly reduced in patients with AD compared with NC. The relationship between ChAT activity and number of epsilon4 allele copies in AD was complex, with ChAT activity lower in patients with either two or no epsilon4 alleles compared with those with one epsilon4 allele. There was no relationship between APOE genotype and synapse loss in AD. Syn density was almost identical across the three genotypes. CONCLUSIONS: Unlike other studies, we failed to detect a linear relationship between ChAT activity and number of epsilon4 allele copies in the midfrontal cortex of this large sample of patients with AD. Our data also show that the presence of epsilon4 allele does not influence midfrontal synapse loss in AD. This suggests that factors other than APOE genotype may be operative in the decline in midfrontal cholinergic function and synapses seen in AD.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Fibras Colinérgicas/patologia , Sinapses/patologia , Idoso , Idoso de 80 Anos ou mais , Alelos , Apolipoproteína E4 , Autopsia , Colina O-Acetiltransferase/análise , Fibras Colinérgicas/enzimologia , Estudos de Coortes , Lobo Frontal/patologia , Dosagem de Genes , Genótipo , Humanos , Modelos Lineares , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sinapses/enzimologiaRESUMO
OBJECTIVE: To evaluate cholinergic activity in diseases with Lewy bodies (LB; LB variant of AD [LBV], diffuse LB disease [DLBD], and Parkinson's disease [PD]) to determine if 1) AD changes are requisite to cholinergic dysfunction, 2) cholinergic activity declines to the same extent in neocortical and archicortical areas, and 3) cholinergic loss is influenced by APOE genotype. BACKGROUND: Like AD, diseases with LB are associated with decreased choline acetyltransferase (ChAT) activity. Increased APOE epsilon4 allele frequency has been reported in LBV. Whether APOE genotype affects cholinergic function in LBV remains unclear. METHODS: An autopsy series of 182 AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria), 49 LBV, 11 PD, 6 DLBD, and 16 normal control (NC) subjects. APOE genotype and ChAT activity (nmol/h/100 mg) in the midfrontal and hippocampal cortices were determined. RESULTS: Mean midfrontal ChAT activity was markedly reduced in diseases with LB (LBV: 53.3 +/- 39.0; PD: 54.8 +/- 35.7; DLBD: 41.3 +/- 24.8) compared to NC (255.4 +/- 134.6; p < 0.001) and AD (122.6 +/- 78.9; p < 0.05). Among diseases with LB, midfrontal ChAT activity was decreased to a similar extent in patients with (LBV) and without (DLBD and PD) AD pathology. Although mean ChAT activity for LBV was less than half that for AD in the midfrontal cortex, it was similar to that for AD in the hippocampus (LBV: 243.5 +/- 189.7; AD: 322.8 +/- 265.6; p > 0.05). However, hippocampal ChAT activity for both AD and LBV was lower than that for NC (666.5 +/- 360.3; p < 0.001). The epsilon4 allele dosage did not influence midfrontal ChAT activity in LBV. CONCLUSION: Marked losses in midfrontal ChAT activity occur in diseases with LB, independent of coexistent AD changes. A greater midfrontal, as opposed to hippocampal, cholinergic deficit may differentiate LBV from AD. The lack of a relationship between epsilon4 allele dosage and midfrontal ChAT activity suggests that other factors may play a role in its decline in LBV.
Assuntos
Fibras Colinérgicas/enzimologia , Doença por Corpos de Lewy/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Apolipoproteína E4 , Apolipoproteínas E/genética , Colina O-Acetiltransferase/metabolismo , Fibras Colinérgicas/patologia , Lobo Frontal/enzimologia , Lobo Frontal/patologia , Lobo Frontal/fisiopatologia , Genótipo , Hipocampo/enzimologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Doença por Corpos de Lewy/genética , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Reductions in neocortical synapses and cholinergic function occur in patients with Alzheimer disease (AD) and in patients with the Lewy body variant of AD (LBV). The relation between these losses and cognitive decline has been reported frequently in patients with AD but remains unclear for patients with LBV. OBJECTIVES: To investigate the relation between clinical markers of disease progression and choline acetyltransferase activity or synaptic density, measured by synaptophysin (Syn) level, in patients with LBV, and to investigate the relation of these neurochemical markers with one another. METHODS: Brain specimens of 41 patients with autopsy-confirmed (National Institute on Aging criteria for AD) LBV were examined. The last Mini-Mental State Examination and Blessed Information-Memory-Concentration test scores before death were reviewed. Midfrontal synapse counts were quantified by a dot-immunobinding assay for Syn. Choline acetyltransferase activity of the midfrontal cortex was assayed by established protocols. RESULTS: The last Mini-Mental State Examination score before death did not correlate significantly with Syn level (n = 25, r = 0.25, P = .24); however, there was a trend toward significance for the relation between last Mini-Mental State Examination score and choline acetyltransferase activity (n = 39, r = 0.31, P = .05). The last Blessed Information-Memory-Concentration test score did not correlate with either Syn level (n = 24, r = -0.17, P = .44) or choline acetyltransferase activity (n = 39, r = -0.16, P = .33). Finally, there was only a modest correlation between Syn level and choline acetyltransferase activity (n = 25, r = 0.38, P = .06), which did not reach statistical significance. CONCLUSION: Unlike AD, neurochemical markers do not appear to correlate well with cognitive decline in LBV.
Assuntos
Doença de Alzheimer/patologia , Química Encefálica/fisiologia , Transtornos Cognitivos/patologia , Doença por Corpos de Lewy/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Biomarcadores , Encéfalo/enzimologia , Colina O-Acetiltransferase/análise , Transtornos Cognitivos/fisiopatologia , Progressão da Doença , Humanos , Doença por Corpos de Lewy/fisiopatologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Escalas de Graduação Psiquiátrica , Sinaptofisina/análiseRESUMO
The loss of neocortical synapses that occurs in Alzheimer's disease (AD) has been shown to correlate with cognitive decline. In addition, marked losses in the cholinergic system in AD, specifically choline acetyltransferase (ChAT) activity and high affinity presynaptic neuronal nicotinic cholinergic receptors (nAChRs), have also been described. We hypothesized that in AD, the loss of [3H]-ligand binding to nAChRs, which are largely presynaptic, would correlate with changes in two other presynaptic markers: synaptophysin (Syn), a measure of synaptic density, and ChAT activity. The midfrontal (MF) cortex of 36 autopsy confirmed (NIA and CERAD criteria) AD patients (mean death age +/- SD 80.1 +/- 8.4 years) who met NINDS-ADRDA criteria for a clinical diagnosis of probable or possible AD, and 11 nondemented controls (mean death age +/- SD 77.9 +/- 8.0) were examined. Synapse counts were quantified by a dotimmunobinding assay for Syn. ChAT activity was assessed by standard biochemical assays. Nicotinic cholinergic receptor binding was assayed using the high affinity nicotinic agonist [3H]-(+/-)-epibatidine ([3H]-EPI). The mean +/- SD Syn in AD (83.4 +/- 31.9 arbitrary units (AU)/mg protein) was significantly lower than controls (126.1 +/- 19.9, p = 0.0003; t-test). The mean ChAT activity in AD (139.0 +/- 75.6 nmol ACh/hr/100 mg protein) was significantly lower than controls (219.6 +/- 70.8, p = 0.004). The mean [3H]-EPI total binding in AD (6.2 +/- 2.8 fmol/mg protein) was significantly lower than controls (14.8 +/- 3.2; p < 0.0001). Syn correlated with [3H]-EPI binding in AD (r = 0.48, p = 0.006; Pearson) but ChAT did not (r = -0.20, p = 0.34). We conclude that loss of high affinity nAChR binding correlates with loss of synapses in AD. The lack of correlation between [3H]-EPI binding and ChAT activity suggests that the targeted receptor populations may not be located exclusively on cholinergic neurons.
Assuntos
Doença de Alzheimer/metabolismo , Receptores Nicotínicos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Colina O-Acetiltransferase/metabolismo , Transtornos Cognitivos/etiologia , Humanos , Agonistas Nicotínicos/metabolismo , Piridinas/metabolismo , Valores de Referência , Sinapses/ultraestrutura , Sinaptofisina/metabolismoRESUMO
Current treatment approaches in Alzheimer's disease are primarily symptomatic, with the major therapeutic strategy based on acetylcholinesterase inhibition. Alzheimer's disease research should advance over ensuing decade(s) to yield better symptomatic therapies, drugs designed to slow the rate of progression, and disease preventing agents. The next generation of cholinergic agents will include long acting cholinesterase inhibitors with a good safety profile and brain specific muscarinic agonists. The most critical advances in Alzheimer's disease treatment, however, will target slowing of disease progression and prevention of dementia. Therapeutic agents are being developed that interfere with the synthesis, deposition and aggregation of beta-amyloid protein. Clinical trials are presently being conducted with small molecules having nerve growth factor like activity (e.g. AIT-082, cerebrolysin). In addition, estrogen, anti-inflammatory agents (e.g. cyclooxygenase inhibitors) and antioxidant approaches (e.g. vitamin E) are currently being proposed or utilized in disease prevention trials.