RESUMO
Alcohol dependence is associated with a wide array of physical and psychiatric complications and is a major cause of morbidity and mortality worldwide. Recent randomized trials of baclofen, with a total daily dose 30 mg administered in 3 divided doses, have supported its efficacy in reducing craving and promoting abstinence from alcohol. Individual case studies support a possible increased effect at higher doses for treatment-resistant patients. Here, we report on 4 alcohol-dependent patients resistant to standard treatments who responded to higher doses of baclofen ranging from 75 to 125 mg daily. Further research into the use of high-dose baclofen for treatment-resistant alcohol dependence is warranted.
Assuntos
Alcoolismo/tratamento farmacológico , Baclofeno/uso terapêutico , Agonistas dos Receptores de GABA-B/uso terapêutico , Adulto , Consumo de Bebidas Alcoólicas/prevenção & controle , Baclofeno/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Agonistas dos Receptores de GABA-B/administração & dosagem , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Sydenham chorea (SC) is an autoimmune response to group A beta-hemolytic streptococcal infection whose clinical and imaging manifestations usually resolve within 6 months. We used ocular motor analysis and neuropsychologic assessment to investigate residual striatal dysfunction in two individuals with histories of childhood SC whose most recent episodes of chorea had occurred 5 and 17 years before testing. Compared with the performance of 33 age-matched control subjects, both SC subjects showed significantly increased anti-saccade latencies. These findings support recent theories that acute episodes of SC may cause long-term corticostriatal changes in some individuals.
Assuntos
Coreia/fisiopatologia , Tempo de Reação/fisiologia , Movimentos Sacádicos/fisiologia , Adolescente , Aprendizagem por Associação/fisiologia , Feminino , Seguimentos , Humanos , Masculino , Testes Neuropsicológicos , Desempenho Psicomotor/fisiologia , Reconhecimento Psicológico/fisiologia , Estudos Retrospectivos , Adulto JovemRESUMO
Beta-amyloid (Abeta) deposition is one of the neuropathological hallmarks of Alzheimer's disease (AD), Abeta burden can be quantified using (11)C PiB PET. Neuropathological studies have shown that the initial plaques are located in the temporal and orbitofrontal cortices, extending later to the cingulate, frontal and parietal cortices (Braak and Braak, 1997). Previous studies have shown an overlap in (11)C PiB PET retention between AD, mild cognitive impairment (MCI) patients and normal elderly control (NC) participants. It has also been shown that there is a relationship between Abeta deposition and memory impairment in MCI patients. In this paper we explored the variability seen in 15 AD, 15 MCI and 18 NC by modeling the voxel data from spatially and uptake normalized PiB images using principal component analysis. The first two principal components accounted for 80% of the variability seen in the data, providing a clear separation between AD and NC, and allowing subsequent classification. The MCI cases were distributed along an apparent axis between the AD and NC group, closely aligned with the first principal component axis. The NC cases that were PiB(+) formed a distinct cluster that was between, but separated from the AD and PiB(-) NC clusters. The PiB(+) MCI were found to cluster with the AD cases, and exhibited a similar deposition pattern. The primary principal component score was found to correlate with episodic memory scores and mini mental status examination and it was observed that by varying the first principal component, a change in amyloid deposition could be derived that is similar to the expected progression of amyloid deposition observed from post mortem studies.
Assuntos
Envelhecimento , Doença de Alzheimer/diagnóstico por imagem , Amiloide , Transtornos Cognitivos/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Tomografia por Emissão de Pósitrons , Idoso , Doença de Alzheimer/patologia , Compostos de Anilina , Benzotiazóis , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Radioisótopos de Carbono , Transtornos Cognitivos/patologia , Feminino , Humanos , Masculino , Modelos Neurológicos , Testes Neuropsicológicos , Análise de Componente Principal , Compostos Radiofarmacêuticos , TiazóisRESUMO
Anecdotal observations suggest that neurological impairments associated with petrol (gasoline) sniffing resolve with abstinence, although these effects have not been proven empirically. Severe exposure to leaded petrol may induce a lead encephalopathy that extends beyond any acute intoxication and requires emergency hospital treatment. Previously, in chronic petrol sniffers, we showed neurological, saccadic, and cognitive abnormalities that were more severe in petrol sniffers with a history of hospitalization for lead encephalopathy, and that correlated with blood lead levels and the length of time of sniffing petrol. Ex-petrol sniffers showed a qualitatively similar but quantitatively less severe pattern of impairment. Petrol sniffing was stopped completely in one of the study communities by modifying social, occupational, and recreational opportunities. After 2 years, we obtained biochemical and neurobehavioral (neurological, saccade, and cognitive) data from all available participants of the earlier study including 10 nonsniffers and 29 chronic petrol sniffers, with six of these individuals previously receiving hospital treatment for lead encephalopathy. Here, we report that blood lead was reduced and that neurobehavioral impairments improved, and in many cases normalized completely. The most severe petrol-related neurobehavioral impairment was observed among individuals who had longer histories of abuse and higher blood lead levels, and among petrol sniffers with a history of lead encephalopathy. Those with the greatest extent of neurobehavioral impairment showed the greatest degree of improvement with abstinence, but were less likely to recover completely. This is the first direct evidence that neurological and cognitive impairment from chronic petrol sniffing ameliorates with abstinence and may recover completely.
Assuntos
Transtornos Cognitivos/psicologia , Gasolina , Doenças do Sistema Nervoso/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adolescente , Austrália , Encefalopatias/sangue , Encefalopatias/induzido quimicamente , Encefalopatias/psicologia , Criança , Transtornos Cognitivos/sangue , Transtornos Cognitivos/induzido quimicamente , Humanos , Chumbo/sangue , Intoxicação por Chumbo/psicologia , Aprendizagem/efeitos dos fármacos , Masculino , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/induzido quimicamente , Exame Neurológico , Testes Neuropsicológicos , Postura/fisiologia , Reflexo/efeitos dos fármacos , Movimentos Sacádicos , Transtornos Relacionados ao Uso de Substâncias/sangueRESUMO
PURPOSE: The objective of the present study was to describe the prevalence of homonymous visual field defects in a defined older urban population and associations with self-reported stroke. METHODS: Homonymous visual field defects were assessed from screening automated visual field tests of both eyes in 3654 persons aged > or =49 years who were participating in the Blue Mountains Eye Study. This represented 82.4% of eligible residents from a defined area west of Sydney, Australia. A detailed eye examination was performed, and the medical history was taken. Masked grading of visual fields was used to classify the presence of homonymous visual field defects. RESULTS: Homonymous visual field defects were found in 25 persons (prevalence 0.8%, 95% CI 0.5% to 1.1%). Stroke history was reported by 194 participants (5.3%, 95% CI 4.6% to 6.1%). A strong relationship was found between homonymous visual field defects and history of stroke, age-, and sex-adjusted odds ratio (OR) 23.4 (95% CI 9.9 to 55.7). Homonymous field defects were present in 8.3% of all persons who reported experiencing a stroke. Among those with homonymous field defects, 52% reported a history of stroke. Only 2 of 10 persons (20%) with homonymous field defects without a history of stroke reported having stopped driving, whereas 6 of 9 (67%) reporting stroke had stopped driving (P=0.07). Increasing age (OR 1.4 per decade, 95% CI 1.2 to 1.8) was significantly associated with homonymous visual field defects, with adjustment for sex, whereas a history of hypertension (OR 2.7, 95% CI 1.2 to 6.1), diabetes (OR 2.1, 95% CI 1.4 to 3.2), and renal impairment (OR 2.8, 95% CI 1.0 to 8.1) also was associated, with adjustment for age and sex. CONCLUSIONS: This study provides accurate prevalence data for homonymous visual field defects in an older population. About half the participants did not report stroke.
Assuntos
Escotoma/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Campos Visuais , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Fatores de Risco , Distribuição por Sexo , População Urbana , Testes VisuaisRESUMO
BACKGROUND: In Alzheimer disease (AD), tests of "first-order capabilities," such as reaction time or motor ability, might measure central nervous system integrity or disability more reliably than those of abstract, conceptual, or cognitive behavior. Saccade system impairments are present in AD, but their sensitivity or specificity remains unevaluated. OBJECTIVES: To determine sensitivity and specificity of saccade measures for AD, precise impairments in AD, and the relationship between dementia severity and saccade system function. DESIGN: Case-control study comparing saccade system function between patients and control subjects, including correlations between saccade system function and dementia severity in patients and standardized scores examining impairment in individual patients. SETTING: Neuropsychiatric research institute. PARTICIPANTS: Two hundred forty-five healthy volunteers from the general population, and 35 patients with AD referred by memory clinics. Age- and sex-matched controls were compared with patients on random saccade (n = 35), predictive saccade (n = 11), and antisaccade (n = 18) tasks. MAIN OUTCOME MEASURES: Saccade latencies, velocities, and accuracies and antisaccade error rates. Sensitivity, specificity, and predictive positive and negative values were calculated using all control data. RESULTS: Patients had longer and more variable latencies, more hypometric and anticipatory random saccades, and higher antisaccade error rates (P<.01 for all comparisons). The antisaccade error rate correlated with dementia severity (Spearman r = -0.59, P =.02). Antisaccade measures were the most specific (0.70-0.90) and random saccade gain the most sensitive (0.87). CONCLUSIONS: Despite AD group impairment, individual patients function within the control range, reducing the sensitivity and specificity of saccade measures for AD. Longitudinal evaluation may provide more reliable classification.
Assuntos
Doença de Alzheimer/fisiopatologia , Movimentos Sacádicos/fisiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Reação , Sensibilidade e EspecificidadeRESUMO
Kava is an extract from the Piper methysticum Forst. f. plant that has been consumed in the Pacific islands for millennia and more recently, among indigenous populations, in northern Australia and throughout the Western world as an herbal medicine. Through alterations on neuronal excitation, kava induces muscle relaxation, anasthesia, and has anxiolytic properties. There have been several isolated reports of psychotic syndromes, severe choreoathetosis and possible seizures following kava use. However, there is no conclusive evidence that kava interferes with normal cognitive processes. We tested a group of current, ex, and nonkava users among an indigenous population in northern Australia, using saccade and cognitive tests that have proven cross-cultural validity and are sensitive to subtle disruptions of the brain arising from substance abuse or neuropsychiatric illness. Despite collecting data from among the heaviest reported kava drinkers in the world, we found no impairment in cognitive or saccade function in individuals who were currently heavy kava users (and had been for up to 18 years), nor was there any impairment in individuals who had been heavy kava users in the past but had abstained for longer than 6 months. Current and ex-kava users showed a higher rate of kava dermopathy, lower body mass index, lowered blood lymphocytes and, in addition, current kava users showed elevated liver enzymes. While there has recently been increasing concern about potentially fatal liver damage attributed to kava use, we have found no evidence of brain dysfunction in heavy and long-term kava users.
Assuntos
Cognição/efeitos dos fármacos , Kava , Movimentos Sacádicos/efeitos dos fármacos , Adolescente , Adulto , Idoso , Análise de Variância , Cognição/fisiologia , Feminino , Humanos , Kava/efeitos adversos , Masculino , Pessoa de Meia-Idade , Movimentos Sacádicos/fisiologiaRESUMO
Some patients with schizophrenia report that their limbs are under the control of an alien force (motor passivity). This is hypothesised to be due to the dysfunction of an internal self-monitoring system that normally permits distinctions between internally generated and external influences on intentional behaviour. Motor imagery is the mental simulation of specific motor actions and it is based upon the internal representation of intended but unexecuted motor actions. Therefore, the generation of motor imagery should be impaired in schizophrenia characterised by passivity phenomena. The generation of motor imagery was compared using the visually guided pointing task (VGPT) and the Florida praxis imagery questionnaire (FPIQ) between patients with schizophrenia characterised by high levels of passivity symptoms (passivity) and patients without passivity symptoms (no-passivity). In both the passivity and no-passivity groups, the speed of real motor sequences on the VGPT was constrained by the distance of the movement and the width of the target in accordance with Fitts' law. For the no-passivity group, the same relationship was found for imagined movements. However, in the passivity group, imagined movements were not constrained by Fitts' law. The effect of a 2-kg load to the limb performing real or imagined movements on the VGPT was identical in both groups. The duration of imagined movements was slowed although the duration of real movements was unaffected. The FPIQ showed that the passivity group had difficulty answering questions that required them to imagine kinaesthetic aspects of performing simple gestures. These results suggest that passivity phenomena in schizophrenia are associated with a specific inability to represent the timing of motor actions internally. This is consistent with the hypothesis that patients with passivity phenomena have difficulty with maintaining an internal representation of intentional behaviour.
Assuntos
Delusões , Imaginação , Desempenho Psicomotor , Psicologia do Esquizofrênico , Volição , Adulto , Análise de Variância , Feminino , Humanos , Masculino , Análise de Regressão , Estatísticas não ParamétricasRESUMO
BACKGROUND: A toxic encephalopathy (or 'lead encephalopathy') may arise from leaded gasoline abuse that is characterised by tremor, hallucinations, nystagmus, ataxia, seizures and death. This syndrome requires emergency and intensive hospital treatment. METHODS: We compared neurological and cognitive function between chronic gasoline abusers with (n=15) and without (n=15) a history of leaded gasoline encephalopathy, and with controls who had never abused gasoline (n=15). RESULTS: Both groups of chronic gasoline abusers had abused gasoline for the same length of time and compared to controls, showed equivalently elevated blood lead levels and cognitive abnormalities in the areas of visuo-spatial attention, recognition memory and paired associate learning. However, where gasoline abusers with no history of leaded gasoline encephalopathy showed only mild movement abnormalities, gasoline abusers with a history of leaded gasoline encephalopathy showed severe neurological impairment that manifest as higher rates of gait ataxia, abnormal rapid finger tapping, finger to nose movements, dysdiadochokinesia and heel to knee movements, increased deep tendon reflexes and presence of a palmomental reflex. CONCLUSIONS: While neurological and cognitive functions are disrupted by chronic gasoline abuse, leaded gasoline encephalopathy is associated with additional and long-lasting damage to cortical and cerebellar functions.
Assuntos
Transtornos Cognitivos/etiologia , Gasolina/efeitos adversos , Gasolina/análise , Chumbo/análise , Síndromes Neurotóxicas/etiologia , Administração por Inalação , Adolescente , Adulto , Atenção/efeitos dos fármacos , Transtornos Cognitivos/diagnóstico , Feminino , Humanos , Chumbo/sangue , Masculino , Transtornos da Memória/induzido quimicamente , Testes Neuropsicológicos , Síndromes Neurotóxicas/diagnóstico , Transtornos da Percepção/induzido quimicamente , Percepção Espacial/efeitos dos fármacos , Percepção Visual/efeitos dos fármacosRESUMO
Although some motor functions of the basal ganglia have been well studied, the oculomotor functions are not well established. We studied eye movements in patients with Parkinson's disease (PD) undergoing pallidotomy to assess the role of the globus pallidus interna (GPi) in oculomotor control. Horizontal visually guided, gap and predictive saccades as well as ocular fixation were studied in patients with advanced PD before and 1 month after unilateral pallidotomy, and in healthy controls on two occasions 1 month apart. There was no difference in saccadic latency or accuracy, the number of saccadic anticipations or the ability to generate predictive saccades between the two assessments for either patients or controls. The number and amplitude of square wave jerks during ocular fixation however increased significantly in patients after pallidotomy. The results imply altered function of frontal or prefrontal cortical regions involved in ocular fixation resulting from a disruption to inhibitory pallidal influences on thalamocortical projections. The posteroventral GPi however appears not to be involved in externally controlled or predictive saccadic function.
Assuntos
Fixação Ocular/fisiologia , Globo Pálido/cirurgia , Doença de Parkinson/cirurgia , Movimentos Sacádicos/fisiologia , Técnicas Estereotáxicas/efeitos adversos , Idoso , Feminino , Lateralidade Funcional , Globo Pálido/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Desempenho Psicomotor , Tempo de Reação , Valores de ReferênciaRESUMO
AIMS: In a previous study, neurological and cognitive deficits reflecting central nervous system (CNS) disruption from chronic inhalant abuse showed substantial recovery after 2 years' abstinence. Functional recovery was progressive, with recovery rates dependent on the degree of impairment prior to abstinence, and severity and duration of initial abuse. Persistent deficits occurred in those with previous 'lead encephalopathy' from leaded petrol abuse. The current study examined recovery in the same cohort 15 years after baseline. DESIGN: Prospective cohort design. SETTING: Two remote Aboriginal communities in Arnhem Land, Australia. PARTICIPANTS: Using baseline group classifications, 27 healthy controls, 60 ex-chronic inhalant abusers and an additional 17 with previous lead encephalopathy were assessed. MEASUREMENTS: Standard neurological, ocular-motor and cognitive functions and blood lead levels. FINDINGS: Chronic (non-encephalopathic) inhalant abusers showed elevated blood lead levels and abnormal scores on most tasks at baseline. At 2 years' abstinence, blood lead was reduced but remained elevated and most scores had normalized. By 15 years, blood lead and all performance scores were equivalent to healthy controls for this group (P > 0.05). The encephalopathic group was more severely impaired on all scores at baseline and showed little improvement, if any, across all tests after both 2 and 15 years' abstinence. Blood lead for this group declined, and was not significantly different to controls after 15 years. CONCLUSIONS: Some inhalant abusers experience severe and persistent neurological deficits, suggesting irrecoverable damage attributable to lead encephalopathy. In the absence of this encephalopathy long-term abstinence from inhalants may allow recovery of normal brain function.
Assuntos
Doenças do Sistema Nervoso Central/etiologia , Transtornos Cognitivos/etiologia , Abuso de Inalantes/psicologia , Adulto , Doenças do Sistema Nervoso Central/etnologia , Doença Crônica , Transtornos Cognitivos/etnologia , Seguimentos , Humanos , Abuso de Inalantes/etnologia , Masculino , Havaiano Nativo ou Outro Ilhéu do Pacífico/etnologia , Northern Territory/etnologia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Estudos Prospectivos , Tempo de Reação/efeitos dos fármacos , Reflexo/efeitos dos fármacos , Movimentos Sacádicos/efeitos dos fármacosRESUMO
Homonymous visual field defects (HVFDs) are among the most common disorders that occur in brain damage, particularly after stroke. They lead to considerable disabilities, particularly with reading and visual exploration. A variety of different approaches, including optical aids and visual training techniques, have been examined for the rehabilitation of these HVFDs. Despite the considerable ingenuity that has been applied and anecdotal evidence that has accumulated, rigorously controlled trials that clearly establish efficacy of any method are lacking.
Assuntos
Hemianopsia/reabilitação , Campos Visuais , Dano Encefálico Crônico/reabilitação , Humanos , Leitura , Ensino de Recuperação , Auxiliares Sensoriais/estatística & dados numéricos , Visão BinocularRESUMO
We report an outbreak of a "rash" syndrome in patients attending methadone clinics in New South Wales. It presents with a pruritic, exanthematous or purpuric rash involving the trunk, limbs, palms and soles, which develops over a week and proceeds in most patients to desquamation (mainly of palms and soles) persisting for 3-4 weeks. Mucosae are not involved, and patients are generally systemically well. To date, the rash has affected 22% of 316 patients attending one methadone clinic in western Sydney, as well as patients in clinics elsewhere in Sydney and rural NSW. The aetiology is as yet unknown.
Assuntos
Surtos de Doenças , Exantema/epidemiologia , Metadona , Centros de Tratamento de Abuso de Substâncias , Adulto , Exantema/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New South Wales/epidemiologiaRESUMO
Results from recent investigations of behavioral and genetic outcomes in older people with mild cognitive impairment (MCI) have been inconsistent. These conflicting results may be attributed to between-study differences in the diagnostic systems employed, as well as the use of unreliable neuropsychological measures. We investigated behavioral and genetic outcomes in older people classified as having MCI according to novel criterion that required evidence of cognitive impairment on three consecutive neurological/neuropsychological assessments. One hundred and seventy four healthy older people were evaluated semi-annually for 12 months. Of these, 23 subjects were rated as having MCI on three consecutive assessments and were compared to 23 matched control subjects. Subjects rated as impaired on one or two of the three semi-annual assessments were also identified. MCI and matched control groups were compared on a range of behavioral measures. The prevalence of the Apolipoprotein E4 (ApoE4) allele was determined in all groups, and estimates of anxiety and depressive symptomatology were obtained. Subjective cognitive complaints were also assessed. Many subjects were classified as impaired on one or two assessments, however relatively few (n = 23) recorded consistent cognitive deficits. The most severe impairment observed in MCI subjects was on a test of pattern-location associative learning, however MCI subjects did not have insight into this impairment. The prevalence of the ApoE4 allele was not different between matched control and MCI groups. These results indicate that individuals with MCI can be differentiated from healthy older people and older people with transient cognitive impairments, but that such differentiation requires serial assessment of cognitive function.
Assuntos
Comportamento , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Idoso , Apolipoproteínas/sangue , Apolipoproteínas/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Testes Neuropsicológicos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Kava is an extract from the Piper methysticum Forst. f. plant that has social and spiritual importance in Pacific islands societies. Herbal remedies that contain kava are used for the psychiatric treatment of anxiety and insomnia. Laboratory studies have found only subtle, if any, changes on cognitive or motor functions from the acute effects of consuming small clinical doses of kava products. Intoxication from recreational doses of kava has not been studied. The performance of individuals intoxicated from drinking kava (n=11) was compared with a control group (n=17) using saccade and cognitive tests. On average, intoxicated individuals had consumed 205 g of kava powder each (approximately 150 times clinical doses) in a group session that went for 14.4 h and ended 8 h prior to testing. Intoxicated kava drinkers showed ataxia, tremors, sedation, blepharospasm and elevated liver enzymes (GGT and ALP), together with saccadic dysmetria, saccadic slowing and reduced accuracy performing a visual search task that only became evident as the task complexity increased. Kava intoxication is characterized by specific abnormalities of movement coordination and visual attention but normal performance of complex cognitive functions. Saccade abnormalities suggest disruption of cerebellar and GABAergic functions.
Assuntos
Cognição/efeitos dos fármacos , Kava/química , Movimentos Sacádicos/efeitos dos fármacos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
OBJECTIVE: Screening of normal older persons for progressive memory decline is a worthwhile strategy in the pursuit of the earliest possible stages of pre-clinical Alzheimer's disease (AD) or mild cognitive impairment (MCI). Reliable tests are needed to both detect MCI and measure the natural history of decline over months rather than years. We aimed to detect memory decline over 1 year in a group of older individuals with well-characterised amnestic MCI. METHODS: The continuous learning task (CLT) from the CogState test battery was administered 8 times in 12 months to 15 individuals with MCI and 35 controls matched for age, education, IQ and gender. All subjects were recruited from an ongoing aging study. The rate of change in CLT performance over the year was compared between groups and also compared to that detected with a word list learning task and a computerised paired associate learning task. RESULTS: At baseline, memory performance in the amnestic MCI group was significantly worse than controls on all memory tests. However, at 12 months the magnitude of the difference between the groups had increased significantly on the CLT due to decline in memory accuracy in the MCI group. No decline over 12 months was detectable on the routine memory tests. CONCLUSIONS: Subtle memory decline is detectable in amnestic MCI using reliable and sensitive tests of memory. Such measures may assist in the early identification of AD and also in trials of putative disease-modifying therapies to be conducted over as little as 12 months.