The memory engram: beginning the search.

Some of the earliest conceptual milestones in memory research with relevance to the physical means through which its preservation is made possible, namely, the 'memory trace' or 'engram', are analysed in this study. The fundamental notions were laid down by Platon and Aristoteles. While Platon regarded memory as an imprint on a 'wax block' in the immortal soul, Aristoteles considered memory a modification in the mortal soul, imprinted like a cast at birth time. The Roman orators were interested in mnemotechnics, and Cicero is credited for the term 'trace' (vestigium) used for the first time. Much later, Descartes described the (memory) 'trace' (trace), linking psychic, and physical processes. Finally, Semon posited innovative concepts and terms centralized by the 'engram' (Engramm). The search of this important question, which begun about two and a half millennia ago, continues in focus, as can be seen through the growing rate of published papers on the subject.

Alguns dos marcos conceituais iniciais na pesquisa de memória, com relevância para o meio físico, pelo qual a preservação desta é possibilitada, a saber, o 'traço de memória' ou 'engrama', são aqui analisados. As noções fundamentais foram formuladas por Platão e Aristóteles. Enquanto Platão via a memória como uma impressão em um 'bloco de cera' na alma imortal, Aristóteles considerava a memória uma modificação na alma mortal, impressa como um molde ao nascimento. Os oradores romanos tinham interesse em mnemotécnica e Cícero tem o crédito de ter usado o termo 'traço' (vestigium) pela primeira vez. Mais tarde, Descartes descreveu o 'traço' (trace) (de memória), ligando processos psíquicos e físicos. Finalmente, Semon propôs conceitos e termos inovadores centralizados pelo 'engrama' (Engramm). A busca dessa importante questão, que começou aproximadamente há dois milênios e meio, continua em foco, como pode ser visto pelo ritmo crescente de artigos publicados sobre o assunto.

An Evolution-Based Model of Causation for Aging-Related Diseases and Intrinsic Mortality: Explanatory Properties and Implications for Healthy Aging.

Aging-related diseases are the most prevalent diseases in advanced countries nowadays, accounting for a substantial proportion of mortality. We describe the explanatory properties of an evolution-based model of causation (EBMC) applicable to aging-related diseases and intrinsic mortality. The EBMC takes the sufficient and component causes model of causation as a starting point and develops it using evolutionary and statistical theories. Genetic component causes are classified as "early-onset" or "late-onset" and environmental component causes as "evolutionarily conserved" or "evolutionarily recent." Genetic and environmental component causes are considered to occur as random events following time-to-event distributions, and sufficient causes are classified according to whether or not their time-to-event distributions are "molded" by the declining force of natural selection with increasing age. We obtain for each of these two groups different time-to-event distributions for disease incidence or intrinsic mortality asymptotically (i.e., for a large number of sufficient causes). The EBMC provides explanations for observations about aging-related diseases concerning the penetrance of genetic risk variants, the age of onset of monogenic vs. sporadic forms, the meaning of "age as a risk factor," the relation between frequency and age of onset, and the emergence of diseases associated with the modern Western lifestyle. The EBMC also provides an explanation of the Gompertz mortality model at the fundamental level of genetic causes and involving evolutionary biology. Implications for healthy aging are examined under the scenarios of health promotion and postponed aging. Most importantly from a public health standpoint, the EBMC implies that primary prevention through changes in lifestyle and reduction of environmental exposures is paramount in promoting healthy aging.

Advancing the Genetics of Lewy Body Disorders with Disease-Modifying Treatments in Mind.

In this article, a caveat for advancing the genetics of Lewy body disorders is raised, given the nosological controversy about whether to consider dementia with Lewy bodies (DLB) and Parkinson's disease (PD) as one entity or two separate entities. Using the framework of the sufficient and component causes model of causation, as further developed into an evolution-based model of causation, it is proposed that a disease of complex etiology is defined as having a relatively high degree of sharing of the component causes (a genetic or environmental factor), that is, a low degree of heterogeneity of the sufficient causes. Based on this definition, only if the sharing of component causes within each of two diseases is similar to their combined sharing can lumping be warranted. However, it is not known whether the separate and combined sharing are similar before conducting the etiologic studies. This means that lumping DLB and PD can be counterproductive as it can decrease the ability to detect component causes despite the potential benefit of conducting studies with larger sample sizes. In turn, this is relevant to the development of disease-modifying treatments, because non-overlapping causal genetic factors may result in distinct pathogenetic pathways providing promising targets for interventions.

Echoes of William Gowers's concept of abiotrophy.

Among William Gowers's many contributions to neurology, the concept of abiotrophy ("an essential failure of vitality") has been relatively overlooked. In this article, we review the echoes of Gowers's concept in neurology, ophthalmology, and aging research. We also argue that abiotrophy is broader than both heredodegeneration and neurodegeneration. Unlike the common view that it simply means premature aging, abiotrophy currently can be understood as a progressive degenerative process of a mature specialized tissue, which is nonsynchronous with normal aging and may affect organs or systems early in life, resulting from the age-dependent effects of genetic mutations or variants, even if environmental factors may also causally contribute to the process. Although the term has largely fallen out of use, there are likely to be everlasting echoes of Gowers's concept, through which he is to be considered a source of the modern thinking about the etiology and nosology of neurological diseases.

Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design.

BACKGROUND: TNK-S2B, an innovative, randomized, seamless phase II/III trial of tenecteplase versus rt-PA for acute ischemic stroke, terminated for slow enrollment before regulatory approval of use of phase II patients in phase III. PURPOSE: (1) To review the trial design and comprehensive type I error rate simulations and (2) to discuss issues raised during regulatory review, to facilitate future approval of similar designs. METHODS: In phase II, an early (24-h) outcome and adaptive sequential procedure selected one of three tenecteplase doses for phase III comparison with rt-PA. Decision rules comparing this dose to rt-PA would cause stopping for futility at phase II end, or continuation to phase III. Phase III incorporated two co-primary hypotheses, allowing for a treatment effect at either end of the trichotomized Rankin scale. Assuming no early termination, four interim analyses and one final analysis of 1908 patients provided an experiment-wise type I error rate of <0.05. RESULTS: Over 1,000 distribution scenarios, each involving 40,000 replications, the maximum type I error in phase III was 0.038. Inflation from the dose selection was more than offset by the one-half continuity correction in the test statistics. Inflation from repeated interim analyses was more than offset by the reduction from the clinical stopping rules for futility at the first interim analysis. LIMITATIONS: Design complexity and evolving regulatory requirements lengthened the review process. CONCLUSIONS: (1) The design was innovative and efficient. Per protocol, type I error was well controlled for the co-primary phase III hypothesis tests, and experiment-wise. (2a) Time must be allowed for communications with regulatory reviewers from first design stages. (2b) Adequate type I error control must be demonstrated. (2c) Greater clarity is needed on (i) whether this includes demonstration of type I error control if the protocol is violated and (ii) whether simulations of type I error control are acceptable. (2d) Regulatory agency concerns that protocols for futility stopping may not be followed may be allayed by submitting interim analysis results to them as these analyses occur.

Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial.

BACKGROUND AND PURPOSE: Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA. METHODS: The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a "best" dose of tenecteplase to carry forward. Once a "best" dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. RESULTS: The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established. CONCLUSION: This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.

Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial. METHODS: We designed and implemented a multicenter trial with an adaptive, two-stage, bias-adjusted, randomized, placebo-controlled, double-blind, Phase II design (n = 185). The primary outcome in both stages was a decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo. RESULTS: Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an accompanying prespecified sensitivity test, and further supplementary analyses. Prespecified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns. INTERPRETATION: CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial.

The memory engram: beginning the search / O engrama de memória: começando a busca

ABSTRACT Some of the earliest conceptual milestones in memory research with relevance to the physical means through which its preservation is made possible, namely, the 'memory trace' or 'engram', are analysed in this study. The fundamental notions were laid down by Platon and Aristoteles. While Platon regarded memory as an imprint on a 'wax block' in the immortal soul, Aristoteles considered memory a modification in the mortal soul, imprinted like a cast at birth time. The Roman orators were interested in mnemotechnics, and Cicero is credited for the term 'trace' (vestigium) used for the first time. Much later, Descartes described the (memory) 'trace' (trace), linking psychic, and physical processes. Finally, Semon posited innovative concepts and terms centralized by the 'engram' (Engramm). The search of this important question, which begun about two and a half millennia ago, continues in focus, as can be seen through the growing rate of published papers on the subject.

RESUMO Alguns dos marcos conceituais iniciais na pesquisa de memória, com relevância para o meio físico, pelo qual a preservação desta é possibilitada, a saber, o 'traço de memória' ou 'engrama', são aqui analisados. As noções fundamentais foram formuladas por Platão e Aristóteles. Enquanto Platão via a memória como uma impressão em um 'bloco de cera' na alma imortal, Aristóteles considerava a memória uma modificação na alma mortal, impressa como um molde ao nascimento. Os oradores romanos tinham interesse em mnemotécnica e Cícero tem o crédito de ter usado o termo 'traço' (vestigium) pela primeira vez. Mais tarde, Descartes descreveu o 'traço' (trace) (de memória), ligando processos psíquicos e físicos. Finalmente, Semon propôs conceitos e termos inovadores centralizados pelo 'engrama' (Engramm). A busca dessa importante questão, que começou aproximadamente há dois milênios e meio, continua em foco, como pode ser visto pelo ritmo crescente de artigos publicados sobre o assunto.

The relationship of Parkinson disease with aging.

Twentieth-century hypotheses attributing a substantive role to aging in Parkinson disease (PD) pathogenesis have been countered by evidence from clinical, pathological, and biochemical investigations. However, age influences the clinical progression of PD. Several studies have demonstrated that advancing age is associated with a faster rate of motor progression, decreased levodopa responsiveness, more severe gait and postural impairment, and more severe cognitive impairment and the development of dementia in patients with PD. A model for the relationship between PD and aging is proposed that incorporates the following 3 elements: (1) There occurs a superposition of a topographic gradient of neuronal loss in brainstem and basal forebrain structures related to the disease process and an aging-related temporal gradient. (2) While PD is a chronic progressive disorder, the most important determinant of clinical progression is advancing age rather than disease duration. (3) The effects of the disease process and aging on nondopaminergic structures involve a biologic interaction. The model implies that understanding the degenerative process in nondopaminergic structures in PD as it relates to molecular mechanisms accompanying the aging of the nervous system may create opportunities for interventions affecting the clinical progression of the disease.

The carotid and vertebral arteries discovery ­ initial findings / A descoberta das artérias carótidas e vertebrais ­ achados iniciais

The studies on the vascular system, including the cervicocephalic arteries (carotid and vertebral arteries), present a long trajectory, having their deep roots in the far past, considering the Western authors, having as representatives the Greek sages Alcmaeon, Diogenes, Hippocrates, Aristoteles, Rufus, and Galenus. They produced pivotal knowledge dissecting mainly cadavers of animals, and established solid bases for the later generations of scholars. The information assembled from these six authors makes it possible to build a quite clear picture of the vascular system, here specifically focused on the cervicocephalic arteries, and mainly of the extracranial segments. Thus, the carotid system became fairly well identified, origin, course, and name, as well as the origin of the still unnamed arteries running through the orifices of the transversal processes of the cervical vertebrae, and entering into the cranium. Almost all that was then known about human anatomy, since this period, and then throughout the Middle Ages, was extrapolated from animal dissections. This state of affairs was maintained until the 14th century, when human corpses dissections were again allowed.

Os estudos do sistema vascular, incluindo as artérias cervicocefálicas (artérias carótidas e vertebrais), apresentam um longo percurso, tendo suas raízes profundas no passado distante, considerando os autores ocidentais, tendo como representantes os doutos gregos Alcméon, Diógenes, Hipócrates, Aristóteles, Rufus e Galenus. Eles produziram conhecimento pivotal, dissecando principalmente cadáveres de animais e estabelecendo bases sólidas para as gerações futuras de estudiosos. A informação reunida desses seis autores permite construir um quadro bastante claro do sistema vascular, aqui focado especificamente nas artérias cervicocefálicas e principalmente nos seus segmentos extracranianos. Assim, o sistema carotídeo ficou bastante bem identificado, origem, trajeto e nome, assim como a origem das ainda não nomeadas artérias que percorrem os orifícios dos processos transversos das vértebras cervicais e entrando no crânio. Quase tudo que era conhecido sobre anatomia humana, desde esse período, e depois ao longo da Idade Média, foi extrapolado a partir de dissecções de animais. Esse estado de coisas foi mantido até o século 14, quando a dissecção de cadáveres humanos foi novamente permitida.

The arterial circle described by Willis, and the contribution of his successors (History of Neurology) / O círculo arterial descrito por Willis e a contribuição de seus sucessores (História da Neurologia)

The description of the base of the human brain and its arteries that form a circle or polygon, as described and depicted by Thomas Willis and collaborators (1664), and that received his name ­ 'circle of Willis', has a long history, where many renowned preceding authors are included ­ the pre-Willisian anatomists, among which the names of Giulio Casserio (1627), Johann Vesling (1647) e Johann Jakob Wepfer (1658) deserve to be highlighted. However, despite a complete description and correct depiction of the arterial components of the circle, their naming lagged behind. After Willis, a large number of renowned authors ­ the post-Willisian anatomists, studied this formation further. This period begun with a poor contribution of Isbrand van Diemerbroeck (1672). Next appeared authors who provided names that became ephemeral, followed by those who presented designations that would remain permanently. Among the latter must be cited initially Joseph Lieutaud (1742) and Albrecht von Haller (1756), followed by Xavier Bichat with his posthumous work (1803), and finally the definitive names being established by Jean Cruveilhier (1834), this period closing with Henry Gray's book (1858), who consolidated the knowledge on the subject.

A descrição da base do cérebro humano e das artérias que formam um círculo ou polígono, como descrito e ilustrado por Thomas Willis e colaboradores (1664) e que recebeu seu nome - 'círculo de Willis', tem uma longa história, onde constam muitos autores de renome que o precederam ­ os anatomistas pré-Willisianos, entre os quais os nomes de Giulio Casserio (1627), Johann Vesling (1647) e Johann Jakob Wepfer (1658) merecem ser destacados. Entretanto, apesar da descrição completa e ilustração correta dos componentes arteriais do círculo, a denominação dos mesmos ficou atrasada. Após Willis, um grande número de autores renomados ­ os anatomistas pós-Willisianos, continuaram a estudar essa formação. Este período começou com uma contribuição pobre de Isbrand van Diemerbroeck (1672). A seguir apareceram autores que proveram nomes que se mostraram efêmeros, seguidos por aqueles que apresentaram designações que iriam permanecer de modo permanente. Entre os últimos devem ser citados inicialmente Joseph Lieutaud (1742) e Albrecht von Haller (1756), seguidos por Xavier Bichat com sua obra póstuma (1803), e finalmente, os nomes definitivos sendo estabelecidos por Jean Cruveilhier (1834), o período fechando com o livro de Henry Gray (1858), que consolidou o conhecimento sobre o tema.

The arterial circle described by Willis, and the contribution of his predecessors / O círculo arterial descrito por Willis e a contribuição de seus predecessores

The description of arteries at the base of the human brain forming an 'arterial circle', named after Thomas Willis, has had a long history after the restoration of human dissection, partly due to the studies of many outstanding anatomists that preceded Willis. He provided, with the collaboration of Richard Lower and Christopher Wren, the first incontestable complete description, as recognized nowadays, accompanied by a superb illustration. Additionally, he presented an explanation for its meaning, indicating for the first time the functional significance of this structure, in health and disease. However, it should be recognized that the initial studies of the arteries of the base of the human brain by Willis' predecessors, as well as those from ancient times, despite their fragmentary descriptions, were certainly pivotal in paving the way for further and more detailed knowledge of this vascular formation.

A descrição das artérias da base do cérebro humano, formando um 'círculo arterial', designado com o nome de Thomas Willis, tem uma longa história após o restauro de dissecções humanas, em parte devido aos estudos de muitos anatomistas de renome que precederam Willis. Ele proveu, com a colaboração de Richard Lower e Christopher Wren, a primeira descrição completa e incontestável, assim como a reconhecida atualmente, acompanhada por uma ilustração soberba. Adicionalmente, apresentou uma explicação quanto ao seu significado, indicando pela primeira vez a importância funcional dessa estrutura, na saúde e na doença. Entretanto, deve ser reconhecido que os estudos iniciais das artérias da base do cérebro humano pelos predecessores de Willis, assim como os de tempos antigos, apesar de suas descrições fragmentárias, certamente foram fulcrais na pavimentação do caminho para o conhecimento mais avançado e detalhado dessa formação vascular.

Contribution of aging to the severity of different motor signs in Parkinson disease.

BACKGROUND: Evidence does not support the view that Parkinson disease (PD) represents an accelerated aging process; however, the additional contribution of aging to the severity of different motor signs in patients with PD is not known. This knowledge may have implications for clinical trials of neuroprotective agents in PD. OBJECTIVE: To investigate the contribution of aging to the severity of the different motor signs of idiopathic PD. SETTING: Center for Parkinson Disease and Other Movement Disorders of the Columbia University Medical Center and a neurology clinic that primarily served individuals from the Washington Heights-Inwood community in New York City. PATIENTS: Sample of patients with a wide range of disease duration and age. DESIGN: Cross-sectional clinic-based study. Patients with PD were evaluated using the Unified Parkinson Disease Rating Scale (UPDRS). The total UPDRS motor score was divided into 6 motor domains (tremor, rigidity, bradykinesia, facial expression, speech, and axial impairment) and 2 subscores that represented predominantly dopaminergic (subscore A: tremor, rigidity, bradykinesia, and facial expression) and nondopaminergic (subscore B: speech and axial impairment) deficiency. Analyses were performed using linear regression models with the UPDRS motor domains and subscores as the outcomes. The variation (adjusted R(2)) of the outcome variables explained by the inclusion of disease duration in the models, adjusting for sex, years of education, levodopa dosage, and use of other antiparkinsonian medications, was calculated. The additional variation explained by adding age at examination to the models was used to gauge the contribution of aging to each motor domain and subscore of the UPDRS. RESULTS: A total of 451 patients participated in the study. Mean age at examination was 62.0 years (SD, 12.6 years; median, 62.0 years; range, 18-93 years), and mean disease duration was 7.2 years (SD, 5.9 years; median, 5.6 years; range, 0.1-41.6 years). The additional variation of the outcome variable explained by including age in the models was higher for subscore B (14.3%; 95% confidence interval [CI], 9.9%-20.4%) than subscore A (4.7%; 95% CI, 2.0%-9.1%). Among the 6 motor domains, the additional variation of the outcome variable explained by including age in the models was highest for axial impairment (13.6%; 95% CI, 9.4%-19.6%). CONCLUSION: Axial (gait and postural) impairment in PD may result from the combined effect of the disease and the aging process on nondopaminergic subcortical structures.

Body mass index in essential tremor.

BACKGROUND: The pathogenesis of essential tremor (ET) is unknown, but it could be neurodegenerative. Weight loss has been observed in patients with neurodegenerative diseases. OBJECTIVES: To compare body mass index (BMI) (calculated as weight in kilograms divided by the square of height in meters) in ET cases and controls and to determine whether BMI is correlated with tremor severity and duration. METHODS: Patients with ET were ascertained from the Neurological Institute of New York, New York, NY. Control subjects were recruited from 2 studies at the same institution. Height and weight were measured and BMI was calculated. Dietary data were collected using a Willett Semi-Quantitative Food-Frequency Questionnaire. Tremor severity was assessed using a clinical scale and the Klove Matthews Motor Steadiness Battery. RESULTS: The 78 cases and 242 controls were of similar age. Mean (SD) BMI in cases vs controls was 26.5 (5.0) vs 28.2 (4.8) (P =.008). This difference remained significant in an unconditional linear regression analysis that adjusted for age, sex, ethnicity, and years of education (P =.02). Mean daily caloric intake was similar in cases and controls. In cases, BMI was negatively correlated with both measures of tremor severity (r = -0.22; P =.05 and r = -0.24; P =.03) and with tremor duration (r = -0.22; P =.05). CONCLUSIONS: The BMI was lower in ET cases than in controls, and lower BMI was associated with disease of greater severity and longer duration. Caloric intake did not differ between groups, suggesting that lower BMI is not due to a reduction in calories. Lower BMI may be due to increased energy expenditure in ET.

Lack of familial aggregation of Parkinson disease and Alzheimer disease.

OBJECTIVE: To investigate the risk of Alzheimer disease (AD) in first-degree relatives of patients with Parkinson disease (PD) compared with first-degree relatives of controls. DESIGN: Case-control study, family history method, and reconstructed cohort approach. METHODS: Probands with PD without dementia and control probands, matched by age strata, sex, and ethnicity, were examined in person and enrolled without knowledge of family history of PD and other neurological disorders. Disease status in first-degree relatives of probands with PD and control probands was ascertained through a structured family history interview administered to the proband and a second informant (self-report or another informant). Cox proportional hazards models with double-censoring techniques for missing information on age of onset of AD were used to analyze the risk of AD in first-degree relatives of patients with PD compared with first-degree relatives of controls. RESULTS: Four hundred eighty-seven probands with PD and 409 control probands provided family history information on 4819 first-degree relatives older than 30 years (2534 relatives of probands with PD and 2285 relatives of control probands). One hundred thirteen first-degree relatives (2.3%; 61 relatives [2.4%] of patients with PD and 52 relatives [2.3%] of controls) were diagnosed with AD. The risk of AD was not increased in relatives of patients with PD compared with relatives of controls (hazard ratio, 1.1; 95% confidence interval, 0.7-1.6; P =.65). Similarly, no significantly increased risk of AD was observed when comparing relatives of patients with early-onset (< or =50 years) and late-onset (>50 years) PD with relatives of controls. CONCLUSION: The lack of familial aggregation of PD and AD does not support the hypothesis of major shared genetic contributions to the etiology of the 2 most common neurodegenerative disorders.

The Saitohin 'Q7R' polymorphism and tau haplotype in multi-ethnic Alzheimer disease and Parkinson's disease cohorts.

In a multi-ethnic cohort we analyzed the Saitohin (STH) gene 'Q7R' polymorphism in 200 late-onset Alzheimer's disease cases (LOAD), 60 Parkinson's disease cases with dementia (PDD), 84 Parkinson's disease cases without dementia and 458 controls. We found no significant differences in genotype or allele frequencies when LOAD or PD cases were compared to controls. Ethnic differences in STH genotype frequencies for cases and controls were observed and these were statistically significant (cases n=344, P<0.03; controls n=458, P<0.001). We also observed a trend in non-Hispanic white PDD cases with the STH 'QQ' (Tau H1/H1) genotype increased (76%) compared to PD cases without dementia (61.7%) and controls (56.6%); however, this difference was not statistically significant (PDD vs. controls OR 2.1; 95% CI: 0.8-5.8, P=0.2).

Diagnosing Parkinson's disease using videotaped neurological examinations: validity and factors that contribute to incorrect diagnoses.

Field work is commonly required in movement disorders research. Sending neurologists into the field can be logistically challenging and costly. Alternatively, neurological examinations may be videotaped and reviewed later. There is little knowledge of the validity of the videotaped neurological examination in the diagnosis of Parkinson's disease (PD). We examined the validity of the videotaped Unified Parkinson's Disease Rating Scale (UPDRS) motor examination in the diagnosis of PD, and sought to determine which factors are associated with incorrect diagnoses. PD patients and controls were enrolled in a familial aggregation study between August of 1998 and June of 2000, and as part of that study each was examined by a physician who performed an in-person UPDRS motor examination. Each also underwent a second, videotaped UPDRS motor examination. Based on the review of this videotape, a neurologist, who was blinded to the previous clinical diagnosis, assigned a diagnosis of PD or normal. A total of 211 of 231 PD patients (sensitivity = 91.3%), and 170 of 172 controls (specificity = 98.8%) were correctly identified based on the videotape. True positives had a higher mean rest tremor score (1.7 vs. 0.3; P < 0.001), action tremor score (0.9 vs. 0.3; P < 0.001), bradykinesia score (11.2 vs. 7.4; P = 0.02), and disease of longer mean duration (8.9 vs. 5.8 years; P = 0.001) than false negatives. False negatives did not differ from true positives in terms of age, total dose of levodopa, Hoehn and Yahr score, or rigidity, gait and posture, or facial masking scores (each assessed during the in-person examination). The videotaped UPDRS motor examination is a useful means of diagnosing PD and provides an alternative approach for the diagnosis of PD in field studies. A limitation is that patients with milder PD of shorter duration may not be recognized as PD.

Memory and executive function impairment predict dementia in Parkinson's disease.

We analyzed the association of neuropsychological test impairment at baseline with the development of dementia in idiopathic Parkinson's disease (PD) patients. A cohort of nondemented PD patients from northern Manhattan, NY was followed annually with neurological and neuropsychological evaluations. The neuropsychological battery included tests of verbal and nonverbal memory, orientation, visuospatial ability, language, and abstract reasoning. The association of baseline neuropsychological tests scores with incident dementia was analyzed using Cox proportional hazards models. The analysis controlled for age, gender, education, duration of PD, and the total Unified Parkinson's Disease Rating Scale motor score at baseline. Forty-five out of 164 patients (27%) became demented during a mean follow-up of 3.7 +/- 2.3 years. Four neuropsychological test scores were significantly associated with incident dementia in the Cox model: total immediate recall (RR: 0.92, 95% CI: 0.87-0.97, P = 0.001) and delayed recall (RR: 0.73, 95% CI: 0.59-0.91, P = 0.005) of the Selective Reminding Test (SRT), letter fluency (RR: 0.87, 95% CI: 0.77-0.99, P = 0.03), and Identities and Oddities of the Mattis Dementia Rating Scale (RR: 0.85, 95% CI: 0.73-0.98, P = 0.03). When the analysis was performed excluding patients with a clinical dementia rating of 0.5 (questionable dementia) at baseline evaluation, total immediate recall and delayed recall were still predictive of dementia in PD. Our results indicate that impairment in verbal memory and executive function are associated with the development of dementia in patients with PD.

Do risk factors for Alzheimer's disease predict dementia in Parkinson's disease? An exploratory study.

The extent to which concomitant Alzheimer's disease (AD) is etiologically related to the development of dementia in Parkinson's disease (PD) remains controversial. We explored the association of four risk factors associated with AD, including head injury, smoking, hypertension, and diabetes mellitus, with incident dementia in PD. A cohort of 180 nondemented PD patients from the Washington Heights community in northern Manhattan, New York, completed a risk factor questionnaire at baseline and was followed annually with neurological and neuropsychological evaluations. The association of baseline variables with incident dementia was analyzed by using Cox proportional hazards models. All analyses controlled for age at baseline, gender, years of education, duration of PD, and total Unified Parkinson's Disease Rating Scale (UPDRS) motor score at baseline. Of 180 patients (mean age, 71.0 +/- 10.3 years), 52 (29%) became demented during a mean follow-up period of 3.6 +/- 2.2 years. Head injury risk ratio ([RR] 0.9; 95% confidence interval [CI], 0.4-2.2; P = 0.9), hypertension (RR, 0.7; 95% CI, 0.4-1.4, P = 0.3), and diabetes mellitus (RR, 0.8; 95% CI, 0.3-2.3; P = 0.7) were not significantly associated with incident dementia in the Cox models. Patients who reported having ever smoked were at increased risk for the development of dementia compared with nonsmokers (RR, 2.0; 95% CI, 1.0-3.9; P = 0.05). Current smoking was significantly associated with incident dementia (RR, 4.5; 95% CI, 1.2-16.4; P = 0.02), whereas past smoking approached significance (RR, 1.9; 95% CI, 0.9-3.7; P = 0.07). Although an inverse association between smoking and PD has been reported in several studies, our study showed a positive association between smoking and dementia in the setting of PD. The association of smoking with incident dementia in PD deserves further study.