Dementia with Lewy bodies and Parkinson's disease

Lewy bodies (LB) in the central nervous system are associated with several different clinical syndromes including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Long term follow up of PD patients finds up to 78% eventually develop dementia, most of these patients exhibiting fluctuating cognition and visual hallucinations similar to DLB and with extensive cortical LB at autopsy. alpha-Synuclein positive, neuritic pathology, in the putamen of DLB and Parkinson's disease dementia (PDD), may contribute to postural-instability gait difficulty, parkinsonism, diminished levodopa responsiveness and increased neuroleptic sensitivity. Cognitive and neuropsychiatric symptoms improve with cholinesterase inhibitor treatment in both patient groups. DLB and PDD should be seen as different points on a spectrum of LB disease. Distinguishing them as separate disorders may be useful in clinical practice, but may be of limited value in terms of investigating and treating the underlying neurobiology.

Examining carer stress in dementia: the role of subtype diagnosis and neuropsychiatric symptoms

INTRODUCTION: Caring for people with dementia incurs significant stress for carers. Stress has been related to the duration of caring role, the number of weekly hours provided and severity of cognitive impairment. What remains less clear is the impact of neuropsychiatric symptoms and subtype of dementia on carer stress and this study aimed to examine these. METHODS: Dementia carers were recruited for people with a range of dementia subtypes. Carers were interviewed using the Neuropsychiatric Inventory with the Carer Distress Scale. Cognitive fluctuations were assessed using the Dementia Cognitive Fluctuations Scale. All patients were also examined with The Cambridge Assessment for mental disorders in the elderly. RESULTS: Dementia diagnostic subtype, the presence of cognitive fluctuations and some neuropsychiatric symptoms (psychosis and mood disturbance) did predict carer stress (all at p < 0.01) but age, gender and severity of cognitive impairment did not (all p > 0.33). Carers of people with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) experienced more stress than those caring for patients with Alzheimer's disease and vascular dementia. Carer stress was associated with higher levels of psychosis, mood disturbances, daytime sleep and cognitive fluctuations in the person with dementia. CONCLUSIONS: This study identified the significant impact on carers of providing care for people with DLB and PDD dementia subtypes and also highlighted the significant impact of providing care for patients with high levels of psychosis, mood disturbances and cognitive fluctuations.

Longitudinal Relationship of Low Leisure Satisfaction but not Depressive Symptoms With Systemic Low-Grade Inflammation in Dementia Caregivers.

Objectives.This study aimed to further elucidate the biobehavioral mechanisms linking dementia caregiving with an increased cardiovascular disease risk. We hypothesized that both elevated depressive symptoms and a behavioral correlate of depression, low leisure satisfaction, are associated with systemic inflammation.Method.We studied 121 elderly Alzheimer's disease caregivers who underwent 4 annual assessments for depressive symptoms, leisure satisfaction, and circulating levels of inflammatory markers. We used mixed-regression analyses controlling for sociodemographic and health-relevant covariates to examine longitudinal relationships between constructs of interest. RESULTS: There were inverse relationships between total leisure satisfaction and tumor necrosis factor-α (TNF-α; p = .047), interleukin-8 (IL-8; p < .001), and interferon-γ (IFG; p = .020) but not with IL-6 (p = .21) and C-reactive protein (p = .65). Lower enjoyment from leisure activities was related to higher levels of TNF-α (p = .045), IL-8 (p < .001), and IFG (p = .002), whereas lower frequency of leisure activities was related only to higher IL-8 levels (p = .023). Depressive symptoms were not associated with any inflammatory marker (all p values > .17). Depressive symptoms did not mediate the relationship between leisure satisfaction and inflammation.Discussion.Lower satisfaction with leisure activities is related to higher low-grade systemic inflammation. This knowledge may provide a promising way of improving cardiovascular health in dementia caregivers through behavioral activation treatments targeting low leisure satisfaction.

Event-relating to potential dementia. Semantic processing in the course of healthy and pathological aging

While most healthy elderly are able to manage their everyday activities, studies showed that there are both stable and declining abilities during healthy aging. For example, there is evidence that semantic memory processes which involve controlled retrieval mechanism decrease, whereas the automatic functioning of the semantic network remains intact. In contrast, patients with Alzheimer’s disease (AD) suffer from episodic and semantic memory impairments aggravating their daily functioning. In AD, severe episodic as well as semantic memory deficits are observable. While the hallmark symptom of episodic memory decline in AD is well investigated, the underlying mechanisms of semantic memory deterioration remain unclear. By disentangling the semantic memory impairments in AD, the present thesis aimed to improve early diagnosis and to find a biomarker for dementia. To this end, a study on healthy aging and a study with dementia patients were conducted investigating automatic and controlled semantic word retrieval. Besides the inclusion of AD patients, a group of participants diagnosed with semantic dementia (SD) – showing isolated semantic memory loss – was assessed. Automatic and controlled semantic word retrieval was measured with standard neuropsychological tests and by means of event-related potentials (ERP) recorded during the performance of a semantic priming (SP) paradigm. Special focus was directed to the N400 or N400-LPC (late positive component) complex, an ERP that is sensitive to the semantic word retrieval. In both studies, data driven topographical analyses were applied. Furthermore, in the patient study, the combination of the individual baseline cerebral blood flow (CBF) with the N400 topography of each participant was employed in order to relate altered functional electrophysiology to the pathophysiology of dementia. Results of the aging study revealed that the automatic semantic word retrieval remains stable during healthy aging, the N400-LPC complex showed a comparable topography in contrast to the young participants. Both patient groups showed automatic SP to some extent, but strikingly the ERP topographies were altered compared to healthy controls. Most importantly, the N400 was identified as a putative marker for dementia. In particular, the degree of the topographical N400 similarity was demonstrated to separate healthy elderly from demented patients. Furthermore, the marker was significantly related to baseline CBF reduction in brain areas relevant for semantic word retrieval. Summing up, the first major finding of the present thesis was that all groups showed semantic priming, but that the N400 topography differed significantly between healthy and demented elderly. The second major contribution was the identification of the N400 similarity as a putative marker for dementia. To conclude, the present thesis added evidence of preserved automatic processing during healthy aging. Moreover, a possible marker which might contribute to an improved diagnosis and lead consequently to a more effective treatment of dementia was presented and has to be further developed.

Altered Electrophysiology of Semantic Word Processing in Alzheimer's Disease and Semantic Dementia

With the progressing course of Alzheimer's disease (AD), deficits in declarative memory increasingly restrict the patients' daily activities. Besides the more apparent episodic (biographical) memory impairments, the semantic (factual) memory is also affected by this neurodegenerative disorder. The episodic pathology is well explored; instead the underlying neurophysiological mechanisms of the semantic deficits remain unclear. For a profound understanding of semantic memory processes in general and in AD patients, the present study compares AD patients with healthy controls and Semantic Dementia (SD) patients, a dementia subgroup that shows isolated semantic memory impairments. We investigate the semantic memory retrieval during the recording of an electroencephalogram, while subjects perform a semantic priming task. Precisely, the task demands lexical (word/nonword) decisions on sequentially presented word pairs, consisting of semantically related or unrelated prime-target combinations. Our analysis focuses on group-dependent differences in the amplitude and topography of the event related potentials (ERP) evoked by related vs. unrelated target words. AD patients are expected to differ from healthy controls in semantic retrieval functions. The semantic storage system itself, however, is thought to remain preserved in AD, while SD patients presumably suffer from the actual loss of semantic representations.

On the comparison of a novel serious game and electroencephalography biomarkers for early dementia screening

Patients with amnestic mild cognitive impairment are at high risk for developing Alzheimer's disease. Besides episodic memory dysfunction they show deficits in accessing contextual knowledge that further specifies a general spatial navigation task or an executive function (EF) virtual action planning. Virtual reality (VR) environments have already been successfully used in cognitive rehabilitation and show increased potential for use in neuropsychological evaluation allowing for greater ecological validity while being more engaging and user friendly. In our study we employed the in-house platform of virtual action planning museum (VAP-M) and a sample of 25 MCI and 25 controls, in order to investigate deficits in spatial navigation, prospective memory, and executive function. In addition, we used the morphology of late components in event-related potential (ERP) responses, as a marker for cognitive dysfunction. The related measurements were fed to a common classification scheme facilitating the direct comparison of both approaches. Our results indicate that both the VAP-M and ERP averages were able to differentiate between healthy elders and patients with amnestic mild cognitive impairment and agree with the findings of the virtual action planning supermarket (VAP-S). The sensitivity (specificity) was 100% (98%) for the VAP-M data and 87% (90%) for the ERP responses. Considering that ERPs have proven to advance the early detection and diagnosis of "presymptomatic AD," the suggested VAP-M platform appears as an appealing alternative.

International validation of a behavioral scale in Parkinson's disease without dementia.

The "Ardouin Scale of Behavior in Parkinson's Disease" is a new instrument specifically designed for assessing mood and behavior with a view to quantifying changes related to Parkinson's disease, to dopaminergic medication, and to non-motor fluctuations. This study was aimed at analyzing the psychometric attributes of this scale in patients with Parkinson's disease without dementia. In addition to this scale, the following measures were applied: the Unified Parkinson's Disease Rating Scale, the Montgomery and Asberg Depression Rating Scale, the Lille Apathy Rating Scale, the Bech and Rafaelsen Mania Scale, the Positive and Negative Syndrome Scale, the MacElroy Criteria, the Patrick Carnes criteria, the Hospital Anxiety and Depression Scale, and the Mini-International Neuropsychiatric Interview. Patients (n = 260) were recruited at 13 centers across four countries (France, Spain, United Kingdom, and United States). Cronbach's alpha coefficient for domains ranged from 0.69 to 0.78. Regarding test-retest reliability, the kappa coefficient for items was higher than 0.4. For inter-rater reliability, the kappa values were 0.29 to 0.81. Furthermore, most of the items from the Ardouin Scale of Behavior in Parkinson's Disease correlated with the corresponding items of the other scales, depressed mood with the Montgomery and Asberg Depression Rating Scale (ρ = 0.82); anxiety with the Hospital Anxiety and Depression Scale-anxiety (ρ = 0.56); apathy with the Lille Apathy Rating Scale (ρ = 0.60). The Ardouin Scale of Behavior in Parkinson's disease is an acceptable, reproducible, valid, and precise assessment for evaluating changes in behavior in patients with Parkinson's disease without dementia. © 2015 International Parkinson and Movement Disorder Society.

Discovering EEG resting state alterations of Semantic Dementia

Objective Diagnosis of semantic dementia relies on cost-intensive MRI or PET, although resting EEG markers of other dementias have been reported. Yet the view still holds that resting EEG in patients with semantic dementia is normal. However, studies using increasingly sophisticated EEG analysis methods have demonstrated that slightest alterations of functional brain states can be detected. Methods We analyzed the common four resting EEG microstates (A, B, C, and D) of 8 patients with semantic dementia in comparison with 8 healthy controls and 8 patients with Alzheimer’s disease. Results Topographical differences between the groups were found in microstate classes B and C, while microstate classes A and D were comparable. The data showed that the semantic dementia group had a peculiar microstate E, but the commonly found microstate C was lacking. Furthermore, the presence of microstate E was significantly correlated with lower MMSE and language scores. Conclusion Alterations in resting EEG can be found in semantic dementia. Topographical shifts in microstate C might be related to semantic memory deficits. Significance This is the first study that discovered resting state EEG abnormality in semantic dementia. The notion that resting EEG in this dementia subtype is normal has to be revised.

Recommendations for dementia caregiver stress interventions based on Intervention Mapping guidelines

Stress can affect a person's psychological and physical health and cause a variety of conditions including depression, immune system changes, and hypertension (Alzheimer's Association, 2010; Aschbacher et al., 2009; Fredman et al., 2010; Long et al., 2004; Mills et al., 2009; von Känel et al., 2008). The severity and consequences of these conditions can vary based on the duration, amount, and sources of stress experienced by the individual (Black & Hyer, 2010; Coen et al., 1997; Conde-Sala et al., 2010; Pinquart & Sörensen, 2007). Caregivers of people with dementia have an elevated risk for stress and its related health problems because they experience more negative interactions with, and provide more emotional support for, their care recipients than other caregivers. ^ This paper uses a systematic program planning process of Intervention Mapping to organize evidence from literature, qualitative research and theory to develop recommendations for a theory- and evidence-based intervention to improve outcomes for caregivers of people with dementia. A needs assessment was conducted to identify specific dementia caregiver stress influences and a logic model of dementia caregiver stress was developed using the PRECEDE Model. Necessary behavior and environmental outcomes are identified for dementia caregiver stress reduction and performance objectives for each were combined with selected determinants to produce change objectives. Planning matrices were then designed to inform effective theory-based methods and practical applications for recommended intervention delivery. Recommendations for program components, their scope and sequence, the completed program materials, and the program protocols are delineated along with ways to insure that the program is adopted and implemented after it is shown to be effective.^

Considering cycling for commuting : the role of mode familiarity : an exploration on the (circular) relation between cycling behaviours and attitudes toward cycling in Vitoria-Gasteiz, Spain

¿La gente utiliza la bicicleta porque les gusta? ¿O es el propio hecho de usarla la razón por la que les gusta hacerlo? ¿O es una combinación de las dos? Este tipo de preguntas reflejan un problema que se puede llamar ‘el círculo de la consideración de la bicicleta’: para poder considerar el uso de la bicicleta en el conjunto de posibles opciones a escoger, un individuo tiene que tener creencias positivas sobre ella, sobre todo en el caso de ‘contextos de bajo uso’. Pero parece poco probable que se formen creencias positivas cuando hay bajos niveles de familiaridad al modo, es decir, con un bajo conocimiento de sus características, su funcionamiento y del imaginario asociado; al mismo tiempo, la familiaridad irá alcanzando niveles más altos conforme aumente el tiempo y la intensidad con la que se utilice la bicicleta a lo largo de la vida de los individuos. El problema parece un circulo recursivo huevo-gallina, ya que es difícil que alguien considere el usar la bicicleta en lugares donde su uso es una práctica poco extendida. En estos lugares, y dentro del conglomerado actual de tecnologías, infraestructuras, reglas, prácticas de los usuarios y preferencias culturales que se han desarrollado alrededor del automóvil (el actual "sistema socio-técnico de la movilidad urbana", Urry 2004; Geels 2005, 2012) usar la bicicleta es considerado por la mayoría como algo difícil, inseguro, y anormal. Como consecuencia, los procesos de aumento de familiaridad con la bicicleta permanecen inactivos. La tesis asume la familiaridad como una fuente de información e influencia sobre las creencias positivas sobre la bicicleta. En ‘contextos de bajo uso’, sin familiaridad al uso de la bicicleta, estas creencias sólo pueden surgir de ciertos rasgos personales (afecto, valores, identidades, voluntad, etc.). Tal como han evidenciado investigaciones recientes, en estos contextos la posibilidad de considerar el uso de la bicicleta (y su eventual adopción), se circunscribe principalmente a los ‘entusiastas’, a los que están dispuestos a “ir contra corriente” (Horton & Parkin 2012), limitando el alcance de las políticas de promoción. La investigación llevada a cabo en esta tesis ofrece un nuevo enfoque al problema del ‘círculo de la consideración de la bicicleta’. Para ello, plantea un modelo en el que se introduce a la familiaridad como un constructo que media entre el comportamiento final –qué modo de transporte elige el individuo– y el conjunto de constructos psicosociales que preceden la elección modal (creencias y actitudes). La familiaridad al uso de la bicicleta se concibe como una medida de la intensidad relativa del uso de una bicicleta, real y percibida (basándose en Diana & Mokhtarian 2009) que puede formarse de manera distinta según sus fines (utilitarios o no utilitarios). El constructo familiaridad con el modo bicicleta está relacionado con la cantidad de tiempo, la intensidad y la regularidad con la que un individuo ha hecho uso de la bicicleta a lo largo de su vida. La familiaridad se concibe así como una condición que permite definir adecuadamente el contexto en el que se toman las decisiones modales de los individuos, en línea con investigaciones que postulan patrones de causalidad alternativos entre los procesos cognitivos de elección y los comportamientos modales (Tardif 1977; Dobson et al. 1978; Golob et al. 1979; Golob 2001; Schwanen et al. 2012; Diana et al. 2009; Vij & Walker 2014). De este modo se plantea que el esquema unidireccional actitudesconductas podría no ser completamente valido en el caso de la consideración de la bicicleta, explorando la hipótesis que sean las propias conductas a influenciar la formación de las actitudes. En esta tesis, el constructo de familiaridad se articula teórica y metodológicamente, y se emplea un instrumento de diseño transversal para contrastarlo. Los resultados de una encuesta telefónica a una muestra representativa de 736 personas en la ciudad española de Vitoria-Gasteiz proveen evidencias que sugieren –aunque de forma preliminar– que la familiaridad juega un papel de mediadora en la relación entre la utilización de la bicicleta y la formación de las creencias y actitudes hacia el su uso. La tesis emplea mediciones para cada individuo con respecto tanto a su consideración como a su familiaridad al uso de la bicicleta. Éstas mediciones se definen haciendo uso del análisis factorial exploratorio (AFE). Por un lado, el AFE arroja una estructura del constructo ‘consideración’ formada por cuatro factores, tres de ellos asociados con elementos positivos y uno con elementos negativos: (1) de cómo el uso de la bicicleta se considera verde e inteligente (G&S); (2) sobre su carácter agradable y adecuado (P&S); (3) sobre su eficacia como modo de transporte para ir al trabajo (E); y (4) sobre los principales inconvenientes de su uso, es decir, las dificultades implícitas (sudoración y estar expuestos a las inclemencias del tiempo) y la sensación de inseguridad que genera (sentirse en riesgo de accidentes y estresarse por el tráfico) (D&T). Por otro lado, la familiaridad al uso de la bicicleta se mide en dos distintas variables ordinales (según se base en el uso utilitario o no utilitario). Como resultado, se puede hablar de que cada individuo se encuentra en una de las siguientes cuatro etapas en orden creciente hacia una familiaridad completa al modo: no familiarizados; apenas familiarizados; moderadamente familiarizados; totalmente familiarizados. El análisis de los datos de los cuatro grupos de sujetos de la muestra, –definidos de acuerdo con cada una de las cuatro etapas de familiaridad definidas– ha evidenciado la existencia de diferencias intergrupo estadísticamente significativas, especialmente para la medida relacionada con el uso utilitario. Asimismo, las personas en los niveles inferiores de familiaridad tienen una consideración menor de los aspectos positivos de la bicicleta y por el contrario presentan preocupaciones mayores hacia las características negativas respecto a aquellas personas que están más familiarizados en el uso utilitario. El uso, aunque esporádico, de una bicicleta para fines utilitarios (ir de compras, hacer recados, etc.), a diferencia de no usarla en absoluto, aparece asociado a unas puntuaciones significativamente más altas en los tres factores positivos (G&S, E, P&S), mientras que parece estar asociado a puntuaciones significativamente más bajas en el factor relacionado con las características negativas (D&U). Aparecen resultados similares cuando se compara un uso moderado, con uno esporádico, sobre todo con respecto a la consideración de las características negativas. Los resultados de esta tesis están en línea con la literatura anterior que se ha basado en variables similares (por ejemplo, de Geus et al. 2008; Stinson & Bhat 2003, 2004; Hunt & Abraham 2006; y van Bekkum et al. 2011a, entre otros), pero en este estudio las diferencias se observan en un contexto de bajo uso y se derivan de un análisis de toda la población de personas que se desplazan a su lugar de trabajo o estudio, lo cual eleva la fiabilidad de los resultados. La posibilidad de que unos niveles más altos de uso de la bicicleta para fines utilitarios puedan llevar a niveles más positivos de su consideración abre el camino a implicaciones teóricas y de políticas que se discuten en la tesis. Con estos resultados se argumenta que el enfoque convencional basado en el cambio de actitudes puede no ser el único y prioritario para lograr cambios a la hora de fomentar el uso de la bicicleta. Los resultados apuntan al potencial de otros esquemas de causalidad, basados en patrones de influencia más descentrados y distribuidos, y que adopten una mirada más positiva hacia los hábitos de transporte, conceptualizándolos como “inteligencia encarnada y pre-reflexiva” (Schwanen et al. 2012). Tales esquemas conducen a un enfoque más práctico para la promoción del uso de la bicicleta, con estrategias que podrían basarse en acciones de ‘degustación’ de su uso o de mayor ‘exposición’ a su uso. Is the fact that people like cycling the reason for them to cycle? Or is the fact that they do cycle the reason for them to like cycling? Or is a combination of the two? This kind of questions reflect a problem that can be called ‘the cycle of cycling consideration’: in order to consider cycling in the set of possible options to be chosen, an individual needs to have positive beliefs about it, especially in the case of ‘low-cycling contexts’. However, positive beliefs seem unlikely to be formed with low levels of mode familiarity, say, with a low acquaintance with mode features, functioning and images; at the same time, higher levels of familiarity are likely to be reached if cycling is practised over relative threshold levels of intensities and extensively across individual life courses. The problem looks like a chicken-egg recursive cycle, since the latter condition is hardly met in places where cycling is little practised. In fact, inside the current conglomerate of technologies, infrastructures, regulations, user practices, cultural preferences that have grown around the automobile (the current “socio-technical system of urban mobility”, Urry 2004; Geels 2005, 2012) cycling is commonly considered as difficult, unsafe, and abnormal. Consequently, the processes of familiarity forming remain disabled, and, as a result, beliefs cannot rely on mode familiarity as a source of information and influence. Without cycling familiarity, origins of positive beliefs are supposed to rely only on personal traits (affect, values, identities, willingness, etc.), which, in low-cycling contexts, confine the possibility of cycling consideration (and eventual adoption) mainly to ‘cycling enthusiasts’ who are willing to “go against the grain” (Horton & Parkin 2012), as it results from previous research. New research conducted by author provides theoretical insights for a different approach of the cycling consideration problem in which the presence of the new construct of cycling familiarity is hypothesised in the relationship between mode choice behaviour and the set of psychosocial constructs that are supposed to precede it (beliefs and attitudes). Cycling familiarity is conceived as a measure of the real and the perceived relative intensity of use of a bicycle (building upon Diana & Mokhtarian 2009) which may be differently formed for utilitarian or non-utilitarian purposes. The construct is assumed to be related to the amount of time, the intensity and the regularity an individual spends in using a bicycle for the two distinct categories of purposes, gaining in this way a certain level of acquaintance with the mode. Familiarity with a mode of transport is conceived as an enabling condition to properly define the decision-making context in which individual travel mode choices are taken, in line with rather disperse research efforts postulating inverse relationships between mode behaviours and mode choices (Tardiff 1977; Dobson et al. 1978; Golob et al. 1979; Golob 2001; Schwanen et al. 2012; Diana et al. 2009; Vij & Walker 2014). The new construct is built theoretically and methodologically, and a cross-sectional design instrument is employed. Results from a telephone survey in a representative sample of 736 commuters in the Spanish city of Vitoria-Gasteiz, provide suggestive –although preliminary– evidence on the role of mode familiarity as a mediator in the relationship between cycling use and the formation of beliefs and attitudes toward cycling. Measures of both cycling consideration and cycling familiarity are defined making use of exploratory factor analysis. On the one hand, four distinct cycling consideration measures are created, based on attitude expressions on four underlying factors relating to the cycling commuting behaviour: on how cycling commuting is considered green and smart (G&S); on its pleasant and suited character (P&S); on its efficiency as a mode of transport for commuting (E); and on the main drawbacks of its use, namely the difficulties implied (sweating and being exposed to adverse weather conditions) and the sense of unsafety it generates (feeling at risk of accidents and getting stressed by traffic) (D&U). On the other hand, dimensions of cycling familiarity are measured on two distinct ordinal variables (whether based on the utilitarian or non-utilitarian use) comprising four stages to a complete mode familiarity: not familiar; barely familiar; moderately familiar; fully familiar. For each of the four stages of cycling familiarity defined, statistical significant differences are found, especially for the measure related to the utilitarian use. Consistently, people at the lower levels of cycling familiarity have a lower consideration of the positive aspects of cycling and conversely they exhibit higher concerns towards the negative characteristics than those individuals that are more familiar in utilitarian cycling. Using a bicycle occasionally for practical purposes, as opposed to not using it at all, seems associated to significant higher scores in the three positive factors (G&S, E, P&S) while it appears to be associated to significant lower scores in the factor relating with the negative characteristics of cycling commuting (D&U). A same pattern also occurs with a moderate use, as opposed to an occasional one, especially for the consideration of the negative characteristics. The results are in line with previous literature based on similar variables (e.g. de Geus et al. 2008; Stinson & Bhat 2003, 2004; Hunt & Abraham 2006; and van Bekkum et al. 2011a, among others), but in this study the differences are observed in a low-cycling context and derive from an analysis of the entire population of commuters, which rises the reliability of results.

Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17

Pallido-ponto-nigral degeneration (PPND) is one of the most well characterized familial neurodegenerative disorders linked to chromosome 17q21–22. These hereditary disorders are known collectively as frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17). Although the clinical features and associated regional variations in the neuronal loss observed in different FTDP-17 kindreds are diverse, the diagnostic lesions of FTDP-17 brains are tau-rich filaments in the cytoplasm of specific subpopulations of neurons and glial cells. The microtubule associated protein (tau) gene is located on chromosome 17q21–22. For these reasons, we investigated the possibility that PPND and other FTDP-17 syndromes might be caused by mutations in the tau gene. Two missense mutations in exon 10 of the tau gene that segregate with disease, Asn279Lys in the PPND kindred and Pro301Leu in four other FTDP-17 kindreds, were found. A third mutation was found in the intron adjacent to the 3′ splice site of exon 10 in patients from another FTDP-17 family. Transcripts that contain exon 10 encode tau isoforms with four microtubule (MT)-binding repeats (4Rtau) as opposed to tau isoforms with three MT-binding repeats (3Rtau). The insoluble tau aggregates isolated from brains of patients with each mutation were analyzed by immunoblotting using tau-specific antibodies. For each of three mutations, abnormal tau with an apparent Mr of 64 and 69 was observed. The dephosphorylated material comigrated with tau isoforms containing exon 10 having four MT-binding repeats but not with 3Rtau. Thus, the brains of patients with both the missense mutations and the splice junction mutation contain aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration.

The neuronal RNA-binding protein Nova-2 is implicated as the autoantigen targeted in POMA patients with dementia

Paraneoplastic opsoclonus myoclonus ataxia (POMA) is a neurologic disorder thought to be mediated by an autoimmune attack against onconeural disease antigens that are expressed by gynecologic or lung tumors and by neurons. One POMA disease antigen, termed Nova-1, has been identified as a neuron-specific KH-type RNA-binding protein. Nova-1 expression is restricted to specific regions of the central nervous system, primarily the hindbrain and ventral spinal cord, which correlate with the predominantly motor symptoms in POMA. However, POMA antisera recognize antigens that are widely expressed in both caudal and rostral regions of the central nervous system, and some patients develop cognitive symptoms. We have used POMA antisera to clone a cDNA encoding a second POMA disease antigen termed Nova-2. Nova-2 is closely related to Nova-1, and is expressed at high levels in neurons during development and in adulthood, and at lower levels in the adult lung. In the postnatal mouse brain, Nova-2 is expressed in a pattern that is largely reciprocal with Nova-1, including high levels of Nova-2 expression in the neocortex and hippocampus. Functional characterization of Nova-2 in RNA selection and nitrocellulose filter-binding assays reveals that Nova-2 binds RNA with high affinity and with sequence specificity that differs from Nova-1. Our results demonstrate that the immune response in POMA targets a family of highly related sequence-specific neuronal RNA-binding proteins. The expression pattern of the Nova-2 protein is likely to underlie the development of cognitive deficits in some POMA patients.

Socioeconomic disadvantage and changes in health risk behaviours in Australia: 1989-90 to 2001

Objective. Lower socioeconomic status (SES) is associated in industrialized countries with unhealthy lifestyle characteristics, such as smoking, physical inactivity and being overweight or obese. This paper examines changes over time in the association between SES and smoking status, physical activity and being overweight or obese in Australia. Methods. Data were taken from three successive national health surveys in Australia carried out in 1989-90 (n = 54 576), 1995 (n = 53 828) and 2001 (n = 26 863). Participants in these surveys were selected using a national probability sampling strategy, and aggregated data for geographical areas are used to determine the changing association between SES and lifestyle over time. Findings. Overall, men had less healthy lifestyles, In 2001 inverse SES trends for both men and women showed that those living in lower SES areas were more likely to smoke and to be sedentary and obese, There were some important socioeconomic changes over the period 1989-90 to 2001. The least socioeconomically disadvantaged areas had the largest decrease in the percentage of people smoking tobacco (24% decrease for men and 12% for women) and the largest decrease in the percentage of people reporting sedentary activity levels (25% decrease for men and 22% for women). While there has been a general increase in the percentage over time of those who are overweight or obese, there is a modest trend for being overweight to have increased (by about 16% only among females) among those living in areas of higher SES. Conclusion. Socioeconomic inequalities have been increasing for several key risk behaviours related to health; this suggests that T specific population-based prevention strategies intended to reduce health inequalities are needed.

Progressive loss of expressive language in a journalist: What news for dementia?

A 77-year-old man with 8 year progressive language deterioration in the face of grossly intact memory was followed. No acute or chronic physiological or psychological event was associated with symptom onset. CT revealed small left basal ganglia infarct. Mild atrophy, no lacunar infarcts, mild diffuse periventricular changes registered on MRI. Gait normal but slow. Speech hesitant and sparse. Affect euthymic; neurobehavioral disturbance absent. MMSE 26/30; clock incorrect, concrete. Neuropsychological testing revealed simple attention intact; complex attention, processing speed impaired. Visuospatial copying and delayed recall of copy average with some perseveration. Apraxia absent. Recall mildly impaired. Mild deficits in planning, organization apparent. Patient severely aphasic, dysarthric without paraphasias. Repetition of automatic speech, recitation moderately impaired; prosody intact. Understanding of written language, nonverbal communication abilities, intact. Frontal release signs developed over last 12 months. Repeated cognitive testing revealed mild deterioration across all domains with significant further decrease in expressive, receptive language. Neurobehavioral changes remain absent to date; he remains interested, engaged and independent in basic ADLs. Speech completely deteriorated; gait and movements appreciably slowed. Although signs of frontal/executive dysfunction present, lack of behavioral abnormalities, psychiatric disturbance, personality change argue against focal or progressive frontal impairment or dementia. Relative intactness of memory and comprehension argue against Alzheimer’s disease. Lack of findings on neuroimaging argue against CVA or tumor. It is possible that the small basal ganglia infarct has resulted in a mild lateral prefrontal syndrome. However, the absence of depression as well as the relatively circumscribed language problem suggests otherwise. The progressive, severe nature of language impairments, with relatively minor impairments in attention and memory, argues for a possible diagnosis of primary progressive aphasia.

The interface between Alzheimer's disease, normal aging, and related disorders

Since the earliest descriptions of Alzheimer's disease (AD), the presence of senile plaques (SP) and neurofibrillary tangles (NFT) have been regarded as the typical pathological hallmarks of the disease. Studies over the last twenty years, however, have reported a considerable degree of heterogeneity within the AD phenotype and as a consequence, an overlap between the pathological features of AD not only with normal aging, but also with disorders related to AD. This review discusses: 1) the degree of heterogeneity within AD, 2) the concept of an 'interface' between disorders, 3) the nature and degree of the interface between AD and normal aging, vascular dementia (VD), the tauopathies, synucleinopathies, and prion disease, and 4) whether the original status of AD should be retained or whether AD, normal aging, and the related disorders should be regarded as representing a 'continuum' of neuropathological change.