Education and APOE-e4 in longitudinal cognitive decline: MacArthur Studies of Successful Aging

Longitudinal data from the MacArthur Study of Successful Aging were used to test for interactions between education and apolipoprotein E (APOE) genotype with respect to time trends in cognitive performance. Interactions between education, APOE-e4 status, and time were found for overall cognitive function, and for subscales measuring memory and naming: The presence of the e4 allele was associated with steeper declines in cognition for those with a greater than eighth-grade education. For those with an eighth-grade education or less, time trends did not differ by APOE genotype. A measure of cognitive impairment (i.e., scores of < or = 7 on the Short Portable Mental Status Questionnaire) yielded parallel though weaker evidence for a similar interaction with respect to risk of cognitive impairment. These findings suggest that the presence of at least one e4 allele appears to reduce the protective effects of education for those with at least a ninth-grade education or more, resulting in steeper cognitive declines with age.     

Lentivector-mediated delivery of GDNF protects complex motor functions relevant to human Parkinsonism in a rat lesion model

Although viral vector-mediated delivery of glial cell-line derived neurotrophic factor (GDNF) to the brain has considerable potential as a neuroprotective strategy in Parkinson's disease (PD), its ability to protect complex motor functions relevant to the human condition has yet to be established. In this study, we used an operant task that assesses the selection, initiation and execution of lateralized nose-pokes in Lister Hooded rats to assess the efficacy with which complex behaviours are protected against neurotoxic lesions by prior injection of a lentiviral vector expressing GDNF. Unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) caused rats to attempt fewer trials and to make more procedural errors. Lesioned rats also developed a pronounced ipsilateral bias, with a corresponding drop in contralateral accuracy. They were also slower to react to contralateral stimuli and to execute movements bilaterally. Rats that were pre-treated 4 weeks prior to lesion surgery with an equine infectious anaemia virus (EIAV) vector carrying GDNF [EIAV-GDNF, injected into the striatum and above the substantia nigra (SN)] performed significantly better on all of these parameters than control rats. In addition to the operant task, EIAV-GDNF successfully rescued contralateral impairments in the corridor, staircase, stepping and cylinder tasks, and prevented drug-induced rotational asymmetry. This study confirms that GDNF can protect against 6-OHDA-induced impairments in complex as well as simple behaviours, and reinforces the use of EIAV-based vectors for the treatment of PD.     

Posttraumatic stress disorder: An exploratory study examining rates of trauma and PTSD and its effect on client outcomes in community mental health

Background

Rates of trauma and Posttraumatic Stress Disorder (PTSD) were examined in order to compare the profile in clients of an Australian Public Mental Health Service with that reported in the international literature for clients with major mental illness and to explore the effect of this on client health outcomes. Potential factors contributing to increased levels of trauma/PTSD in this group of clients and the issue of causality between PTSD and subsequent mental illness was also explored.

Methods

A convenience sample of 29 clients was screened for trauma and PTSD using the Posttraumatic Stress Diagnostic Scale? (PDS) and selected outcome measures. Paired and independent samples t-test and ANOVA were applied to the data.

Results

High levels of undocumented trauma and PTSD were found. Twenty clients, (74%) reported exposure to multiple traumatic events; 33.3% (9) met DSM IV diagnostic criteria for PTSD. Significant difference was found for PTSD symptomatology, severity and impairment and for client and clinician-rated scores of Quality of Life (QOL) outcomes in the PTSD group. No effect for PTSD symptomatology on the Working Alliance (WA) was found. Factors that may influence higher rates of PTSD in this group were identified and included issues associated with the population studied, the predominance of assaultive violence found, and vulnerability and risks factors associated with re-traumatisation within the social and treating environments.

Conclusion

A similar trauma and PTSD profile to that reported in the international literature, including greater levels of trauma and PTSD and a poorer QOL, was found in this small sample of clients. It is postulated that the increased levels of trauma/PTSD as reported for persons with major mental illness, including those found in the current study, are primarily related to the characteristics of the population that access public mainstream psychiatric services and that these factors have specific implications for service delivery, and raise issues of efficiency and effectiveness of resource use in achieving successful outcomes in public mental health services for clients with co-morbid PTSD. Further research with a more rigorous design is needed to test these preliminary findings within Australian Community Mental Health Services.     

A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia Aging Study

BACKGROUND: The course of weight loss associated with dementia is unclear, particularly prior to and around the onset of the clinical syndrome. OBJECTIVE: To compare the natural history of weight change from mid to late life in men with and without dementia in late life. DESIGN AND SETTING: The Honolulu-Asia Aging Study, a 32-year, prospective, population-based study of Japanese American men who had been weighed on 6 occasions between 1965 and 1999 and who had been screened for dementia 3 times between 1991 and 1999. PARTICIPANTS: Of 1890 men (aged 77-98 years), 112 with incident dementia were compared with 1778 without dementia at the sixth examination (1997-1999). MAIN OUTCOME MEASURE: Weight change up to and including the sixth examination was treated as the dependent variable and estimated using a repeated measures analysis. RESULTS: Groups with and without dementia did not differ with respect to baseline weight or change in weight from mid to late life (first 26 years' follow-up). In the late-life examinations (final 6 years), mean age- and education-adjusted weight loss was -0.22 kg/y (95% confidence intervals, -0.26 to -0.18) in participants without dementia. Men with incident dementia at the same examination had an additional yearly weight loss of -0.36 kg (95% confidence interval, -0.53 to -0.19). This was not changed substantially with adjustment for risk factors for vascular disease or functional impairment and was significant for both Alzheimer disease and vascular dementia subtypes. CONCLUSIONS: Dementia-associated weight loss begins before the onset of the clinical syndrome and accelerates by the time of diagnosis. The potential impact on prognosis should be considered in the case of elderly persons at risk for dementia.     

A cross-national comparison of lifestyle between China and the United States, using a comprehensive cross-national measurement tool of the healthfulness of lifestyles: the Lifestyle Index

BACKGROUND: Extensive studies have revealed the importance of a healthy lifestyle and the role of each lifestyle factor in health. However, lifestyle factors have rarely been studied simultaneously. The authors propose an integrated approach to summarize total healthfulness of lifestyles and to enhance understanding of lifestyle patterns across countries. METHODS: The authors created an overall measure of lifestyle called the Lifestyle Index (LI), integrating diet, physical activity, smoking, and alcohol use to provide a global tool of monitoring healthfulness and patterns of lifestyles. Using the LI, the authors conducted a cross-national comparison between China (n = 8352) and the United States (n = 9750). RESULTS: The LI effectively reflected the healthfulness of lifestyle components in both countries. The mean of the LI scores was slightly higher in China than the US. Scores of diet quality, physical activity, and smoking were higher in China, but scores of alcohol behavior were higher in the US. Similar lifestyle patterns but different unhealthy behaviors were identified in these countries. CONCLUSIONS: An assessment of total healthfulness of lifestyles and a better understanding of lifestyle patterns across countries using the LI can provide practical guidance to developing and targeting public health promotion activities to improve global public health.     

Insulin resistance and executive dysfunction in older persons

OBJECTIVES: To evaluate the association between insulin resistance (IR) and executive dysfunction in a large, population-based study of older persons without diabetes mellitus (DM) or dementia. DESIGN: Cross-sectional study. SETTING: Outpatient clinic in Greve in Chianti and Bagno a Ripoli, Italy. PARTICIPANTS: A total of 597 subjects aged 65 to 93 without DM or dementia. MEASUREMENTS: Anthropometric measurements; plasma fasting levels of glucose, insulin, cholesterol (total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol), and insulin-like growth factor-1 (IGF-1); homeostasis model assessment (HOMA) to estimate degree of IR; Trail Making Test (TMT) A; TMT-B; TMT-B minus TMT-A (DIFF B-A); and Mini-Mental State Examination (MMSE). RESULTS: IR (HOMA) was associated with longer TMT-B (correlation coefficient (r)=0.11; P=.006) and DIFF B-A times (r=0.10; P=.022). Subjects in the upper tertile of IR were older and had longer TMT-B and DIFF B-A than participants in the lowest tertile. After adjusting for age, sex, and years of formal education, IR was significantly correlated with TMT-A, TMT-B, and DIFF B-A. After adjusting for age, sex, education, body mass index, waist:hip girth ratio, HDL-C, triglycerides, IGF-1, hypertension, drug intake, and physical activity, the results did not significantly change. After introducing MMSE score into the model, IR continued to be an independent determinant of TMT-A (beta=11.005; P=.021), TMT-B (beta=28.379; P<.001), and DIFF B-A (beta=17.374; P=.011). CONCLUSION: IR is independently associated with frontal cortex function evidenced by poor TMT times in older persons without DM or dementia.     

C57BL/6J and DBA/2J mice differ in extinction and renewal of extinguished conditioned fear

While a number of studies have examined the acquisition and expression of conditioned fear in inbred mice, very few have examined extinction of conditioned fear in inbred mice and few attempts have been made to compare extinction learning between inbred strains. Because inbred strains differ in a number of physiological and biochemical variables, differences in extinction learning may provide insight into the genetic influence of extinction learning. The purpose of this study was to examine extinction and renewal of conditioned fear in two common inbred strains of mice. C57BL/6J and DBA/2J mice were conditioned with pairings of either a tone or light and foot shock in a single session. On the following 4 days, mice were given extinction training, consisting of tone or light alone trials (Experiment 1A). C57 mice exhibited robust spontaneous recovery between sessions, but did extinguish both within and between sessions. DBA mice extinguished more quickly relative to C57 mice, and this extinction was stable between sessions (i.e., DBA mice did not exhibit spontaneous recovery). The rapid loss of fear in DBA relative to C57 mice was extinction-dependent and not merely due to poor long-term memory (Experiment 1B). Renewal testing (Experiment 2) replicated the strain difference in extinction and also showed that DBA mice have a deficit in the context specificity of extinction. C57 mice, but not DBA mice showed renewal of extinguished fear when tested in a context different from the one in which extinction training took place. These data suggest that the nature of extinction learning is influenced by characteristics of the inbred mouse strain.     

Parkinsonian signs and substantia nigra neuron density in decendents elders without PD

Substantia nigra (SN) neurons were counted on single, transverse caudal midbrain sections from 217 male participants in the Honolulu-Asia Aging Study, aged 74-97 years at death. Quadrants areas within the SN were determined with a planimeter and neuronal density was expressed as neurons/mm(2) for 10 Parkinson's disease (PD) cases, 29 incidental Lewy body cases, and 178 controls with neither condition. Mean densities in all quadrants were significantly lower in the PD group compared with the other groups (p = 0.006). This relationship was strongest in the ventrolateral quadrant. In a subgroup of 50 controls who were examined with the Unified Parkinson's Disease Rating Scale an average of 2.1 years prior to death, there was an association of stooped posture (p = 0.009), postural instability (p = 0.013), body bradykinesia (p = 0.048), and gait disturbance (p = 0.05) with neuron density in the dorsolateral quadrant; and impaired speech (p = 0.014), abnormal facial expression (p = 0.022), and difficulty rising from a chair (p = 0.032) with neuron density in the dorsomedial quadrant. There was a significant association of increasing number of signs present with decreasing neuron density in both quadrants (p = 0.001 for trend). Low SN neuron density may be the basis for parkinsonian signs in the elderly without PD.     

Spatially and temporally restricted chemoattractive and chemorepulsive cues direct the formation of the nigro-striatal circuit

Identifying cellular and molecular mechanisms that direct the formation of circuits during development is thought to be the key to reconstructing circuitry lost in adulthood to neurodegenerative disorders or common traumatic injuries. Here we have tested whether brain regions situated in and around the developing nigro-striatal pathway have particular chemoattractive or chemorepulsive effects on mesencephalic dopamine axons, and whether these effects are temporally restricted. Mesencephalic explants from embryonic day (E)12 rats were either cultured alone or with coexplants from the embryonic, postnatal or adult medial forebrain bundle region (MFB), striatum, cortex, brain stem or thalamus. Statistical analysis of axon growth responses revealed a potent chemoattraction to the early embryonic MFB (i.e. E12-15) that diminished (temporally) in concert with the emergence of chemoattraction to the striatum in the late embryonic period (i.e. E19+). Repulsive responses by dopaminergic axons were obvious in cocultures with embryonic brain stem and cortex, however, there was no effect by the thalamus. Such results suggest that the nigro-striatal circuit is formed via spatially and temporally distributed chemoattractive and chemorepulsive elements that: (i) orientate the circuit in a rostral direction (via brain stem repulsion); (ii) initiate outgrowth (via MFB attraction); (iii) prevent growth beyond the target region (via cortical repulsion); and (iv) facilitate target innervation (via striatal chemoattraction). Subsequent studies will focus on identifying genes responsible for these events so that their products may be exploited to increase the integration of neuronal transplants to the mature brain, or provide a means to (re)establish the nigro-striatal circuit in vivo.