Marinesco bodies and substantia nigra neuron density in Parkinson's disease.

AIM: Marinesco bodies (MB) are intranuclear inclusions in pigmented neurons of the substantia nigra (SN). While rare in children, frequency increases with normal ageing and is high in Alzheimer's disease, dementia with Lewy bodies and other neurodegenerative disorders. Coinciding with the age-related rise in MB frequency is initiation of cell death among SN neurons. Whether MB have a role in this process is unknown. Our aim is to examine the association of MB with SN neuron density in Parkinson's disease (PD) in the Honolulu-Asia Aging Study. METHODS: Data on MB and neuron density were measured in SN transverse sections in 131 autopsied men aged 73-99 years at the time of death from 1992 to 2007. RESULTS: Marinesco body frequency was low in the presence vs. absence of PD (2.3% vs. 6.6%, P < 0.001). After PD onset, MB frequency declined as duration of PD increased (P = 0.006). Similar patterns were observed for SN neuron density. When MB frequency was low, neuron density was noticeably reduced in the SN ventrolateral quadrant, the region most vulnerable to PD neurodegeneration. Low MB frequency was unique to PD as its high frequency in non-PD cases was unrelated to parkinsonian signs and incidental Lewy bodies. Frequency was high in the presence of Alzheimer's disease and apolipoprotein ε4 alleles. CONCLUSIONS: While findings confirm that MB frequency is low in PD, declines in MB frequency continue with PD duration. The extent to which MB have a distinct relationship with PD warrants clarification. Further studies of MB could be important in understanding PD processes.

Phytoestrogen consumption and risk for cognitive decline and dementia: With consideration of thyroid status and other possible mediators.

It is predicted that around 20% of the worlds population will be age 60 or above by 2050. Prevalence of cognitive decline and dementia is high in older adults and modifiable dietary factors may be able to reduce risk for these conditions. Phytoestrogens are bioactive plant chemicals found in soy, which have a similarity in structure to natural estradiol (the most abundant circulating estrogen). This structural likeness enables phytoestrogens to interact with estrogen receptors in the brain, potentially affecting cognition. However, findings in this domain are largely inconsistent, with approximately 50% of studies showing positive effects of phytoestrogens on cognition and the other half resulting in null/negative findings. This paper provides an updated review of the relationship between consumption of phytoestrogens and risk for cognitive decline and/or dementia. In particular, possible mediators were identified to explain discrepant findings and for consideration in future research. A case can be made for a link between phytoestrogen consumption, thyroid status and cognition in older age, although current findings in this area are very limited. Evidence suggests that inter-individual variants that can affect phytoestrogen bioavailability (and thus cognitive outcome) include age and ability to breakdown ingested phytoestrogens into their bioactive metabolites. Factors of the study design that must be taken into account are type of soy product, dosage, frequency of dietary intake and type of cognitive test used. Guidelines regarding optimal phytoestrogen dosage and frequency of intake are yet to be determined.

Ventral striatal volume is associated with cognitive decline in older people: a population based MR-study.

Striatal degeneration may contribute to cognitive impairment in older people. Here, we examine the relation of degeneration of the striatum and substructures to cognitive decline and dementia in subjects with a wide range of cognitive function. Data are from the prospective community-based Honolulu Asia Aging Study of Japanese American men born 1900-1919. Brain magnetic resonance imaging (MRI) (1.5 T) was acquired on a stratified subsample (n = 477) that included four groups defined by cognitive status relative to the scan date: subjects without dementia (n = 347), subjects identified as demented 2-3 years before brain scanning (n = 30), at the time of scanning (n = 58), and 3-5 years after scanning (n = 42). Volumes of the striatum, including the accumbens, putamen, and caudate nucleus were automatically estimated from T1 MR images. Global cognitive function was measured with the cognitive ability screening instrument (CASI), at four examinations spanning an 8-year interval. Trajectories of cognitive decline were estimated for each quartile of striatal volume using mixed models, controlling for demographic variables, measures of cerebro-vascular damage, global brain atrophy, and hippocampal volume. Diagnosis of dementia before, during, and after brain scanning was associated with smaller volumes of n. accumbens and putamen, but not with caudate nucleus volume. Subjects in the lowest quartile of n. accumbens volume, both in the total sample and in the subjects not diagnosed with dementia during the study, had a significantly (p < 0.0001) steeper decline in cognitive performance compared with those in the highest quartile. In conclusion, volumes of the n. accumbens and putamen are closely associated with the occurrence of dementia and n. accumbens volume predicts cognitive decline in older people. These associations were found independent of the magnitude of other pivotal markers of cognitive decline, i.e. cerebro-vascular damage and hippocampal volume. The present study suggests a role for the ventral striatum in the development of clinical dementia.

Parkinson-related genetics in patients treated with deep brain stimulation.

OBJECTIVES: To analyze the frequency of mutations associated with Parkinson's disease (PD) in a general PD population compared to patients with PD selected for deep brain stimulation (DBS) and evaluate the outcome of surgery. MATERIAL AND METHODS: A total of 630 consecutive patients with PD were genetically screened, and 60 had DBS surgery, 37 subthalamic nucleus (STN), 21 ventrointermediate nucleus of thalamus (VIM), and two globus pallidus internus (GPi). RESULTS: Mutations in LRRK2, PRKN, and PINK1 were found: the first two of these being overrepresented in STN-operated patients, but none being found in VIM-operated patients. Clinical outcome of the surgery was similar in patients with mutations compared to those without. CONCLUSIONS: In a consecutive PD population, patients treated with STN-DBS are overrepresented for PD-related mutations and they seem to benefit from DBS as well as patients without mutations.

The actual dielectric response function for a colloidal suspension of spherical particles.

In this paper, we present a theoretical analysis of the dielectric response of a dense suspension of spherical colloidal particles based on a self-consistent cell model. Particular attention is paid to (a) the relationship between the dielectric response and the conductivity response and (b) the connection between the real and imaginary parts of these responses based on the Kramers-Kronig relations. We have thus clarified the analysis of Carrique et al. (Carrique, F.; Criado, C.; Delgado, A. V. J. Colloid Interface Sci. 1993, 156, 117). We have shown that both the conduction and displacement current components are complex quantities with both real and imaginary parts being frequency dependent. The dielectric response exhibits characteristics of two relaxation phenomena: the Maxwell-Wagner and the alpha-relaxations, with the imaginary part being the more sensitive instrument. The inverse Fourier transform of the simulated dielectric response is compared with a phenomenological, two-exponential response function with good agreement obtained. The two fitted decay times also compare well with times extracted from the explicit simulations.

High-frequency behavior of the dynamic mobility and dielectric response of concentrated colloidal dispersions.

A matched asymptotic analysis of the system of equations governing the electrokinetic cell model of ref 4 (Ahualli, S.; Delgado, A.; Miklavcic, S.; White, L. R. Langmuir 2006, 22, 7041) is performed. Asymptotic expressions are obtained for the dynamic mobility and complex conductivity response of a dense suspension of charged spherical particles to an applied electric field. The asymptotic expressions are compared with full numerical calculations of the linear response functions as a function of surface (zeta) potential, electrolyte strength, and particle density. We find that the numerical procedure used is robust and highly accurate at a very high frequency under a wide range of double-layer conditions. The asymptotic form for the dielectric response of the system is accurate to megahertz frequencies. The asymptotic formulas for the other response functions have limited viability as predictive tools within the current range of experimentally accessible frequencies but are useful as checks on numerical calculations.

Visual evoked potential and spatial frequency in migraine: a longitudinal study.

OBJECTIVES: Reduced habituation of visual evoked potentials (VEP) has been reported in migraine. We aimed to study if preattack excitability changes were related to check size using a paired longitudinal design. MATERIALS AND METHODS: Magnocellular and parvocellular functions were studied with monocular 31 and 62 checks in 33 adult migraine patients without aura (MwoA), 8 with aura (MA) and 31 controls. VEP was recorded in four blocks of 50 stimuli. N1P1 and P1N2 amplitudes were measured. Sessions were classified as preattack or interictal. RESULTS: MA patients had significantly higher P1N2 and N1P1 amplitude than the controls and MwoA. VEP amplitude habituation was not found in controls. Migraine patients had significantly higher P1N2 amplitude before the attack compared with a paired interictal recording for large checks. CONCLUSIONS: Cortical excitability is high in MA. Headache severity affects visual excitability. Increased P1N2 VEP amplitude before the attack suggests a cyclic decreased intracortical inhibition in extrastriate magnocellular pathways in migraine.

Dynamic dielectric response of concentrated colloidal dispersions: comparison between theory and experiment.

The cell-model electrokinetic theory of Ahualli et al. Langmuir 2006, 22, 7041; Ahualli et al. J. Colloid Interface Sci. 2007, 309, 342; and Bradshaw-Hajek et al. Langmuir 2008, 24, 4512 is applied to a dense suspension of charged spherical particles, to exhibit the system's dielectric response to an applied electric field as a function of solids volume fraction. The model's predictions of effective permittivity and complex conductivity are favorably compared with published theoretical calculations and experimental measurements on dense colloidal systems. Physical factors governing the volume fraction dependence of the dielectric response are discussed.

Cerebrospinal fluid cytokine levels in migraine, tension-type headache and cervicogenic headache.

Cytokines have been measured in cerebrospinal fluid (CSF) from headache patients [infrequent episodic tension-type headache (TTH) and migraine with or without aura, all during attack, and cervicogenic headache] and compared with levels in pain-free individuals. Both proinflammatory [interleukin (IL)-1beta, tumour necrosis factor-alpha and monocyte chemoattractant protein-1 (MCP-1)] and anti-inflammatory cytokines [IL-1 receptor antagonist (IL-1ra), IL-4, IL-10 and transforming growth factor-beta1 (TGF-beta1)] were included. There were significant group differences in IL-1ra, TGF-beta1 and MCP-1 in episodic TTH and migraine compared with controls, and a significant difference in MCP-1 between cervicogenic headache and migraine with aura. Intrathecal MCP-1 correlated with IL-1ra, IL-10 and TGF-beta1 in episodic TTH, and MCP-1 with IL-10 in migraine with aura. Cytokine increases were modest compared with those often accompanying serious neurological conditions, and may represent a mild response to pain. We believe this to be the first comparative study of CSF cytokine levels in connection with headache.

Frequency-dependent electrical conductivity of concentrated dispersions of spherical colloidal particles.

This paper outlines the application of a self-consistent cell-model theory of electrokinetics to the problem of determining the electrical conductivity of a dense suspension of spherical colloidal particles. Numerical solutions of the standard electrokinetic equations, subject to self-consistent boundary conditions, are implemented in formulas for the electrical conductivity appropriate to the particle-averaged cell model of the suspension. Results of calculations as a function of frequency, zeta potential, volume fraction, and electrolyte composition, are presented and discussed.

Hippocampal shape analysis in Alzheimer's disease: a population-based study.

BACKGROUND: Hippocampal atrophy--particularly of the CA1 region--may be useful as a biomarker for Alzheimer's disease (AD) or the risk for AD. The extent to which the AD hippocampus can be distinguished in vivo from changes due to normal aging or other processes that affect the hippocampus is of clinical importance and is an area of active research. In this study, we use structural imaging techniques to model hippocampal size and regional shape differences between elderly men with incident AD and a non-demented comparison group of elderly men. METHODS: Participants are Japanese-American men from the Honolulu Asia Aging Study (HAAS). The HAAS cohort has been followed since 1965. The following analysis is based on a sub-group of men who underwent MRI examination in 1994-1996. Participants were diagnosed with incident AD (n=24: age=82.5+/-4.6) or were not demented (n=102: age=83.0+/-5.9). One reader, blinded to dementia diagnosis, manually outlined the left and right hippocampal formation using published criteria. We used 3D structural shape analysis methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal diameter between the AD cases and the non-demented comparison group. RESULTS: Mean total hippocampal volume was 11.5% smaller in the AD cases than the non-demented controls (4903+/-857 mm(3) vs. 5540+/-805 mm(3)), with a similar size difference for the median left (12.0%) and median right (11.6%) hippocampus. Shape analysis showed a regional pattern of shape difference between the AD and non-demented hippocampus, more evident for the hippocampal body than the head, and the appearance of more consistent differences in the left hippocampus than the right. While assignment to a specific sub-region is not possible with this method, the surface changes primarily intersect the area of the hippocampus body containing the CA1 region (and adjacent CA2 and distal CA3), subiculum, and the dentate gyrus-hilar region.

Use of a cell model for the evaluation of the dynamic mobility of spherical silica suspensions.

In this paper we evaluate the validity of a cell model for the calculation of the dynamic mobility of concentrated suspensions of spheres. The key point is the consideration of the boundary conditions (electrical and hydrodynamic) at the boundary of the fluid cell surrounding a single probe particle. The model proposed is based on a universal criterion for the averages of fluid velocity, electric potential, pressure field or electrochemical properties in the cell. The calculations are checked against a wide set of experimental data on the dynamic mobility of silica suspensions with two different radii, several ionic strengths, and two particle concentrations. The comparison reveals an excellent agreement between theory and experiment, and the model appears to be extremely suitable for correctly predicting the behavior of the dynamic mobility, including the changes in the zeta potential, zeta, with ionic strength, the frequency and amplitude of the Maxwell-Wagner-O'Konski relaxation, and the inertial relaxation occurring at the top of the frequency range accessible to our experimental device.

PINK1 mutation heterozygosity and the risk of Parkinson's disease.

BACKGROUND: Mutations in the PTEN-induced kinase 1 (PINK1) gene have been identified in recessively inherited and sporadic early-onset parkinsonism (EOP). METHODS: A total of 131 Norwegian patients diagnosed with Parkinson's disease were included. Of them, 89 participants had EOP (onset < or = 50 years); the remaining had familial late-onset disease (mean age at onset 64 years). PINK1 analysis included sequencing and gene dose assessment. Mutations were examined in 350 controls. RESULTS: Heterozygous missense mutations in PINK1 were found in 3 of 131 patients; none of the patients carried homozygous or compound heterozygous mutations. One of these three patients had a father affected by Parkinson's disease, and he carried the mutation. Three new and seven known polymorphic variants were identified, although none seemed to be associated with disease risk. CONCLUSIONS: PINK1 mutations are rare in Norwegian patients with EOP and familial Parkinson's disease. However, the data suggest that some heterozygous mutations might increase the risk of developing Parkinson's disease.

Stable van der Waals-induced deformations of the air-water interface. Theoretical predictions and a suggestion for an experiment.

This article concerns the stability of the air-water interface subjected to a 2D attractive van der Waals stress. The physical problem models the setup of a Wilhelmy plate experiment prior to three-phase contact line formation. We present and employ an unambiguous condition to quantify the stability limit in terms of the distance of closest approach of a solid cylindrical plate of parabolic cross section to the fluid surface as a function of the strength of the van der Waals surface force and plate geometry. A numerical study spanning 4 orders of magnitude of the Hamaker constant and nearly 6 orders of magnitude of solid geometry characterizes the dependence of the stability limit on these physical parameters. Comparisons are also made with a previously published analytical condition guaranteeing a stable deformation of the fluid interface. A possible experiment for testing the theory is also described. Used together with the theory, the technique could be used as an independent means of determining system properties such as the surface tension or Hamaker constant.

Dynamic electrophoretic mobility of concentrated dispersions of spherical colloidal particles. On the consistent use of the cell model.

This paper outlines a complete and self-consistent cell model theory of the electrokinetics of dense spherical colloidal suspensions for general electrolyte composition, frequency of applied field, zeta potential, and particle size. The standard electrokinetic equations, first introduced for any given particle configuration, are made tractable to computation by averaging over particle configurations. The focus of this paper is on the systematic development of suitable boundary conditions at the outer cell boundary obtained from global constraints on the suspension. The approach is discussed in relation to previously published boundary conditions that have often been introduced in an ad hoc manner. Results of a robust numerical calculation of high-frequency colloidal transport properties, such as dynamic mobility, using the present model are presented and compared with some existing dense suspension models.

Analysis and validation of automated skull stripping tools: a validation study based on 296 MR images from the Honolulu Asia aging study.

As population-based epidemiologic studies may acquire images from thousands of subjects, automated image post-processing is needed. However, error in these methods may be biased and related to subject characteristics relevant to the research question. Here, we compare two automated methods of brain extraction against manually segmented images and evaluate whether method accuracy is associated with subject demographic and health characteristics. MRI data (n = 296) are from the Honolulu Asia Aging Study, a population-based study of elderly Japanese-American men. The intracranial space was manually outlined on the axial proton density sequence by a single operator. The brain was extracted automatically using BET (Brain Extraction Tool) and BSE (Brain Surface Extractor) on axial proton density images. Total intracranial volume was calculated for the manually segmented images (ticvM), the BET segmented images (ticvBET) and the BSE segmented images (ticvBSE). Mean ticvBSE was closer to that of ticvM, but ticvBET was more highly correlated with ticvM than ticvBSE. BSE had significant over (positive error) and underestimated (negative error) ticv, but net error was relatively low. BET had large positive and very low negative error. Method accuracy, measured in percent positive and negative error, varied slightly with age, head circumference, presence of the apolipoprotein eepsilon4 polymorphism, subcortical and cortical infracts and enlarged ventricles. This epidemiologic approach to the assessment of potential bias in image post-processing tasks shows both skull-stripping programs performed well in this large image dataset when compared to manually segmented images. Although method accuracy was statistically associated with some subject characteristics, the extent of the misclassification (in terms of percent of brain volume) was small.

Brain lesions on MRI and endogenous sex hormones in elderly men.

We investigated the association between MRI detected brain lesions and levels of endogenous sex hormones in Japanese-American men aged 74-95 years. Logistic regression was used to estimate the association (OR (95% CI)) of MRI outcome with tertiles of bioavailable testosterone, 17beta estradiol and sex hormone binding globulin (SHBG). There was a significantly increased risk for cerebral atrophy in the highest tertile of testosterone (3.1 (1.2-7.8)) compared to the lowest. We also found that men with the highest estradiol had a higher risk of lacunes (1.92 (1.1-3.2)). These relationships did not change with adjustment for the other sex hormones, cardiovascular risk factors, or other brain lesions. In contrast, men with the highest SHBG had a lower risk both of cerebral atrophy and lacunes, after adjusting for sex hormones and cardiovascular risk factors. There were no associations between sex hormones and hippocampal atrophy, white matter lesions, and large infarcts. Because the levels of hormone were measured close in time to the acquisition of the MRI, these associations may reflect neurodegeneration in brain regions regulating hormone levels.

Excessive daytime sleepiness and subsequent development of Parkinson disease.

OBJECTIVE: To determine if excessive daytime sleepiness (EDS) can predate future Parkinson disease (PD). METHODS: EDS was assessed in 3,078 men aged 71 to 93 years in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent PD and dementia. Follow-up for incident PD was based on three repeat neurologic assessments from 1994 to 2001. RESULTS: During the course of follow-up, 43 men developed PD (19.9/10,000 person-years). After age adjustment, there was more than a threefold excess in the risk of PD in men with EDS vs men without EDS (55.3 vs 17.0/10,000 person-years; odds ratio [OR] = 3.3; 95% CI = 1.4 to 7.0; p = 0.004). Additional adjustment for insomnia, cognitive function, depressed mood, midlife cigarette smoking and coffee drinking, and other factors failed to alter the association between EDS and PD (OR = 2.8; 95% CI = 1.1 to 6.4; p = 0.014). Other sleep related features such as insomnia, daytime napping, early morning grogginess, and frequent nocturnal awakening showed little relation with the risk of PD. CONCLUSIONS: Excessive daytime sleepiness may be associated with an increased risk of developing Parkinson disease.

Consumption of milk and calcium in midlife and the future risk of Parkinson disease.

OBJECTIVE: To examine the relation between milk and calcium intake in midlife and the risk of Parkinson disease (PD). METHODS: Findings are based on dietary intake observed from 1965 to 1968 in 7,504 men ages 45 to 68 in the Honolulu Heart Program. Men were followed for 30 years for incident PD. RESULTS: In the course of follow-up, 128 developed PD (7.1/10,000 person-years). Age-adjusted incidence of PD increased with milk intake from 6.9/10,000 person-years in men who consumed no milk to 14.9/10,000 person-years in men who consumed >16 oz/day (p = 0.017). After further adjustment for dietary and other factors, there was a 2.3-fold excess of PD (95% CI 1.3 to 4.1) in the highest intake group (>16 oz/day) vs those who consumed no milk. The effect of milk consumption on PD was also independent of the intake of calcium. Calcium from dairy and nondairy sources had no apparent relation with the risk of PD. CONCLUSIONS: Findings suggest that milk intake is associated with an increased risk of Parkinson disease. Whether observed effects are mediated through nutrients other than calcium or through neurotoxic contaminants warrants further study.