Long‐term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease

We report the 5 to 6 year follow‐up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinson's disease (PD) patients. Thirty‐five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinson's Disease Rating Scale (UPDRS) assessed with a prospective cross‐over double‐blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off‐ and on‐medication states with and without stimulation, activities of daily living (ADL), anti‐PD medications, and dyskinesias. In double‐blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off‐stimulation, regardless of the sequence of stimulation. In open assessment, both STN‐ and GPi‐DBS significantly improved the off‐medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti‐PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long‐term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN‐DBS patients and fewer adverse events in the GPi‐DBS group. © 2010 Movement Disorder Society     

Prolonged cholinergic enrichment influences regional cortical activation in early Alzheimer's disease

Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) indicate that the short and long term actions of ChEIs are dissimilar. fMRI studies of the ChEI rivastigmine have focused on its short term action. In this exploratory study the effect of prolonged (20 weeks) rivastigmine treatment on regional brain activity was measured with fMRI in patients with mild AD. Eleven patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. There was an increase in task-related brain activity after treatment with activations more like those of normal healthy elderly. Behaviorally, however, there were no significant differences between baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Variable patient response and drug dynamic/kinetic factors in small patient groups will inevitably bias (either way) the effect size of any relevant drug related changes in activation. Future studies should take drug response into account to provide more insight into the benefits of ChEI drugs at the individual level.     

The development of adrenal homolog of rainbow trout<Emphasis Type="Italic"> Oncorhynchus mykiss</Emphasis>: an immunohistochemical and ultrastructural study

In this work we describe the adrenal homolog of the rainbow trout Oncorhynchus mykiss during development. At the histological level, the interrenal primordium is clearly evident in larvae 25 days after fertilization (dpf), and the immunohistochemical reactions for tyrosine hydroxylase (TH) and phenylethanolamine-N-methyltransferase (PNMT), which mark the chromaffin cells, appear as early as 27 dpf. Both reactions are evident in cells localized in the head kidney and in some, probably migrating, cells close to the notochord. In 27-dpf larvae, the ultrastructural analysis shows the presence of the interrenal cells with mitochondria with tubulovesicular cristae, typical of steroidogenic cells, sometimes surrounded by smooth endoplasmic reticulum (SER) cisternae, indicating that in this stage the cells have the capacity for steroid synthesis and secretion. In the same stage the chromaffin cells are characterized by few and small membrane-bound granules containing cores of heterogeneous electron density. Both types of cells show large nuclei, numerous free or clumped ribosomes, developed rough endoplasmic reticulum (RER), and scarce SER. Rare nerve endings contacting chromaffin cells are present. In the subsequent developmental stages, a further differentiation of both types of cells is evidenced by modifications of cell organelles as mitochondria, chromaffin granules, RER, SER, and so on. A clear discrimination of the two types of catecholamine-containing cells, adrenaline and noradrenaline cells, is evident only 5 days after hatching. The presence of different interrenal cell types in larvae at 5 and 10 days after hatching probably indicates the activation of a physiological cellular cycle. The immunohistochemical and ultrastructural results are compared with those obtained by other authors in the same and other vertebrate species.     

Left mediotemporal structures mediate the retrieval of episodic autobiographical mental images

The aim of this functional magnetic resonance imaging (fMRI) study was to investigate the neuroanatomical substrates associated with the process of mental generation of specific (i.e., exemplar) and episodic autobiographical (i.e., an image of a unique life episode connected with an object) images. The fMRI paradigm in this experiment included a non-image generation baseline and two activation conditions requiring the generation of either specific or episodic autobiographical images. Image generation times and brain activation were recorded. Behavioral results showed that generating specific mental images took significantly less than generating episodic autobiographical images. Individuals generated specific images that were well distinct from the episodic autobiographical ones, semantic in nature without an episodic reference. Episodic autobiographical images did not show a significant bias towards preferential retrieval from any particular life period but were retrieved from across the entire life span. Conjunction analysis of the fMRI data showed that the two image generation conditions significantly activated a common set of neural structures, including mediofrontal areas. This shared pattern of activation might be the result of an underlying similar format and characteristics (e.g., richness in details) between the two types of images and might reflect the involvement of similar cognitive processes. Distinct patterns of significant activation were also present. Activation in the right parietal regions, cuneus, precuneus and left temporal regions was associated solely with the generation of specific images. Regions more specifically devoted to episodic memory retrieval and imagery, such as the left parahippocampal gyrus and precuneus, and the posterior cingulate cortex bilaterally, were significantly activated exclusively by the generation of episodic autobiographical images.     

Chromaffin cells in the adrenal homolog of Aphanius fasciatus (teleost fish) express piecemeal degranulation in response to osmotic stress: a hint for a conservative evolutionary process

The effect of severe osmotic stress on the ultrastructural morphology of chromaffin cells in the adrenal homolog of Aphanius fasciatus, a small eurhyaline teleost living in saltpans, was evaluated by electron microscopy quantitative analysis. Fishes were transferred from salt water, whose salinity was 3.7%, to dechlorinated tap water and chromaffin cells were studied at resting condition and after 2 and 48 hr from the beginning of the experiment. Ultrastructural examination revealed a series of granule and cytoplasmic changes highly specific for piecemeal degranulation (PMD), a secretory process based on vesicular transport of cargoes from within granules for extracellular release, which was previously described in chromaffin cells of the mouse, rat, and human adrenal medulla. There was indeed a significant trend toward loss of content material from chromaffin granules accompanied by enlargement of granule size. Remarkably, chromaffin granules maintained their individual close structure during the whole releasing process and eventually transformed into large empty containers. A dramatic increase in the density of small, membrane-bound, variably electron-dense vesicles free in the cytoplasm or attached to granules was recognized during the first 2 hr of stress response. These features fell to control levels after 48 hr. A similar time-course pattern was observed concerning the formation of budding projections from the surface of chromaffin granules. This study provides new insight into PMD physiology and suggests that PMD is part of an adaptive secretory response to severe osmotic stress in fishes. From an evolutionary point of view, this study lends support to the concept that PMD is a secretory mechanism highly conserved throughout vertebrate classes.     

Combining neuropsychological and structural neuroimaging indicators of conversion to Alzheimer's disease in amnestic mild cognitive impairment

Morphometric and neuropsychological retrospective studies of amnestic mild cognitive impairment (MCI) have demonstrated that regional atrophies and cognitive impairments may differentiate stable from progressing MCI. No measure has proved helpful prospectively. In this study, twenty five amnestic MCI patients and 25 healthy controls underwent structural MRI and comprehensive neuropsychological assessment. The groups' grey matter volumes were compared with voxel based morphometry and were also correlated with scores obtained on paired associates learning and category fluency tasks. MCI patients had significantly reduced grey matter volume in left mediotemporal and other neocortical regions compared with controls. Atrophy in perirhinal and anterior inferior temporal cortex was associated with poor scores on both category fluency and paired associates learning tasks. After 36 months, 44% of the MCI sample converted to dementia. Converter and non-converter MCI subgroups differed in paired associates learning and in category fluency scores, and showed limited differences in grey matter loss in the hippocampal complex. Variable atrophy in the hippocampus was not a relevant element in the converter/non converter distinction, but converters had significant volumetric reductions in the perhirinal cortex and in other anterior temporal and frontal neocortical areas. A high proportion of converters (91%) could be identified from baseline data using a combination of measures of regional atrophy in left temporal association cortex and poor scores on paired associates learning and category fluency tasks. This combined approach may offer a better option than using each measure alone to prospectively identify individuals at more immediate risk of conversion to dementia in the MCI population. The clinical advantage of this combination of structural MRI and neuropsychological measures in predicting conversion to dementia will need additional prospective validation.     

The influence of regulatory T cells and diurnal hormone rhythms on T helper cell activity

Symptoms of diseases such as rheumatoid arthritis, which is T helper 1 (Th1) dependent, and asthma, which is T helper 2 (Th2) dependent, are influenced by diurnal rhythms and natural regulatory T cells (nTreg). However, the mechanisms responsible for the diurnal rhythm of disease activity have not been identified and it is unclear whether nTreg activity is diurnal rhythm‐dependent. We therefore investigated whether a 24‐hr diurnal cycle affected the ability of various helper T‐cell populations to generate immunomodulatory and pro‐inflammatory cytokines, as well as its suppression by nTreg cells. Using a within‐subject crossover design, sleep versus continuous wakefulness was compared over a 24‐hr period in healthy young volunteers under defined environmental conditions. Venous blood was drawn periodically every 5 hr and the function of T cells was explored in vitro. We demonstrated that interleukin (IL)‐2, interferon‐γ (IFN‐γ), tumour necrosis factor‐α (TNF‐α) and IL‐10 secretion by naïve CD4⁺ T cells follows a diurnal rhythm. Furthermore, multiple regression analysis, as well as subsequent in vitro experiments, suggested that serum levels of cortisol and prolactin are part of the underlying mechanism. Additionally, we observed that nTreg suppressed the secretion of IFN‐γ, IL‐2 and TNF‐α, but not the secretion of IL‐4, IL‐6, IL‐10 and IL‐17A. However, the abrogation of IL‐2 release was reversed upon inhibiting CD25 on nTreg. Highly purified nTreg secreted IL‐6, IL‐10 and IL‐17A, but not IL‐2, IL‐4, IFN‐γ or TNF‐α. Taken together, our results demonstrate that hormones and nTreg modulate the diurnal rhythm of T helper cell activity.