A 30-d course of oral administration of a semipurified extract of the root of Withania somnifera consisting predominantly of withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation of β-amyloid peptides (Aβ) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease transgenic mice. It was similarly effective in reversing behavioral deficits and plaque load in APPSwInd mice (line J20). The temporal sequence involved an increase in plasma Aβ and a decrease in brain Aβ monomer after 7 d, indicating increased transport of Aβ from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aβ-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Aβ levels. However, significant increase in liver LRP and NEP occurred much earlier, at 7 d, and were accompanied by a rise in plasma sLRP, a peripheral sink for brain Aβ. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain Aβ, indicating that increase in liver LRP and sLRP occurring independent of Aβ concentration could result in clearance of Aβ. Selective down-regulation of liver LRP, but not NEP, abrogated the therapeutic effects of the extract. The remarkable therapeutic effect of W. somnifera mediated through up-regulation of liver LRP indicates that targeting the periphery offers a unique mechanism for Aβ clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.herbal extract | dementia | neurodegenerative disease A lzheimer's disease (AD) is characterized by progressive dysfunction of memory and higher cognitive functions. Pathological hallmarks include senile plaques, neurofibrillary tangles, dystrophic neurites, gliosis, and neuroinflammation. Cholinesterase inhibitors and the NMDA antagonist memantine, the commonly used drugs for AD, provide symptomatic relief but do not alter the course of disease. No curative treatment is available, and research focuses on drugs for slowing disease progression or providing prophylaxis.The majority of AD cases are sporadic in nature. The small fraction of familial cases are caused primarily by mutations in three genes: amyloid precursor protein (APP), presenilin1 (PS1), and presenilin 2 (PS2). These mutations result in abnormal processing of APP and increased generation of β amyloid peptide 1-42 (Aβ42), which aggregates as β sheets (1). Treatment strategies have focused on reducing β-amyloid load through (i) inhibition of γ-or β-secretases or activation of α-secretase; (ii) inhibition of Aβ aggregation; (iii) activation of proteases, such as neprilysin (NEP); and (iv) active and passive immunotherapy (2, 3).Among other mechanisms, influx and efflux of brain Aβ are regulated by receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein (LRP), respectively (4). The soluble form of LRP in plasma (sLRP) is a peripheral sink for Aβ that aids i...

Many Australian medical students and doctors are interested in research, especially part-time. Perceived obstacles include job insecurity, low funding rates and salary. Respondents underestimated clinical and research salary differences. This article is protected by copyright. All rights reserved.

People diagnosed with Parkinson's disease (PD) frequently experience visual and non-visual hallucinations often with comorbid psychosis, however, there is currently no gold standard tool for accurately assessing these symptoms. To address this problem, we designed a novel questionnaire to evaluate the presence of hallucinatory and psychotic symptoms in PD, as well as related symptoms, such as attentional dysfunction and sleep disturbance. We administered the 20-item Psychosis and Hallucinations Questionnaire (PsycH-Q) and three common questionnaire measures in a large cohort of 197 patients with idiopathic PD via a postal survey. We established concurrent validity, convergent validity, and internal consistency of the questionnaire and then assessed test-retest reliability in a subcohort of 44 patients. PsycH-Q was found to be a valid instrument when analogous items were compared across three other existing tools (Spearman's rho range: 0.34-0.64; P < 0.01). PsycH-Q demonstrated a strong relationship between self-reported hallucinations and psychosis and symptoms of the broader hallucinatory phenotype (Kendall's tau = 0.41; P < 0.01; positive predictive value = 0.97). PsycH-Q also displayed a high level of internal consistency (Cronbach's alpha = 0.900; range, 0.696-0.923) and reproducibility (intraclass correlation coefficient = 0.928). PsycH-Q is a simple, valid, self-completed instrument that reliably identifies hallucinations and psychosis in PD and has the ability to characterize related patterns of attentional and sleep impairments. As such, PsycH-Q is a highly valuable tool for use in both clinical and research settings.The evolution of psychotic symptoms is common in Parkinson's disease (PD) and not surprisingly, the presence of visual hallucinations (VH) represents a strong predictor for the development of more florid psychosis, 1 impaired quality of life, 2 and frequently leads to nursing home placement. 3,4 Patients vary in their ability to self-identify these symptoms, making accurate diagnosis and treatment problematic in both the clinical and research setting. 5 Many patients are unable to understand the medical terminology associated with these symptoms, leading to potential under-reporting. Indeed, a recent task force concluded that a novel questionnaire encompassing the broad phenomenology of the disorder would help to increase the sensitivity of the diagnosis of psychosis and VH in PD. 5,6 In addition, hallucinations in PD have consistently been shown to occur in the presence of broader phenotypic abnormalities, including problems with attention, 7-10 general cognition, 8,10 and sleep, 11-13 thus highlighting the specific domains that can be targeted to better characterize the broader phenomenology of psychosis and hallucinations in PD.In an attempt to solve these two related issues, we designed a novel self-report questionnaire-the Psychosis and Hallucinations Questionnaire (PsycH-Q). The questionnaire has been specifically written in "nonscientific" language with a focus on the phen...