Cerebrovascular risk factors for dementia : the breakdown of cerebrocortical capillary integrity in Alzheimer's disease, experimental cerebral hypoperfusion and chronic hypertension

De ziekte van Alzheimer is een prominente neurologische aandoening tijdens veroudering die samengaat met een geleidelijk afnemende geheugencapaciteit en opmerkelijke neuropathologische veranderingen in de hersenen. Naast de pathologie van het hersenweefsel is ook de bloedvoorziening van het brein bij deze ziekte sterk verminderd. In dit proefschriftt wordt de ultrastructuele afbraak van de hersencapillairen behandeld in de hersenen van patienten lijdende aan dementie en in proefdiermodellen waarbij het functionele verband tussen een verminderde hersendoorbloeding en microvasculaire morfologische afwijkingen wordt bestudeerd. Verder wordt in het bijzonder aandacht besteed aan de rol van de intracellulaire calcium homeostase bij het onstaan van schade aan hersencappillairen. ... Zie: Nederlandse Samenvatting.

Case Record

UNDIFFERENTIATED SCHIZOPHRENIA: Mr. R was reported to be normal 4 years back, he was found to be preoccupied and not communicating well with his family members and preferred to stay alone. He was talking and laughing to self. When asked he said that he heard voices speaking to him and he were replying to it. Gradually his sleep decreased and he would sleep only for 3 to 4 hours at night. He did not attend classes. He was started washing his room many times. He was taking bath frequently. He was started worshiping god Anjanaya many times a day and also avoiding to speak with female family members. This continued for 2 months after which he started to be abusive and assaultive others for no reason. So he was taken to a psychiatrist, was admitted for 10 days and treated with ECT. After discharge he would discontinue medications on and off during which his symptoms would get exacerbated. He continued his studies but performance was poor. He also exhibited suicidal gestures on three occasions in the form of cutting his harms and carrying kerosene and matchbox inside the bathroom, saved by family members. Again the mother took him to psychiatrist and continued medication the symptoms were under the control. He completed his course but did not complete his studies. Then he got employment into Ford Company, his performance was average, he continued his job for 5 months with medication. After discontinue of treatment he became self-withdrawn, slowly he was neglecting self-care, attempted suicide, coworkers informed to his parents. Hence he was brought to IMH and admitted. No H/O sad mood, crying spells. No H/O tall claims, spending spree. No H/O thoughts being known to others or withdrawn. No H/O substance use. No H/O head injury, LOC, seizures. No H/O fever or any prolonged drug intake. SUBSTANCE INDUCED MOOD DISORDER: The patient was introduced to using betelnut along with his friends around 18 years of age. Later be continued to use tobacco in the form of Panparag, Hans, Shanthi betelnut 4-6 packets per day. Later after 3 years of tobacco intake, he started consuming alcohol for the first time along with his friends on some occasion, he consumed beer around 200ml. As he enjoyed the high produced by the drink, he continued to take alcohol at regular interval. After 1 year of beginning alcohol intake, he got married, after 6months of marriage life he started consuming alcohol in the form of brandy almost every night. He would become intoxicated, come home, abuse and assault his wife frequently. Due to frequent marrital dishormony his wife left and living with her grand parants for past 8 months. Now according to his be continued to drink alcohol, but the past two months he was engaged in some temple work, where he is supposedto have been introduced to cannabis.After consuming cannabis, his behavior became unmanageble. He frequently keep standing in the middle of the road and appear to make gesturesas if regulating the traffic. He would keep talking excessively and laugh for unprovoked reasons. His sleep patterns also worsened. All through out the night he would keep wandering in the street. And also he was started talking irrelevantly and would not be able to brought back home. He would also talk high about himself. He would claim himself to be God and capable of doing lot of things and able to grant wishes to all people. His selfcare also deteriorated, he started picking up quarrles and assaulted others. Nighbours made complaint against him. So, the family members brought him in the confused state to IMH. He was treated with Ing. Lorazepam 4 mg IM stat and referred to GGH for favour ofadmission and rule out other causes of delirium. He was treated at GGH for one week with Inj. Haloperidal 5 mg, Inj. Lorazepam 4 mg im, Inj.Thiamine and has been referred to IMH for further management. No h/o head injury/LOC/seizures. No h/o low mood/crying spells/suicidal attempts. No h/o hearing voices No h/o repititive washing/cheeking etc., DELUSIONAL DISORDER-MIXED: The patient was reported to be normal till one year eight months back. She claimed hat her co-tenant Mr. V called her for sexual relationship and she refused after that she started telling that he is setting people against her to harm her and also setup prostitutes as a co-tenants, to move her away from the place She also says that he tried to kill her with ambulance 108 and milk van by using his political influence. Patient gave complaint in nearby police station about Mr. Enquiry done. But the police Also turned against her by his political influence. So, she used to go to SP office, collector office daily and shout to arrest Mr. V. Mean while she vacated that house and shifted to Mr. S house who is friend of her brother. He is a widower, living alone. After 2 months of shifting to new house she started believing that the house owner was deeply loved with her whom she understands by his Gestures. And he did not admit his love for her has he did not want others to know. She was fought with the co-tenant once for silly reason. They were assaulted her with an aluminum mug and broken house hold article. And she assumed that Mr. V. only arranged them to fight with her. And also without any reason the patient was fought with the female Co-tenants whoever talking to Mr. S. She uses to tell everybody that the Mr. S. loves with her. The house owner warned them to vacate the house. But she did not vacate the house. The house owner slowly cut power supply, water supply to her portion. After 4 months she vacated the house to Next Street. Even after vacating, patient goes to Mr. S. house and starts quarrel with the new tenants that they should vacate and only because of them he is avoiding her. Every day she was going to her old house and tells everybody that the house owner loves with her. The husband told her not to go there, but she poured kerosene on him and try to kill him. So, the house owner filed a case against her, she was arrested and kept in observation at IMH. During observation she was continuously blaming the old co-tenant that all because him only it happen. Still the house owner his loves with her, she also loves him deeply. DEMENTIA IN ALZHEIMER’S DISEASE: The patient was reported to be normal till one year back. Then, her daughter noticed that the patient repeatedly searched for certain things in the house. She would forget simple things in the house like the way for going to toilet. At times she also found it difficult to return to her house after going for a walk. In course of time, she was not able to identify her close relatives. She was not able to remember whether she had taken her food or not. Her personal hygiene decreased gradually. She did not take bath and did not dress properly. She would pass urine inside the house itself at times. She slept for very little time and would wake up in the middle of the night and keep pacing inside the house.Slowly she was not able to identify her own family members. MENTAL RETARDATION-MILD: Patient was born out of non consanguineous marriage, full term normal delivery. Mother was 22 yrs and fathers age was 298 yrs. No history of any drug intake, fever or exanthematous eruptions in the ante natal period. No ante natal checkup was done. No history of radiation, injury, malnutrition, or vaginal bleeding. Delivery was conducted by local dhai; h/o prolonged 2nd stage of labor, the baby cried soon after birth and was breast fed after a short while. No h/o neonatal seizures or difficulty in feeding. No h/o of jaundice, breast fed up to 10 months, and there were no weaning difficulties

Phyto-Therapeutic and Nanomedicinal Approaches to Cure Alzheimer’s Disease: Present Status and Future Opportunities

Alzheimer’s disease (AD) is characterized by cognitive inability manifested due to the accumulation of β-amyloid, formation of hyper phosphorylated neurofibrillary tangles, and a malfunctioned cholinergic system. The degeneration integrity of the neuronal network can appear long after the onset of the disease. Nanotechnology-based interventions have opened an exciting area via theranostics of AD in terms of tailored nanomedicine, which are able to target and deliver drugs across the blood–brain barrier (BBB). The exciting interface existing between medicinal plants and nanotechnology is an emerging marvel in medicine, which has delivered promising results in the treatment of AD. In order to assess the potential applications of the medicinal plants, their derived components, and various nanomedicinal approaches, a review of literature was deemed as necessary. In the present review, numerous phytochemicals and various feats in nanomedicine for the treatment of AD have been discussed mechanistically for the first time. Furthermore, recent trends in nanotechnology such as green synthesis of metal nanoparticles with reference to the treatment of AD have been elaborated. Foreseeing the recent progress, we hope that the interface of medicinal plants and nanotechnology will lead to highly effective theranostic strategies for the treatment of AD in the near future

L-deprenyl attenuates the rotenone-induced dopaminergic neurotoxicity: experimental evidences in rats

Parkinson disease (PD) is progressive neurological disorder because of massive degeneration of nigrostriatal dopaminergic neurons. The pathogenesis of PD is unknown, but considerable evidence suggests multifactorial factors including genetic, mitochondrial dysfunction, oxidative stress, excitotoxicity, calcium cytotoxicity, environmental factors and apoptosis. We investigated the role of oxidative damage produced by intranigral infusion of a potent mitochondrial complex-I inhibitor, rotenone and studied the neuroprotective effects with a well-known antiparkinsonian drug L-deprenyl in rats. Unilateral stereotaxic intranigral infusion of rotenone 6 lg caused significant decrease in dopamine levels. L-deprenyl (10 mg/kg) treatment significantly attenuated the DA depletion caused by rotenone. Parallely, a significant decrease in the concentration of GSH was also observed in the SN was reverted by L-deprenyl treatment. L-deprenyl significantly attenuated the rotenone-induced decrease in tyrosine hydroxylase immunoreactivity in striatum. The results suggest that L-deprenyl can rescue the dopaminergic neurons from the rotenone mediated neurodegeneration in this experimental animal model

toxines et signalisation

Collection Rencontres en toxinologie ISSN: 1760-6004 ; http://sfet.asso.fr/images/stories/SFET/pdf/EBook-RT17-2009-signets.pdfInternational audienc

The role of high-fat diet in an APP/PS1 model of familial Alzheimer disease = Efecto de una dieta rica en grasas en ratones APP/PS1, modelo familiar de la enfermedad de Alzheimer

[spa] La obesidad es una pandemia mundial, la cual según estudios recientes afecta a más de 2.000 millones de personas en todo el mundo y conlleva una fuerte presión de los sistemas sanitarios globales. El problema se ve aumentado no sólo por los costes directos asociados al sobrepeso, sino también por las comorbilidades relacionadas, entre ellas el incremento del riesgo de desarrollo de enfermedades neurodegenerativas, como por ejemplo la enfermedad de Alzheimer (EA), principal causa de demencia senil. Hasta el momento, la industria farmacéutica no ha sido capaz de desarrollar estrategias eficaces para el tratamiento de la EA. Por ello, ha surgido la necesidad de plantearse nuevos mecanismos moleculares que puedieran explicar el declive cognitivo de esta enfermedad. La presente tesis doctoral trata sobre los efectos provocados por la ingesta de una dieta rica en grasa (high-fat diet, HFD) en ratones salvajes C57/Bl6 (wild-type, WT) y en ratones APPswe/PS1dE9 (APP/PS1), como modelo experimental de EA familiar. Dichos ratones fueron alimentados con dieta estándar a partir del destete (21 días) hasta los 3 meses. Por otro lado se estableció un nueva línea de investigación en la cual los animales fueran alimentados con dieta estándar o HFD hasta los 6 meses de edad. Se detectó hiperfosforilación de la proteína tau, amiloidogénesis y deterioro de la señalización mitocondrial en el hipocampo de los ratones APP/PS1 a 3 meses de edad. Por otro lado, los ratones presentaban un fenotipo exacerbado a 6 meses. Además, presentaban defectos cognitivos, anomalías en la vía de señalización de la insulina en el hipocampo y alteraciones en el metabolismo periférico de la glucosa y de la insulina. La ingesta de la HFD indujo obesidad y desarrollo de síndrome metabólico, tanto en el grupo de ratones WT como en APP/PS1. Ambos grupos presentaron pérdida de memoria, alteración del metabolismo periférico de la glucosa, así como anomalías en la vía de señalización de la insulina y en el metabolismo mitocondrial en hipocampo, desarrollando un fenotipo casi diabético en el caso de los ratones APP/PS1. En los extractos corticales de estos animales alimentados con HFD se detectaron niveles de Aβ insoluble (1-42) significativamente más elevados en comparación con los alimentados con dieta estándar. En los animales transgénicos con predisposición al desarrollo de EA, la introducción de una dieta hipercalórica provocó un empeoramiento significativo del fenotipo, tanto en la periferia como en el hipocampo. En general, nuestros resultados parecen indicar que el síndrome metabólico, la diabetes y las comorbilidades asociadas podrían causar un empeoramiento significativo de los síntomas de EA.[eng] Global obesity is a pandemic status, estimated to affect over 2 billion people, and has resulted in an enormous strain on healthcare systems worldwide. The situation is compounded by the fact that apart from the direct costs associated with overweight pathology, obesity presents itself with a number of comorbidities, including an increased risk for the development of neurodegenerative disorders. Alzheimer disease (AD), the main cause of senile dementia, is no exception. Spectacular failure of the pharmaceutical industry to come up with effective AD treatment strategies is forcing scientific community to rethink the underlying molecular mechanisms leading to cognitive decline. Research described in this doctoral thesis is focused on the effects of a high-fat diet (HFD) versus control chow in C57/Bl6 Wild-type (WT) and APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. WT and APP/PS1 mice were fed control chow from the time of weaning (21 days) until the age of 3 months. In addition, a separate group of animals were fed either a control or a HFD from the time of weaning until 6 months of age. We have detected tau hyperphosphorylation, amyloidogenesis and impaired mitochondrial signaling in the hippocampi of 3-month-old APP/PS1 mice. By the time the mice reached 6 months of age this phenotype was exacerbated. In addition, 6-month-old APP/PS1 mice present with cognitive deficits, hippocampal insulin signaling abnormalities and impairments in peripheral glucose and insulin tolerance. On a HFD, diet-induced obesity and metabolic syndrome were present both in the WT and APP/PS1 groups. Both groups demonstrate memory loss and impaired peripheral glucose metabolism as well as abnormal hippocampal insulin signaling and mitochondrial metabolism, with APP/PS1 mice exhibiting a nearly diabetic phenotype. Significantly higher levels of insoluble Aβ (1-42) were detected in the cortical extracts of HFD-fed APP/PS1 mice versus APP/PS1 animals on a control chow. In transgenic animals predisposed to AD development, the introduction of hypercaloric diet significantly worsened existing phenotype both at the periphery and in the hippocampal networks. Overall, our results suggest that metabolic syndrome, diabetes and related comorbidities clearly do have a potential to significantly worsen the symptoms of AD disease

Cholinesterase Research

This collection of 10 papers includes original as well as review articles focused on the cholinesterase structural aspects, drug design and development of novel cholinesterase ligands, but also contains papers focused on the natural compounds and their effect on the cholinergic system and unexplored effects of donepezil

THE ROLE OF GPR30 IN MEDIATING ESTROGEN EFFECTS ON NEURONS AND COGNITIVE PERFORMANCE

Basic and clinical research suggests the loss of estradiol following menopause may contribute to accelerated brain aging and the increased risk of age-related cognitive decline and dementia. Novel estrogenic compounds may confer positive cognitive effects without the added risk of side effects associated with current agents. G-1 is a recently developed agonist for the novel transmembrane estrogen receptor (ER) GPR30. Activation of the GPR30 pathway is independent of either the classical ER α or β pathways, raising the possibility of using G-1 as a novel estrogenic agent while avoiding the risks associated with other estrogenic compounds. Previous work in our laboratory has shown that estradiol enhances cognitive performance via effects on basal forebrain cholinergic neurons. We hypothesize the effects of estradiol on cholinergic function and cognitive performance are mediated by GPR30. If correct, then selective GPR30 agonists may provide useful alternatives to current estrogenic therapies. To test this hypothesis the first goal was to characterize GPR30 expression in the rat forebrain, focusing on co-expression by cholinergic neurons. A RT-PCR assay was developed to quantify GPR30 mRNA in specific brain regions. GPR30 protein and mRNA expression were found in regions of the brain important for spatial learning and memory. Moreover, GPR30 protein appears to be expressed by the vast majority of cholinergic neurons. The second goal was to examine the effects of GPR30 activation on cholinergic neurons. In vivo microdialysis and HPLC analysis of acetylcholine levels in dialysates were used to compare effects on acetylcholine release. Administration of a GPR30 agonist or estradiol (E2) to ovariectomized (OVX) rats produced a 3-fold increase in potassium-stimulated acetylcholine release in the hippocampus relative to vehicle-treated controls. The third goal was to test the ability of GPR30 agonists and antagonists to enhance or impair cognitive performance in rats. GPR30 agonism enhanced the rate of acquisition on a delayed matching-to-position (DMP) T-maze task in OVX rats similar to estradiol while GPR30 antagonism dose-dependently impaired performance in gonadally intact and OVX+E2 rodents. Hence, GPR30 appears to play an important role in mediating direct effects of estradiol on basal forebrain cholinergic neurons, with corresponding effects on cognitive performance