scispace - formally typeset
Search or ask a question

Showing papers in "Journal of Neural Transmission in 2013"


Journal ArticleDOI
TL;DR: The therapeutic strategies that have been tested until now on the STZ-icv animal model have been reviewed and the comparability of the drugs’ efficacy in this non-transgenic sAD model and the results from clinical trials on sAD patients, evaluated.
Abstract: Experimental models that faithfully mimic the developmental pathology of sporadic Alzheimer's disease (sAD) in humans are important for testing the novel therapeutic approaches in sAD treatment. Widely used transgenic mice AD models have provided valuable insights into the molecular mechanisms underlying the memory decline but, due to the particular β-amyloid-related gene manipulation, they resemble the familial but not the sporadic AD form, and are, therefore, inappropriate for this purpose. In line with the recent findings of sAD being recognised as an insulin resistant brains state (IRBS), a new, non-transgenic, animal model has been proposed as a representative model of sAD, developed by intracerebroventricular application of the betacytotoxic drug streptozotocin (STZ-icv). The STZ-icv-treated animals (mostly rats and mice) develop IRBS associated with memory impairment and progressive cholinergic deficits, glucose hypometabolism, oxidative stress and neurodegeneration that share many features in common with sAD in humans. The therapeutic strategies (acetylcholinesterase inhibitors, antioxidants and many other drugs) that have been tested until now on the STZ-icv animal model have been reviewed and the comparability of the drugs' efficacy in this non-transgenic sAD model and the results from clinical trials on sAD patients, evaluated.

208 citations


Journal ArticleDOI
TL;DR: An antidepressant effect of a new transcutaneous auricular nerve stimulation technique has been shown for the first time in this controlled pilot study.
Abstract: Invasive vagus nerve stimulation has been demonstrated to be an effective treatment in major depressive episodes. Recently, a novel non-invasive method of stimulating the vagus nerve on the outer canal of the ear has been proposed. In healthy subjects, a prominent fMRI BOLD signal deactivation in the limbic system was found. The present pilot study investigates the effects of this novel technique of auricular transcutaneous electric nerve stimulation in depressed patients for the first time. A total of 37 patients suffering from major depression were included in two randomized sham controlled add-on studies. Patients were stimulated five times a week on a daily basis for the duration of 2 weeks. On days 0 and 14, the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI) were assessed. In contrast to sham-treated patients, electrically stimulated persons showed a significantly better outcome in the BDI. Mean decrease in the active treatment group was 12.6 (SD 6.0) points compared to 4.4 (SD 9.9) points in the sham group. HAMD score did not change significantly in the two groups. An antidepressant effect of a new transcutaneous auricular nerve stimulation technique has been shown for the first time in this controlled pilot study. Regarding the limitations of psychometric testing, the risk of unblinding for technical reasons, and the small sample size, further studies are necessary to confirm the present results and verify the practicability of tVNS in clinical fields.

190 citations


Journal ArticleDOI
TL;DR: The NeuroAD system offers a novel, safe and effective therapy for improving cognitive function in AD and improves cognitive score and Neuropsychiatric Inventory.
Abstract: Cortical excitability can be modulated using repetitive transcranial magnetic stimulation (rTMS). Previously, we showed that rTMS combined with cognitive training (rTMS-COG) has positive results in Alzheimer’s disease (AD). The goal of this randomized double-blind, controlled study was to examine the safety and efficacy of rTMS-COG in AD. Fifteen AD patients received 1-h daily rTMS-COG or sham treatment (seven treated, eight placebo), five sessions/week for 6 weeks, followed by biweekly sessions for 3 months. The primary outcome was improvement of the cognitive score. The secondary outcome included improvement in the Clinical Global Impression of Change (CGIC) and Neuropsychiatric Inventory (NPI). There was an improvement in the average ADAS-cog score of 3.76 points after 6 weeks in the treatment group compared to 0.47 in the placebo group and 3.52 points after 4.5 months of treatment, compared to worsening of 0.38 in the placebo (P = 0.04 and P = 0.05, respectively). There was also an improvement in the average CGIC score of 3.57 (after 6 weeks) and 3.67 points (after 4.5 months), compared to 4.25 and 4.29 in the placebo group (mild worsening) (P = 0.05 and P = 0.05, respectively). NPI improved non-significantly. In summary, the NeuroAD system offers a novel, safe and effective therapy for improving cognitive function in AD.

166 citations


Journal ArticleDOI
TL;DR: The present state of knowledge generally supports limbic and cortical prefrontal involvement as originally proposed in the neuroanatomical hypothesis of panic disorder, and the assumption of a generally hyperactive amygdala in PD seems to apply more to state than trait characteristics of PD.
Abstract: In 2000, Gorman et al. published a widely acknowledged revised version of their 1989 neuroanatomical hypothesis of panic disorder (PD). Herein, a 'fear network' was suggested to mediate fear- and anxiety-related responses: panic attacks result from a dysfunctional coordination of 'upstream' (cortical) and 'downstream' (brainstem) sensory information leading to heightened amygdala activity with subsequent behavioral, autonomic and neuroendocrine activation. Given the emergence of novel imaging methods such as fMRI and the publication of numerous neuroimaging studies regarding PD since 2000, a comprehensive literature search was performed regarding structural (CT, MRI), metabolic (PET, SPECT, MRS) and functional (fMRI, NIRS, EEG) studies on PD, which will be reviewed and critically discussed in relation to the neuroanatomical hypothesis of PD. Recent findings support structural and functional alterations in limbic and cortical structures in PD. Novel insights regarding structural volume increase or reduction, hyper- or hypoactivity, laterality and task-specificity of neural activation patterns emerged. The assumption of a generally hyperactive amygdala in PD seems to apply more to state than trait characteristics of PD, and involvement of further areas in the fear circuit, such as anterior cingulate and insula, is suggested. Furthermore, genetic risk variants have been proposed to partly drive fear network activity. Thus, the present state of knowledge generally supports limbic and cortical prefrontal involvement as originally proposed in the neuroanatomical hypothesis. Some modifications might be suggested regarding a potential extension of the fear circuit, genetic factors shaping neural network activity and neuroanatomically informed clinical subtypes of PD potentially guiding future treatment decisions.

148 citations


Journal ArticleDOI
TL;DR: Overall, botulinum neurotoxin type A products exhibit low clinically detectable levels of antibodies when compared with other approved biologic products.
Abstract: Botulinum neurotoxins are formulated biologic pharmaceuticals used therapeutically to treat a wide variety of chronic conditions, with varying governmental approvals by country. Some of these disorders include cervical dystonia, post-stroke spasticity, blepharospasm, migraine, and hyperhidrosis. Botulinum neurotoxins also have varying governmental approvals for cosmetic applications. As botulinum neurotoxin therapy is often continued over many years, some patients may develop detectable antibodies that may or may not affect their biological activity. Although botulinum neurotoxins are considered “lower risk” biologics since antibodies that may develop are not likely to cross react with endogenous proteins, it is possible that patients may lose their therapeutic response. Various factors impact the immunogenicity of botulinum neurotoxins, including product-related factors such as the manufacturing process, the antigenic protein load, and the presence of accessory proteins, as well as treatment-related factors such as the overall toxin dose, booster injections, and prior vaccination or exposure. Detection of antibodies by laboratory tests does not necessarily predict the clinical success or failure of treatment. Overall, botulinum neurotoxin type A products exhibit low clinically detectable levels of antibodies when compared with other approved biologic products. This review provides an overview of all current botulinum neurotoxin products available commercially, with respect to the development of neutralizing antibodies and clinical response.

138 citations


Journal ArticleDOI
TL;DR: There is at present an urgent need for real disease-modifying therapies for AD and the MTDL approach makes a breakthrough for the development of new drugs capable of addressing the biological complexity of this disorder.
Abstract: Alzheimer's disease (AD) is a complex neuro- degenerative disorder with a multifaceted pathogenesis. There are at present three Food and Drug Administration- approved drugs based on the ''one drug, one target'' para- digm (donepezil, galantamine and rivastigmine) that improve symptoms by inhibiting acetylcholinesterase. However, apart from the beneficial palliative properties, cholinergic drugs have shown little efficacy to prevent the progression of the disease evidencing the unsuitability of this strategy for the complex nature of AD. By contrast, the multifactorial nature of this neurodegenerative disorder supports the most current innovative therapeutic approach based on the ''one drug, multiple targets'' paradigm, which suggests the use of compounds with multiple activities at different target sites. Accordingly, the also called multitar- get-directed ligand (MTDL) approach has been the subject of increasing attention by many research groups, which have developed a variety of hybrid compounds acting on very diverse targets. The therapeutic potential of monoamine oxidase inhibitors (MAOI) in AD has been suggested due to their demonstrated neuroprotective properties besides their enhancing effect on monoaminergic transmission. Espe- cially, those containing a propargylamine moiety are of particular interest due to their reported beneficial actions. Therefore, targeting MAO enzymes should be considered in therapeutic interventions. This review makes a special emphasis on MTDLs that commonly target MAO enzymes. There is at present an urgent need for real disease-modifying therapies for AD and the MTDL approach makes a break- through for the development of new drugs capable of addressing the biological complexity of this disorder.

122 citations


Journal ArticleDOI
TL;DR: The extant literature concerning diffusion tensor imaging studies of brain WM development in healthy individuals is reviewed, trends of normal development of human brain WM are summarized, and possible future research directions are suggested.
Abstract: Delineating the normal development of brain white matter (WM) over the human lifespan is crucial to improved understanding of underlying WM pathology in neuropsychiatric and neurological conditions. We review the extant literature concerning diffusion tensor imaging studies of brain WM development in healthy individuals available until October 2012, summarise trends of normal development of human brain WM and suggest possible future research directions. Temporally, brain WM maturation follows a curvilinear pattern with an increase in fractional anisotropy (FA) from newborn to adolescence, decelerating in adulthood till a plateau around mid-adulthood, and a more rapid decrease of FA from old age onwards. Spatially, brain WM tracts develop from central to peripheral regions, with evidence of anterior-to-posterior maturation in commissural and projection fibres. The corpus callosum and fornix develop first and decline earlier, whilst fronto-temporal WM tracts like cingulum and uncinate fasciculus have protracted maturation and decline later. Prefrontal WM is most vulnerable with greater age-related FA reduction compared with posterior WM. Future large scale studies adopting longitudinal design will better clarify human brain WM changes over time.

107 citations


Journal ArticleDOI
TL;DR: Results from behavioral studies show that patients with FOG experience impairments in executive functioning and response selection which predict that motor learning may be compromised, and a FOG-related reduction of cognitive resources implies that adaptation of rehabilitation interventions is indicated for patients withFOG to promote the consolidation of learning.
Abstract: Freezing of gait (FOG) is a very disabling symptom affecting up to half of the patients with Parkinson's disease (PD). Evidence is accumulating that FOG is caused by a complex interplay between motor, cognitive and affective factors, rather than being a pure motor phenomenon. In the current paper, we review the evidence on the specific role of cognitive factors in FOG. Results from behavioral studies show that patients with FOG experience impairments in executive functioning and response selection which predict that motor learning may be compromised. Brain imaging studies strengthen the neural basis of a potential association between FOG and cognitive impairment, but do not clarify whether it is a primary or secondary determinant of FOG. A FOG-related reduction of cognitive resources implies that adaptation of rehabilitation interventions is indicated for patients with FOG to promote the consolidation of learning.

93 citations


Journal ArticleDOI
TL;DR: The findings among recipients of subcutaneous apomorphine infusion or intrajejunal levodopa/carbidopa intestinal gel suggest that nonmotor PD symptoms or complications may improve in tandem with motor improvement, a necessary first step toward establishing whether CDS is, in fact, an important determinant of clinical efficacy.
Abstract: The complications of long-term levodopa therapy for Parkinson’s disease (PD) include motor fluctuations, dyskinesias, and also nonmotor fluctuations—at least equally common, but less well appreciated—in autonomic, cognitive/psychiatric, and sensory symptoms. In seeking the pathophysiologic mechanisms, the leading hypothesis is that in the parkinsonian brain, intermittent, nonphysiological stimulation of striatal dopamine receptors destabilizes an already unstable system. Accordingly, a major goal of PD treatment in recent years has been the attainment of continuous dopaminergic stimulation (CDS)—or, less theoretically (and more clinically verifiable), continuous drug delivery (CDD). Improvements in the steadiness of the plasma profiles of various dopaminergic therapies may be a signal of progress. However, improvements in plasma profile do not necessarily translate into CDS, or even into CDD to the brain. Still, it is reassuring that clinical studies of approaches to CDD have generally been positive. Head-to-head comparative trials have often failed to uncover evidence favoring such approaches over an intermittent therapy. Nevertheless, the findings among recipients of subcutaneous apomorphine infusion or intrajejunal levodopa/carbidopa intestinal gel suggest that nonmotor PD symptoms or complications may improve in tandem with motor improvement. In vivo receptor binding studies may help to determine the degree of CDS that a dopaminergic therapy can confer. This may be a necessary first step toward establishing whether CDS is, in fact, an important determinant of clinical efficacy. Certainly, the complexities of optimal PD management, and the rationale for an underlying strategy such as CDS or CDD, have not yet been thoroughly elucidated.

87 citations


Journal ArticleDOI
TL;DR: None of the rating scales used at present has been rigorously tested for responsiveness to detect significant changes in clinical status after therapeutic interventions, so further research is needed to develop a valid and reliable instrument.
Abstract: Botulinum neurotoxin is the therapy of choice for all forms of cervical dystonia (CD), but treatment regimens still vary considerably. The interpretation of treatment outcome is mainly based on the clinical experience and on the scientific value of the rating scales applied. The aim of this review is to describe the historical development of rating scales for the assessment of CD and to provide an appraisal of their advantages and drawbacks. The Tsui score and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) have been widely employed in numerous clinical studies as specific instruments for CD. The obvious advantage of the Tsui score is its simplicity so that it can be easily implemented in clinical routine. The TWSTRS allows a more sophisticated assessment of functional features of CD, but only the Tsui score includes a rating for tremor. Other benefits of the TWSTRS are the disability and pain subscales, but despite its value in clinical trials, it might be too complex for routine clinical practice. None of the rating scales used at present has been rigorously tested for responsiveness to detect significant changes in clinical status after therapeutic interventions. Moreover, clinical data support a new classification of CD leading to a differentiation between head and neck subtypes. As the current rating scales are not able to cover all these aspects of the disorder, further research is needed to develop a valid and reliable instrument which considers the most current classification of CD.

78 citations


Journal ArticleDOI
TL;DR: Improvements in speech performance can be demonstrated in PD patients after the introduction of antiparkinsonian therapy, and changes in speech articulation and pitch variability appear to be related with dopaminergic responsiveness of bradykinesia and rigidity.
Abstract: Despite the initial reports showing beneficial effects of dopaminergic treatment on speech in Parkinson’s disease (PD), more recent studies based upon valid measurements have not approved any improvement of speech performance under pharmacotherapy. The aim of this study was to analyze the effect of treatment initiation on the progression of speech impairment in PD, using novel evaluation criteria. Nineteen de novo patients with PD were tested and retested within 2 years after the introduction of antiparkinsonian therapy. As controls, 19 age-matched individuals were recorded. Speech examination included sustained phonation, fast syllable repetition, reading text, and monolog. Quantitative acoustic analyses of the key aspects of speech based on Gaussian kernel distribution, statistical decision-making theory, and healthy speech observation were used to assess the improvement or deterioration of speech. A trend for speech performances to improve was demonstrated after treatment mainly in quality of voice, intensity variability, pitch variability, and articulation. The treatment-related improvement differed in various aspects of speech for individual PD patients. Improvements in vowel articulation and pitch variability correlated with treatment-related changes in bradykinesia and rigidity, whereas voice quality and loudness variability improved independently. Using a novel approach of acoustic analysis and advanced statistics, improvements in speech performance can be demonstrated in PD patients after the introduction of antiparkinsonian therapy. Moreover, changes in speech articulation and pitch variability appear to be related with dopaminergic responsiveness of bradykinesia and rigidity. Therefore, speech may be a valuable marker of disease progression and treatment efficacy in PD.

Journal ArticleDOI
TL;DR: A high index of suspicion is required to make an early diagnosis and initiate appropriate treatment to provide symptomatic relief and to prevent other systemic complications related to the autoimmune process.
Abstract: Movement disorders (MDs), particularly chorea, may be the presenting neurological complication of systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS), but the association is not often initially recognized. Current evidence suggests an autoimmune mechanism related to antiphospholipid antibodies in these two conditions, although the antigenic target within the central nervous system has not yet been identified. Based on a comprehensive review of the literature, this article summarizes the current knowledge on MDs in SLE and APS. A high index of suspicion is required to make an early diagnosis and initiate appropriate treatment to provide symptomatic relief and to prevent other systemic complications related to the autoimmune process.

Journal ArticleDOI
TL;DR: This work assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD.
Abstract: Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0–16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.

Journal ArticleDOI
TL;DR: Folate deficiency is a risk factor for neural tube defects and late in life for cognitive decline and Alzheimer's dementia (AD) as discussed by the authors, which induces several Alzheimer pathomechanisms like oxidative stress, Ca(++) influx, accumulation of hyperphosphorylated tau and β-amyloid.
Abstract: Folate is necessary for DNA and mtDNA integrity and via folate/B12-dependent methionine cycle for methylation of multiple substrates (epigenetic DNA and enzymes) and methylation of homocysteine. During embryogenesis, folate deficiency is a risk factor for neural tube defects and late in life for cognitive decline and Alzheimer's dementia (AD). It induces several Alzheimer pathomechanisms like oxidative stress, Ca(++) influx, accumulation of hyperphosphorylated tau and β-amyloid. But impact of folic acid supplementation on prevention or delay of dementia is a matter of debate. Six out of seven randomized controlled trials (RCT) with B vitamin intervention periods between 2 and 5.4 years reported about cognitive benefits in the supplemented groups mainly for those subjects with high homocysteine or low folate levels at baseline. This review tries to demonstrate the connection between folate deficiency and AD, analyses selected epidemiologic studies and RCT on folate/B12/homocysteine with long-observation periods (≥ 2 years RCT; ≥ 4 years observational) and attempts to find explanations for the controversy in literature like short follow-up, heterogeneity of subjects concerning age, recruitment, baseline cognition, inclusion criteria and probably "misleading"(not representative for the past) folate/B12/homocysteine levels due to not reported short-term use of multivitamins or food-fortification. Population-based studies-epidemiologic and interventional-starting in the fourth decade would provide the best information about the impact of folate on later development of AD. Mandatory folate fortification areas will be important future field studies for-like neural tube defects-hopefully declining AD incidence and disproving safety concerns.

Journal ArticleDOI
TL;DR: Cognitive abnormalities are relatively frequent in multiple system atrophy and this involves primarily frontal-executive functions and their contribution to clinical disability and disease progression needs to be addressed in larger prospective studies.
Abstract: Imaging and neuropathology studies have demonstrated significant abnormalities not only in subcortical, but also in cortical regions of patients with multiple system atrophy (MSA). This raises the possibility that cognitive dysfunction may contribute to the clinical spectrum of this disorder to a greater extent than it is currently not widely appreciated. In this cross-sectional multicenter study from the European multiple system atrophy study group ( http://www.emsa-sg.org ), we applied an extensive neuropsychological test battery in a series of 61 clinically diagnosed probable MSA patients. The results demonstrated that general cognitive decline as assessed by MMSE was uncommon (2 out of 61 patients <24). In contrast, frontal lobe-related functions (as measured by FAB) were impaired in 41 % of patients, with abstract reasoning and sustained attention less compromised. This pattern was similar to our control group of 20 patients with Parkinson's disease (matched for disease duration and age at onset). There was no difference in cognitive performance between MSA patients with the parkinsonian versus the cerebellar variant. Behaviourally, MSA patients had greater depression than PD and in the case of MSA of the cerebellar variant significantly lower anxiety. Our data show that cognitive abnormalities are relatively frequent in multiple system atrophy and this involves primarily frontal-executive functions. Their contribution to clinical disability and disease progression needs to be addressed in larger prospective studies.

Journal ArticleDOI
TL;DR: Resveratrol showed significant cerebroprotective action mediated by anti-oxidant and anti-inflammatory mechanisms against cerebral infarction induced by ischemia and reperfusion injury in Wistar rats.
Abstract: Oxidative stress and inflammation are two important pathological mechanisms involved in cerebral ischemia and reperfusion injury. In pathological conditions such as cerebral infarction, the free radical production is greater than that of elimination by endogenous anti-oxidant system, by this undesirable effect brain is highly injured. Resveratrol is reported to have anti-oxidant and anti-inflammatory, athero-protective activities. Therefore, the aim of the present study is to evaluate the therapeutic potential of resveratrol against cerebral infarction induced by ischemia and reperfusion injury in Wistar rats. Bi-common carotid occlusion followed by 4 h reperfusion model was used to induce cerebral infarction. Percent infarction, oxidative stress markers (malondialdehyde, catalase, superoxide dismutase) and inflammatory markers (myeloperoxidase, TNF-α, IL-6, ICAM-1 and IL-10) were measured. TNF-α, IL-6, IL-10, and intracellular adhesive molecule-I (ICAM-1) levels were quantified by enzyme-linked immunosorbent assay (ELISA). Resveratrol produced significant dose-dependent reduction in percent cerebral infarct volume. At resveratrol 20 mg/kg dose, there was a significant reduction in oxidative stress and inflammatory markers like malondialdehyde, TNF-α, IL-6, myeloperoxidase and ICAM-I and in contrast there was a significant increase in anti-oxidants and anti-inflammatory markers like superoxide dismutase, catalase and IL-10 levels. Resveratrol showed significant cerebroprotective action mediated by anti-oxidant and anti-inflammatory mechanisms.

Journal ArticleDOI
TL;DR: In this paper, a three-dimensional topographic map of the healthy and Parkinson's foveal pit was created, where the difference becomes evident in an annular zone between 0.5 and 2 mm from the foveola and the optimal zone is from 0.75 to 1.5 mm.
Abstract: To quantify the thickness of the inner retinal layers in the foveal pit where the nerve fiber layer (NFL) is absent, and quantify changes in the ganglion cells and inner plexiform layer. Pixel-by-pixel volumetric measurements were obtained via Spectral-Domain optical coherence tomography (SD-OCT) from 50 eyes of Parkinson disease (PD) (n = 30) and 50 eyes of healthy control subjects (n = 27). Receiver operating characteristics (ROC) were used to classify individual subjects with respect to sensitivity and specificity calculations at each perifoveolar distance. Three-dimensional topographic maps of the healthy and PD foveal pit were created. The foveal pit is thinner and broader in PD. The difference becomes evident in an annular zone between 0.5 and 2 mm from the foveola and the optimal (ROC-defined) zone is from 0.75 to 1.5 mm. This zone is nearly devoid of NFL and partially overlaps the foveal avascular zone. About 78 % of PD eyes can be discriminated from HC eyes based on this zone. ROC applied to OCT pixel-by-pixel analysis helps to discriminate PD from HC retinae. Remodeling of the foveal architecture is significant because it may provide a visible and quantifiable signature of PD. The specific location of remodeling in the fovea raises a novel concept for exploring the mechanism of oxidative stress on retinal neurons in PD. OCT is a promising quantitative tool in PD research. However, larger scale studies are needed before the method can be applied to clinical follow-ups.

Journal ArticleDOI
TL;DR: In this article, the authors provide converging evidence that while DMT is a substance which produces powerful psychedelic experiences, it is better understood not as a hallucinogenic drug of abuse, but rather an agent of significant adaptive mechanisms that can also serve as a promising tool in the development of future medical therapies.
Abstract: N,N-dimethyltryptamine (DMT) is classified as a naturally occurring serotonergic hallucinogen of plant origin. It has also been found in animal tissues and regarded as an endogenous trace amine transmitter. The vast majority of research on DMT has targeted its psychotropic/psychedelic properties with less focus on its effects beyond the nervous system. The recent discovery that DMT is an endogenous ligand of the sigma-1 receptor may shed light on yet undiscovered physiological mechanisms of DMT activity and reveal some of its putative biological functions. A three-step active uptake process of DMT from peripheral sources to neurons underscores a presumed physiological significance of this endogenous hallucinogen. In this paper, we overview the literature on the effects of sigma-1 receptor ligands on cellular bioenergetics, the role of serotonin, and serotoninergic analogues in immunoregulation and the data regarding gene expression of the DMT synthesizing enzyme indolethylamine-N-methyltransferase in carcinogenesis. We conclude that the function of DMT may extend central nervous activity and involve a more universal role in cellular protective mechanisms. Suggestions are offered for future directions of indole alkaloid research in the general medical field. We provide converging evidence that while DMT is a substance which produces powerful psychedelic experiences, it is better understood not as a hallucinogenic drug of abuse, but rather an agent of significant adaptive mechanisms that can also serve as a promising tool in the development of future medical therapies.

Journal ArticleDOI
TL;DR: A significant number of people with PD reported that they experienced problems with olfaction, taste, nocturia and constipation prior to diagnosis and these may help to serve as a future biomarker for the condition.
Abstract: Parkinson’s disease (PD) can be manifested in many different ways. Although motor dysfunction represents the best characterised of the symptoms, the non-motor symptoms (NMS) of the condition can be equally disabling for people. These have been highlighted as being an issue of particular importance by people with PD. A comprehensive postal survey of members of the charity Parkinson’s UK took place in 2008. This resulted in returns from 10,101 people with PD. The self-completed Non-Motor Questionnaire (NMSQuest) and quality of life scale (PDQ-8) were contained within the survey. The results showed that the percentage of people with PD experiencing NMS increased with the duration of the disease. However, people who had the younger onset form of the condition reported a greater impact of NMS, particularly in the areas of memory, depression and sleep function. There is an inverse correlation between NMS and (PDQ-8 scale). A significant number of people with PD reported that they experienced problems with olfaction, taste, nocturia and constipation prior to diagnosis and these may help to serve as a future biomarker for the condition. Although our understanding of PD-associated NMS has increased considerably in the recent past, there is still a general lack of awareness of the importance of NMS for people with PD. Further research is required to identify the best treatments that should be employed to address them.

Journal ArticleDOI
TL;DR: Assessment of cholinergic function in Parkinson's disease patients with RBD and without RBD indicated that RBD is an important determinant of MCI in PD, and SAI abnormalities suggest aCholinergic dysfunction in PD patients who develop cognitive impairment.
Abstract: Central cholinergic dysfunction has been reported in patients with Parkinsonʼs disease (PD) and hallucinations by evaluating short latency afferent inhibition (SAI), a transcranial magnetic stimulation protocol which gives the possibility to test an inhibitory cholinergic circuit in the human brain. REM sleep behavior disorder (RBD) was also found to be associated with cognitive impairment in PD patients. The objective of the study was to assess the cholinergic function, as measured by SAI, in PD patients with RBD (PD-RBD) and PD patients without RBD (PD-nRBD). We applied the SAI technique in 10 PD-RBD patients, in 13 PD-nRBD patients and in 15 age-matched normal controls. All PD patients and control subjects also underwent a comprehensive battery of neuropsychological tests. Mean SAI was significantly reduced in PD-RBD patients when compared with PD-nRBD patients and controls. Neuropsychological examination showed mild cognitive impairment in 9 out of the 10 PD-RBD patients, and in 5 out of the 13 PD-nRBD. SAI values correlated positively with neuropsychological tests measuring episodic verbal memory, executive functions, visuoconstructional and visuoperceptual abilities. Similar to that previously reported in the idiopathic form of RBD, SAI abnormalities suggest a cholinergic dysfunction in PD patients who develop cognitive impairment, and present findings indicate that RBD is an important determinant of MCI in PD.

Journal ArticleDOI
TL;DR: Primary progressive multiple sclerosis is the prototype neurodegenerative disease, and the relapsing-remitting form in younger population represents the modifying effect of steroids on metabolic functions of the central nervous system.
Abstract: The precise pathogenesis of multiple sclerosis is unknown. The assumption of a primary immunopathogenesis of the disease is seriously flawed and has failed to deliver an effective therapy for most patients. The progressive degeneration of grey and white matter is integral to the natural history of the disease and is reflected in the atrophy of brain and spinal cord. Demyelination is an essential component of this primary neurodegenerative process rather than the target of a systemic immune response. The primary pathology of multiple sclerosis is a process of neurodegeneration based on the integrity of the blood-brain barrier. Primary progressive multiple sclerosis is the prototype neurodegenerative disease, and the relapsing-remitting form in younger population represents the modifying effect of steroids (vitamin D, sex and stress hormones) on metabolic functions of the central nervous system.

Journal ArticleDOI
TL;DR: Data from a systematic literature review in olfactory function in child and adolescent psychiatric disorders is presented and two unpublished data sets of autism and obsessive–compulsive disorder are reported.
Abstract: There is substantial evidence that olfactory function may serve as biomarker in adult neuropsychiatric disorders, e.g. overall diminished olfaction in Parkinson’s disease as parameter for early pre-motor and differential diagnosis. Here, we present data from a systematic literature review in olfactory function in child and adolescent psychiatric disorders and report two unpublished data sets of autism and obsessive–compulsive disorder. The overall number of olfaction studies is low—even after taking into account adult samples. In addition, heterogeneity of findings is high due to methodological limitations such as the use of different olfactory tests and odours targeting the olfactory and/or the trigeminal system and neglecting possible confounders, e.g., intelligence or oto-rhino-laryngological affections. Despite these limitations, there is some indication for specific alterations of olfactory function especially in disorders with dopaminergic pathology (e.g. attention deficit/hyperactivity disorder, autism, schizophrenia, 22q11 deletion syndrome). Dopamine is a relevant modulator of early processes in the olfactory bulb. Our systematic review provides the basis for future confirmatory studies investigating olfaction as putative biomarker in child and adolescent psychiatric disorders. We further propose studies of thorough and elaborate methodological standards in combination with imaging techniques and the investigation of the influence of genetic variation on olfactory function.

Journal ArticleDOI
TL;DR: This review will summarize advanced treatment strategies and novel approaches which are currently under investigation in Intracerebral hemorrhage.
Abstract: Intracerebral hemorrhage (ICH) is one of the most detrimental sub-types of stroke and accounts for 10-15% of all strokes Qureshi et al. (Lancet 373(9675):1632-1644, 2009). ICH has an incidence of 10-30 cases per 100,000 people/year which is increasing and expected to double by the year 2050 Qureshi et al. (N Engl J Med 344 (19):1450-1460, 2001). Mortality rates still remain poor (30-50%) and functional dependency after ICH is high (~75%) van Asch et al. (Lancet Neurol 9 (2):167-176, 2010). Up to now, all randomized controlled trials investigating treatment approaches in ICH have failed to document improvements on clinical endpoints Mayer et al. (N Engl J Med 358 (20):2127-2137, 2008); Brouwers and Goldstein (Neurotherapeutics 9 (1):87-98, 2012). Only a specialized treatment of severely injured patients at dedicated neuro intensive care units [NICU] has been shown to be beneficial Qureshi et al. (Lancet 373(9675):1632-1644, 2009); Suarez et al. (Crit Care Med 32 (11):2311-2317, 2004). Currently, ongoing trials are investigating aggressive blood pressure lowering, hemostatic therapies, different operative strategies, intraventricular thrombolysis as well as neuroprotective approaches, and brain edema therapies. This review will summarize advanced treatment strategies and novel approaches which are currently under investigation.

Journal ArticleDOI
TL;DR: Findings suggest that above four compounds and nobiletin in the Nchinpi extract mainly cooperated to facilitate potently CRE-mediated transcription linked to the upstream cAMP/PKA/ERK/CREB pathway in hippocampal neurons.
Abstract: cAMP/PKA/ERK/CREB signaling linked to CRE-mediated transcription is crucial for learning and memory. We originally found nobiletin as a natural compound that stimulates this intracellular signaling and exhibits anti-dementia action in animals. Citrus reticulata or C. unshiu peels are employed as "chinpi" and include a small amount of nobiletin. We here provide the first evidence for beneficial pharmacological actions on the cAMP/PKA/ERK/CREB cascade of extracts from nobiletin-rich C.reticulata peels designated as Nchinpi, the nobiletin content of which was 0.83 ± 0.13% of the dry weight or 16-fold higher than that of standard chinpi extracts. Nchinpi extracts potently facilitated CRE-mediated transcription in cultured hippocampal neurons, whereas the standard chinpi extracts showed no such activity. Also, the Nchinpi extract, but not the standard chinpi extract, stimulated PKA/ERK/CREB signaling. Interestingly, treatment with the Nchinpi extract at the concentration corresponding to approximately 5 μM nobiletin more potently facilitated CRE-mediated transcriptional activity than did 30 μM nobiletin alone. Consistently, sinensetin, tangeretin, 6-demethoxynobiletin, and 6-demethoxytangeretin were also identified as bioactive substances in Nchinpi that facilitated the CRE-mediated transcription. Purified sinensetin enhanced the transcription to a greater degree than nobiletin. Furthermore, samples reconstituted with the four purified compounds and nobiletin in the ratio of each constituent's content in the extract showed activity almost equal to that of the Nchinpi extract to stimulate CRE-mediated transcription. These findings suggest that above four compounds and nobiletin in the Nchinpi extract mainly cooperated to facilitate potently CRE-mediated transcription linked to the upstream cAMP/PKA/ERK/CREB pathway in hippocampal neurons.

Journal ArticleDOI
TL;DR: The results demonstrate significant and sustained benefit over a long observation period in motor complications and in quality of life following a change from oral pulsatile to continuous levodopa delivery.
Abstract: Duodenal levodopa infusion represents an effective strategy to manage motor and non-motor complications in patients with advanced Parkinson's disease (PD) However, most published clinical series regard small numbers of patients and do not exceed 1 year follow-up In this multi-national observational cohort study conducted in seven specialised PD clinics and university hospitals we assessed long-term safety and outcome of chronic treatment with intra-duodenal levodopa infusions in a large population of patients with advanced PD The starting population consisted of 98 treated patients (safety population) We report clinical outcomes of 73 patients with subsequent efficacy assessment(s) (efficacy population) over a follow-up period up to 2 years Follow-up periods and collection of clinical observations varied based on individual routine care program At last follow-up there was a significant (p ≤ 005) reduction in duration of "Off" periods as well as dyskinesia duration and severity that was associated with an improvement of quality of life Twenty three patients (253 % of the safety population) withdraw, due to adverse drug reaction (5), procedure and device related events (7), compliance (3) and lack of efficacy (8) The mean duration for last value reported after baseline (LV) was 608 ± 292 days (median: 697 days) Our results demonstrate significant and sustained benefit over a long observation period in motor complications and in quality of life following a change from oral pulsatile to continuous levodopa delivery The relatively large number of withdrawals reflects the current use of duodenal levodopa infusion in very advanced PD patients

Journal ArticleDOI
TL;DR: The group of NBIA syndromes is introduced and the main clinical features and investigational findings are reviewed, with clinical overlap between the different N BIA disorders and other diseases including spastic paraplegias, leukodystrophies, and neuronal ceroid lipofuscinosis.
Abstract: Regulation of iron metabolism is crucial: both iron deficiency and iron overload can cause disease. In recent years, our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. These are characterized by excessive iron deposition in the brain, mainly the basal ganglia. Pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2) are the core syndromes, but several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). These conditions show a wide clinical and pathological spectrum, with clinical overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies, and neuronal ceroid lipofuscinosis. Lewy body pathology was confirmed in some clinical subtypes (C19orf12-associated neurodegeneration and PLAN). Research aims at disentangling the various NBIA genes and their related pathways to move towards pathogenesis-targeted therapies. Until then treatment remains symptomatic. Here we will introduce the group of NBIA syndromes and review the main clinical features and investigational findings.

Journal ArticleDOI
TL;DR: It is proposed in this review that induced pluripotent stem cells, derived from dermal fibroblasts of AD patients, and differentiated into cholinergic neurons, might be a promising novel tool for disease modelling and drug discovery for the sporadic form of AD.
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder that leads to a progressive decline in a person’s memory and ability to communicate and carry out daily activities. The brain pathology in AD is characterized by extensive neuronal loss, particularly of cholinergic neurons, intracellular neurofibrillary tangles composed of the tau protein (NFTs) and extracellular deposition of plaques composed of β-amyloid (Aβ), a cleavage product of the amyloid precursor protein (APP). These two insoluble protein aggregates are accompanied by a chronic inflammatory response and extensive oxidative damage. Whereas dys-regulation of APP expression or processing appears to be important for the familial, early-onset form of AD, controversy exists between the “Baptists” (in favour of Aβ) and the “Tauists” (in favour of tau) as to which of these two protein dysfunctions occur at the earliest stages or are the most important contributors to the disease process in sporadic AD. However, more and more “non-amyloid” and “non-tau” causes have been proposed, including, glycation, inflammation, oxidative stress and dys-regulation of the cell cycle. However, to get an insight into the ultimate cause of AD, and to prove that any drug target is valuable in AD, disease-relevant models giving insight into the pathogenic processes in AD are urgently needed. In the absence of a good animal model for sporadic AD, we propose in this review that induced pluripotent stem cells, derived from dermal fibroblasts of AD patients, and differentiated into cholinergic neurons, might be a promising novel tool for disease modelling and drug discovery for the sporadic form of AD.

Journal ArticleDOI
TL;DR: In these open-label studies, adjunctive rotigotine was efficacious with an acceptable safety and tolerability profile in patients with advanced PD for up to 6 years.
Abstract: Open-label extensions [studies SP516 (NCT00501969) and SP715 (NCT00594386)] of the CLEOPATRA-PD and PREFER studies were conducted to evaluate the safety, tolerability and efficacy of the dopaminergic agonist, rotigotine, over several years of follow-up in patients with advanced Parkinson’s disease (PD). Eligible subjects completing the double-blind trials received open-label adjunctive rotigotine (≤16 mg/24 h) for up to 4 and 6 years in Studies SP516 and SP715, respectively. Safety and tolerability were assessed using adverse events, vital signs and laboratory parameters, and efficacy assessed using the unified Parkinson’s disease rating scale (UPDRS). Of the 395 and 258 patients enrolled in the SP516 and SP715 studies, 48 and 45 % completed, respectively. Adverse events were typically dopaminergic effects [e.g., somnolence (18–25 %/patient-year), insomnia (5–7 %/patient-year), dyskinesias (4–8 %/patient-year) and hallucinations (4–8 %/patient-year)], or related to the transdermal application of a patch (application site reactions: 14–15 %/patient-year). There were no clinically relevant changes in vital signs or laboratory parameters in either study. Mean UPDRS part II (activities of daily living) and part III (motor function) total scores improved from double-blind baseline during dose titration, then gradually declined over the maintenance period. In study SP516, mean UPDRS part II and III total scores were 0.8 points above and 2.8 points below double-blind baseline, respectively, at end of treatment. In study SP715, mean UPDRS part II and III total scores were 4.1 points above and 0.2 points below baseline, respectively, at end of treatment. In these open-label studies, adjunctive rotigotine was efficacious with an acceptable safety and tolerability profile in patients with advanced PD for up to 6 years.

Journal ArticleDOI
TL;DR: An up to date overview of the available strategies for dopaminergic drug delivery via apomorphine or Duodopa pumps and stereotactical interventions for Parkinson's disease is provided.
Abstract: Levodopa/Carbidopa, respectively, Levodopa/Benserazide is the most effective treatment for Parkinson’s disease and during the progress of the disease, patients will inevitably need to be treated with it. Nonetheless, after a certain time period most of the patients experience side effects. Mainly disturbing are motor and non-motor fluctuations and dyskinesia. Numerous options from changing the medication regimen, to continuos dopaminergic drug delivery via apomorphine or Duodopa pumps and stereotactical interventions are available. The physician’s responsibility is to choose the right therapeutic procedure for each timepoint of the patient’s disease. In this review, we provide an up to date overview of the available strategies.

Journal ArticleDOI
TL;DR: The changes produced by EC in the neurochemical, neuroendocrine and behavioral parameters evaluated suggest that EC rats could show a better coping during an acute stress challenge.
Abstract: The present study was designed to investigate the modulation of the stress responses by the environmental conditions and its putative neurobiological mechanisms. For that an integrative study on the effects of environmental enrichment and isolation housing on (1) the corticosterone, dopamine and acetylcholine responses to acute restraint stress in the prefrontal cortex (PFC) of the awake rat; (2) the mRNA levels of glucocorticoid receptors (GRs) in the PFC, and (3) the behavioral responses to stress, related to the PFC (habituation to a novel environment, spatial-working memory and inhibitory avoidance response) was performed. Male Wistar rats were maintained from 3 to 6 months of age in two different conditions: enriched (EC) or impoverished (IC). Animals were stereotaxically implanted with bilateral guide cannulae in the PFC to perform microdialysis experiments to evaluate the concentrations of corticosterone, dopamine and acetylcholine. EC animals showed lower increases of corticosterone and dopamine but not of acetylcholine than IC animals in the PFC in response to acute restraint stress (20 min). In the PFC, GR mRNA levels showed a trend towards an enhancement in EC animals. EC reduced the days to learn the spatial working memory task (radial-water maze). Spatial working memory, however, was not different between groups in either basal or stress conditions. Inhibitory avoidance response was reduced in EC rats. The changes produced by EC in the neurochemical, neuroendocrine and behavioral parameters evaluated suggest that EC rats could show a better coping during an acute stress challenge.