Screening for C9orf72 repeat expansions in parkinsonian syndromes

Parkinsonism might precede, coincide, or follow the behavioral or language-predominant cognitive impairments characteristic of frontotemporal dementia (FTD). In this study, we analyze the hexanucleotide repeat expansions within C9orf72 gene in various parkinsonian syndromes because it is a recently identified important genetic cause of FTD. The expanded hexanucleotide repeat is only identified in our familial FTD patients but not in patients with predominant parkinsonism. The lack of association between abnormal C9orf72 repeat expansion and parkinsonian syndromes might imply pathogenic mechanisms other than tau or Lewy body pathology.     

Grooved pegboard test as a biomarker of nigrostriatal denervation in Parkinson's disease

Recent pharmacotherapy trials in Parkinson's disease (PD) using dopaminergic neuroimaging as outcome parameter failed to show significant relationships between imaging and clinical results. One possible explanation is that there is a non-linear relationship between striatal denervation and motor performance reflecting a statistical "floor" effect in the imaging data with advanced disease. Both the motor manifestations and the striatal dopamine denervation of idiopathic PD, however, are typically asymmetric and more meaningful associations may be found by comparing data from the least denervated striatum with motor performance in the corresponding body side. PD patients (n=28) underwent [11C]beta-CFT dopamine transporter (DAT) positron emission tomography (PET) and grooved pegboard testing. Voxel-based analysis of DAT PET and bimanual pegboard scores demonstrated significant correlation clusters within the bilateral striata (P<0.001). However, findings were most prominent in the least denervated striatum. There was a significant inverse correlation between pegboard scores of the least affected arm and DAT binding of the least denervated striatum (Rs=-0.69, P<0.0001) but no significant correlation between pegboard scores of the clinically most affected arm and DAT binding of the most denervated striatum (Rs=-0.15, ns). These data indicate that the robustness of the grooved pegboard test as a biomarker for nigrostriatal denervation in PD mainly reflects the relationship between test performance of the clinically least affected limb and the least denervated striatum. These findings indicate that there is both a statistical "floor" and "ceiling" effect for the most affected striatal and body sides that must be considered when employing imaging as an outcome measure in clinical trials in PD.     

Muscarinic cholinergic receptor subtypes in cerebral cortex of Fisher 344 rats: a light microscope autoradiography study of age-related changes

The density and localization of muscarinic cholinergic M1-M5 receptor subtypes was investigated in frontal and occipital cortex of male Fisher 344 rats aged 6 months (young-adult), 15 months (mature) and 22 months (senescent) by combined kinetic and equilibrium binding and light microscope autoradiography. In 6-month-old rats, the rank order density of muscarinic cholinergic receptor subtypes was M1>M2>M4>M3>M5 both in frontal and occipital cortex. A not homogeneous distribution of different receptor subtypes throughout cerebrocortical layers of frontal or occipital cortex was found. In frontal cortex silver grains corresponding to the M1 and M2 receptor subtypes were decreased in 15- and 22-month-old groups. The M3 receptor density was remarkably and moderately decreased in layers II/III and V, respectively, of rats aged 15 and 22 months. A reduced M4 receptor density was observed in layer I and to a lesser extent in layer V of mature and senescent rats, whereas no age-related changes of M5 receptor were found. In occipital cortex a diminution of M1 receptor was observed in layers II/III and V of mature and senescent rats. The M2 receptor expression decreased in layer I of 15- and 22-month-old senescent rats, whereas M3-M5 receptors were unchanged with exception of a slight decrease of the M4 receptor in layer IV and of M5 receptor in layers II/III. These findings indicate a different sensitivity to aging of muscarinic receptor subtypes located in various cerebrocortical layers. This may account for the difficulty in obtaining relevant results in manipulating cholinoceptors to counter age-related impairment of cholinergic system.     

Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications

Adenosine A2A receptors have a unique cellular and regional distribution in the basal ganglia, being particularly concentrated in areas richly innervated by dopamine such as the caudate-putamen and the globus pallidus. Adenosine A2A receptors are selectively located on striatopallidal neurons and are capable of forming functional heteromeric complexes with dopamine D2 and metabotropic glutamate mGlu5 receptors. Based on the unique cellular and regional distribution of this receptor and in line with data showing that A2A receptor antagonists improve motor symptoms in animal models of Parkinson's disease (PD) and in initial clinical trials, A2A receptor antagonists have emerged as an attractive non-dopaminergic target to improve the motor deficits that characterize PD. Experimental data have also shown that A2A receptor antagonists do not induce neuroplasticity phenomena that complicate long-term dopaminergic treatments. The present review provides an updated summary of results reported in the literature concerning the biochemical characteristics and basal ganglia distribution of A2A receptors. We subsequently aim to examine the effects of adenosine A2A antagonists in rodent and primate models of PD and of l-DOPA-induced dyskinesia. Finally, concluding remarks are made on post-mortem human brains and on the translation of adenosine A2A receptor antagonists in the treatment of PD.     

Staging Alzheimer's disease progression with multimodality neuroimaging

Rapid developments in medical neuroimaging have made it possible to reconstruct the trajectory of Alzheimer's disease (AD) as it spreads through the living brain. The current review focuses on the progressive signature of brain changes throughout the different stages of AD. We integrate recent findings on changes in cortical gray matter volume, white matter fiber tracts, neuropathological alterations, and brain metabolism assessed with molecular positron emission tomography (PET). Neurofibrillary tangles accumulate first in transentorhinal and cholinergic brain areas, and 4-D maps of cortical volume changes show early progressive temporo-parietal cortical thinning. Findings from diffusion tensor imaging (DTI) for assessment fiber tract integrity show cortical disconnection in corresponding brain networks. Importantly, the developmental trajectory of brain changes is not uniform and may be modulated by several factors such as onset of disease mechanisms, risk-associated and protective genes, converging comorbidity, and individual brain reserve. There is a general agreement between in vivo brain maps of cortical atrophy and amyloid pathology assessed through PET, reminiscent of post mortem histopathology studies that paved the way in the staging of AD. The association between in vivo and post mortem findings will clarify the temporal dynamics of pathophysiological alterations in the development of preclinical AD. This will be important in designing effective treatments that target specific underlying disease AD mechanisms.     

The serotonergic system in ageing and Alzheimer's disease

Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression. Numerous studies have confirmed the pathophysiological role of the 5-HT system in AD and that several drugs enhancing 5-HT neurotransmission are effective in treating the AD-related cognitive and behavioural deficits. Here we present a comprehensive overview of the role of serotonergic neurotransmission in brain development, maturation and ageing, discuss its role in higher brain function and provide an in depth account of pathological modifications of serotonergic transmission in neurological diseases and AD.     

Early involvement of the cerebral cortex in Parkinson's disease: Convergence of multiple metabolic defects

Parkinson's disease (PD) has been considered a paradigm of degenerative diseases of the nervous system characterized by motor impairment (parkinsonism) due to malfunction and loss of dopaminergic neurons of the substantia nigra pars compacta. However, PD is a systemic disease of the nervous system with variegated clinical symptoms appearing before parkinsonism and due to the involvement of selected nuclei of the medulla oblongata, pons, autonomic nervous system and olfactory structures, among others. Furthermore, recent clinical data have shown modifications in behavior, personality changes and cognitive impairment leading to dementia. Lewy pathology, hallmark of PD, in the cerebral cortex does not correlate with cognitive impairment. However, recent studies have shown abnormal mitochondria content and function, and increased oxidative stress and oxidative responses in the cerebral cortex in PD. Furthermore, several key PD-related proteins are oxidatively damaged, including α-synuclein, β-synuclein, superoxide dismutases, parkin, DJ1, UCHL1 and enzymes involved in glycolysis and energy metabolism. DNA and RNA are also targets of oxidative damage. Furthermore, abnormal phosphorylation of α-synuclein and tau occurs at the cortical synapses. Finally, abnormal cortical metabolism has been revealed with neuroimaging methods. These data demonstrate early involvement of the cerebral cortex in PD due to the convergence of multiple metabolic defects. Lewy pathology is a relative late event, geared to isolate unremoved damaged protein, with little significance on cortical neurological deficits.     

Calcium dysregulation in Alzheimer's disease: From mechanisms to therapeutic opportunities

Calcium is involved in many facets of neuronal physiology, including activity, growth and differentiation, synaptic plasticity, and learning and memory, as well as pathophysiology, including necrosis, apoptosis, and degeneration. Though disturbances in calcium homeostasis in cells from Alzheimer's disease (AD) patients have been observed for many years, much more attention was focused on amyloid-β (Aβ) and tau as key causative factors for the disease. Nevertheless, increasing lines of evidence have recently reported that calcium dysregulation plays a central role in AD pathogenesis. Systemic calcium changes accompany almost the whole brain pathology process that is observed in AD, including synaptic dysfunction, mitochondrial dysfunction, presenilins mutation, Aβ production and Tau phosphorylation. Given the early and ubiquitous involvement of calcium dysregulation in AD pathogenesis, it logically presents a variety of potential therapeutic targets for AD prevention and treatment, such as calcium channels in the plasma membrane, calcium channels in the endoplasmic reticulum membrane, Aβ-formed calcium channels, calcium-related proteins. The review aims to provide an overview of the current understanding of the molecular mechanisms involved in calcium dysregulation in AD, and an insight on how to exploit calcium regulation as therapeutic opportunities in AD.     

Biomarkers of Parkinson's disease and Dementia with Lewy bodies

Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are progressive and disabling neurodegenerative disorders, in which signs and symptoms overlap with each other and with other neurodegenerative conditions. Currently, diagnosis, measurement of progression, and response to therapeutic intervention rely upon clinical observation. However, there remains a critical need for validated biomarkers in each of these areas. A definitive diagnostic test would improve clinical management and enrollment into clinical trials. An objective measure of progression is vitally important in identifying neuroprotective interventions. Biomarkers may also provide insight into pathogenesis, and might therefore suggest possible novel targets for therapeutic intervention. In addition, certain biomarkers might be of use in monitoring the biochemical and physiological effects of therapeutic interventions. Development of diagnostic biomarkers has focused until recently upon imaging techniques based upon measuring loss of dopamine neurons. Additionally, advances in understanding the genetic contribution to neurodegenerative disorders, in particular in PD, have identified multiple causative genes and risk factors that in some cases may help estimate PD risk. However, recent availability of increasingly sophisticated bioinformatics technology has rendered development of fluid biomarkers feasible, opening the possibility of generally accessible blood or cerebrospinal fluid (CSF) tests that could impact upon diagnosis, management, and research in PD, PDD, and DLB.     

RACK1 has the nerve to act: structure meets function in the nervous system

The receptor for activated protein kinase C 1 (RACK1) is an intracellular adaptor protein. Accumulating evidence attributes to this member of the tryptophan-aspartate (WD) repeat family the role of regulating several major nervous system pathways. Structurally, RACK1 is a seven-bladed-beta-propeller, interacting with diverse proteins having distinct structural folds. When bound to the IP3 receptor, RACK1 regulates intracellular Ca2+ levels, potentially contributing to processes such as learning, memory and synaptic plasticity. By binding to the NMDA receptor, it dictates neuronal excitation and sensitivity to ethanol. When bound to the stress-induced acetylcholinesterase variant AChE-R, RACK1 is implicated in stress responses and behavior, compatible with reports of RACK1 modulations in brain ageing and in various neurodegenerative diseases. This review sheds new light on both the virtues and the variety of neuronal RACK1 interactions and their physiological consequences.     

The serotonergic system in Parkinson's disease

Although the cardinal manifestations of Parkinson's disease (PD) are attributed to a decline in dopamine levels in the striatum, a breadth of non-motor features and treatment-related complications in which the serotonergic system plays a pivotal role are increasingly recognised. Serotonin (5-HT)-mediated neurotransmission is altered in PD and the roles of the different 5-HT receptor subtypes in disease manifestations have been investigated. The aims of this article are to summarise and discuss all published preclinical and clinical studies that have investigated the serotonergic system in PD and related animal models, in order to recapitulate the state of the current knowledge and to identify areas that need further research and understanding.     

The ubiquitin proteasome system in neurodegenerative diseases: Culprit,accomplice or victim?

A shared hallmark for many neurodegenerative disorders is the accumulation of toxic protein species which is assumed to be the cause for these diseases. Since the ubiquitin proteasome system (UPS) is the most important pathway for selective protein degradation it is likely that it is involved in the aetiology neurodegenerative disorders. Indeed, impairment of the UPS has been reported to occur during neurodegeneration. Although accumulation of toxic protein species (amyloid β) are in turn known to impair the UPS the relationship is not necessarily causal. We provide an overview of the most recent insights in the roles the UPS plays in protein degradation and other processes. Additionally, we discuss the role of the UPS in clearance of the toxic proteins known to accumulate in the hallmarks of neurodegenerative diseases. The present paper will focus on critically reviewing the involvement of the UPS in specific neurodegenerative diseases and will discuss if UPS impairment is a cause, a consequence or both of the disease.