Neurodegenerative Disease Populations Research Articles

Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1

Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using invivo two-photon imaging in behaving spinocerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory circuit element (molecular layer interneurons [MLINs]) that becomes prematurely hyperexcitable, compromising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcitable MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibition of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level deficits upstream of PNs are one of the main disease triggers in SCA1.

Multi sequence average templates for aging and neurodegenerative disease populations

Magnetic resonance image (MRI) processing pipelines use average templates to enable standardization of individual MRIs in a common space. MNI-ICBM152 is currently used as the standard template by most MRI processing tools. However, MNI-ICBM152 represents an average of 152 healthy young adult brains and is vastly different from brains of patients with neurodegenerative diseases. In those populations, extensive atrophy might cause inevitable registration errors when using an average template of young healthy individuals for standardization. Disease-specific templates that represent the anatomical characteristics of the populations can reduce such errors and improve downstream driven estimates. We present multi-sequence average templates for Alzheimer’s Dementia (AD), Fronto-temporal Dementia (FTD), Lewy Body Dementia (LBD), Mild Cognitive Impairment (MCI), cognitively intact and impaired Parkinson’s Disease patients (PD-CIE and PD-CI, respectively), individuals with Subjective Cognitive Impairment (SCI), AD with vascular contribution (V-AD), Vascular Mild Cognitive Impairment (V-MCI), Cognitively Intact Elderly (CIE) individuals, and a human phantom. We also provide separate templates for males and females to allow better representation of the diseases in each sex group.

Multi-Sequence Average Templates for Aging and Neurodegenerative Disease Populations

Multi-Sequence Average Templates for Aging and Neurodegenerative Disease Populations

Contribution of astrocytes to neuropathology of neurodegenerative diseases

Classically, the loss of vulnerable neuronal populations in neurodegenerative diseases was considered to be the consequence of cell autonomous degeneration of neurons. However, progress in the understanding of glial function, the availability of improved animal models recapitulating the features of the human diseases, and the development of new approaches to derive glia and neurons from induced pluripotent stem cells obtained from patients, provided novel information that altered this view. Current evidence strongly supports the notion that non-cell autonomous mechanisms contribute to the demise of neurons in neurodegenerative disorders, and glia causally participate in the pathogenesis and progression of these diseases. In addition to microglia, astrocytes have emerged as key players in neurodegenerative diseases and will be the focus of the present review. Under the influence of pathological stimuli present in the microenvironment of the diseased CNS, astrocytes undergo morphological, transcriptional, and functional changes and become reactive. Reactive astrocytes are heterogeneous and exhibit neurotoxic (A1) or neuroprotective (A2) phenotypes. In recent years, single-cell or single-nucleus transcriptome analyses unraveled new, disease-specific phenotypes beyond A1/A2. These investigations highlighted the complexity of the astrocytic responses to CNS pathology.The present review will discuss the contribution of astrocytes to neurodegenerative diseases with particular emphasis on Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal dementia. Some of the commonalties and differences in astrocyte-mediated mechanisms that possibly drive the pathogenesis or progression of the diseases will be summarized. The emerging view is that astrocytes are potential new targets for therapeutic interventions. A comprehensive understanding of astrocyte heterogeneity and disease-specific phenotypic complexity could facilitate the design of novel strategies to treat neurodegenerative disorders.

Conducting focus groups in neurodegenerative disease populations: ethical and methodological considerations

BackgroundInvolvement of vulnerable populations in research is critical to inform the generalisability of evidence-based medicine to all groups of the population.ObjectiveIn this communication, we reflect on our previous research, and...

Vision loss and hallucinations: perspectives from neurology and ophthalmology.

The aim of this article is to summarize the evidence for visual impairment as a risk factor for visual hallucinations in neurologic disease and recent advances in our understanding of the central visual pathways that mediate this association. Recent studies have described the prevalence Charles Bonnet syndrome and questioned its lack of association with cognitive impairment, used advanced neuroimaging to show that disinhibition of the occipital lobe is involved in the pathogenesis of visual hallucinations in Parkinson's disease, and demonstrated that visual impairment because of eye disease is a consistent risk factor for visual hallucinations across a number of different neurodegenerative disease populations. Through connections between the primary visual cortex and other brain structures, visual function is closely tied to visual hallucinations. Given that the vast majority of vision loss is caused by ophthalmic disease, much of which is preventable or treatable, the detection and treatment of vision loss in at-risk populations may reduce the burden and consequences of visual hallucinations in older adults.

Chronic intermittent hypoxia induces oxidative stress and inflammation in brain regions associated with early-stage neurodegeneration.

Sleep apnea is a common comorbidity of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Previous studies have shown an association between elevated oxidative stress and inflammation with severe sleep apnea. Elevated oxidative stress and inflammation are also hallmarks of neurodegenerative diseases. We show increased oxidative stress and inflammation in a manner consistent with early stages of neurodegenerative disease in an animal model of mild sleep apnea. Male rats were exposed to 7 days chronic intermittent hypoxia (CIH) for 8 h/day during the light period. Following CIH, plasma was collected and tested for circulating oxidative stress and inflammatory markers associated with proinflammatory M1 or anti‐inflammatory M2 profiles. Tissue punches from brain regions associated with different stages of neurodegenerative diseases (early stage: substantia nigra and entorhinal cortex; intermediate: hippocampus; late stage: rostral ventrolateral medulla and solitary tract nucleus) were also assayed for inflammatory markers. A subset of the samples was examined for 8‐hydroxydeoxyguanosine (8‐OHdG) expression, a marker of oxidative stress‐induced DNA damage. Our results showed increased circulating oxidative stress and inflammation. Furthermore, brain regions associated with early‐stage (but not late‐stage) AD and PD expressed oxidative stress and inflammatory profiles consistent with reported observations in preclinical neurodegenerative disease populations. These results suggest mild CIH induces key features that are characteristic of early‐stage neurodegenerative diseases and may be an effective model to investigate mechanisms contributing to oxidative stress and inflammation in those brain regions.

Assessment of capacity to consent in a Huntington disease clinical trial: implications for future clinical trial design in neurodegenerative disease populations (P2.004)

Assessment of capacity to consent in a Huntington disease clinical trial: implications for future clinical trial design in neurodegenerative disease populations (P2.004)

Mobility in the elderly – dual task training a therapeutic modality in neurological patients

Gait impairments in simultaneous motor-cognitive tasks have been well documented in neurodegenerative disease populations, including Parkinson’s disease, and Alzheimer’s disease. The consequences of these gait impairments in patient populations include an increased fall risk, sedentariness, functional decreases, decreases in self-efficacy, and overall reduced quality of life. Therefore, improving gait performance in dual-task situations is becoming an important focus of rehabilitation for people with neurological disorders. Despite the growing interest in training dual-task performance for people with motor and/or cognitive impairments as a treatment, there is currently a limited amount of available literature, and studies vary in overall quality and methodological rigor. In this narrative review, the objective was to describe the effectiveness of dual-task interventions in different patient populations. Overall, multicomponent interventions incorporating both physical and cognitive components demonstrated promising results for improving gait velocity and other gait parameters in patient populations. However, the results are inconsistent across studies. The discrepancies are not surprising given the differences in study populations, measures of dual-task performance, task difficulty, task prioritization, intervention duration and intensity. Future studies need to explore further the design of successful training interventions as well as the transfer of training-related benefits for enhancing activities of daily living in different clinical populations.

Connected brains and minds—The UMCD repository for brain connectivity matrices

We describe the USC Multimodal Connectivity Database (http://umcd.humanconnectomeproject.org), an interactive web-based platform for brain connectivity matrix sharing and analysis. The site enables users to download connectivity matrices shared by other users, upload matrices from their own published studies, or select a specific matrix and perform a real-time graph theory-based analysis and visualization of network properties. The data shared on the site span a broad spectrum of functional and structural brain connectivity information from humans across the entire age range (fetal to age 89), representing an array of different neuropsychiatric and neurodegenerative disease populations (autism spectrum disorder, ADHD, and APOE-4 carriers). An analysis combining 7 different datasets shared on the site illustrates the diversity of the data and the potential for yielding deeper insight by assessing new connectivity matrices with respect to population-wide network properties represented in the UMCD.

A systematic review of the validity and reliability of apathy scales in neurodegenerative conditions.

There are several scales used to detect apathy in disease populations. Since apathy is a prevalent symptom in many neurodegenerative diseases, this is an especially important context in which to identify and compare scales. To provide an overview of apathy scales validated in generic and specific neurodegenerative disease populations, compare validation studies' methodological quality and the psychometric properties of the validated apathy scales. A systematic review of literature was conducted of articles published between 1980 and 2013. The final articles selected for review were rated on methodological quality and the psychometric properties of the scales used were interpreted. Sixteen articles validating apathy scales were included in the review, five in a generic neurodegenerative sample and eleven in specific neurodegenerative samples. The methodological quality of specific studies varied from poor to excellent. The highest quality, which had psychometrically favorable scales, were the dementia apathy interview and rating (DAIR) and the apathy evaluation scale-clinical version (AES-C) in Alzheimer's disease and the Lille apathy rating scale (LARS) in Parkinson's disease. Generic neurodegenerative disease validation studies were of average methodological quality and yielded inconsistent psychometric properties. Several instruments can be recommended for use in some specific neurodegenerative diseases. Other instruments should either be validated or developed to assess apathy in more generic populations.

Mapping of Neurotrophins and their Receptors in the Adult Mouse Brain and their Role in the Pathogenesis of a Transgenic Murine Model of Bovine Spongiform Encephalopathy

Neurotrophins are a family of growth factors that act on neuronal cells. The neurotrophins include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3, -4 and -5. The action of neurotrophins depends on two transmembrane-receptor signalling systems: (1) the tropomyosin-related kinase (Trk) family of tyrosine kinase receptors (Trk A, Trk B and Trk C) and (2) the p75 neurotrophin receptor (p75(NTR)). The interaction between neurotrophic factors and their receptors may be involved in the mechanisms that regulate the differential susceptibility of neuronal populations in neurodegenerative diseases. The aim of the present study was to evaluate the role of neurotrophins in the pathogenesis of bovine spongiform encephalopathy (BSE) using a transgenic mouse overexpressing bovine prnp (BoTg 110). Histochemistry for Lycopersicum esculentum agglutinin, haematoxylin and eosin staining and immunohistochemistry for the abnormal isoform of the prion protein (PrP(d)), glial fibrillary acidic protein (GFAP), NGF, BDNF, NT-3 and the receptors Trk A, Trk B, Trk C and p75(NTR) was performed. The lesions and the immunolabelling patterns were assessed semiquantitatively in different areas of the brain. No significant differences in the immunolabelling of neurotrophins and their receptors were observed between BSE-inoculated and control animals, except for p75(NTR), which showed increased expression correlating with the distribution of lesions, PrP(d) deposition and gliosis in the BSE-inoculated mice.

Progress and prospects: stem cells and neurological diseases

The central nervous system has limited capacity of regenerating lost tissue in slowly progressive, degenerative neurological conditions such as Parkinson's disease (PD), Alzheimer's disease or Huntington's disease (HD), or in acute injuries resulting in rapid cell loss for example, in cerebrovascular damage (for example, stroke) or spinal cord injury. Although the adult brain contains small numbers of stem cells in restricted areas, they do not contribute significantly to functional recovery. Transplantation of stem cells or stem cell-derived progenitors has long been seen as a therapeutic solution to repair the damaged brain. With the advent of the induced pluripotent stem cells technique a new and potentially better source for transplantable cells may be available in future. This review aims to highlight current strategies to replace lost cellular populations in neurodegenerative diseases with the focus on HD and PD and traumatic brain injuries such as stroke, discussing many of the technical and biological issues associated with central nervous system cell transplantation.

Interplay between Cytosolic Dopamine, Calcium, and α-Synuclein Causes Selective Death of Substantia Nigra Neurons

The basis for selective death of specific neuronal populations in neurodegenerative diseases remains unclear. Parkinson's disease (PD) is a synucleinopathy characterized by a preferential loss of dopaminergic neurons in the substantia nigra (SN), whereas neurons of the ventral tegmental area (VTA) are spared. Using intracellular patch electrochemistry to directly measure cytosolic dopamine (DA(cyt)) in cultured midbrain neurons, we confirm that elevated DA(cyt) and its metabolites are neurotoxic and that genetic and pharmacological interventions that decrease DA(cyt) provide neuroprotection. L-DOPA increased DA(cyt) in SN neurons to levels 2- to 3-fold higher than in VTA neurons, a response dependent on dihydropyridine-sensitive Ca2+ channels, resulting in greater susceptibility of SN neurons to L-DOPA-induced neurotoxicity. DA(cyt) was not altered by alpha-synuclein deletion, although dopaminergic neurons lacking alpha-synuclein were resistant to L-DOPA-induced cell death. Thus, an interaction between Ca2+, DA(cyt), and alpha-synuclein may underlie the susceptibility of SN neurons in PD, suggesting multiple therapeutic targets.

Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration.

Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L). Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.