Visual hallucinations in the psychosis spectrum and comparative information from neurodegenerative disorders and eye disease

Much of the research on visual hallucinations (VHs) has been conducted in the context of eye disease and neurodegenerative conditions, but little is known about these phenomena in psychiatric and nonclinical populations. The purpose of this article is to bring together current knowledge regarding VHs in the psychosis phenotype and contrast this data with the literature drawn from neurodegenerative disorders and eye disease. The evidence challenges the traditional views that VHs are atypical or uncommon in psychosis. The weighted mean for VHs is 27% in schizophrenia, 15% in affective psychosis, and 7.3% in the general community. VHs are linked to a more severe psychopathological profile and less favorable outcome in psychosis and neurodegenerative conditions. VHs typically co-occur with auditory hallucinations, suggesting a common etiological cause. VHs in psychosis are also remarkably complex, negative in content, and are interpreted to have personal relevance. The cognitive mechanisms of VHs in psychosis have rarely been investigated, but existing studies point to source-monitoring deficits and distortions in top-down mechanisms, although evidence for visual processing deficits, which feature strongly in the organic literature, is lacking. Brain imaging studies point to the activation of visual cortex during hallucinations on a background of structural and connectivity changes within wider brain networks. The relationship between VHs in psychosis, eye disease, and neurodegeneration remains unclear, although the pattern of similarities and differences described in this review suggests that comparative studies may have potentially important clinical and theoretical implications.

Effectiveness of selective dorsal rhizotomy in 2 patients with progressive spasticity due to neurodegenerative disease

Selective dorsal rhizotomy at the lumbar level is a neurosurgical procedure, which reduces spasticity in the legs. Its effect has mainly been studied in children with spastic cerebral palsy. Little is known about the outcome of selective dorsal rhizotomy in patients with neurodegenerative disorders. We report the clinical course after selective dorsal rhizotomy in 2 patients with progressive spasticity. Leg spasticity was effectively and persistently reduced in both patients, facilitating care and improving sitting comfort. However, spasticity of the arms and other motor disturbances, such as spontaneous extension spasms and the ataxia, increased gradually in time. Selective dorsal rhizotomy leads to a disappearance of leg spasticity in patients with a neurodegenerative disease. Other motor signs are not influenced and may increase due to the progressive nature of the underlying disease.

A Missense Change in the ATG4D Gene Links Aberrant Autophagy to a Neurodegenerative Vacuolar Storage Disease.

Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine neurodegenerative disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus and behavioral changes. Histological examination revealed unique pathological changes, including profound neuronal cytoplasmic vacuolization in the nervous system, as well as spheroid formation and cytoplasmic aggregation of vacuoles in secretory epithelial tissues and mesenchymal cells. Genetic analyses uncovered a missense change, c.1288G>A; p.A430T, in the autophagy-related ATG4D gene on canine chromosome 20 with a highly significant disease association (p = 3.8 x 10-136) in a cohort of more than 2300 Lagotto Romagnolo dogs. ATG4D encodes a poorly characterized cysteine protease belonging to the macroautophagy pathway. Accordingly, our histological analyses indicated altered autophagic flux in affected tissues. The knockdown of the zebrafish homologue atg4da resulted in a widespread developmental disturbance and neurodegeneration in the central nervous system. Our study describes a previously unknown canine neurological disease with particular pathological features and implicates the ATG4D protein as an important autophagy mediator in neuronal homeostasis. The canine phenotype serves as a model to delineate the disease-causing pathological mechanism(s) and ATG4D function, and can also be used to explore treatment options. Furthermore, our results reveal a novel candidate gene for human neurodegeneration and enable the development of a genetic test for veterinary diagnostic and breeding purposes.

The role of autophagy in anticancer therapy: promises and uncertainties

Autophagy (literally self-eating) is a catabolic mechanism involved in the recycling and turnover of cytoplasmic constituents. Although often referred to as type II programmed cell death, autophagy is primarily a survival rather than a cell death mechanism in response to different stress stimuli. Autophagy is a process in which part of the cytoplasm or entire organelles are sequestered into double-membrane vesicles, called autophagosomes, which ultimately fuse with lysosomes to degrade their contents. Studies show that autophagy is associated with a number of pathological conditions, including cancer, infectious diseases, myopathies and neurodegenerative disorders. With respect to cancer, it has been suggested that the early stages of tumourigenesis are associated with downregulation of autophagy-related (ATG) genes. Indeed, several ATG genes display tumour suppressor function, including Beclin1, which is frequently hemizygously deleted in breast cancer cells. Conversely, in advanced stages of tumourigenesis or during anticancer therapy, autophagy may promote survival of tumour cells in adverse environmental conditions. Therefore, a thorough understanding of autophagy in different cancer types and stages is a prerequisite to determine an autophagy-activating or autophagy-inhibiting treatment strategy.

Cataract and cognitive impairment: a review of the literature

Acquired cataract and cognitive impairment are both common age-related problems, and ophthalmologists are increasingly likely to encounter patients who have both. Patients with dementia types who display early visuoperceptual impairment may present first to ophthalmology services. When these patients have coexisting cataract, it may be difficult to distinguish visual complaints due to cataract from those due to dementia. The interaction between visual impairment due to cataract and neurodegenerative disorders affecting the central visual pathways, is not fully understood. Visual impairment due to cataract may stress impaired attentional mechanisms and cataract extraction may improve cognitive performance in some patients with early cognitive impairment; however, the benefits of cataract surgery in established dementia are less clear. In this study, the literature on this subject was reviewed and the implications for practice were considered.

Republished review: cataract and cognitive impairment: a review of the literature

Acquired cataract and cognitive impairment are both common age-related problems, and ophthalmologists are increasingly likely to encounter patients who have both. Patients with dementia types who display early visuoperceptual impairment may present first to ophthalmology services. When these patients have coexisting cataract, it may be difficult to distinguish visual complaints due to cataract from those due to dementia. The interaction between visual impairment due to cataract and neurodegenerative disorders affecting the central visual pathways, is not fully understood. Visual impairment due to cataract may stress impaired attentional mechanisms and cataract extraction may improve cognitive performance in some patients with early cognitive impairment; however, the benefits of cataract surgery in established dementia are less clear. In this study, the literature on this subject was reviewed and the implications for practice were considered.

The formyl peptide receptor like-1 and scavenger receptor MARCO are involved in glial cell activation in bacterial meningitis

Recent studies have suggested that the scavenger receptor MARCO (macrophage receptor with collagenous structure) mediates activation of the immune response in bacterial infection of the central nervous system (CNS). The chemotactic G-protein-coupled receptor (GPCR) formyl-peptide-receptor like-1 (FPRL1) plays an essential role in the inflammatory responses of host defence mechanisms and neurodegenerative disorders such as Alzheimer's disease (AD). Expression of the antimicrobial peptide cathelicidin CRAMP/LL-37 is up-regulated in bacterial meningitis, but the mechanisms underlying CRAMP expression are far from clear.

Huntington's disease: new aspects on phenotype and genotype

Huntington's disease typically presents with involuntary movements, cognitive decline and behavioural abnormalities; however, new data show a greater spectrum and more complexity in the mode of presentation than previously appreciated. On one hand efforts are under way to better assess all aspects of the evolving phenotype over the course of the disease, on the other hand large cohorts have been prospectively followed-up and similar efforts are now being started in China. In this communication, we briefly review the most salient findings from the last couple of years. The recently established large cohorts allow the performance of accurate studies examining correlation of genetic polymorphisms with specific aspects of the phenotype thus allowing for some mechanistic insight into the causes of phenotypic variation. While Huntington's disease is the most frequent hereditary cause of chorea, other disorders with similar clinical phenotypes, including neuroacanthocytosis, are now better known, including a better understanding of the primary cause as well as the pathophysiology at the molecular level. Studies on the mechanisms of disease in these different disorders may shed light on the respective pathomechanisms and may open new approaches to a better understanding and additional treatment options for choreatiform neurodegenerative disorders.

Brain atrophy in pure and complicated hereditary spastic paraparesis: a quantitative 3D MRI study

Hereditary spastic paraparesis (HSP) is a heterogeneous group of neurodegenerative disorders with progressive lower limb spasticity, categorized into pure (p-HSP) and complicated forms (c-HSP). The purpose of this study was to evaluate if brain volumes in HSP were altered compared with a control population. Brain volumes were determined in patients suffering from HSP, including both p-HSP (n = 21) and c-HSP type (n = 12), and 30 age-matched healthy controls, using brain parenchymal fractions (BPF) calculated from 3D MRI data in an observer-independent procedure. In addition, the tissue segments of grey and white matter were analysed separately. In HSP patients, BPF were significantly reduced compared with controls both for the whole patient group (P < 0.001) and for both subgroups, indicating considerable brain atrophy. In contrast to controls who showed a decline of brain volumes with age, this physiological phenomenon was less pronounced in HSP. Therefore, global brain parenchyma reduction, involving both grey and white matter, seems to be a feature in both subtypes of HSP. Atrophy was more pronounced in c-HSP, consistent with the more severe phenotype including extramotor involvement. Thus, global brain atrophy, detected by MRI-based brain volume quantification, is a biological marker in HSP subtypes.

Functional imaging of visuospatial processing in Alzheimer's disease

Alzheimer's disease (AD) is known to cause a variety of disturbances of higher visual functions that are closely related to the neuropathological changes. Visual association areas are more affected than primary visual cortex. Additionally, there is evidence from neuropsychological and imaging studies during rest or passive visual stimulation that the occipitotemporal pathway is less affected than the parietal pathway. Our goal was to investigate functional activation patterns during active visuospatial processing in AD patients and the impact of local cerebral atrophy on the strength of functional activation. Fourteen AD patients and fourteen age-matched controls were measured with functional magnetic resonance imaging (fMRI) while they performed an angle discrimination task. Both groups revealed overlapping networks engaged in angle discrimination including the superior parietal lobule (SPL), frontal and occipitotemporal (OTC) cortical regions, primary visual cortex, basal ganglia, and thalamus. The most pronounced differences between the two groups were found in the SPL (more activity in controls) and OTC (more activity in patients). The differences in functional activation between the AD patients and controls were partly explained by the differences in individual SPL atrophy. These results indicate that parietal dysfunction in mild to moderate AD is compensated by recruitment of the ventral visual pathway. We furthermore suggest that local cerebral atrophy should be considered as a covariate in functional imaging studies of neurodegenerative disorders.

Restorative neuroscience: concepts and perspectives

There is increasing interest in the search for therapeutic options for diseases and injuries of the central nervous system (CNS), for which currently no effective treatment strategies are available. Replacement of damaged cells and restoration of function can be accomplished by transplantation of cells derived from different sources, such as human foetal tissue, genetically modified cell lines, embryonic or somatic stem cells. Preclinical and clinical trials have shown promising results in neurodegenerative disorders, like Parkinson's and Huntington's disease, but also ischaemic stroke, intracerebral haemorrhage, demyelinating disorders, epilepsy and traumatic lesions of the brain and spinal cord. Other studies have focused on finding new ways to activate and direct endogenous repair mechanisms in the CNS, eg, by exposure to specific neuronal growth factors or by inactivating inhibitory molecules. Neuroprotective drugs may offer an additional tool for improving neuronal survival in acute or chronic CNS diseases. Importantly however, a number of scientific issues need to be addressed in order to permit the introduction of these experimental techniques in the wider clinical setting.

Repeatability analysis of global and local metrics of brain structural networks

Computational network analysis provides new methods to analyze the human connectome. Brain structural networks can be characterized by global and local metrics that recently gave promising insights for diagnosis and further understanding of neurological, psychiatric and neurodegenerative disorders. In order to ensure the validity of results in clinical settings the precision and repeatability of the networks and the associated metrics must be evaluated. In the present study, nineteen healthy subjects underwent two consecutive measurements enabling us to test reproducibility of the brain network and its global and local metrics. As it is known that the network topology depends on the network density, the effects of setting a common density threshold for all networks were also assessed. Results showed good to excellent repeatability for global metrics, while for local metrics it was more variable and some metrics were found to have locally poor repeatability. Moreover, between subjects differences were slightly inflated when the density was not fixed. At the global level, these findings confirm previous results on the validity of global network metrics as clinical biomarkers. However, the new results in our work indicate that the remaining variability at the local level as well as the effect of methodological characteristics on the network topology should be considered in the analysis of brain structural networks and especially in networks comparisons.

Proteostasis impairment in ALS.

In physiological conditions the maintenance of the cellular proteome is a prerequisite for optimal cell functioning and cell survival. Additionally, cells need to constantly sense and adapt to their changing environment and associated stressors. Cells achieve this via a set of molecular chaperones, protein clearance pathways as well as stress-associated signaling networks which work together to prevent protein misfolding, its aggregation and accumulation in subcellular compartments. These processes together form the proteostasis network which helps in maintaining cellular proteostasis. Imbalance or impairment in this processes is directly linked to ageing associated disorders such as diabetes, cancer, stroke, metabolic disorders, pulmonary fibrosis, inflammation and neurodegenerative diseases. In this review, we provide insights into the proteostasis process and how its failure governs neurodegenerative disorders with a special focus on Amyotrophic lateral sclerosis (ALS).

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

Neurodegenerative diseases in domestic animals: a comparative review

Neurodegenerative diseases are characterised by selective damage to specific neurons in the nervous system. Interest in such diseases in humans has resulted in considerable progress in the molecular understanding of these disorders in recent decades. Numerous neurodegenerative diseases have also been described in domestic animals but relatively little molecular work has been reported. In the present review, we have classified neurodegenerative disease according to neuroanatomical criteria. We have established two large groups, based on whether the neuronal cell body or its axon was primarily affected. Conditions such as motor neuron diseases, cerebellar degenerations and neuroaxonal dystrophies are discussed in terms of their clinical and neuropathological features. In the most studied disorders, we also present what is known about underlying pathomechanisms, and compare them with their human counterparts. The purpose of this review is to re-kindle interest in this group of diseases and to encourage veterinary researchers to investigate molecular mechanisms by taking advantage of current diagnostic tools.