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.

Magnetic field exposure and neurodegenerative diseases--recent epidemiological studies

OBJECTIVES: To analyse the results of recent studies not yet included in a 2003 report of the International Commission on Non-Ionizing Radiation Protection (ICNIRP) on occupational exposure to low-frequency electromagnetic fields as potential risk factor for neurodegenerative diseases. METHODS: A literature search was conducted in the online databases of PubMed, ISI Web of Knowledge, DIMDI and COCHRANE, as well as in specialised databases and journals. Eight studies published between January 2000 and July 2005 were included in the review. RESULTS: The findings of these studies contribute to the evidence of an association between occupational magnetic field exposure and the risk of dementia. Regarding amyotrophic lateral sclerosis, the recent results confirm earlier observations of an association with electric and electronic work and welding. Its relationship with magnetic field exposure remains unsolved. There are only few findings pointing towards an association between magnetic field exposure and Parkinson's disease. CONCLUSIONS: The epidemiological evidence for an association between occupational exposure to low-frequency electromagnetic fields and the risk of dementia has increased during the last five years. The impact of potential confounders should be evaluated in further studies.

Mortality from neurodegenerative disease and exposure to extremely low-frequency magnetic fields: 31 years of observations on Swiss railway employees

AIMS: The objective of the present study was to investigate the relationship between extremely low-frequency magnetic field (ELF-MF) exposure and mortality from several neurodegenerative conditions in Swiss railway employees. METHODS: We studied a cohort of 20,141 Swiss railway employees with 464,129 person-years of follow-up between 1972 and 2002. For each individual, cumulative exposure was calculated from on-site measurements and modelling of past exposure. We compared cause-specific mortality in highly exposed train drivers (mean exposure: 21 microT) with less exposed occupational groups (for example station masters: 1 microT). RESULTS: The hazard ratio for train drivers compared to station masters was 1.96 [95% confidence interval (CI) = 0.98-3.92] for senile dementia and 3.15 (95% CI = 0.90-11.04) for Alzheimer's disease. For every 10 microT years of cumulative exposure senile dementia mortality increased by 5.7% (95% CI = 1.3-10.4), Alzheimer's disease by 9.4% (95% CI = 2.7-16.4) and amyotrophic lateral sclerosis by 2.1% (95% CI = -6.8 to 11.7). There was no evidence for an increase in mortality from Parkinson's disease and multiple sclerosis. CONCLUSIONS: This study suggests a link between exposure to ELF-MF and Alzheimer's disease and indicates that ELF-MF might act in later stages of the disease process.

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.

Residence near power lines and mortality from neurodegenerative diseases: longitudinal study of the Swiss population

The relation between residential magnetic field exposure from power lines and mortality from neurodegenerative conditions was analyzed among 4.7 million persons of the Swiss National Cohort (linking mortality and census data), covering the period 2000-2005. Cox proportional hazard models were used to analyze the relation of living in the proximity of 220-380 kV power lines and the risk of death from neurodegenerative diseases, with adjustment for a range of potential confounders. Overall, the adjusted hazard ratio for Alzheimer's disease in persons living within 50 m of a 220-380 kV power line was 1.24 (95% confidence interval (CI): 0.80, 1.92) compared with persons who lived at a distance of 600 m or more. There was a dose-response relation with respect to years of residence in the immediate vicinity of power lines and Alzheimer's disease: Persons living at least 5 years within 50 m had an adjusted hazard ratio of 1.51 (95% CI: 0.91, 2.51), increasing to 1.78 (95% CI: 1.07, 2.96) with at least 10 years and to 2.00 (95% CI: 1.21, 3.33) with at least 15 years. The pattern was similar for senile dementia. There was little evidence for an increased risk of amyotrophic lateral sclerosis, Parkinson's disease, or multiple sclerosis.

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.

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.

Autophagy: in: Cell Death

Autophagy is a conserved proteolytic mechanism that degrades cytoplasmic material including cell organelles. Although the importance of autophagy for cell homeostasis and survival has long been appreciated, our understanding of how autophagy is regulated at a molecular level just recently evolved. The importance of autophagy for the quality control of proteins is underscored by the fact that many neurodegenerative and myodegenerative diseases are characterized by an increased but still insufficient autophagic activity. Similarly, if the cellular stress, leading to deoxyribonucleic acid (DNA) damage, mitochondrial damage and/or damaged proteins, does not result in sufficient autophagic repair mechanisms, cells seem to be prone to transform into tumour cells. Therefore, autophagy has multiple roles to play in the causation and prevention of human diseases.

The status of olfactory function and the striatal dopaminergic system in drug-induced parkinsonism

Olfactory impairment has been reported in drug-induced parkinsonism (DIP), but the relationship between dopaminergic dysfunction and smell deficits in DIP patients has not been characterized. To this end, we studied 16 DIP patients and 13 patients affected by Parkinson's disease (PD) using the "Sniffin' Sticks" test and [(123)I] FP-CIT SPECT (single-photon emission computed tomography). DIP patients were divided based on normal (n = 9) and abnormal (n = 7) putamen dopamine transporter binding. Nineteen healthy age- and sex-matched subjects served as controls of smell function. Patients with DIP and pathological putamen uptake had abnormal olfactory function. In this group of patients, olfactory TDI scores (odor threshold, discrimination and identification) correlated significantly with putamen uptake values, as observed in PD patients. By contrast, DIP patients with normal putamen uptake showed odor functions-with the exception of the threshold subtest-similar to control subjects. In this group of patients, no significant correlation was observed between olfactory TDI scores and putamen uptake values. The results of our study suggest that the presence of smell deficits in DIP patients might be more associated with dopaminergic loss rather than with a drug-mediated dopamine receptor blockade. These preliminary results might have prognostic and therapeutic implications, as abnormalities in these individuals may be suggestive of an underlying PD-like neurodegenerative process.

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.

Nonmotor disturbances in Parkinson's disease

Nonmotor disturbances (NMDs) affect most patients with Parkinson's disease (PD) and often have a profound impact on their quality of life. NMDs such as depression, anxiety, fatigue, REM sleep behavior disorder, constipation, delayed gastric emptying, altered olfaction and pain can precede the onset of motor symptoms. Other NMDs, including hallucinations, dementia, excessive daytime sleepiness, insomnia, orthostatic hypotension and bladder disturbances, typically appear later in the course of PD. For most NMDs of PD, nondopaminergic and non-nigrostriatal mechanisms (e.g. neurodegeneration of other transmitter systems in the cortex and brainstem, side effects of medications, genetic and psychosocial factors) are considered more relevant than the 'classical' dopaminergic-nigrostriatal dysfunction. The recognition of NMDs requires a high degree of clinical suspicion, the use of specific questionnaires and ancillary tests. Pharmacological and nonpharmacological approaches can be effective, but for most forms of treatment of NMDs, the scientific evidence is limited.