Sensation of effort is altered in Huntington's disease

In this study, we investigated sensation of effort in Huntington disease (HD). We tested the hypothesis that the basal ganglia are involved in processing effort sensation. The experimental paradigm consisted in a contralateral matching procedure where normal subjects (N=6) and HD patients (N=6) were required to lift a reference weight with their non-dominant index, and then compare the target-weight with variable weights lifted by the dominant index. Two kinds of sequences were administered: (1) increasing, where the first weight was lighter than the reference weight and progressively increased in 20g steps, (2) decreasing, where trials started with a heavier weight and progressively decreased. We calculated the discrimination threshold (DT) across sequences as the weight for which the subject's response changed sign. The difference between the higher and the lower threshold was defined as "uncertain area". We predicted that controls should overestimate the reference weight lifted by their non-dominant hand because the same effort produces more force when applied to stronger muscles. If the basal ganglia mediates sensation of effort, patients' capability to discriminate weights should be degraded. As expected, normal subjects overestimated the reference weight lifted by their non-dominant index and showed a restricted uncertain area, thus, indicating that were able to discriminate minimal differences in generated forces. By contrast, patients with HD underestimated the reference weight lifted by their non-dominant hand and showed a broad uncertain area, thus, demonstrating that they could detect only important differences in the matched efforts. These results suggest that effort sensation critically involves the basal ganglia. In normal conditions, in parallel with the efferent command of force, an efferent copy reflecting the magnitude of the voluntary motor command is transmitted to sensory centres. This signal and/or the integration of sensory feedback which generates what is experienced as the sense of effort, would be altered in HD.     

Temporo‐frontal functional connectivity during auditory change detection is altered in Alzheimer's disease

Cortico‐cortical connections might be disturbed in patients with Alzheimer's disease (AD). This study aimed to investigate the alterations of functional connectivity in AD during auditory change detection processing by measuring the local neuronal activation and functional connectivity between cortical regions. Magnetoencephalographic responses to deviant and standard sounds were recorded in 16 AD patients, 18 young controls and 16 elderly controls. Larger source amplitudes and shorter peak latencies were found in the right temporal magnetic mismatch responses of young controls compared with elderly controls and AD patients. During deviant stimuli, the right theta temporal‐frontal phase synchrony was significantly smaller in AD than in young controls and elderly controls. Moreover, the left temporal‐frontal synchronization at theta and alpha bands was reduced in AD and elderly controls compared with young controls. In conclusion, the loss in temporo‐frontal theta synchronization might be an electrophysiological hallmark of AD. Hum Brain Mapp 35:5565–5577, 2014. © 2014 Wiley Periodicals, Inc.     

The speed of lexical activation is altered in Parkinson's disease

Disturbed comprehension of complex noncanonical sentences in Parkinson's disease (PD) has been linked to dopamine depletion and delayed lexical retrieval. The aim of the present study was to replicate findings of delayed lexical activation in PD patients with noncanonical sentence processing difficulties, and investigate the influence of dopamine depletion on these changes to lexical access. In the first experiment, 20 patients with PD (tested whilst 'on' dopaminergic medication) and 23 controls participated in a list priming experiment. In this paradigm, stimuli are presented as a continuous list of words/nonwords, and semantic priming effects were measured across inter-stimulus intervals (ISIs) of 500 ms, 1000 ms and 1500 ms, with data analyzed using multivariate analyses of variance. The results revealed longer delays in lexical activation for PD patients with poor comprehension of noncanonical sentences, suggesting that the speed of lexical access may be compromised in PD, and that this feature may contribute to certain sentencecomprehension difficulties. In the second experiment, 7 patients with PD who participated in the first experiment, performed the same lexical decision task while 'off' their dopaminergic medication. Semantic priming effects were measured across ISIs of 500 ms and 1500 ms. Within group comparisons revealed a different pattern of semantic priming for the PD patients when 'on' compared to 'off' medication, providing further support for a dopaminergic influence on the speed of information processing and lexical activation.     

Platelet phosphatidylinositol kinase activity is not altered in Alzheimer disease

We previously reported a specific decline in phosphatidylinositol (PI) kinase activity in the neocortex of patients with Alzheimer disease (AD) as compared to controls, whereas phosphatidylinositol phosphate (PIP) kinase activity appeared not to be affected (Jolles et al., 1992). In search of a possible systemic effect of AD, in the present study we investigated phosphoinositide kinase activity in platelets from patients with AD and from control subjects. The study was based on the notion that disease-specific abnormalities in the brain could be reflected in blood platelets. PI kinase activity was studied in platelet homogenates and in a salt-solubilized protein fraction of platelets, because of the difference in subcellular localization of the different types of PI kinases. In addition, NADH cytochrome-C reductase was measured in platelet homogenates as a marker for the endoplasmic reticulum, to detect a possible proliferation of the endoplasmic reticulum. AD patients and normal elderly controls showed no difference in PI kinase activity in either enzyme fraction. Furthermore, NADH cytochrome-C reductase activity and the protein/phospholipid ratio per 10⁶ platelets were the same for AD patients and controls. This was taken as an indication that platelets in AD patients do not show proliferation of intracellular membranes.     

Cardiovagal modulation upon postural change is altered in Huntington's disease

Background:  Cardiac autonomic nervous system (ANS) dysfunction in Huntington's disease (HD) might affect both the sympathetic and parasympathetic branch of the ANS.
Results and Conclusions:  The pattern of linear heart rate variability we found in mid stage HD patients points towards a predominately reduced cardiovagal modulation compared with healthy subjects, which might influence HD patients' susceptibility for cardiovascular complications such as syncopes and cardiac arrhythmias.     

Neuroinflammation in Alzheimer's disease and prion disease

Alzheimer's disease (AD) and prion disease are characterized neuropathologically by extracellular deposits of Abeta and PrP amyloid fibrils, respectively. In both disorders, these cerebral amyloid deposits are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase protein, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the cerebral Abeta and PrP deposits are closely associated with a locally induced, non-immune-mediated chronic inflammatory response. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins, which are associated with Abeta plaques, are genetic risk factors for AD. Transgenic mice studies have established the role of amyloid associated acute-phase proteins in Alzheimer amyloid formation. In contrast to AD, there is a lack of evidence that cytokines and acute-phase proteins can influence disease progression in prion disease. Clinicopathological and neuroradiological studies have shown that activation of microglia is a relatively early pathogenetic event that precedes the process of neuropil destruction in AD patients. It has also been found that the onset of microglial activation coincided in mouse models of prion disease with the earliest changes in neuronal morphology, many weeks before neuronal loss and subsequent clinical signs of disease. In the present work, we review the similarities and differences between the involvement of inflammatory mechanisms in AD and prion disease. We also discuss the concept that the demonstration of a chronic inflammatory-like process relatively early in the pathological cascade of both diseases suggests potential therapeutic strategies to prevent or to retard these chronic neurodegenerative disorders.     

Dentate filter function is altered in a proepileptic fashion during aging

PURPOSE: The elderly have an increased incidence and prevalence for seizure disorders. Further, since up to 50% of these cases have no identifiable antecedent, it has been hypothesized that aging of the central nervous system itself may be epileptogenic. Aged rats, compared to adults, exhibit a greater susceptibility to and severity of seizures associated with hippocampal activation. Whether this aging-related change reflects proconvulsive changes in limbic circuitry is unknown and thus was the focus of this study. METHODS: Hippocampal slices from adult and aged Fischer 344 rats were examined using electrophysiological techniques. The dentate gyrus was our model region since it is involved with both wet-dog shakes and limbic seizures, and it is affected preferentially with age. RESULTS: No differences were noted between groups in field potential activity elicited with low frequency stimulation. In contrast, 5-Hz molecular layer stimulation could evoke multiple population spikes in approximately 40% of aged versus 0% of adult slices. Further, recording in CA3 revealed that this stimulation paradigm could elicit multiple spikes in aged, but not adult, slices that frequently evolved into spontaneous epileptiform bursts. This change in the capacity of the dentate to respond to and filter afferent input was associated with an aging-related decrease in the frequency of spontaneous IPSPs and an increased propensity for large amplitude prolonged EPSPs following disinhibition. CONCLUSIONS: These epileptogenic changes in dentate function and circuitry could contribute to the exacerbated susceptibility for hippocampal seizures in aged rodents, as well as the aging-related decline in spatial learning and memory.     

Copper and prion disease

The prion protein is a cell surface glyco-protein expressed by neurones. Its function has remained elusive until it was recently shown to be a copper binding protein. There is now strong evidence that the prion protein has a role in normal brain copper metabolism. Prion protein expression alters copper uptake into cells and enhances copper incorporation into superoxide dismutase. Furthermore the prion protein itself can act as a superoxide dismutase. One aspect of prion disease is the conversion of functional prion protein into an aggregated amyloid. This conversion may alter the function of the prion protein or abolish it. These results suggest that prion disease may involve disturbance to brain copper homeostasis.     

Decreased cell surface prion protein in mouse models of prion disease

Transmissible spongiform encephalopathies are infectious neurodegenerative diseases caused by prions, composed of ordered aggregates of misfolded cellular prion protein. Neural antigen density of prion protein, Thy-1 and glial fibrillary acidic protein was analyzed using flow cytometry of dissociated mouse brain cells after inoculation with mouse-adapted transmissible spongiform encephalopathy agents. Transmissible spongiform encephalopathy gliosis was demonstrated by increased intracellular immunoreactivity for glial fibrillary acidic protein compared with controls. Immunoreactivity for cell surface prion protein was reduced 2.8-3.8-fold compared with control brain cells, whereas surface Thy-1 protein was reduced 1.5-4-fold. Double-staining protocols revealed loss of brain cells highly immunoreactive for prion protein and Thy-1, with a preferential reduction of prion protein, suggesting that prion protein expression, trafficking or consumption may be affected early in disease.     

The visual kinetic depth effect is altered with Parkinson's disease

BackgroundPeople with Parkinson's disease (PD) often have visual-perceptual disorders. The goal of this study was to learn if they can develop a three dimensional (3D) percept that depends on the kinetic depth effect; that is, the viewer's ability to spatially integrate over time images that are moving along many trajectories.MethodsSixteen patients with PD and 12 healthy matched controls were presented with stimuli that were comprised of a circular region of randomly placed dots that moved as orthographic projections of a sphere. With a normal kinetic depth effect, the Training stimuli appear as an opaque rotating ball and the Test stimuli appear as a rotating transparent ball.ResultsWhereas all controls and all PD patients reported seeing the Training stimuli as a rotating ball, the patients with PD were significantly less likely to report the Test stimuli appearing as a 3D “ball” than were the healthy participants. Instead, seven PD patients often reported these bidirectional stimuli appeared “flat.”ConclusionsThis study has revealed that some patients with PD have impaired spatio-temporal integration of bidirectional visual motions, but the mechanism accounting for this loss, as well as why only some patients had this deficit, needs further study. When the driver of a moving vehicle fixates upon a stationary target in the surroundings, bidirectional retinal image motions may occur. Failure to perceive 3D structure in such moving scenes can be plausibly suspected to contribute to adverse events such as auto accidents.     

Cerebral amyloid in human prion disease

The clinical and neuropathological features of 21 patients with prion disease were reviewed with special reference to the morphology and immunoreactivity of cerebral amyloid. Six cases had a mutation at codon 102 of the prion protein (PrP) gene and in these the characteristic pathology was the formation of multicentric amyloid plaques which were stained with PrP antibody, whereas spongiform changes were absent in one and minimal in two. In one case, with a 216 base-pair insertion in the PrP gene, there was no spongiform encephalopathy (SE) but cerebellar amyloid was a prominent feature of the pathology. One case with a PrP gene mutation at codon 200 had severe SE but no amyloid. Two iatrogenic and 11 sporadic cases had SE and some form of amyloid was identified in all but three. Amyloid angiopathy and senile neuritic plaques, which stained with antibody to β-protein, were present in familial as well as in sporadic cases, including some who were rather young to be regarded as having Alzheimer's disease. Cerebellar amyloid and degeneration of granule and Purkinje cells were particularly common findings in sporadic as well as in genetically determined cases. This study serves to emphasize the association between prion disease and amyloid deposition in the brain. PrP is a component of some amyloid plaques in a high proportion of cases with inherited prion disease but may also be found in cases of sporadic SE without known mutations or base-pair insertions in the PrP gene.     

Neuroimaging findings in human prion disease

Imaging occupies an important role in the investigation of dementia and neurodegenerative disease. The role of imaging in prion disease used to be one of exclusion of other conditions. Over the past decade, the non-invasive nature of MRI, the improved range of magnetic resonance sequences and the availability of clinical and neuropathological correlation have led to a more prominent position of MRI and its inclusion in the diagnostic criteria for variant Creutzfeldt-Jakob disease. As experience of imaging in human prion disease increases, patterns of change related to strain and genotype may improve the diagnostic potential of imaging in the future, may reduce the need for more invasive testing and prove useful in future therapeutic trials. This paper reviews the current knowledge of imaging appearances in human prion disease.     

Complement activation in human prion disease

The central event in the neuropathological process of prion diseases (PrD) is the accumulation of abnormal prion protein accompanied by severe neuronal loss. Despite the infectious nature of these diseases, no prominent immune response has been detected yet. However, recent studies have shown that complement, a component of the innate immune system, is involved in the early pathogenesis of experimental prion infection. Here we demonstrate, in the diseased human brains, the presence of active compounds of the complement system, like C1q and C3b, in extracellular disease-associated prion protein deposits and the membrane attack complex in neurons. The neuronal localization of the membrane attack complex correlates well with the severity of disease-specific pathology and TUNEL labeling of neurons, irrespective of genotype or molecular phenotype of human prion diseases.     

Akt is altered in an animal model of Huntington's disease and in patients

The insulin-like growth factor I (IGF-1)/Akt pathway plays a crucial role in Huntington's disease by phosphorylating the causative protein, polyQ-huntingtin, and abolishing its toxic properties [Humbert et al. (2002)Dev. Cell, 2, 831-837; Rangone et al. (2004)Eur. J. Neurosci., 19, 273-279]. Therefore, dysregulation of this pathway may be essential for disease progression. In the present report, we thus aimed to analyse the status of Akt in brain or in peripheral tissues in Huntington's disease. Using a genetic model of Huntington's disease in rat that reproduces neuronal dysfunction and death, we show a progressive alteration of Akt during neuronal dysfunction and prior neurodegeneration. By analysing a limited number of lymphoblasts and lymphocytes, we detected modifications of Akt in Huntington's disease patients confirming a dysregulation of Akt in the disease process. Finally, we demonstrate that during late stages of the disease, Akt is cleaved into an inactive form by caspase-3. These observations demonstrate a progressive but marked alteration of this pro-survival pathway in Huntington's disease, and further implicate it as a key transduction pathway regulating the toxicity of huntingtin.     

Recombinant prion protein induces a new transmissible prion disease in wild-type animals

Prion disease is a neurodegenerative malady, which is believed to be transmitted via a prion protein in its abnormal conformation (PrP^Sc). Previous studies have failed to demonstrate that prion disease could be induced in wild-type animals using recombinant prion protein (rPrP) produced in Escherichia coli. Here, we report that prion infectivity was generated in Syrian hamsters after inoculating full-length rPrP that had been converted into the cross-β-sheet amyloid form and subjected to annealing. Serial transmission gave rise to a disease phenotype with highly unique clinical and neuropathological features. Among them were the deposition of large PrP^Sc plaques in subpial and subependymal areas in brain and spinal cord, very minor lesioning of the hippocampus and cerebellum, and a very slow progression of disease after onset of clinical signs despite the accumulation of large amounts of PrP^Sc in the brain. The length of the clinical duration is more typical of human and large animal prion diseases, than those of rodents. Our studies establish that transmissible prion disease can be induced in wild-type animals by inoculation of rPrP and introduce a valuable new model of prion diseases.     

Cyclooxygenase-2 is highly expressed in microglial-like cells in a murine model of prion disease

Prion diseases, or transmissible spongiform encephalopathies, are a relatively rare group of chronic degenerative disorders afflicting both animals and humans, characterized by typical histopathological signs such as amyloid deposition, neuronal loss and spongiform changes. Despite the absence of a typical acute inflammatory response, the consistent microglial activation and astrocytosis, that are found in human pathologies as well as in animal models, suggests the existence of an ongoing inflammatory response in these neurodegenerative diseases. To investigate the role of cyclooxygenase-2 (COX-2) activity in the pathogenesis of chronic neurodegenerative diseases, we studied immunohistochemically the expression of this key enzyme in the formation of prostaglandins during inflammatory responses in a well characterized murine model of prion disease. We found that COX-2 is selectively up-regulated in glial cells presenting the typical morphology of activated microglia and that the number of COX-2-positive cells increases with the progression of the disease. The extensive microglial expression of COX-2, that is likely to be followed by a sustained enzymatic activity leading to the generation of prostaglandins as well as of oxygen free radicals, might have important effects on chronic neurodegeneration. Further functional experiments are required to elucidate the role of COX-2 activity in the pathogenesis of chronic neurodegenerative diseases.     

White matter is altered with parental family history of Alzheimer's disease

BackgroundBrain alterations in structure and function have been identified in people with risk factors for sporadic type Alzheimer's disease (AD), suggesting that alterations can be detected decades before AD diagnosis. Although the effect of apolipoprotein E (APOE) ?4 on the brain is well-studied, less is known about the effect of family history of AD. We examined the main effects of family history and APOE ?4 on brain integrity, in addition to assessing possible additive effects of these two risk factors.MethodsDiffusion tensor imaging was performed in 136 middle-aged asymptomatic participants stratified on family history and APOE ?4. Mean diffusivity and fractional anisotropy (FA) were entered in factorial analyses to test the effect of AD risk on microstructural brain integrity. We performed a post hoc analysis of the three principal diffusivities (λ1, λ2, λ3) to provide potential additional insight on underlying tissue differences.ResultsParental family history of AD was associated with lower FA in regions of the brain known to be affected by AD, including cingulum, corpus callosum, tapetum, uncinate fasciculus, hippocampus, and adjacent white matter. Contrary to previous reports, there was no main effect of APOE ?4; however, there was an additive effect of family history and APOE ?4 in which family history–positive participants who were also APOE ?4 carriers had the lowest FA compared with the other groups.ConclusionsThe data indicate that unknown risk factors contained in family history are associated with changes in microstructural brain integrity in areas of the brain known to be affected by AD. Importantly, the results provide further evidence that AD pathology might be detected before cognitive changes, perhaps decades before disease onset.     

Molecular neurology of prion disease

Prions are infectious pathogens principally composed of abnormal forms of a protein encoded in the host genome. They cause lethal neurodegenerative conditions including CJD, GSS, and kuru in humans and scrapie and bovine spongiform encephalopathy in domestic animals. Remarkably, distinct strains of prions occur despite absence of an agent-specific genome: misfolded proteins themselves may encode strain diversity--with wide implications in biology. The arrival of variant CJD, and the experimental confirmation that it is caused by infection with BSE-like prions, has focussed research on early diagnosis and treatment. Recent advances lead to considerable optimism that effective human therapies may now be developed. While several drugs have been tried in small numbers of patients, there is no clear evidence of efficacy of any agent and controlled clinical trials are urgently needed. Importantly, there is increasing recognition that fundamental processes involved in prion propagation--seeded aggregation of misfolded host proteins--are of far wider significance, not least in understanding the commoner neurodegenerative diseases that pose such a major and increasing challenge for healthcare in an ageing population.