The Potential of Immersive Virtual Reality for Cognitive Training in Elderly.

The number of elderly is growing rapidly, including those that struggle with cognitive decline and, consequently, activities of daily living. Developing interventions that slow down cognitive decline would greatly benefit the autonomy of these elderly, as well as their caretakers. Virtual reality (VR) is an immersive and interactive human-computer interface with real-time simulation that is suggested to be a promising tool to improve cognitive functioning. This literature review discusses the features of immersive VR, including its opportunities and limitations, that are of special relevance for improving cognition in elderly. First, the high flexibility of VR allows for personalized and safe training of potentially harmful situations and isolated aspects of tasks. Second, VR's dynamic and real-time feedback on performance provides a labor-extensive tool for caretakers in elderly care. Third, the acquisition of high resolution data enables the exposure of subtle changes over time, relevant for detecting the nature and extent of cognitive changes in elderly, including those with dementia. Fourth, immersive VR has been related to cybersickness. Finally, VR is immersive and enables the perception and expression of emotions, motor behaviors, and multiple senses. Aged subjects are found to have sparing of emotional learning and show increased reliance on multisensory integration for learning. Moreover, they experience high levels of flow, motivation, and presence in VR setups. Despite the clear potential of immersive VR, the studies available are small scale and have not been replicated. The digital illiteracy of elderly and healthcare personnel form an additional barrier for implementation. Hence, while replication of outcomes and standardization of VR interventions is required before it can be used in standard care, VR may provide a particularly effective tool for training cognition in elderly.

Potential Adverse Effects of Violent Video Gaming: Interpersonal- Affective Traits Are Rather Impaired Than Disinhibition in Young Adults.

The increasing trend of mass shootings, which were associated with excessive use of violent video games, fueled the debate of possible effects violent video games may have on adolescents and young adults. The aim of this study was to investigate the possible link between violent video gaming effects and the disposition of adverse behavior traits such as interpersonal-affective deficits and disinhibition. Data of 167 young adults, collected by an online questionnaire battery, were analyzed for lifetime video game exposure differences (i.e., non-gamers, non-violent video gamers, stopped violent video game users, and ongoing violent video game users) as well as for recent exposure effects on adverse behavior traits (Levenson's Psychopathy Scale), while controlling for other potentially confounding lifestyle factors. While interpersonal-affective deficits were significantly higher in participants with ongoing violent video game exposure compared to non-gamers and non-violent video gamers, disinhibition was significantly higher in both - stopped and ongoing - violent video game exposure groups compared to non-gamers. Recent violent video game exposure was a stronger predictor for interpersonal-affective deficits, but was also significant for disinhibition. Considering that we observed small to medium effects in a sample of young adults with little to moderate use of violent video games highlights the importance of further investigating the potential adverse effects of violent video games on quality of social relationships.

The Test Your Memory (TYM) Test Outperforms the MMSE in the Detection of MCI and Dementia.

OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy and clinical usability of a Dutch translation of the Test Your Memory (TYM) test in patients with mild cognitive impairment (MCI) and dementia as compared to the Mini-Mental State Examination (MMSE), in the setting of the memory clinic of a general hospital. METHODS: Fourty-two participants referred to the memory clinic with memory problems and fourty-two healthy controls were assessed using the TYM and the MMSE. We evaluated the sensitivity, specificity and diagnostic accuracy of the TYM and MMSE. Both instruments were tested against recently established clinical diagnostic criteria of MCI, Alzheimer's disease (AD) and vascular dementia (VD). RESULTS: The TYM demonstrated to be more sensitive in detecting dementia than the MMSE. The TYM also was better at discriminating between healthy controls and patients with MCI than the MMSE. CONCLUSION: Our data suggest that the TYM is more suitable as a practical tool for the early detection of dementia than the MMSE.

Enhanced sensitivity of dopaminergic neurons to rotenone-induced toxicity with aging.

Rotenone has been reported to induce various degrees of Parkinsonism in rats. We tested whether advancing age alters the sensitivity of dopaminergic neurons to rotenone. A low, systemic dose of rotenone had no effect on young rats, but led to a 20-30% reduction of tyrosine hydroxylase-positive neurons in the substantia nigra of older rats. The effect was specific to nigral dopaminergic neurons and may be associated with the increase of glial cell activation in older rats. These data suggest that age enhances the sensitivity of dopaminergic neurons to rotenone and should be considered when assessing models of Parkinson's disease.

Mapping of rat brain using the Synuclein-1 monoclonal antibody reveals somatodendritic expression of alpha-synuclein in populations of neurons homologous to those vulnerable to Lewy body formation in human synucleopathies.

The neuronal protein alpha-synuclein has been implicated in the pathogenesis of Parkinson disease and other neurodegenerative diseases. Although many studies report that alpha-synuclein expression is restricted to neuronal presynaptic terminals, this protein aggregates in Lewy bodies in somata that are typically distant from their axon terminals. Few studies have addressed this paradox and there has been no compelling explanation proposed for the apparent discrepancy between the locus of neuronal alpha-synuclein expression and the loci of Lewy bodies in the majority of Parkinson disease cases. We explored this issue by extensively characterizing the monoclonal antibody Synuclein-1 (Syn-1) and using this highly selective antibody to map the distribution of alpha-synuclein throughout rat brain and in human substantia nigra (SN). Additionally, alpha-synuclein expression in rat SN detected by 2 polyclonal antibodies against alpha-synuclein was compared with that detected by the Syn-1 antibody. In contrast with many previous reports, alpha-synuclein was detected by Syn-1 in neuronal somata and dendrites in restricted brain regions, as well as more ubiquitously in axons and terminals. The strongest alpha-synuclein neuronal expression in rat was found in brainstem and cortical regions that are homologous to regions prone to Lewy body formation in humans. The Syn-1 antibody labeled abundant somatodendritic alpha-synuclein in both rat and human SN, a major locus of Lewy body formation and neurodegeneration in Parkinson disease. By contrast, very few immunoreactive somata in the rat SN were labeled by the 2 polyclonal antibodies. We explore possible explanations for the differences in conflicting reports of patterns of alpha-synuclein expression in brain, including differences among antibodies.

Presence of tissue transglutaminase in granular endoplasmic reticulum is characteristic of melanized neurons in Parkinson's disease brain.

Parkinson's disease (PD) is characterized by the accumulation of α-synuclein aggregates and degeneration of melanized neurons. The tissue transglutaminase (tTG) enzyme catalyzes molecular protein cross-linking. In PD brain, tTG-induced cross-links have been identified in α-synuclein monomers, oligomers and α-synuclein aggregates. However, whether tTG and α-synuclein occur together in PD affected neurons remains to be established. Interestingly, using immunohistochemistry, we observed a granular distribution pattern of tTG, characteristic of melanized neurons in PD brain. Apart from tTG, these granules were also positive for typical endoplasmic reticulum (ER)-resident chaperones, that is, protein disulphide isomerase, ERp57 and calreticulin, suggesting a direct link to the ER. Additionally, we observed the presence of phosphorylated pancreatic ER kinase (pPERK), a classical ER stress marker, in tTG granule positive neurons in PD brain, although no subcellular colocalization of tTG and pPERK was found. Our data therefore suggest that tTG localization to granular ER compartments is specific for stressed melanized neurons in PD brain. Moreover, as also α-synuclein aggregates were observed in tTG granule positive neurons, these results provide a clue to the cellular site of interaction between α-synuclein and tTG.

Pinhole SPECT imaging of dopamine transporters correlates with dopamine transporter immunohistochemical analysis in the MPTP mouse model of Parkinson's disease.

The in vivo analysis of dopaminergic degeneration in animal models of Parkinson's disease (PD), using pinhole single photon emission computed tomography (SPECT), ideally should afford a serial study design, enabling the analysis of the degenerative process as well as the potential neuroprotective and/or restorative properties of drugs over time in living animals. Previously, we demonstrated that striatal dopamine transporter (DAT) levels in rats could be analyzed reproducibly, using pinhole SPECT with the DAT probe [(123)I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane (FP-CIT). However, the capacity of this approach to accurately detect a range of striatal DAT levels in the most widely used animal model of PD, i.e., the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse, remains to be determined. For this purpose, various levels of DAT were induced by treating c57BL/6J mice for 1, 3, or 5 days with MPTP (25 mg/kg ip), respectively. [(123)I]FP-CIT SPECT scans were performed 5 days after the last MPTP injection. Mice were perfused 6 days after the last MPTP injection, and the SPECT data were compared to ex vivo striatal and nigral DAT levels as measured by immunohistochemistry within the same animals. The analysis of striatal DAT levels using SPECT and DAT immunohistochemistry yielded highly comparable results on the percentage of DAT reduction in each MPTP group. The in vivo data showed a decrease of specific striatal to non-specific binding ratios by 59%, 82%, and 76% in mice treated for 1, 3, and 5 days, respectively. Moreover, a strong, positive correlation was observed between the in vivo and ex vivo parameters. The present study provides the first evidence that [(123)I]FP-CIT pinhole SPECT allows the accurate detection of a range of striatal DAT (i.e., losses of approximately 60-80%) levels in mice. Since such large dopaminergic lesions could be detected, this SPECT method may at least be useful for analyzing neuroprotective treatment with a clear-cut positive (i.e., complete protection) or negative (i.e., not any protection) effect. Whether this method is also useful for analyzing more subtle effects of neuroprotective treatment (partial protection) remains to be established, by studying mice with small dopaminergic lesions.

Dendritic cell-induced activation of adaptive and innate antitumor immunity.

While studying Ag-pulsed syngeneic dendritic cell (DC) immunization, we discovered that surprisingly, unpulsed DCs induced protection against tumor lung metastases resulting from i.v. injection of a syngeneic BALB/c colon carcinoma CT26 or a syngeneic C57BL/6 lung carcinoma LL/2. Splenocytes or immature splenic DCs did not protect. The protection was mediated by NK cells, in that it was abrogated by treatment with anti-asialo-GM1 but not anti-CD8, and was induced by CD1(-/-) DCs unable to stimulate NKT cells, but did not occur in beige mice lacking NK cells. Protection correlated with increased NK activity, and increased infiltration of NK but not CD8(+) cells in lungs of tumor-bearing mice. Protection depended on the presence of costimulatory molecules CD80, CD86, and CD40 on the DCs, but surprisingly did not require DCs that could make IL-12 or IL-15. Unexpectedly, protection sensitive to anti-asialo-GM1 and increased NK activity were still present 14 mo after DC injection. As NK cells lack memory, we found by depletion that CD4(+) not CD8(+) T cells were required for induction of the NK antitumor response. The role of DCs and CD4(+) T cells provides a novel mechanism for NK cell induction and innate immunity against cancer that may have potential in preventing clinical metastases.

TCH346 prevents motor symptoms and loss of striatal FDOPA uptake in bilaterally MPTP-treated primates.

The neuroprotective efficacy of the propargylamine TCH346 was studied in the primate model of Parkinson's disease, the bilaterally MPTP-treated monkey. Male rhesus monkeys received 2.5 mg MPTP into the left carotid artery and, 8 weeks later, 1.25 mg MPTP into the right carotid artery. Starting 2 h after the second MPTP infusion, either 0.014 mg/kg TCH346 or its solvent was subcutaneously injected twice per day for 14 days. The first MPTP treatment induced mild Parkinson symptoms, reduced right limb movements, and reduced FDOPA uptake in the left striatum. The second MPTP treatment made Parkinson symptoms worse, reduced left limb movements, and reduced FDOPA uptake in the right striatum of solvent-treated monkeys. In contrast, the second MPTP treatment did not further worsen motor symptoms and did not decrease FDOPA uptake in the right striatum of TCH346-treated monkeys. Although the effects of the second MPTP treatment were largely prevented, the effects of the first MPTP treatment were not reversed by TCH346. Immunohistochemical examination confirmed the dramatic loss of dopamine cells in vehicle-treated monkeys and the preservation of these neurons in the right brain side of the TCH346-treated animals. In conclusion, systemic administration of TCH346 prevented motor symptoms and nigrostriatal degeneration induced by MPTP in primates.