Elsevier BV

Previous studies showed that cognitive training can improve cognitive performance in various neurodegenerative diseases but little is known about the effects of cognitive training on the brain. Here, we investigated the effects of our cognitive training paradigm, COGTIPS, on regional white matter microstructure and structural network topology. We previously showed that COGTIPS has small, positive effects on processing speed. A subsample of 79 PD patients (N = 40 cognitive training group, N = 39 active control group) underwent multi-shell diffusion-weighted imaging pre- and post-intervention. Our pre-registered analysis plan (osf.io/cht6g) entailed investigating white matter microstructural integrity (e.g., fractional anisotropy) in five tracts of interest, including the anterior thalamic radiation (ATR), whole-brain tract-based spatial statistics (TBSS), and the topology of the structural network. Relative to the active control condition, cognitive training had no effect on topology of the structural network or whole-brain TBSS. Cognitive training did lead to a reduction in fractional anisotropy in the ATR (B [SE]: − 0.32 [0.12], P = 0.01). This reduction was associated with faster responses on the Tower of London task (r = 0.42, P = 0.007), but this just fell short of our statistical threshold (P < 0.006). Post hoc “fixel-based” analyses showed that this was not due to changes in fiber density and cross section. This suggests that the observed effect in the ATR is due to training-induced alterations in neighboring fibers running through the same voxels, such as intra-striatal and thalamo-striatal fibers. These results indicate that 8 weeks of cognitive training does not alter network topology, but has subtle local effects on structural connectivity.

While the peripheral nervous system is able to repair itself following injury and disease, recovery is often slow and incomplete, with no available treatments to enhance the effectiveness of regeneration. Using knock-out and transgenic overexpressor mice, we previously reported that BACE1, an aspartyl protease, as reported by Hemming et al. (PLoS One 4:12, 2009), negatively regulates peripheral nerve regeneration. Here, we investigated whether pharmacological inhibition of BACE may enhance peripheral nerve repair following traumatic nerve injury or neurodegenerative disease. BACE inhibitor-treated mice had increased numbers of regenerating axons and enhanced functional recovery after a sciatic nerve crush while inhibition increased axonal sprouting following a partial nerve injury. In the SOD1G93A ALS mouse model, BACE inhibition increased axonal regeneration with improved muscle re-innervation. CHL1, a BACE1 substrate, was elevated in treated mice and may mediate enhanced regeneration. Our data demonstrates that pharmacological BACE inhibition accelerates peripheral axon regeneration after varied nerve injuries and could be used as a potential therapy.

Long noncoding RNAs (lncRNAs) are implicated in the autophagic-lysosomal pathway (ALP) and are closely linked to Parkinson’s disease (PD) pathology. β-Glucocerebrosidase (GCase) has also been reported to be correlated with α-synuclein (α-syn) proteostasis. However, lncRNAs and α-syn in neural-derived L1CAM exosomes and GCase activity in the plasma of PD patients have not been studied. This study used an ultrasensitive methodology, fluorescence nanoparticle tracking analysis (NTA), to measure plasma L1CAM exosomes and Quanterix Simoa to measure α-syn concentrations in L1CAM exosomes. Eighty-five healthy controls and 93 PD patients were enrolled, and several scales were used to rate the severity of PD. Receiver operating characteristic (ROC) curves were applied to map the diagnostic accuracy of categorizing PD patients and healthy subjects. We found increased Linc-POU3F3 and α-syn concentrations in L1CAM exosomes and decreased GCase activity in PD patients compared with controls. The three biomarkers displayed obvious differences among PD patients based on gender, H-Y stage, and UPDRS-III distribution. Interestingly, Linc-POU3F3 was significantly positively correlated with α-syn in L1CAM exosomes and inversely correlated with GCase activity in PD patients. Significant correlations were observed among L1CAM exosomal Linc-POU3F3 levels, GCase activity, and PD severity, including motor/cognitive dysfunction. Additionally, the combination of Linc-POU3F3 and α-syn in L1CAM exosomes and GCase activity could discriminate PD patients from controls. These results suggest that L1CAM exosomal Linc-POU3F3, L1CAM exosomal α-syn, and GCase activity may shed light on the mechanism underlying the autophagic-lysosomal system in the pathogenesis of PD and could be used to assess the severity of PD.

Medical care of patients with dementia often occurs within a physician—patient relationship whose features differ from relationships with patients without dementia. Many basic assumptions of the physician—patient relationship may not completely hold true, and certain aspects of the patient role may be shared by others besides the patient. For example, the entire premise of consent to the patient role may be inapplicable to patients who lack insight into their illness. In addition, caring for cognitively impaired patients who do not comprehend the purpose of the physician—patient interaction may render physicians vulnerable to losing empathy with their patients and objectifying them. This can lead to viewing patients as collections of symptoms rather than as humans suffering with illnesses and burdens. The fact that certain medical interventions, such as treatment of neuropsychiatric disturbances that do not trouble the patient, may appear to be initiated for the primary purpose of alleviating caregiver emotional stress also affects the physician—patient relationship. The present review examines how this relationship may be altered and presents a framework within which these alterations can be considered.

Prostaglandin-E2 (PGE2), an important mediator of inflammation, achieves its functions via four different G protein–coupled receptors (EP1, EP2, EP3, and EP4). We previously demonstrated that the EP2 receptor plays a proinflammatory and neurodegenerative role after status epilepticus (SE). We recently developed TG8-260 as a second-generation highly potent and selective EP2 antagonist. Here, we investigate whether TG8-260 is anti-inflammatory and combats neuropathology caused by pilocarpine-induced SE in rats. Adult male Sprague–Dawley rats were injected subcutaneously with pilocarpine (380–400 mg/kg) to induce SE. Following 60 min of SE, the rats were administered three doses of TG8-260 or vehicle and were allowed to recover. Neurodegeneration, neuroinflammation, gliosis, and blood–brain barrier (BBB) integrity were examined 4 days after SE. The results confirmed that pilocarpine-induced SE results in hippocampal neurodegeneration and a robust inflammatory response that persists days after SE. Furthermore, inhibition of the EP2 receptor by TG8-260 administered beginning 2 h after SE significantly reduced hippocampal neuroinflammation and gliosis but, in distinction to the earlier generation EP2 antagonist, did not mitigate neuronal injury or BBB breakdown. Thus, attenuation of neuroinflammation and gliosis is a common feature of EP2 inhibition following SE.

CAG repeat expansion is the genetic cause of nine incurable polyglutamine (polyQ) diseases with neurodegenerative features. Silencing repeat RNA holds great therapeutic value. Here, we developed a repeat-based RNA-cleaving DNAzyme that catalyzes the destruction of expanded CAG repeat RNA of six polyQ diseases with high potency. DNAzyme preferentially cleaved the expanded allele in spinocerebellar ataxia type 1 (SCA1) cells. While cleavage was non-allele-specific for spinocerebellar ataxia type 3 (SCA3) cells, treatment of DNAzyme leads to improved cell viability without affecting mitochondrial metabolism or p62-dependent aggresome formation. DNAzyme appears to be stable in mouse brain for at least 1 month, and an intermediate dosage of DNAzyme in a SCA3 mouse model leads to a significant reduction of high molecular weight ATXN3 proteins. Our data suggest that DNAzyme is an effective RNA silencing molecule for potential treatment of multiple polyQ diseases.

An early feature of Alzheimer’s disease (AD) is region-specific declines in brain glucose metabolism. Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult human brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function. The hypometabolism seen in AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies (KB), which include acetoacetate, β-hydroxybutyrate, and acetone. KB are normally produced from fat stores when glucose supplies are limited, such as during prolonged fasting. KB have been induced both by direct infusion and by the administration of a high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain’s normal reliance on glucose. Research into the therapeutic potential of KB and ketosis represents a promising new area of AD research.