Abstract Introduction Alzheimer’s disease is a neurocognitive disorder that affects elderly people by slowly impaired cognition, dementia, and gets worse with age. It slowly impacts the quality of life. Clinically, it is distinguished by a transition from episodic memory to a gradual reduction in cognitive ability leading to cognitive dysfunction. Neurofibrillary tangles and amyloid plaques are unique structures that are thought to have a role in the pathogenesis of Alzheimer's disease. In this review, we focus our attention on the risk factors, pathophysiology, etiology, epidemiology, stages, diagnosis, treatment, mechanisms, pathways, ongoing clinical trials data and risks potentially associated with the development of Alzheimer's disease. Short summary This review aims to extrapolate the information about Alzheimer's disease. Preliminary research was done by selecting reviews on PubMed, Elsevier, and Google open-access publications using the keywords like “Alzheimer, dementia, neurodegenerative, memory, amyloid β, mechanism of action, pathways”. Conclusion Here we show the discussion and interpretation of several signaling pathways in the pathogenesis of Alzheimer's disease such as amyloid β plaque cleavage, Metal ion hypothesis, amyloid β degradation, initiation of amyloidogenic and non-amyloidogenic pathway, oxidative stress hypothesis, Metabolic syndrome, insulin resistance and tau phosphorylation associated apolipoprotein- cholesterol, neurofibrillary tangles accumulation, and insulin resistance which are significant for better understanding of the disease initiation and progression. On studying the ongoing clinical trials, it was found that current drugs being tested are crenezumab, gantenerumab and sodium oligonucleotide. Graphical Abstract 

pdf/targeting-the-molecular-web-of-alzheimers-disease-unveiling-4x1rja2mz2.pdf

Targeting the molecular web of Alzheimer’s disease: unveiling pathways for effective pharmacotherapy

Aging, frontotemporal dementia (FTD), and Alzheimer's dementia (AD) manifest electroencephalography (EEG) alterations, particularly in the beta-to-theta power ratio derived from linear power spectral density (PSD). Given the brain's nonlinear nature, the EEG nonlinear features could provide valuable physiological indicators of aging and cognitive impairment. Multiscale dispersion entropy (MDE) serves as a sensitive nonlinear metric for assessing the information content in EEGs across biologically relevant time scales. 

Beta-to-Theta Entropy Ratio of EEG in Aging, Frontotemporal Dementia, and Alzheimer's Dementia

Diffusion-weighted imaging negative M232R familial Creutzfeldt-Jakob disease.

•PSEN2 variants are associated with various neurodegenerative disorders and phenotypes •Most variants cause Alzheimer's disease (AD) or Lewy body dementia (LB-D) •PSEN2 Ile149Thr variant can yield juvenile dystonia-parkinsonism with voiceless whispering stereotypies •At onset, PSEN2 Ile149Thr cognitive phenotype may resemble an atypical AD-PCA, in the advanced stage a LB-D spectrum •PSEN2 could act as a phenotypic modifier of complex neurodegenerative diseases 

Rare causes of dystonia-parkinsonism with cognitive impairment, behavioral abnormalities, and voiceless whispering stereotypies: Describing the long-term evolution of the neurological phenotype in a patient with the PSEN2 Ile149Thr variant

Electroencephalography (EEG) stands as a pivotal non-invasive tool, capturing brain signals with millisecond precision and enabling real-time monitoring of individuals' mental states. Using appropriate biomarkers extracted from these EEG signals and presenting them back in a neurofeedback loop offers a unique avenue for promoting neural compensation mechanisms. This approach empowers individuals to skillfully modulate their brain activity. Recent years have witnessed the identification of neural biomarkers associated with aging, underscoring the potential of neuromodulation to regulate brain activity in the elderly.Within the framework of an EEG-based brain-computer interface, this study focused on three neural biomarkers that may be disturbed in the aging brain: Peak Alpha Frequency, Gamma-band synchronization, and Theta/Beta ratio. The primary objectives were twofold: (1) to investigate whether elderly individuals with subjective memory complaints can learn to modulate their brain activity, through EEG-neurofeedback training, in a rigorously designed double-blind, placebo-controlled study; and (2) to explore potential cognitive enhancements resulting from this neuromodulation.A significant self-modulation of the Gamma-band synchronization biomarker, critical for numerous higher cognitive functions and known to decline with age, and even more in Alzheimer's disease (AD), was exclusively observed in the group undergoing EEG-neurofeedback training. This effect starkly contrasted with subjects receiving sham feedback. While this neuromodulation did not directly impact cognitive abilities, as assessed by pre- versus post-training neuropsychological tests, the high baseline cognitive performance of all subjects at study entry likely contributed to this result.The findings of this double-blind study align with a key criterion for successful neuromodulation, highlighting the significant potential of Gamma-band synchronization in such a process. This important outcome encourages further exploration of EEG-neurofeedback on this specific neural biomarker as a promising intervention to counter the cognitive decline that often accompanies brain aging and, eventually, to modify the progression of AD. 

Self-Modulation of Gamma-Band Synchronization through EEG-Neurofeedback Training in the Elderly

Dear Editor, Creutzfeldt-Jakob disease (CJD) is a typically fatal neurodegenerative disease, and 90% of CJD patients die within 1 year of diagnosis. Of all CJD cases, 10–15% are autosomal dominant disorders of the prion protein gene (PRNP) in chromosome 20, classified as genetic or familial CJD. Familial CJD has an younger onset and has a lengthier disease progression than sporadic CJD.1 In the past, clinical patterns of CJD with M232R mutation (CJD232) were like sporadic CJD. However, CJD232 cases that reveal longer clinical courses and periodic sharp and wave complexes distinctively found in an eletroencephalography (EEG) are not observed have been recently reported.2 The authors report cases of patients diagnosed with familial CJD revealed slow progress like Alzheimer’s disease. A 62-year-old male patient visited our hospital because he had gait disturbance 2 years ago and symptoms of memory deterioration, etc. occurred 1 year ago. In his medical history, Familial Creutzfeldt-Jakob Disease with M232R Mutation Progressed Slowly like Alzheimer’s Disease

/pdf/familial-creutzfeldt-jakob-disease-with-m232r-mutation-5a0n19m8mi.pdf

Familial Creutzfeldt-Jakob Disease with M232R Mutation Progressed Slowly like Alzheimer's Disease

Early-onset Alzheimer’s disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer’s disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G>A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future.

/pdf/a-possible-pathogenic-psen2-gly56ser-mutation-in-a-korean-35z8ciq5.pdf

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic dysfunction and associated with abnormalities in the cholinergic system. However, the relationship between PD and cholinergic dysfunction, particularly in exosomes, is not fully understood.We enrolled 37 patients with PD and 44 healthy controls (HC) to investigate acetylcholinesterase (AChE) activity in CD9-positive and L1CAM-positive exosomes. Exosomes were isolated from plasma using antibody-coupled magnetic beads, and their sizes and concentrations were assessed using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Subsequently, the AChE activity in these exosomes was analyzed in relation to various clinical parameters.A significant decrease in AChE activity was observed in CD9-positive exosomes derived from patients with PD, whereas no significant differences were found in L1CAM-positive exosomes. Further analysis with a larger sample size confirmed a substantial reduction in AChE activity in CD9-positive exosomes from the PD plasma, with moderate diagnostic accuracy. The decrease in AChE activity of CD9-positive exosomes did not show an association with cognitive impairment but displayed a trend toward correlation with PD progression.The reduction in AChE activity in CD9-positive exosomes suggests potential peripheral cholinergic dysfunction in PD, independent of the central cholinergic system. The observed alterations in AChE activity provide valuable insights into the association between cholinergic dysfunction and the pathogenesis of PD.

Assessment of acetylcholinesterase activity in CD9-positive exosomes from patients with Parkinson’s disease

A patient with hepatocellular carcinoma(HCC) staged Barcelona Clinic for Liver Cancer stage B started chemotherapy because of intrahepatic recurrence after hepatic segmentectomy. Regorafenib was started as a second-line treatment due to refractory to sorafenib treatment, but was discontinued after 26 months due to side effects. After two years of follow-up, the patients achieved unexpected long-term regression. We present the potential of regorafenib effect for anti-tumor immunity through possible pharmacological mechanisms.

https://www.karger.com/Article/Pdf/529139

Long-Term Regression after Discontinuation of Regorafenib Administered for Sorafenib-Refractory Hepatocellular Carcinoma

Received August 6, 2017 Revised November 27, 2017 Accepted November 27, 2017 Address for correspondence: Sang-Won Ha, MD Departments of Neurology, Veteran Healthcare Service Medical Center, 53 Jinhwangdo-ro 61-gil, Gangdong-gu, Seoul 05368, Korea Tel: +82-2-2225-1324 Fax: +82-2-2225-1327 E-mail: hippocam@naver.com 당뇨, 허혈심질환이 있는 72세 남자가 기상 시 지남력장애 및 혼동을 보였다. 뇌량팽대에 확산강조영상에서는 고신호강도, 겉보 기확산계수지도에서는 저신호강도병변이 보였다(Fig. A, B). 당시 혈당은 36 mg/dL였고, 포도당 정주 직후에 의식이 회복되었다. 발 생 6일 후 시행한 확산강조영상에서 병변은 사라졌다. 가역뇌량팽대병변경도뇌병증(mild encephalopathy with reversible splenial lesion)은 특징적인 임상영상증후군으로 감염 또는 독성-대사뇌병증에 의해 유발된다. 겉보기확산계수지도에서의 확 산제한으로 세포독성부종으로 추정하지만 왜 가역적인지, 왜 뇌량 팽대에만 선택적으로 나타나는지는 알려져 있지 않다.

/pdf/mild-encephalopathy-with-reversible-splenial-lesion-by-1skyy4nvrb.pdf

Mild Encephalopathy with Reversible Splenial Lesion by Hypoglycemia: Magnetic Resonance Spectroscopy and Diffusion Tensor Image Findings

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