Neurodegenerative disease

Neurodegenerative diseases are characterized by deterioration of neurons or their myelin sheath, disrupting transmission of sensory information, movement control, and more. Because these cells are not easily regenerated, buildup of amyloid plaques can lead to disorders such as Alzheimer’s and Parkinson’s disease, and non-amyloid-related degeneration can cause amyotrophic lateral sclerosis and multiple sclerosis.

Contact sports athletes and military personnel who suffered a repetitive mild traumatic brain injury (rmTBI) are at high risk of neurodegenerative diseases such as advanced dementia and chronic traumatic encephalopathy (CTE). However, due to the lack of specific biological indicators in clinical practice, the diagnosis and treatment of repetitive mild traumatic brain injury are quite limited.

Zhang et al. used 2-methacryloyloxyethyl phosphorylcholine (MPC)-nanocapsules to deliver immunoglobulins (IgG), which can increase the delivery efficiency and specific target of IgG while reducing the effective therapeutic dose of the drug.

The results demonstrated that MPC-capsuled immunoglobulins (MPC-n (IgG)) significantly alleviated cognitive impairment, hippocampal atrophy, p-Tau deposition, and myelin injury in rmTBI mice compared with free IgG. Furthermore, MPC-n (IgG) can also effectively inhibit the activation of microglia and the release of inflammatory factors.

In the present study, Zhang et al. put forward an efficient strategy for the repetitive mild traumatic brain injury treatment of related cognitive impairment and provide evidence for the administration of low-dose IgG 1)

The underlying causes are not yet fully understood, but different mechanisms such as cell stress and chronic inflammation have been described as contributing factors.

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurodegenerative diseases that affect white matter (WM) in the brain 2).

Neurodegenerative changes have been observed in the vicinity of brain tumors, typically around slowly growing benign lesions. Moreover, in-vitro data suggest a potential induction of pathological tau deposits also in glioblastoma.

Post-mortem brain tissue of 22 patients with glioblastoma was evaluated immunohistochemically for phosphorylated tau, amyloid beta, alpha-synuclein and phosphorylated TDP-43. Additionally, the autophagy marker p62 and the microglial marker HLA-DR were investigated. The data were compared to 22 control cases and ten cases with other space occupying brain lesions. An increase of p62-immunoreactivity was observed within and adjacent to the glioblastoma tumor tissue. Moreover, dense microglial infiltration in the tumor tissue and the immediate surrounding brain tissue was a constant feature. Deposition of neurodegeneration-associated proteins was found in the majority of cases (86.4%) but in distant sites. These findings suggested a preexisting neurodegenerative pathology, which followed a typical distributional pattern: ten cases with Alzheimer disease neuropathological changes, including two severe cases, eight cases with primary age-related tauopathy, six cases with aging-related tau astrogliopathy and one case with progressive supranuclear palsy. Collectively, our data suggests enhanced autophagy in glioblastoma tumor cells and the surrounding brain. The variety and distribution of distant neurodegeneration-associated protein aggregates observed in the majority of cases, suggest a preexisting rather than a tumor-induced neurodegenerative condition 3).

GDF15 may be a potential biomarker for neurodegenerative diseases. Xue et al. aimed to quantitative analysis the levels of GDF15 in patients with neurological diseases and in health control, and then to determine its potential diagnostic utility.

Two researchers separately conducted a systematic search of the relevant studies up to January 2021 in Embase, PubMed, and Web of Science. Effect sizes were estimated to use the standardized mean difference (SMD) with 95% confidence interval (CI). Sensitivity and specificity were calculated by the summary receiver operating characteristics curve (SROC) method. The sensitivity analysis was performed by the “one-in/one-out” approach. Considering the considerable heterogeneity among studies, random-effects model was used for the meta-analysis investigation.

A total of eight articles were included in this meta-analysis and systematic review. The pooled results of the random effect model indicated GDF15 levels were significantly higher in patients with neurodegenerative disease than healthy people (SMD = 0.92, 95% CI: 0.44-1.40, Z = 3.75, p < 0.001). Sensitivity and specificity of biomarker of GDF15 were 0.90 (95% CI: 0.75-0.97), 0.77 (95% CI: 0.67-0.65), and AUC = 0.87 (95% CI: 0.84-0.90), respectively.

GDF15 levels were higher in patients with neurodegenerative disease than healthy people. And serum levels of GDF15 were a better marker for diagnostic utility of neurodegenerative disease 4).

Zhang C, Wei C, Huang X, Hou C, Liu C, Zhang S, Zhao Z, Liu Y, Zhang R, Zhou L, Li Y, Yuan X, Zhang J. MPC-n (IgG) improves long-term cognitive impairment in the mouse model of repetitive mild traumatic brain injury. BMC Med. 2023 May 30;21(1):199. doi: 10.1186/s12916-023-02895-7. PMID: 37254196.
Bouchard HC, Sun D, Dennis EL, Newsome MR, Disner SG, Elman J, Silva A, Velez C, Irimia A, Davenport ND, Sponheim SR, Franz CE, Kremen WS, Coleman MJ, Williams MW, Geuze E, Koerte IK, Shenton ME, Adamson MM, Coimbra R, Grant G, Shutter L, George MS, Zafonte RD, McAllister TW, Stein MB, Thompson PM, Wilde EA, Tate DF, Sotiras A, Morey RA. Age-dependent white matter disruptions after military traumatic brain injury: Multivariate analysis results from ENIGMA brain injury. Hum Brain Mapp. 2022 Mar 15. doi: 10.1002/hbm.25811. Epub ahead of print. PMID: 35289463.
Klotz S, Ricken G, Preusser M, Dieckmann K, Widhalm G, Rössler K, Fischer P, Kalev O, Wöhrer A, Kovacs GG, Gelpi E. Enhanced expression of autophagy-related p62 without increased deposits of neurodegeneration-associated proteins in glioblastoma and surrounding tissue - An autopsy-based study. Brain Pathol. 2022 Mar 1:e13058. doi: 10.1111/bpa.13058. Epub ahead of print. PMID: 35229396.
Xue XH, Tao LL, Su DQ, Guo CJ, Liu H. Diagnostic utility of GDF15 in neurodegenerative diseases: A systematic review and meta-analysis. Brain Behav. 2022 Jan 24:e2502. doi: 10.1002/brb3.2502. Epub ahead of print. PMID: 35068064.
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