Brainstem Quadruple Aberrant Hyperphosphorylated Tau, Beta-Amyloid, Alpha-Synuclein and TDP-43 Pathology, Stress and Sleep Behavior Disorders

Abstract

Quadruple aberrant hyperphosphorylated tau (p-τ), amyloid-β peptide, alpha-synuclein and TDP-43 brainstem and supratentorial pathology are documented in forensic ≤40y autopsies in Metropolitan Mexico City (MMC), and p-τ is the major aberrant protein. Post-traumatic stress disorder (PTSD) is associated with an elevated risk of subsequent dementia, and rapid eye movement sleep behavior disorder (RBD) is documented in PD, AD, Lewy body dementia and ALS. This study aimed to identify an association between PTSD and potential pRBD in Mexico. An anonymous online survey of 4502 urban college-educated adults, 29.3 ± 10.3 years; MMC, n = 1865; non-MMC, n = 2637, measured PTSD symptoms using the Impact of Event Scale–Revised (IES-R) and pRBD symptoms using the RBD Single-Question. Over 50% of the participants had IES-R scores ≥33 indicating probable PTSD. pRBD was identified in 22.6% of the participants across Mexico and 32.7% in MMC residents with PTSD. MMC subjects with PTSD had an OR 2.6218 [2.5348, 2.7117] of answering yes to the pRBD. PTSD and pRBD were more common in women. This study showed an association between PTSD and pRBD, strengthening the possibility of a connection with misfolded proteinopathies in young urbanites. We need to confirm the RBD diagnosis using an overnight polysomnogram. Mexican women are at high risk for stress and sleep disorders.

Metals, Nanoparticles, Particulate Matter, and Cognitive Decline

“…The targeted domains involved, point toward progressive brainstem involvement and the temporal-parietal-frontal circuit involvement (21,(47)(48)(49)(50)(51)(52). The targeted domains information is critical, because we have shown in consecutive forensic autopsies of MMC individuals, extensive brainstem pathology including progressive quadruple abnormal proteins, and neuroinflammation, and clinically: abnormal brainstem auditory-evoked potentials, and stress and sleep behavior disorders (21,53,54). We suggest that for MMC residents, cognitive deficits at a young, productive age could be associated with the progression from tau pre-tangles to neurofibrillary tangles (NFT) stages I-II to NFT stages III-V in the first four decades of life, as reported in forensic autopsies (19).…”

Influence of sleep disruption on protein accumulation in neurodegenerative diseases

“…Moreover, the volume of the PVN in the hypothalamus is also decreased. Furthermore, TDP-43-positive inclusions are observed in the PVN, lateral hypothalamus and fornix [80] . TDP-43 inclusions are also presented in the reticular formation in the brainstem, which has an important role in the rhythmical cycle of sleep and wakefulness [81] .…”

“…The TDP-43 pathology is presented in about 97% of ALS patients and 45 % FTD patients [79] . In ALS patients, the volume of the hypothalamus is decreased [80] . Moreover, the volume of the PVN in the hypothalamus is also decreased.…”

TDP-43 CSF Concentrations Increase Exponentially with Age in Metropolitan Mexico City Young Urbanites Highly Exposed to PM2.5 and Ultrafine Particles and Historically Showing Alzheimer and Parkinson’s Hallmarks. Brain TDP-43 Pathology in MMC Residents Is Associated with High Cisternal CSF TDP-43 Concentrations

“…TDP-43 immunocytochemical profiles in children and young MMC adults have shown loss of nuclear expression and powdery cytoplasmic particles in the substantia nigrae pars compacta and non-motor neurons, as well as significant involvement of mesencephalic, pontine and medullary reticular formation [ 2 , 41 , 42 , 43 , 44 ]. Of particular concern, we have reported sleep disorders in MMC residents [ 45 ] along key brainstem sleep and arousal hubs, showing solid UFPM from anthropogenic combustion, mainly diesel exhaust, as well as non-exhaust sources coming from tire and brake wearing and from engineered NPs [ 46 , 47 , 48 ]. Although FTD and ALS epidemiological data are not extensively studied in Mexico [ 49 , 50 ], the presence of overlapping quadruple pathologies in MMC children and young adults [ 2 , 45 , 46 ] raises the question of why such diagnoses are missing in our populations.…”

“…Of particular concern, we have reported sleep disorders in MMC residents [ 45 ] along key brainstem sleep and arousal hubs, showing solid UFPM from anthropogenic combustion, mainly diesel exhaust, as well as non-exhaust sources coming from tire and brake wearing and from engineered NPs [ 46 , 47 , 48 ]. Although FTD and ALS epidemiological data are not extensively studied in Mexico [ 49 , 50 ], the presence of overlapping quadruple pathologies in MMC children and young adults [ 2 , 45 , 46 ] raises the question of why such diagnoses are missing in our populations. Providing an early ALS diagnosis is clinically difficult [ 51 ], and development of research criteria for the diagnosis of prodromal behavioral variant frontotemporal dementia (bvFTD) is ongoing [ 52 ].…”