Pathological Relevance of Post-translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy

Aggregated alpha-synuclein (-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of -synuclein exist, including phosphorylated and nitrated forms. It is unclear which -synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three -synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 -synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 -synuclein in MSA. Quantification of the LB scores revealed that pS129 -synuclein was the dominant and earliest -synuclein PTM followed by nY39 -synuclein, while lower amounts of pSer87 -synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.

Pathological relevance of post-translationally modified alpha-synuclein (pSer87, pSer129, nTyr39) in idiopathic Parkinson's disease and Multiple System Atrophy.

Aggregated alpha-synuclein (α-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson′s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of α-synuclein exist, including phosphorylated and nitrated forms. It is unclear which α-synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant α-synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three α-synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 α-synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 α-synuclein in MSA. Quantification of the LB scores revealed that pS129 α-synuclein was the dominant and earliest α-synuclein PTM followed by nY39 α-synuclein, while lower amounts of pSer87 α-synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.

RNA Quality in Post-mortem Human Brain Tissue Is Affected by Alzheimer’s Disease

Gene expression studies of human post-mortem brain tissue are useful for understanding the pathogenesis of neurodegenerative disease. These studies rely on the assumption that RNA quality is consistent between disease and neurologically normal cases; however, previous studies have suggested that RNA quality may be affected by neurodegenerative disease. Here, we compared RNA quality in human post-mortem brain tissue between neurologically normal cases (n = 14) and neurodegenerative disease cases (Alzheimer’s disease n = 10; Parkinson’s disease n = 11; and Huntington’s disease n = 9) in regions affected by pathology and regions that are relatively devoid of pathology. We identified a statistically significant decrease in RNA integrity number (RIN) in Alzheimer’s disease tissue relative to neurologically normal tissue (mixed effects model, p = 0.04). There were no statistically significant differences between neurologically normal cases and Parkinson’s disease or Huntington’s disease cases. Next, we investigated whether total RNA quality affected mRNA quantification, by correlating RIN with qPCR threshold cycle (CT). CT values for all six genes investigated were strongly correlated with RIN (p < 0.05, Pearson correlation); this effect was only partially mitigated by normalization to RPL30. Our results indicate that RNA quality is decreased in Alzheimer’s disease tissue. We recommend that RIN should be considered when this tissue is used in gene expression analyses.

Age-dependent formation of TMEM106B amyloid filaments in human brain

Many age-dependent neurodegenerative diseases, like Alzheimer's and Parkinson's, are characterised by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β (Aβ), α-synuclein and TDP-43 are the most common. Here, we used electron cryo-microscopy (cryo-EM) structure determination to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in the human brain. We solved cryo-EM structures of TMEM106B filaments from the brains of 22 individuals with neurodegenerative conditions, including sporadic and inherited tauopathies, Aβ-amyloidoses, synucleinopathies and TDP-43opathies, as well as from the brains of two neurologically normal individuals. We observed three different TMEM106B folds, with no clear relationship between folds and diseases. The presence of TMEM106B filaments correlated with that of a 29 kDa sarkosyl-insoluble fragment of the protein on Western blots. The presence of TMEM106B filaments in the brains of older, but not younger, neurologically normal individuals indicates that they form in an age-dependent manner.

Neurologic Associations With Cardiac, Pulmonary, Renal, Hepatobiliary, and Hematologic Disease

The brain has a higher demand for cardiac output than any other organ, and it strictly relies on oxygen and glucose metabolism. Consequently, the brain is exquisitely sensitive to homeostatic disturbances and extraneural organ dysfunction leading to cardiac, pulmonary, renal, hepatobiliary, and hematologic diseases. The primary neurologic manifestation of extraneural organic dysfunction is diffuse bihemispheric dysfunction or encephalopathy, which often lacks lateralizing or localizing signs. Common clinical findings are lethargy, difficulty with attention and orientation, sleep-wake disturbance, and psychomotor slowing. As organic dysfunction progresses, a moderate encephalopathy ensues, with worsening cognitive function, gross disorientation, hypoactive or hyperactive psychomotor state, frontal release signs, asterixis, and myoclonus. If organ failure (eg, hepatic or renal) progresses further, stupor and coma may result unless organ function improves. Patients with underlying organic brain disease from degenerative dementia can decompensate out of proportion to neurologically normal counterparts, resulting in encephalopathy even from minor organ dysfunction or infection.

Electroencephalogram patterns with the presence of an unknown musical stimulus

The cerebral activity presents different behaviors in different situations and levels of consciousness, especially under musical stimulation. Signals of the central nervous system may disclose bioelectrical patterns, since listening to rhythmic sequences activates specific brain areas. In this paper, we analyze 42 neurologically normal Brazilian individuals, submitted to musical stimulation based on a procedure consisting of three different steps, during which the volunteer is kept with closed eyes. The first step is associated with the preliminary control silence period, without any stimulus, as the volunteer remains at rest. The second step consisted of unknown music stimulation. Finally, the third step involves post-music rest. Quantitative signal analysis computes the power spectrum time variations. Results point out stronger changes in gamma and high gamma waves (30 – 100 Hz). Even though the clinical rhythms (0 – 30 Hz) change throughout the whole period of the experiment, quantitative differences at gamma and high gamma bands are remarkably greater. Particularly, when comparing the initial silent period and the final post-stimulation silent one, bioelectrical differences are only highlighted by gamma and high gamma rhythms. In consequence, this paper points out that the EEG analysis of cognitive issues related to musical perception cannot disregard gamma and high gamma waves.

Measurements of coherence in eeg signal in brazilian people: a comparison of different consciousness states

Critically ill patients admitted to intensive care units require special care and the early diagnosis of the possible outcome of this coma is clinically important. Electroencephalographic signals are collected daily in critically ill patients and can be used to aid in the early diagnosis of neurological pathologies in such patients. Therefore, this study aimed to quantitatively describe the coherence values measured by the EEG signal of Brazilian individuals. The first group with comatose patients (N = 75), favorable (to live) or unfavorable (dying) outcomes, and various etiology. The second group was made by neurologically normal people, named the control group (N = 100). In addition, a number of statistical comparisons were made in order to verify the difference in coherence behavior according to the levels of consciousness. The coherence index of the comatose group is smaller than the control group. Besides, different hospitalization results, living or dying, as well as different etiologies, may be associated with particular values of cerebral coherence. It was observed that the etiology of coma does not influence the measured values of coherence in terms of diagnosis due to brain death, which may become a biomarker of this outcome. Another important consideration was that neurologically healthy patients did not present high values of cerebral coherence at all electrodes, as seen in the temporal region of the brain.

Post-encoding modulation of spatial memory by a GABAA-agonist

We investigated the role of the post-encoding period for consolidation of self-centered (egocentric) and world-centered (allocentric) spatial memory in neurologically normal human subjects. We used the GABAA-ergic anesthetic propofol to transiently modulate neural activity during the early stage of spatial memory consolidation. A total of 52 patients undergoing minor surgery learned to navigate to a target in a five-armed maze derived from animal experiments immediately prior to injection of propofol (early group) or more than 60 minutes before injection (late group). Two hundred and forty minutes after anesthesia, subjects were tested for memory-guided navigation. Our results show a selective impairment of memory-guided navigation in the early group and near-normal performance in the late group. Both egocentric and allocentric navigation were affected, albeit with distinct error patterns. In the egocentric condition, early group patients navigated significantly more often to a wrong alley of the maze but showed normal navigation times, thus suggesting a deficit mainly for memory of sequences of path segments. By contrast, in the allocentric condition, early group patients mostly navigated to the correct alley of the maze but showed a significant increase in detours and prolonged navigation times, thus suggesting a weakened representation of the relationship between landmarks. We conclude that presumably hippocampus-dependent networks contribute to early consolidation of representations underlying both egocentric and allocentric memory-guided navigation. Distinct aspects of these representations are susceptible to GABAA-ergic modulation within a post-encoding time-window of less than 60 minutes, indicating a redistribution and reconfiguration of spatial memory networks early during consolidation.

Complete recovery of right forebrain signs from presumptive cerebrovascular origin in an eight-year-old sport horse

In this case report, an eight-year-old Warmblood gelding is described with a presumptive vascular event resulting in severe head turn and circling to the right. The horse recovered completely from the clinical signs. Pathologies that cause asymmetrical forebrain signs in horses could be excluded. Magnetic resonance imaging revealed a flow difference in the venous sinuses that was presumably caused by cerebral venous sinus thrombosis. The horse was treated with prednisolone, antibiotics, vitamin E and B1 and acetylsalicylic acid. He was represented one month after the initial clinical signs and was clinically and neurologically normal. The horse subsequently returned to his previous level of jumping.