The role of membrane trafficking and retromer complex in Parkinson's and Alzheimer's disease.

Membrane trafficking is a physiological process encompassing different pathways involved in transporting cellular products across cell membranes to specific cell locations via encapsulated vesicles. This process is required for cells to mature and function properly, allowing them to adapt to their surroundings. The retromer complex is a complex composed of nexin proteins and peptides that play a vital role in the endosomal pathway of membrane trafficking. In humans, any interference in normal membrane trafficking or retromer complex can cause profound changes such as those seen in neurodegenerative disorders such as Alzheimer's and Parkinson's. Several studies have explored the potential causative mechanisms in developing both disease processes; however, the role of retromer trafficking in their pathogenesis is becoming increasingly significant with promising therapeutic applications. This manuscript describes the processes involved in membrane transport and the roles of the retromer in the onset and progression of Alzheimer's and Parkinson's. Moreover, we will also explore how these aberrant mechanisms may serve as possible avenues for treatment development in both diseases and the prospect of its future application.

Working memory in action: inspecting the systematic and unsystematic errors of spatial memory across saccades.

Our ability to interact with the world depends on memory buffers that flexibly store and process information for short periods of time. Current working memory research, however, mainly uses tasks that avoid eye movements, whereas in daily life we need to remember information across saccades. Because saccades disrupt perception and attention, the brain might use special transsaccadic memory systems. Therefore, to compare working memory systems between and across saccades, the current study devised transsaccadic memory tasks that evaluated the influence of memory load on several kinds of systematic and unsystematic spatial errors, and tested whether these measures predicted performance in more established working memory paradigms. Experiment 1 used a line intersection task that had people integrate lines shown before and after saccades, and it administered a 2-back task. Experiments 2 and 3 asked people to point at one of several locations within a memory array flashed before an eye movement, and we tested change detection and 2-back performance. We found that unsystematic transsaccadic errors increased with memory load and were correlated with 2-back performance. Systematic errors produced similar results, although effects varied as a function of the geometric layout of the memory arrays. Surprisingly, transsaccadic errors did not predict change detection performance despite the latter being a widely accepted measure of working memory capacity. Our results suggest that working memory systems between and across saccades share, in part, similar neural resources. Nevertheless, our data highlight the importance of investigating working memory across saccades.

Identifying delay in glymphatic clearance of labeled protons post-acute head trauma utilizing 3D ASL MRI (arterial spin labeling): a pilot study.

This study correlated mild traumatic brain injury (mTBI) cognitive changes with ASL-MRI glymphatic clearance rates (GCRs) and recovery with GCR improvement. mTBI disrupts the blood brain barrier (BBB), reducing capillary mean transit time and GCRs. mTBI is clinically diagnosed utilizing history/examination findings with no physiologic biomarkers. 3D TGSE (turbo-gradient spin-echo) pulsed arterial spin-labeling 3T MRI with 7 long inversion times (TIs) assessed the signal clearance of labeled protons 2800-4000 ms postlabeling in bifrontal, bitemporal, and biparietal regions within 7 days of mTBI and once clinically cleared to resume activities. The Sport Concussion Assessment Tool Version 5 (SKAT5) and Brief Oculomotor/Vestibular Assessment evaluated injured athletes' cognitive function prior to MRIs. The pilot study demonstrated significant GCRs improvement (95% CI - 0.06 to - 0.03 acute phase; to CI-recovery CI 0.0772 to - 0.0497; P < 0.001 in frontal lobes; and parietal lobes (95% CI - 0.0584 to - 0.0251 acute; CI - 0.0727 to - 0.0392 recovery; P = 0.024) in 9 mTBI athletes (8 female, 1 male). Six age/activity-matched controls (4 females, 2 males) were also compared. mTBI disrupts the BBB, reducing GCR measured using the 3D ASL MRI technique. ASL MRI is a potential noninvasive biomarker of mTBI and subsequent recovery.

Antioxidant, anti-inflammatory and epigenetic potential of curcumin in Alzheimer's disease.

Alzheimer's disease (AD) constitutes a multifactorial neurodegenerative pathology characterized by cognitive deterioration, personality alterations, and behavioral shifts. The ongoing brain impairment process poses significant challenges for therapeutic interventions due to activating multiple neurotoxic pathways. Current pharmacological interventions have shown limited efficacy and are associated with significant side effects. Approaches focusing on the early interference with disease pathways, before activation of broad neurotoxic processes, could be promising to slow down symptomatic progression of the disease. Curcumin-an integral component of traditional medicine in numerous cultures worldwide-has garnered interest as a promising AD treatment. Current research indicates that curcumin may exhibit therapeutic potential in neurodegenerative pathologies, attributed to its potent anti-inflammatory and antioxidant properties. Additionally, curcumin and its derivatives have demonstrated an ability to modulate cellular pathways via epigenetic mechanisms. This article aims to raise awareness of the neuroprotective properties of curcuminoids that could provide therapeutic benefits in AD. The paper provides a comprehensive overview of the neuroprotective efficacy of curcumin against signaling pathways that could be involved in AD and summarizes recent evidence of the biological efficiency of curcumins in vivo.

Investigation of light-induced lacrimation and pupillary responses in episodic migraine.

The purpose of this pilot study was to investigate the light-induced pupillary and lacrimation responses mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) in migraine. Ten participants with episodic migraine and normal tear production, as well as eleven visually normal controls participated in this study. Following an initial baseline trial (no light flash), participants received seven incremental and alternating red and blue light flashes. Pupillometry recording of the left eye and a 1-min anesthetized Schirmer's test of the right eye (using 0.5% proparacaine) were performed simultaneously. Intrinsic and extrinsic ipRGC photoactivities did not differ between migraine participants and controls across all intensities and wavelengths. Migraine participants, however, had significantly lower lacrimation than controls following the highest blue intensity. A positive correlation was found between melanopsin-driven post-illumination pupillary responses and lacrimation following blue stimulation in both groups. Our results show that participants with self-reported photophobia have normal ipRGC-driven responses, suggesting that photophobia and pupillary function may be mediated by distinct ipRGC circuits. The positive correlation between melanopsin-driven pupillary responses and light-induced lacrimation suggests the afferent arm of the light-induced lacrimation reflex is melanopsin-mediated and functions normally in migraine. Lastly, the reduced melanopsin-mediated lacrimation at the highest stimulus suggests the efferent arm of the lacrimation reflex is attenuated under certain conditions, which may be a harbinger of dry eye in migraine.

Ocular Topical Anesthesia Does Not Attenuate Light-Induced Discomfort Using Blue and Red Light Stimuli.

Purpose: To investigate whether melanopsin-containing ophthalmic trigeminal ganglion cells provide significant input to mediate light-induced discomfort. This is done by studying the effect of ocular topical anesthesia on light-induced discomfort threshold to blue light and red light stimuli using a psychophysical approach. Method: Ten visually normal participants completed the experiment consisting of two trials: an anesthesia trial in which light stimuli were presented to both eyes following 0.5% proparacaine eye drops administration, and a placebo trial in which normal saline drops were used. In each trial, a randomized series of 280 blue and red light flashes were presented over seven intensity steps with 20 repetitions for each color and light intensity. Participants were instructed to report whether they perceived each stimulus as either "uncomfortably bright" or "not uncomfortably bright" by pressing a button. The proportion of "uncomfortable" responses was pooled to generate individual psychometric functions, from which 50% discomfort thresholds (defined as the light intensity at which the individuals perceived the stimulus to be uncomfortably bright/unpleasant 50% of the time) were calculated. Results: When blue light was presented, there was no significant difference in the light-induced discomfort thresholds between anesthesia and placebo trials (P = 0.44). Similarly, when red light was used, no significant difference in threshold values was found between the anesthesia and placebo trials (P = 0.28). Conclusions: Ocular topical anesthesia does not alter the light-induced discomfort thresholds to either blue or red light, suggesting that the melanopsin-containing ophthalmic trigeminal ganglion cells provide little or no significant input in mediating light-induced discomfort under normal physiologic conditions.

Binocular Summation in Postillumination Pupil Response Driven by Melanopsin-Containing Retinal Ganglion Cells.

Purpose: To investigate how melanopsin-mediated intrinsically photosensitive retinal ganglion cell (ipRGC) signals are integrated binocularly using chromatic pupillometry. We hypothesized that if the melanopsin system is summative, there will be a greater postillumination pupillary response (PIPR) under binocular conditions after viewing bright blue light. Methods: Pupillary responses in 10 visually normal participants were recorded with an eye tracker following full-field stimulation of red (long wavelength) and blue (short wavelength) light of equal intensity (dim: 0.1 cd [candela]/m2, bright: 60 cd/m2) and duration (400 ms). Individual monocular (left eye) pupil responses were measured first, followed by binocular responses. Each participant repeated the same protocol on 3 separate days, at similar times of day. PIPR was recorded for bright red and blue conditions only, whereas maximum pupillary constriction (MPC) was measured under both bright and dim conditions during red and blue light stimulation. Results: Bright blue light stimulation induced greater PIPR under binocular than monocular viewing conditions (F(1,9) = 79.52, P < 0.001). Bright red light stimulation induced minimal PIPR and showed no significant difference between viewing conditions post Bonferroni correction (F(1,9) = 5.49, P = 0.04). MPC was greater during binocular than monocular viewing conditions for all light stimuli, but was greatest following blue compared to red light stimulation. Conclusions: A larger PIPR was induced using a binocular than a monocular full-field stimulus of equal intensity and duration, demonstrating that melanopsin-mediated ipRGC signals are summated binocularly. This study expands our current understanding of the melanopsin system and may be used as an additional marker to stratify diseases according to their etiologies.

A Novel Visual Psychometric Test for Light-Induced Discomfort Using Red and Blue Light Stimuli Under Binocular and Monocular Viewing Conditions.

Purpose: To develop an objective psychophysical method to quantify light-induced visual discomfort, and to measure the effects of viewing condition and stimulus wavelength. Methods: Eleven visually normal subjects participated in the study. Their pupils were dilated (2.5% phenylephrine) before the experiment. A Ganzfeld system presented either red (1.5, 19.1, 38.2, 57.3, 76.3, 152.7, 305.3 cd/m2) or blue (1.4, 7.1, 14.3, 28.6, 42.9, 57.1, 71.4 cd/m2) randomized light intensities (1 s each) in four blocks. Constant white-light stimuli (3 cd/m2, 4 s duration) were interleaved with the chromatic trials. Participants reported each stimulus as either "uncomfortably bright" or "not uncomfortably bright." The experiment was done binocularly and monocularly in separate sessions, and the order of color/viewing condition sequence was randomized across participants. The proportion of "uncomfortable" responses was used to generate individual psychometric functions, from which 50% discomfort thresholds were calculated. Results: Light-induced discomfort was higher under blue compared with red light stimulation, both during binocular (t(10) = 3.58, P < 0.01) and monocular viewing (t(10) = 3.15, P = 0.01). There was also a significant difference in discomfort between viewing conditions, with binocular viewing inducing more discomfort than monocular viewing for blue (P < 0.001), but not for red light stimulation. Conclusions: The light-induced discomfort characteristics reported here are consistent with features of the melanopsin-containing intrinsically photosensitive retinal ganglion cell light irradiance pathway, which may mediate photophobia, a prominent feature in many clinical disorders. This is the first psychometric assessment designed around melanopsin spectral properties that can be customized further to assess photophobia in different clinical populations.

The Relation Between Light-Induced Lacrimation and the Melanopsin-Driven Postillumination Pupil Response.

Purpose: To investigate the chromatic characteristics and intensity-response function of light-induced reflex lacrimation and its correlation with the melanopsin-driven postillumination pupil response (PIPR). Methods: Eleven visually normal participants completed the experiment. Lacrimation was measured in one eye by placing a calibrated filter paper strip in the conjunctival sac over a 1 minute-interval (Schirmer's test) during which participants received either no light stimulation (baseline trial) or one flash of blue or red light stimuli presented binocularly with a Ganzfeld stimulator, while the pupil response was recorded simultaneously from the fellow eye by using an eye tracker. Light stimulation trials were presented in alternating fashion at seven incremental intensity steps (0.1, 1, 3.16, 10, 31.6, 100, and 400 cd/m2). Postillumination pupil response was defined as the mean pupil constriction from 10 to 30 seconds post illumination. Results: The amount of lacrimation in response to 10 to 400 cd/m2 blue light was significantly greater than baseline and increased monotonically with increasing light intensity. Red light did not induce significant reflex lacrimation until the brightest stimulation at 400 cd/m2. There was a positive linear correlation between PIPR and lacrimation in response to blue light (r = 0.74, P < 0.001) but not to red light (r = 0.13, P = 0.25). Conclusions: The chromatic characteristics and intensity-response of light-induced lacrimation are highly consistent with the features of melanopsin phototransduction. This finding is the first in vivo evidence in humans, supporting the hypothesis that light-induced reflex lacrimation is mediated primarily by melanopsin photoactivity, and provides new insight into the putative mechanisms of photophobia.