Orexin and Sleep Disturbances in Alpha-Synucleinopathies: a Systematic Review.

PURPOSE OF REVIEW: Sleep disturbances are amongst most frequent non-motor symptoms of Parkinson's Disease (PD), and they are similarly frequently reported in other alpha-syncleinopathies, such as Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). More recently, the orexin system has been implicated in control of arousal based on salient environmental set points, and its dysregulation in sleep issues in alpha-synucleinopathies suggested by the findings from the translational animal models. However, its role in the patients with alpha-synucleinopathies remains unclear. We thus set to systematically review, and to critically assess, contemporary evidence on the association of the orexinergic system and sleep disturbances in alpha-synucleinopathies. In this systematic review, studies investigating orexin and sleep in alpha-synucleinopathies (Rapid Eye Movement (REM) Behaviour Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) were identified using electronic database searches of PubMed, Web of Science and PsychINFO using MeSH terms, keywords, and title words such as "Alpha-synucleinopathies" AND "Orexin" AND "Sleep Disturbances". RECENT FINDINGS: 17 studies were included in this systemic review, of which 2 studies on RBD, 10 on PD, 4 on DLB, and 1 on MSA patients. Taken together, RBD and PD studies suggest a potential adaptive increase in orexin levels in early stages of the neurodegenerative process, with reduced levels more often reported for later, more advanced stages of illness. To date, no differences in orexin levels were demonstrated between MSA patients and healthy controls. There is a dearth of studies on the role of orexin levels in alpha-synucleinopathies. Moreover, significant methodologic limitations in the current body of work, including use of non-standardised research protocols and lack of prospective, multi-centre studies, disallow for any finite conclusion in regards to underlying pathomechanisms. Nonetheless, a picture of a complex, multifaceted relationship between the dysregulation of the orexinergic pathway and sleep disturbances in alpha-synucleinopathies is emerging. Hence, future studies disentangling orexinergic pathomechanisms of alpha-syncleinopathies are urgently needed to obtain a more comprehensive account of the role of orexinergic pathway in alpha-synucleinopathies. Pharmacological manipulations of orexins may have multiple therapeutic applications in treatment strategies, disease diagnosis, and might be effective for treating both motor and non-motor symptoms.

Tonic REM sleep muscle activity is the strongest predictor of phenoconversion risk to neurodegenerative disease in isolated REM sleep behaviour disorder.

Previous studies have shown that rapid eye movement sleep without atonia during polysomnography can predict the risk of phenoconversion to neurodegenerative disease in patients with isolated rapid eye movement sleep behaviour disorder. Discrepancy remains with regards to the morphology of rapid eye movement sleep without atonia that best predicts phenoconversion risk. This study aimed to ascertain the predictive value of tonic, phasic and mixed rapid eye movement sleep without atonia in patients with isolated rapid eye movement sleep behaviour disorder, at time of diagnosis. Sixty-four patients with polysomnography-confirmed isolated rapid eye movement sleep behaviour disorder, including 19 who phenoconverted during follow-up, were identified from an existing database. Tonic, phasic, mixed and "any" rapid eye movement sleep without atonia activity from the mentalis, tibialis anterior and flexor digitorum superficialis muscles was analysed blind to status using the diagnostic polysomnography. Rapid eye movement sleep without atonia variables were compared between converters and non-converters. Rapid eye movement sleep without atonia cut-offs predicting phenoconversion were established using receiver-operating characteristic analysis. The mean follow-up duration was 5.50 ± 4.73 years. Phenoconverters (n = 19) had significantly higher amounts of tonic (22.2 ± 19.1%, p = 0.0014), mixed (18.1 ± 14.1%, p = 0.0074) and "any" (mentalis muscle; 58.7 ± 28.0%, p = 0.0009) and all muscles (68.0 ± 20.8%, p = 0.0049) rapid eye movement sleep without atonia at diagnosis than non-converters. Optimal rapid eye movement sleep without atonia cut-off values predicting phenoconversion were 5.8% for tonic (73.7% sensitivity; 75.6% specificity), 7.3% for mixed (68.4% sensitivity; 73.3% specificity) and 43.6% for "any" (mentalis muscle; 68.4% sensitivity; 80.0% specificity) activity. "Any" (mentalis muscle) rapid eye movement sleep without atonia had the highest area under the curve (0.809) followed by tonic (0.799). The percentage of tonic rapid eye movement sleep without atonia was the strongest biomarker of phenoconversion in this cohort of patients with isolated rapid eye movement sleep behaviour disorder.

Validation of the REM behaviour disorder phenoconversion-related pattern in an independent cohort.

BACKGROUND: A brain glucose metabolism pattern related to phenoconversion in patients with idiopathic/isolated REM sleep behaviour disorder (iRBDconvRP) was recently identified. However, the validation of the iRBDconvRP in an external, independent group of iRBD patients is needed to verify the reproducibility of such pattern, so to increase its importance in clinical and research settings. The aim of this work was to validate the iRBDconvRP in an independent group of iRBD patients. METHODS: Forty iRBD patients (70 ± 5.59 years, 19 females) underwent brain [18F]FDG-PET in Seoul National University. Thirteen patients phenoconverted at follow-up (7 Parkinson disease, 5 Dementia with Lewy bodies, 1 Multiple system atrophy; follow-up time 35 ± 20.56 months) and 27 patients were still free from parkinsonism/dementia after 62 ± 29.49 months from baseline. We applied the previously identified iRBDconvRP to validate its phenoconversion prediction power. RESULTS: The iRBDconvRP significantly discriminated converters from non-converters iRBD patients (p = 0.016; Area under the Curve 0.74, Sensitivity 0.69, Specificity 0.78), and it significantly predicted phenoconversion (Hazard ratio 4.26, C.I.95%: 1.18-15.39). CONCLUSIONS: The iRBDconvRP confirmed its robustness in predicting phenoconversion in an independent group of iRBD patients, suggesting its potential role as a stratification biomarker for disease-modifying trials.

Locus Coeruleus and Noradrenergic Pharmacology in Neurodegenerative Disease.

Adrenoceptors (ARs) throughout the brain are stimulated by noradrenaline originating mostly from neurons of the locus coeruleus, a brainstem nucleus that is ostensibly the earliest to show detectable pathology in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The α1-AR, α2-AR, and ß-AR subtypes expressed in target brain regions and on a range of cell populations define the physiological responses to noradrenaline, which includes activation of cognitive function in addition to modulation of neurometabolism, cerebral blood flow, and neuroinflammation. As these heterocellular functions are critical for maintaining brain homeostasis and neuronal health, combating the loss of noradrenergic tone from locus coeruleus degeneration may therefore be an effective treatment for both cognitive symptoms and disease modification in neurodegenerative indications. Two pharmacologic approaches are receiving attention in recent clinical studies: preserving noradrenaline levels (e.g., via reuptake inhibition) and direct activation of target adrenoceptors. Here, we review the expression and role of adrenoceptors in the brain, the preclinical studies which demonstrate that adrenergic stimulation can support cognitive function and cerebral health by reversing the effects of noradrenaline depletion, and the human data provided by pharmacoepidemiologic analyses and clinical trials which together identify adrenoceptors as promising targets for the treatment of neurodegenerative disease.

Alpha-synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder.

Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson's disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson's disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson's disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson's disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P < 0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P < 0.001). We provide evidence that the α-synuclein RT-QuIC assay enables the molecular detection of neuronal α-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of α-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of α-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt α-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity.

REM sleep absence in patients referred to polysomnography for REM sleep behavior disorder.

Detection of REM sleep behavior disorder (RBD) with polysomnography (PSG) is relevant for the diagnosis of α-synucleinopathies. However, some patients referred for suspicion of RBD do not present REM sleep at PSG (NoREMSusRBD), rendering the study inconclusive. Our objective was to investigate disorders possibility associated with REM sleep absence in patients referred to PSG for investigation of RBD, in particular α-synucleinopathies. A sleep-lab database was revised to select NoREMSusRBD (n = 15) and patients: with no REM sleep referred for suspicion of other sleep disorder (NoREMSusOther, n = 28); referred for RBD suspicion with negative PSG (NegativeRBD, n = 24); α-synucleinopathies with no REM sleep (NoREMα, n = 23) and idiopathic RBD (iRBD, n = 26). NoREMSusRBD patients were compared with the other groups regarding PSG data and the emergence of prodromal features or established criteria for α-synucleinopathy. Severe Obstructive Sleep Apnea (OSA) was significantly more frequent in the NoREMsusRBD compared to the NoREMα and iRBD groups. No patient in the NoREMSusRBD developed a α-synucleinopathy (2 cases on the iRBD group). The prevalence of prodromal features in NoREMSusRBD (n = 7, 46.7%) was similar to that of iRBD (n = 18, 69.2%) and significantly higher than in the other groups. Apnea-Hypopnea Indices (AHI) were significantly higher in the NoREMSusRBD compared with iRBD and NoREMα. Our study suggests that the absence of REM sleep in NoREMSusRBD could be caused by OSA but does not exclude the possibility of underlying α- synucleinopathy, suggested by an increased prevalence of prodromal features. These data support the need for excluding OSA in patients suspected for RBD and recommends follow-up of NoREMSusRBD patients to uncover a possible α- synucleinopathy.

Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles (and engineered Ti-rich nanorods). The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract a key brainstem portal.

Fine particulate air pollution (PM2.5) exposures are linked with Alzheimer's and Parkinson's diseases (AD,PD). AD and PD neuropathological hallmarks are documented in children and young adults exposed lifelong to Metropolitan Mexico City air pollution; together with high frontal metal concentrations (especially iron)-rich nanoparticles (NP), matching air pollution combustion- and friction-derived particles. Here, we identify aberrant hyperphosphorylated tau, ɑ synuclein and TDP-43 in the brainstem of 186 Mexico City 27.29 ± 11.8y old residents. Critically, substantia nigrae (SN) pathology seen in mitochondria, endoplasmic reticulum and neuromelanin (NM) is co-associated with the abundant presence of exogenous, Fe-, Al- and Ti-rich NPs.The SN exhibits early and progressive neurovascular unit damage and mitochondria and NM are associated with metal-rich NPs including exogenous engineered Ti-rich nanorods, also identified in neuroenteric neurons. Such reactive, cytotoxic and magnetic NPs may act as catalysts for reactive oxygen species formation, altered cell signaling, and protein misfolding, aggregation and fibril formation. Hence, pervasive, airborne and environmental, metal-rich and magnetic nanoparticles may be a common denominator for quadruple misfolded protein neurodegenerative pathologies affecting urbanites from earliest childhood. The substantia nigrae is a very early target and the gastrointestinal tract (and the neuroenteric system) key brainstem portals. The ultimate neural damage and neuropathology (Alzheimer's, Parkinson's and TDP-43 pathology included) could depend on NP characteristics and the differential access and targets achieved via their portals of entry. Thus where you live, what air pollutants you are exposed to, what you are inhaling and swallowing from the air you breathe,what you eat, how you travel, and your occupational longlife history are key. Control of NP sources becomes critical.

Diagnosing multiple system atrophy at the prodromal stage.

Identifying individuals at the earliest disease stage becomes crucial as we aim to develop disease-modifying treatments for neurodegenerative disorders. Prodromal diagnostic criteria were recently developed for Parkinson's disease (PD) and are forthcoming for dementia with Lewy bodies (DLB). The latest 2008 version of diagnostic criteria for multiple system atrophy (MSA) have improved diagnostic accuracy in early disease stages compared to previous criteria, but we do not yet have formal criteria for prodromal MSA. Building on similar approaches as for PD and DLB, we can identify features on history-taking, clinical examination, and ancillary clinical testing that can predict the likelihood of an individual developing MSA, while also distinguishing it from PD and DLB. The main clinical hallmarks of MSA are REM sleep behavior disorder (RBD) and autonomic dysfunction (particularly orthostatic hypotension and urogenital symptoms), and may be the primary means by which patients with potential prodromal MSA are identified. Preserved olfaction, absence of significant cognitive deficits, urinary retention, and respiratory symptoms such as stridor and respiratory insufficiency can be clinical features that help distinguish MSA from PD and DLB. Finally, ancillary test results including neuroimaging as well as serological and cerebrospinal fluid (CSF) biomarkers may lend further weight to quantifying the likelihood of phenoconversion into MSA. For prodromal criteria, the primary challenges are MSA's lower prevalence, shorter lead time to diagnosis, and strong overlap with other synucleinopathies. Future prodromal criteria may need to first embed the diagnosis into a general umbrella of prodromal alpha-synucleinopathies, followed by identification of features that suggest prodromal MSA as the specific cause.

Positron Emission Tomography (PET) and Neuroimaging in the Personalized Approach to Neurodegenerative Causes of Dementia.

Generally, dementia should be considered an acquired syndrome, with multiple possible causes, rather than a specific disease in itself. The leading causes of dementia are neurodegenerative and non-neurodegenerative alterations. Nevertheless, the neurodegenerative group of diseases that lead to cognitive impairment and dementia includes multiple possibilities or mixed pathologies with personalized treatment management for each cause, even if Alzheimer's disease is the most common pathology. Therefore, an accurate differential diagnosis is mandatory in order to select the most appropriate therapy approach. The role of personalized assessment in the treatment of dementia is rapidly growing. Neuroimaging is an essential tool for differential diagnosis of multiple causes of dementia and allows a personalized diagnostic and therapeutic protocol based on risk factors that may improve treatment management, especially in early diagnosis during the prodromal stage. The utility of structural and functional imaging could be increased by standardization of acquisition and analysis methods and by the development of algorithms for automated assessment. The aim of this review is to focus on the most commonly used tracers for differential diagnosis in the dementia field. Particularly, we aim to explore 18F Fluorodeoxyglucose (FDG) and amyloid positron emission tomography (PET) imaging in Alzheimer's disease and in other neurodegenerative causes of dementia.

Alzheimer's disease and alpha-synuclein pathology in the olfactory bulbs of infants, children, teens and adults ≤ 40 years in Metropolitan Mexico City. APOE4 carriers at higher risk of suicide accelerate their olfactory bulb pathology.

There is growing evidence that air pollution is a risk factor for a number of neurodegenerative diseases, most notably Alzheimer's (AD) and Parkinson's (PD). It is generally assumed that the pathology of these diseases arises only later in life and commonly begins within olfactory eloquent pathways prior to the onset of the classical clinical symptoms. The present study demonstrates that chronic exposure to high levels of air pollution results in AD- and PD-related pathology within the olfactory bulbs of children and relatively young adults ages 11 months to 40 years. The olfactory bulbs (OBs) of 179 residents of highly polluted Metropolitan Mexico City (MMC) were evaluated for AD- and alpha-synuclein-related pathology. Even in toddlers, hyperphosphorylated tau (hTau) and Lewy neurites (LN) were identified in the OBs. By the second decade, 84% of the bulbs exhibited hTau (48/57), 68% LNs and vascular amyloid (39/57) and 36% (21/57) diffuse amyloid plaques. OB active endothelial phagocytosis of red blood cell fragments containing combustion-derived nanoparticles (CDNPs) and the neurovascular unit damage were associated with myelinated and unmyelinated axonal damage. OB hTau neurites were associated mostly with pretangle stages 1a and 1b in subjects ≤ 20 years of age, strongly suggesting olfactory deficits could potentially be an early guide of AD pretangle subcortical and cortical hTau. APOE4 versus APOE3 carriers were 6-13 times more likely to exhibit OB vascular amyloid, neuronal amyloid accumulation, alpha-synuclein aggregates, hTau neurofibrillary tangles, and neurites. Remarkably, APOE4 carriers were 4.57 times more likely than non-carriers to die by suicide. The present findings, along with previous data that over a third of clinically healthy MMC teens and young adults exhibit low scores on an odor identification test, support the concept that olfactory testing may aid in identifying young people at high risk for neurodegenerative diseases. Moreover, results strongly support early neuroprotective interventions in fine particulate matter (PM2.5) and CDNP's exposed individuals ≤ 20 years of age, and the critical need for air pollution control.

Review: The spectrum of clinical features seen with alpha synuclein pathology.

It has been recognized for many years that a number of chronic neurodegenerative diseases of the CNS are characterized by the development of intracellular inclusion bodies, but it is only relatively recently that the core proteins defining these pathologies have been defined. One such protein is alpha synuclein, that was found to be the main component of Lewy bodies in the late 1990s, and this discovery reinforced the emerging view that alpha synuclein was intimately linked to diseases characterized by this type of pathology--namely Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Furthermore at around this time, this same protein was also found within the glial inclusion bodies of patients dying with multiple system atrophy (MSA). These three disorders constitute the majority of patients with an 'alpha synucleinopathy', although there are a number of rarer conditions that can also cause this pathology including inherited metabolic disorders such as Gaucher's disease (GD). In this review, we will concentrate on PD, the commonest alpha synucleinopathy, and its associated dementia (PDD), as well as discussing DLB and MSA and will highlight how the clinical features of these conditions vary as a function of pathology.

Sleep, Cognition and Dementia.

The older patient population is growing rapidly around the world and in the USA. Almost half of seniors over age 65 who live at home are dissatisfied with their sleep, and nearly two-thirds of those residing in nursing home facilities suffer from sleep disorders. Chronic and pervasive sleep complaints and disturbances are frequently associated with excessive daytime sleepiness and may result in impaired cognition, diminished intellect, poor memory, confusion, and psychomotor retardation all of which may be misinterpreted as dementia. The key sleep disorders impacting patients with dementia include insomnia, hypersomnolence, circadian rhythm misalignment, sleep disordered breathing, motor disturbances of sleep such as periodic leg movement disorder of sleep and restless leg syndrome, and parasomnias, mostly in the form of rapid eye movement (REM) sleep behavior disorder (RBD). RBD is a pre-clinical marker for a class of neurodegenerative diseases, the "synucleinopathies", and requires formal polysomnographic evaluation. Untreated sleep disorders may exacerbate cognitive and behavioral symptoms in patients with dementia and are a source of considerable stress for bed partners and family members. When left untreated, sleep disturbances may also increase the risk of injury at night, compromise health-related quality of life, and precipitate and accelerate social and economic burdens for caregivers.

Protein aggregation and prionopathies.

Prion protein and prion-like proteins share a number of characteristics. From the molecular point of view, they are constitutive proteins that aggregate following conformational changes into insoluble particles. These particles escape the cellular clearance machinery and amplify by recruiting the soluble for of their constituting proteins. The resulting protein aggregates are responsible for a number of neurodegenerative diseases such as Creutzfeldt-Jacob, Alzheimer, Parkinson and Huntington diseases. In addition, there are increasing evidences supporting the inter-cellular trafficking of these aggregates, meaning that they are "transmissible" between cells. There are also evidences that brain homogenates from individuals developing Alzheimer and Parkinson diseases propagate the disease in recipient model animals in a manner similar to brain extracts of patients developing Creutzfeldt-Jacob's disease. Thus, the propagation of protein aggregates from cell to cell may be a generic phenomenon that contributes to the evolution of neurodegenerative diseases, which has important consequences on human health issues. Moreover, although the distribution of protein aggregates is characteristic for each disease, new evidences indicate the possibility of overlaps and crosstalk between the different disorders. Despite the increasing evidences that support prion or prion-like propagation of protein aggregates, there are many unanswered questions regarding the mechanisms of toxicity and this is a field of intensive research nowadays.

Cerebrospinal-fluid biomarkers for predicting phenoconversion in patients with isolated rapid-eye movement sleep behavior disorder.

STUDY OBJECTIVES: Patients with isolated rapid-eye-movement sleep behavior disorder (iRBD) have an increased risk of developing neurodegenerative diseases. This study assessed cerebrospinal-fluid (CSF) biomarkers of neurodegeneration and blood-brain barrier (BBB) alteration in patients with iRBD compared to controls and ascertain whether these biomarkers may predict phenoconversion to alpha-synucleinopathies (Parkinson's Disease (PD), Dementia with Lewy bodies (DLB), Multiple System Atrophy (MSA)). METHODS: Patients and controls underwent between 2012 and 2016 a neurological assessment, a lumbar puncture for CSF biomarker analysis (ß-amyloid42 - Aß42; total-tau, and phosphorylated tau), and BBB alteration (CSF/serum albumin ratio). All patients with iRBD were followed until 2021 and then classified into patients who converted to alpha-synucleinopathies (iRBD converters, cRBD) or not (iRBD non-converters, ncRBD). RESULTS: Thirty-four patients with iRBD (mean age 67.12 ±â€…8.14) and 33 controls (mean age 64.97 ±â€…8.91) were included. At follow-up (7.63 ±â€…3.40 years), eight patients were ncRBD and 33 patients were cRBD: eleven converted to PD, 10 to DLB, and two to MSA. Patients with iRBD showed lower CSF Aß42 levels and higher CSF/serum albumin ratio than controls. Cox regression analysis showed that the phenoconversion rate increases with higher motor impairment (hazard ratio [HR] = 1.23, p = 0.032). CSF Aß42 levels predicted phenoconversion to DLB (HR = 0.67, p = 0.038) and BBB alteration predicted phenoconversion to PD (HR = 1.20, p = 0.038). DISCUSSION: This study showed that low CSF Aß42 levels and high BBB alteration may predict the phenoconversion to DLB and PD in patients with iRBD, respectively. These findings highlight the possibility to discriminate phenoconversion in iRBD patients through CSF biomarkers; however, further studies are needed.

Synucleinopathies Take Their Toll: Are TLRs a Way to Go?

The misfolding and subsequent abnormal accumulation and aggregation of α-Synuclein (αSyn) as insoluble fibrils in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson's disease (PD) and several neurodegenerative disorders. A combination of environmental and genetic factors is linked to αSyn misfolding, among which neuroinflammation is recognized to play an important role. Indeed, a number of studies indicate that a Toll-like receptor (TLR)-mediated neuroinflammation might lead to a dopaminergic neural loss, suggesting that TLRs could participate in the pathogenesis of PD as promoters of immune/neuroinflammatory responses. Here we will summarize our current understanding on the mechanisms of αSyn aggregation and misfolding, focusing on the contribution of TLRs to the progression of α-synucleinopathies and speculating on their link with the non-motor disturbances associated with aging and neurodegenerative disorders.

Secondary Protein Aggregates in Neurodegenerative Diseases: Almost the Rule Rather than the Exception.

The presence of protein aggregates is a hallmark of many neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). Traditionally, each disease has been associated with the aggregation of specific proteins, which serve as disease-specific biomarkers. For example, aggregates of α-synuclein (α-syn) are found in α-synucleinopathies such as PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Similarly, AD is characterized by aggregates of amyloid-beta (Aß) and tau proteins. However, it has been observed that these protein aggregates can also occur in other neurodegenerative diseases, contributing to disease progression. For instance, α-syn aggregates have been detected in AD, Down syndrome, Huntington's disease, prion diseases, and various forms of FTLD. Similarly, Aß aggregates have been found in conditions like DLB and PD. Tau aggregates, in addition to being present in primary tauopathies, have been identified in prion diseases, α-synucleinopathies, and cognitively healthy aged subjects. Finally, aggregates of TDP-43, typically associated with FTLD and amyotrophic lateral sclerosis (ALS), have been observed in AD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), MSA, DLB, and other neurodegenerative diseases. These findings highlight the complexity of protein aggregation in neurodegeneration and suggest potential interactions and common mechanisms underlying different diseases. A deeper understating of this complex scenario may eventually lead to the identification of a better elucidation of the pathogenetic mechanisms of these devastating conditions and hopefully new therapeutic stragegies.

Sex differences in alpha-synucleinopathies: a systematic review.

Background: Past research indicates a higher prevalence, incidence, and severe clinical manifestations of alpha-synucleinopathies in men, leading to a suggestion of neuroprotective properties of female sex hormones (especially estrogen). The potential pathomechanisms of any such effect on alpha-synucleinopathies, however, are far from understood. With that aim, we undertook to systematically review, and to critically assess, contemporary evidence on sex and gender differences in alpha-synucleinopathies using a bench-to-bedside approach. Methods: In this systematic review, studies investigating sex and gender differences in alpha-synucleinopathies (Rapid Eye Movement (REM) Behavior Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) from 2012 to 2022 were identified using electronic database searches of PubMed, Embase and Ovid. Results: One hundred sixty-two studies were included; 5 RBD, 6 MSA, 20 DLB and 131 PD studies. Overall, there is conclusive evidence to suggest sex-and gender-specific manifestation in demographics, biomarkers, genetics, clinical features, interventions, and quality of life in alpha-synucleinopathies. Only limited data exists on the effects of distinct sex hormones, with majority of studies concentrating on estrogen and its speculated neuroprotective effects. Conclusion: Future studies disentangling the underlying sex-specific mechanisms of alpha-synucleinopathies are urgently needed in order to enable novel sex-specific therapeutics.

Alpha-Synuclein in Peripheral Tissues as a Possible Marker for Neurological Diseases and Other Medical Conditions.

The possible usefulness of alpha-synuclein (aSyn) determinations in peripheral tissues (blood cells, salivary gland biopsies, olfactory mucosa, digestive tract, skin) and in biological fluids, except for cerebrospinal fluid (serum, plasma, saliva, feces, urine), as a marker of several diseases, has been the subject of numerous publications. This narrative review summarizes data from studies trying to determine the role of total, oligomeric, and phosphorylated aSyn determinations as a marker of various diseases, especially PD and other alpha-synucleinopathies. In summary, the results of studies addressing the determinations of aSyn in its different forms in peripheral tissues (especially in platelets, skin, and digestive tract, but also salivary glands and olfactory mucosa), in combination with other potential biomarkers, could be a useful tool to discriminate PD from controls and from other causes of parkinsonisms, including synucleinopathies.

Scoring sleep in neurodegenerative diseases: A pilot study in the synucleinopathies.

BACKGROUND: Neurodegenerative diseases often alter sleep architecture, complicating the application of the standard sleep scoring rules. There are no recommendations to overcome this problem. Our aim was to develop a scoring method that incorporates the stages previously applied in dementia with Lewy Bodies (DLB), anti-IgLON5 disease, and fatal insomnia, and to test it in patients with alpha-synucleinopathies. METHODS: Video-polysomnographies (VPSG) of nine patients (DLB:3, Parkinson's disease (PD):3, and multiple system atrophy (MSA):3) selected for their difficulty in applying standard rules were scored independently by two authors, using additional Sleep/Wake stages. These included Abnormal Wake, Subwake, Undifferentiated NREM sleep (UNREM), Poorly structured N2 (P-S N2) and abnormal REM sleep including REM without atonia (RWA), REM without low-amplitude, mixed-frequency EEG activity (RWL) and REM without rapid eye movements (RWR). RESULTS: Patients (4 females) had a median age of 74 (range 63-85). Six patients (all with PD or DLB) had abnormal EEG awake and Subwake stage. UNREM sleep was present in all patients, typically at sleep onset, and was the most common sleep stage in five. P-S N2 was recorded only in the three patients with MSA. Periods of normal and abnormal NREM coexisted in three patients. RWA was the predominant REM subtype, RWR occurred mainly in patients with MSA and RWL in those with DLB. Six patients had brief REM episodes into NREM sleep which we termed "Encapsulated RBD". CONCLUSION: Our scoring system allows an accurate description of the complex sleep-wake changes in patients with alpha-synucleinopathies.