Evolution of Motor and Nonmotor Characteristics in an Idiopathic/Isolated REM Sleep Behavior Disorder Cohort.

Our objective was to examine whether rapid eye movement (REM) sleep behavior disorder occurs in disproportionally greater frequency in multiple system atrophy (MSA), Parkinson's disease (PD), and dementia with Lewy bodies (DLB), collectively known as the synucleinopathies, compared to other nonsynucleinopathy neurodegenerative disorders. In study 1, we reviewed the clinical records of 398 consecutive patients evaluated at Mayo Clinic Rochester for parkinsonism and/or cognitive impairment. The frequency of suspected and polysomnogram (PSG)-confirmed REM sleep behavior disorder (RBD) among subjects with the synucleinopathies MSA, PD, or DLB was compared to the frequency among subjects with the nonsynucleinopathies Alzheimer's disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), mild cognitive impairment (MCI), primary progressive aphasia (PPA), and posterior cortical atrophy (PCA). In study 2, we reviewed the clinical records of 360 consecutive patients evaluated at Mayo Clinic Jacksonville for parkinsonism and/or cognitive impairment. The frequency of probable RBD among patients with PD and DLB was compared to the frequency among patients with AD and MCI. In study 3, we reviewed the brain biopsy or postmortem autopsy diagnoses of 23 Mayo Clinic Rochester patients who had been clinically examined for possible RBD and a neurodegenerative disorder. In study 1, patients with MSA, PD, or DLB were more likely to have probable and PSG-confirmed RBD compared to subjects with the nonsynucleinopathies (probable RBD 77/120=64% vs. 7/278=3%, p < 0.01; PSG-confirmed RBD 47/120=39% vs. 1/278=0%, p < 0.01). In study 2, patients with PD and DLB were more likely to have probable RBD compared to those with AD and MCI (56% vs. 2%, p < 0.01). In study 3, of the 23 autopsied patients who had been questioned about possible RBD, 10 were clinically diagnosed with RBD. The neuropathologic diagnoses in these 10 included Lewy body disease in nine, and MSA in one. Of the other 13 cases, 12 did not have a history suggesting RBD, and the one case who did had normal electromyographic atonia during REM sleep on PSG and autopsy findings of PSP. Only one of these 13 had a synucleinopathy. The positive predictive values for RBD indicating a synucleinopathy for studies 1-3 were 91.7%, 94.3%, and 100.0%, respectively. Clinically suspected and PSG-proven RBD occurs with disproportionally greater frequency in MSA, PD, and DLB compared to other neurodegenerative disorders. In the setting of degenerative dementia and/or parkinsonism, we hypothesize that RBD is a manifestation of an evolving synucleinopathy.

The ε4-allele of apolipoprotein E (APOE-ε4) presents an elevated risk not only for Alzheimer's disease (AD), but also for Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). Indeed, the independent influence of APOE-ε4 on the promotion and exacerbation of α-synuclein pathology has recently been suggested. However, the precise phenotypic associations of APOE-ε4 in α-synucleinopathies are variable. The primary objective of this first, comprehensive systematic review was to identify biomarkers, phenotypes, or other clinicopathological characteristics that reliably associate with APOE-ε4 in α-synucleinopathies [Parkinson's disease (PD), DLB, PDD, and multiple system atrophy (MSA)], which may in turn uncover important pathophysiological mechanisms.Electronic databases were systematically searched from January 1st , 1995 through December 31st , 2020, as per the PRISMA guidelines. Studies evaluating the association of APOE-ε4 with clinicopathological, cognitive, neuropsychiatric, and neuroimaging phenotypes in clinically and/or pathologically diagnosed cases of PD, PDD, DLB, and MSA cases were reviewed.A total of 136 studies were eligible for inclusion (Figure). APOE-ε4 was found to be consistently associated with: 1) lower cerebrospinal fluid levels of amyloid-β 1-42 in PDD and DLB, 2) cognitive deficits in the memory domain in PD, PDD, and DLB, 3) mediotemporal cortical atrophy primarily in DLB, 3) cerebral amyloid angiopathy, shorter survival, and accelerated decline in global cognition in DLB, as well as 4) the co-occurrence of AD-type neuropathological features. Furthermore, APOE-ε4 was associated, albeit inconsistently, with: 1) the presence and severity of diffuse neocortical Lewy body pathology and, 2) elevated tracer retention on amyloid positron emission tomography in PD, PDD, and DLB, 3) greater odds of dementia in PD, and 4) other genetic and pathophysiological factors to enhance the cumulative risk for DLB. APOE-ε4 was not associated with disease risk or α-synuclein pathology in MSA. Studies also highlighted the relationship of APOE-ε4 with neuropsychiatric, epigenetic (DNA methylation), sleep, immunohistochemical, and biochemical factors in α-synucleinopathies, which will be presented.In addition to its role in AD, APOE-ε4 influences the disease presentation and progression particularly in PDD and DLB. Guided by reliable biomarkers, further research to unravel the underlying mechanisms will assist in developing early prevention strategies targeting the APOE protein.

Purpose of ReviewSleep 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 findings17 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.SummaryThere 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.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia notable for its association with the later development of diseases with pathological α-synuclein deposition, including Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). The goal of this review is to summarize the recent advances in characterizing the clinical deficits, neuroimaging characteristics, and biomarker assay development of individuals with RBD. Clinical research indicates that many people with RBD are presenting to clinical attention for reasons other than dream enactment behavior. They experience deficits in neuropsychiatric, autonomic, and motor domains and co-presentation of these features with RBD predict a faster rate of phenoconversion to PD, DLB, or MSA. RBD is considered a prodromal synucleinopathy with early abnormalities in α-synuclein protein pathways, together with inflammation and mitochondrial dysfunction being recognized as key pathophysiological mechanisms. Seed amplification assays for α-synuclein in various tissue types hold tremendous promise for antemortem diagnosis. RBD is clearly an at-risk population for neurodegenerative disease with well-defined measures that can refine enrollment and better target prodromal populations for interventional clinical trials. The first neuroprotective trials are underway.

Although systemic inflammation triggered by alterations in microbiota from various body sites has been proposed as a potential mechanism underlying Lewy body diseases (LBDs), the association between the blood microbiome and LBDs remains uncertain. This study aimed to investigate the blood microbiome profiles across the REM sleep behavior disorder (RBD)-LBD continuum and to explore their potential as biomarkers reflecting disease phenotypes and clinical severity. Blood samples were collected from 106 patients across the RBD-LBD continuum, including 41 with isolated RBD (iRBD), 45 Parkinson's disease with probable RBD, and 20 dementia with Lewy bodies with probable RBD, as well as from 94 healthy controls. All patients were evaluated with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and comprehensive neuropsychological tests. Microbiome taxonomic compositions were analyzed using 16S rRNA metagenomic sequencing. Significant microbial shifts were observed in the RBD-LBD continuum group compared to controls, with reduced microbial alpha diversity and distinct beta diversity patterns. Specifically, the genus Stenotrophomonas was enriched, while the genera Acetobacter, Enhydrobacter, and Lactobacillus were depleted in the RBD-LBD continuum group. The combined model using these genera demonstrated high predictive accuracy for the RBD-LBD continuum, with the area under the receiver-operating-characteristic curve (AUC) of 0.970 (95% confidence interval [CI]: 0.950-0.980). This model also successfully distinguished the iRBD subgroup from controls, achieving an AUC of 0.956 (95% CI, 0.914-0.987). Alpha and beta diversity were significantly associated with MDS-UPDRS Parts I and II scores in the RBD-LBD continuum group. Our findings suggest that patients within the RBD-LBD continuum may share specific blood microbiome signatures.

Violent and other clinical manifestations of REM sleep behaviour disorder (RBD), presenting in sleep laboratories for diagnostic work-up, have been shown to precede the clinical syndrome of neurodegenerative diseases associated with the misprocessing of α-synuclein. At the time of RBD diagnosis, it is still impossible to foresee whether idiopathic RBD will eventually evolve to Parkinson’s disease (PD), multiple system atrophy (MSA) or dementia with Lewy bodies (DLB). Conversely, in newly diagnosed PD, a meta-analysis of published studies has shown that RBD has been identified in a mean 23.6% (range, 4.3–69.4%) of patients and appears to indicate a specific phenotypically defined subtype of the disease. Although not all PD patients with RBD show violent dream-enacting behaviours and RBD severity may vary from night to night, RBD is an important differential diagnosis for abnormal nocturnal behaviours in PD patients as the disease progresses, encompassing also night-time confusional states, hallucinations and periodic limb movements (PLM). Moreover, the appearance of RBD during the course of PD has been shown to indicate the entrance to a more advanced stage of the disease. In MSA the prevalence of RBD has been determined at 88%. While RBD manifestations prodromal to MSA onset are described by many patients, dream-enacting behaviours seem to disappear over time, and physiologic sleep structure becomes severely disturbed. So far, attempts to differentiate the different types of MSA by sleep analysis have failed, and longitudinal sleep laboratory data are insufficient. Recently a small series of patients with pure autonomic failure (PAF) was published, and these patients had developed RBD during the course of the disease, indicating that PAF may be a mild form of CNS α-synucleinopathy.

The Discovery of α-Synuclein in Lewy Pathology of Parkinson's Disease: The Inspiration of a Revolution.

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.

In this issue of Internal Medicine, Chen et al. (1) documented the case of a 30-year-old man who presented with an 11-month history of abnormal nocturnal behavior related to vivid dreams. Brain magnetic resonance images revealed lesions involving the pontomesencephalic junction and the upper pons, and polysomnography (PSG) findings confirmed a diagnosis of rapid eye movement (REM) sleep behavior disorder (RBD). A brainstem biopsy revealed diffuse large B-cell lymphoma. Notably, chemotherapy for lymphoma resulted in the disappearance of the lesions and reduced the frequency of RBD symptoms in the patient. RBD is a parasomnia characterized by dream-enacting behaviors and a loss of normal muscle atonia during REM sleep. The estimated prevalence of this disorder was reported to be 0.5% in a survey of approximately 4,900 subjects between the ages of 15 and 100 years (2). The dreams of patients with RBD usually include unpleasant and aggressive content, and the patient’s abnormal behavior is typically aggressive and violent, often resulting in serious injury to the patient or their bed partner (3). Based on the International Classification of Sleep Disorders, second edition (4), the use of PSG is essential for diagnosing RBD. The following criteria should be met: A, the presence of REM sleep without atonia, including excessive amounts of sustained or intermittent elevations of submental electromyographic (EMG) tone or excessive phasic submental or limb EMG twitching; B, abnormal REM sleep behavior based on the patient’s history and/or PSG findings; C, the absence of electroencephalogram (EEG) epileptiform activity during REM sleep; and D, the sleep disturbance is not better explained by medication use or another sleep, medical, neurological, mental or substance use disorder. In almost 90% of patients with RBD, the administration of clonazepam (0.5 to 1.5 mg) at bedtime is effective. Additionally, melatonin, pramipexole and Yi-Gan San alone or in conjunction with clonazepam may effectively treat RBD. The anatomic substrate for REM sleep control in humans includes a “REM-off” region, which consists of the ventrolateral part of the periaqueductal gray matter and lateral pontine tegmentum, and a “REM-on” region, which consists of the precoeruleus, sublaterodorsal nucleus, extended portion of the ventrolateral preoptic nucleus, locus coeruleus, laterodorsal tegmental nucleus, pedunculopontine nucleus and raphe nucleus (5). Motor behaviors in patients with RBD may reflect brainstem impairment, while the frightening dreams of RBD may reflect amygdala dysfunction (6). In humans, RBD can be caused secondarily by brain lesions including the brainstem nuclei, which regulate REM sleep, and the supratentorial structures, including the posterior hypothalamus, anterior thalamus and limbic system, which connect with the brainstem nuclei. Brain tumors, demyelinating plaque, strokes and limbic encephalitis have been reported to cause RBD (6), and narcolepsy is associated with RBD. Several medications can cause RBD, including antidepressants such as tricyclics, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (3). In 1996, Schenck et al. (7) first reported the delayed emergence of Parkinsonian disorders in 38% of 29 older men initially diagnosed with idiopathic RBD, with a mean interval of 3.7 years after RBD diagnosis and a mean interval of 12.7 years after RBD onset. After an additional 7year follow-up, the conversion rate from idiopathic RBD to neurodegenerative diseases increased to 65%. Additionally, Iranzo et al. (8) reported that 45% of 44 patients with idiopathic RBD developed neurodegenerative diseases (n=9, Parkinson’s disease (PD); n=6, dementia with Lewy bodies (DLB); n=4, mild cognitive impairment; n=1, multiple system atrophy) at a mean follow-up of 5.1 years and a mean of 11.5 years after RBD onset. Postuma et al. (9) reported that 28% of 93 patients with idiopathic RBD developed neurodegenerative diseases (n=14, PD; n=7, DLB; n=4, Al-

The study aimed to review recent updates of our understanding of REM sleep behavior disorder (RBD) and other sleep disorders in non-Alzheimer’s disease (AD) dementias. Numerous recent discoveries have provided insight into the role of RBD and sleep in patients with non-AD dementias. Imaging modalities such as DaTscan and cerebral blood flow may be useful for monitoring phenoconversion in idiopathic RBD patients to Parkinson’s disease (PD) or dementia with Lewy bodies (DLB). Patients with isolated REM sleep without atonia have non-motor signs of neurodegenerative disease. Colon mucosal biopsies in iRBD patients have shown presence of α-synuclein aggregates. Recent genetic models of RBD and neuroimaging have furthered evidence for the locus subcoeruleus/sublateral dorsal nucleus as the center for the generation and maintenance of REM muscle atonia. Circadian rhythm disturbances likely play a large role in nighttime insomnia, daytime sleepiness, autonomic symptoms, motor variations, and hallucinations in PD and DLB. Early onset stridor in patients with multiple system atrophy (MSA) portends a worse prognosis than late onset stridor, and treatment of stridor is associated with survival. Our ability to predict phenoconversion in idiopathic RBD is improving and will be highly important as “high risk” phenoconverters are identified for enrollment in neuroprotective clinical trials. Treatments of RBD improve but do not fully eliminate DEB; therefore, the risk for sleep-related injury remains a concern even among seemingly well-treated patients. Excessive daytime sleepiness (EDS) secondary to neuropathology, sedating medications, sleep disordered breathing (SDB), restless legs syndrome (RLS), and circadian rhythm alterations are common in the non-AD dementias, leading to significant caregiver burden and worsening of cognition. Addressing primary sleep disorders is the mainstay of treatment for EDS. RLS is a frequent co-morbidity in non-AD dementias. Initial management of RLS includes ensuring serum a ferritin level of >75 μg/L and therapy with gabapentin encarbil (which is less likely to cause augmentation than dopamine agonists). All MSA patients should be evaluated for the presence of nocturnal stridor, which should be treated if present. Therapies targeting the circadian system are often an underutilized therapeutic avenue in the management of sleep, motor, autonomic, and psychiatric symptoms in PD and DLB patients.

Parkinsonian disorders, including Parkinson’s disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS), present overlapping early symptoms, complicating accurate diagnosis. Predicting the conversion of prodromal conditions like REM behavior disorder (RBD) to PD, MSA, or DLB is also complex. Extracellular vesicles (EVs), small structures released by cells, carry cell-state-specific biomarkers that can cross the blood-brain barrier, providing a window into the brain’s biochemistry. Blood-isolated CNS-originating EVs have become a popular diagnostic tool. Yet, challenges remain in replicating and validating these findings. We conducted a PRISMA-guided systematic review and meta-analysis of 15 studies involving 1,455 persons with PD, 206 with MSA, 21 with DLB, 172 with PSP, 152 with CBS, 189 with RBD, and 1,045 healthy controls (HCs). Diagnostic accuracy for distinguishing persons with PD from HCs was moderate but showed high heterogeneity and significant publication bias. This indicates that studies with non-significant or lower effect sizes were less likely to be published. Differentiating persons with PD from those with PSP or CBS is limited due to the small number of involved studies. Our analyses suggest that biomarkers from CNS-originating EVs may not reliably differentiate persons with MSA or RBD from HCs due to variable accuracy and high heterogeneity. Our findings highlight the moderate diagnostic accuracy of EV biomarkers in differentiating Parkinsonian disorders, emphasizing substantial heterogeneity and significant publication bias. The need for larger, more standardized, and unbiased studies is underscored to validate the utility of EV biomarkers as diagnostic tools.

Background and objectiveParkinsonian disorders, including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS), exhibit overlapping early-stage symptoms, complicating definitive diagnosis despite heterogeneous cellular and regional pathophysiology. Additionally, the progression and the eventual conversion of prodromal conditions such as REM behavior disorder (RBD) to PD, MSA, or DLB remain challenging to predict. Extracellular vesicles (EVs) are small, membrane-enclosed structures released by cells, playing a vital role in communicating cell-state-specific messages. Due to their ability to cross the blood–brain barrier into the peripheral circulation, measuring biomarkers in blood-isolated speculative CNS enriched EVs has become a popular diagnostic approach. However, replication and independent validation remain challenging in this field. Here, we aimed to evaluate the diagnostic accuracy of speculative CNS-enriched EVs for parkinsonian disorders.MethodsWe conducted a PRISMA-guided systematic review and meta-analysis, covering 18 studies with a total of 1695 patients with PD, 253 with MSA, 21 with DLB, 172 with PSP, 152 with CBS, 189 with RBD, and 1288 HCs, employing either hierarchical bivariate models or univariate models based on study size.ResultsDiagnostic accuracy was moderate for differentiating patients with PD from HCs, but revealed high heterogeneity and significant publication bias, suggesting an inflation of the perceived diagnostic effectiveness. The bias observed indicates that studies with non-significant or lower effect sizes were less likely to be published. Although results for differentiating patients with PD from those with MSA or PSP and CBS appeared promising, their validity is limited due to the small number of involved studies coming from the same research group. Despite initial reports, our analyses suggest that using speculative CNS-enriched EV biomarkers may not reliably differentiate patients with MSA from HCs or patients with RBD from HCs, due to their lesser accuracy and substantial variability among the studies, further complicated by substantial publication bias.ConclusionOur findings underscore the moderate, yet unreliable diagnostic accuracy of biomarkers in speculative CNS-enriched EVs in differentiating parkinsonian disorders, highlighting the presence of substantial heterogeneity and significant publication bias. These observations reinforce the need for larger, more standardized, and unbiased studies to validate the utility of these biomarkers but also call for the development of better biomarkers for parkinsonian disorders.

The pedunculopontine (PPT) and laterodorsal (LDT) tegmental nuclei are involved in control of REM sleep and thalamocortical arousal. REM sleep behavior disorder (RBD) is a feature of multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), which is also associated with visual hallucinations and cognitive fluctuations. We sought to determine the degree of PPT/LDT involvement in DLB compared to MSA. We counted the cholinergic neurons in the PPT and LDT in 13 patients with neuropathologically confirmed DLB, 11 patients with MSA, and 11 control cases. Five patients with DLB and eight patients with MSA had history or polysomnographic evidence of RBD. Ten patients with DLB and no patient with MSA had history of visual hallucinations or cognitive fluctuations. There was a significant loss of PPT and LDT neurons in both DLB and MSA. Cell loss in both the PPT and LDT was more severe in MSA than in DLB. The number of cells/section for the PPT were 148 +/- 21 in controls, 54 +/- 10 in DLB (p < 0.001), and 20 +/- 3 in MSA (p < 0.001), and for the LDT, 112 +/- 16 in controls, 49 +/- 8 in DLB (p < 0.01), and 16 +/- 2 in MSA (p < 0.001). Severity of neuronal loss in MSA or DLB did not relate to the presence or absence of history of RBD. Loss of cholinergic pedunculopontine tegmental nuclei/laterodorsal tegmental nuclei neurons occurs in both dementia with Lewy bodies and multiple system atrophy but is probably not the primary mechanism of REM sleep behavior disorder in these disorders.

Consumption of low- and no-calorie sweeteners (LNCSs) has been associated with adverse health outcomes. However, little is known about the association between consumption of LNCSs and cognition. The aim of this study was to investigate the association between consumption of LNCSs and cognitive decline. We conducted a longitudinal observational study using data from civil servants aged 35+ years at baseline who were enrolled in the Brazilian Longitudinal Study of Adult Health and evaluated across 3 study waves (2008-10, 2012-14, and 2017-19). Participants with incomplete dietary data, extreme caloric intake (<1st percentile or >99th percentile), and incomplete data for cognitive tests and covariates at baseline were excluded. A Food Frequency Questionnaire was used to calculate combined and individual consumption of 7 LNCSs (aspartame, saccharin, acesulfame k, erythritol, xylitol, sorbitol, and tagatose). We estimated z-scores across 6 cognitive tests. The association of LNCSs with cognitive decline was evaluated using linear mixed-effects models. Among 12,772 participants (mean age 51.9 ± 9.0 years, 54.8% women, 43.2% Black/mixed race), the mean consumption of LNCSs was 92.1 ± 90.1 mg/d. Among participants aged younger than 60 years, consumption of combined LNCSs in the highest tertiles was associated with a faster decline in verbal fluency (second tertile: β = -0.016, 95% CI -0.040 to -0.008; third tertile: β = -0.040, 95% CI -0.064 to -0.016) and global cognition (second tertile: β = -0.008, 95% CI -0.024 to 0.008; third tertile: β = -0.024, 95% CI -0.040 to -0.008). There was no association between tertiles of LNCSs and cognitive decline in participants aged 60+ years. Consumption of aspartame, saccharin, acesulfame k, erythritol, sorbitol, and xylitol was associated with a faster decline in global cognition, particularly in memory and verbal fluency domains. Consumption of combined LNCSs in the highest tertiles was associated with a faster decline in verbal fluency and global cognition in participants without diabetes and faster decline in memory and global cognition in participants with diabetes. Consumption of LNCSs was associated with an accelerated rate of cognitive decline during 8 years of follow-up. Our findings suggest the possibility of long-term harm from LNCS consumption, particularly artificial LNCSs and sugar alcohols, on cognitive function. Study limitations include self-reported dietary data, selection bias from attrition, and residual confounding from co-occurring health behaviors.

ObjectiveReview the effect of orthostatic hypotension (OH) and rapid-eye-movement sleep behavioural disorder (RBD) on survival, cognitive impairment and postural stability, and discuss pathogenic mechanisms involved in the association of these...