Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3.

BACKGROUND AND OBJECTIVES: In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxia type 1 (SCA1) and 3 (SCA3) to provide essential markers for therapeutic interventions. We looked for clinical, imaging, or biological markers that are present at an early stage of the disease. METHODS: We enrolled carriers of a pathologic ATXN1 or ATXN3 expansion and controls from 18 US and 2 European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between expansion carriers with and without ataxia and controls. RESULTS: We enrolled 200 participants: 45 carriers of a pathologic ATXN1 expansion (31 patients with ataxia [median Scale for the Assessment and Rating of Ataxia: 9; 7-10] and 14 expansion carriers without ataxia [1; 0-2]) and 116 carriers of a pathologic ATXN3 expansion (80 patients with ataxia [7; 6-9] and 36 expansion carriers without ataxia [1; 0-2]). In addition, we enrolled 39 controls who did not carry a pathologic expansion in ATXN1 or ATXN3. Plasma NfL levels were significantly higher in expansion carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL [p < 0.0001], SCA3: 19.8 pg/mL [p < 0.0001]). Expansion carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 p = 0.0003, SCA3 p = 0.003) and by the presence of sensor impairment and diplopia in SCA3 (p = 0.0448 and 0.0445, respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in expansion carriers with ataxia than those without ataxia. Ataxic SCA3 participants showed extrapyramidal signs, urinary dysfunction, and lower motor neuron signs significantly more often than expansion carriers without ataxia. DISCUSSION: READISCA showed the feasibility of harmonized data acquisition in a multinational network. NfL alterations, early sensory ataxia, and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and expansion carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT03487367.

Positive Airway Pressure and Cognitive Disorders in Adults With Obstructive Sleep Apnea: A Systematic Review of the Literature.

BACKGROUND AND OBJECTIVES: Alzheimer's disease (AD) and other forms of dementia represent a rising global public health crisis. As effective treatments to prevent, cure, or slow progression of dementia are unavailable, identification of treatable risk factors that increase dementia risk, such as obstructive sleep apnea (OSA), could offer promising means to modify dementia occurrence or severity. Here we systematically reviewed the impact of positive airway pressure (PAP) therapy on incidence of cognitive disorders and cognitive decline among middle-aged and older adults with OSA. METHODS: A systematic search of MEDLINE, EMBASE, Scopus, and CINAHL was performed prior to May 2021 to identify articles that focused on associations between PAP therapy use and cognitive disorders. We included studies that examined the effects of PAP treatment on: 1) incidence of cognitive disorders among individuals ages 40 or older diagnosed with OSA; and 2) progression of cognitive decline among people with pre-existing cognitive disorders and OSA. RESULTS: Eleven studies (three clinical trials and eight observational studies) were identified. In these studies, 96% participants had OSA (n= 60,840) and n=5,826 had baseline cognitive impairment (mild cognitive impairment [MCI] or AD). Of all study participants, n=43,973 obtained PAP therapy, and n=16,397 were untreated or in a placebo group. Most studies reported a protective effect of PAP therapy on MCI and AD incidence, e.g., delayed age at MCI onset, reduced MCI or AD incidence, slower cognitive decline, or progression to AD. DISCUSSION: These findings suggest a role of OSA as a modifiable risk factor for cognitive decline. The burden of cognitive disorders on aging adults and their families calls for identification of modifiable risk factors to alleviate their impact among aging adults and their families. Future research should build on this review and focus on PAP interventions as a potential means to alleviate the incidence of cognitive disorders and cognitive decline, particularly among ethnoracial minority groups who have been underrepresented and under-investigated in the extant literature.