Giant diffusion of nanomechanical rotors in a tilted washboard potential

We present an experimental realization of a biased optical periodic potential in the low friction limit. The noise-induced bistability between locked (torsional) and running (spinning) states in the rotational motion of a nanodumbbell is driven by an elliptically polarized light beam tilting the angular potential. By varying the gas pressure around the point of maximum intermittency, the rotational effective diffusion coefficient increases by more than 3 orders of magnitude over free-space diffusion. These experimental results are in agreement with a simple two-state model that is derived from the Langevin equation through using timescale separation. Our work provides a new experimental platform to study the weak thermal noise limit for diffusion in this system

Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker

Asteroseismology and Interferometry

Asteroseismology provides us with a unique opportunity to improve our understanding of stellar structure and evolution. Recent developments, including the first systematic studies of solar-like pulsators, have boosted the impact of this field of research within Astrophysics and have led to a significant increase in the size of the research community. In the present paper we start by reviewing the basic observational and theoretical properties of classical and solar-like pulsators and present results from some of the most recent and outstanding studies of these stars. We centre our review on those classes of pulsators for which interferometric studies are expected to provide a significant input. We discuss current limitations to asteroseismic studies, including difficulties in mode identification and in the accurate determination of global parameters of pulsating stars, and, after a brief review of those aspects of interferometry that are most relevant in this context, anticipate how interferometric observations may contribute to overcome these limitations. Moreover, we present results of recent pilot studies of pulsating stars involving both asteroseismic and interferometric constraints and look into the future, summarizing ongoing efforts concerning the development of future instruments and satellite missions which are expected to have an impact in this field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume 14, Issue 3-4, pp. 217-36

First presentation with neuropsychiatric symptoms in autosomal dominant Alzheimer\u27s disease: The Dominantly Inherited Alzheimer\u27s Network Study

Behavioural changes and neuropsychiatric symptoms (NPS) commonly occur in Alzheimer’s disease (AD) but may not be recognised as AD-related when they are the presenting feature. NPS are important as they are associated with greater functional impairment, poorer quality of life, accelerated cognitive decline and worsened caregiver burden.1 Autosomal dominant AD (ADAD), although \u3c 1% of total AD cases, provides a valuable opportunity to study the clinical heterogeneity of AD. The young age at onset reduces the prevalence of age-related comorbid pathologies and the near 100% penetrance of pathogenic mutations reduces the likelihood of misdiagnosis.2 Anxiety and depression commonly occur in ADAD family members, with increased levels of depression having been found among predementia female mutation carriers.3 Subsequent studies, however, have shown that anxiety and/or depression are common regardless of mutation status, occurring in almost one in three at-risk individuals, with one study reporting a higher rate of depression in non-carriers (17%) than asymptomatic carriers (5%).4 5 Despite the high frequency of NPS in ADAD families, relatively little is known about the proportion of ADAD cases who present with predominantly behavioural symptoms. Our aims were to assess the first reported clinical change in symptomatic ADAD, to compare presentations across genotypes, and to compare cognitive performance between behavioural and cognitive-led presentations

Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease

Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment. Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally. Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%–98.2%]) and improved prediction beyond established methods based on familial age of onset. Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.Fil: Keret, Ophir. University of California; Estados UnidosFil: Staffaroni, Adam M.. University of California; Estados UnidosFil: Ringman, John M.. University of Southern California; Estados UnidosFil: Cobigo, Yann. University of California; Estados UnidosFil: Goh, Sheng Yang M.. University of California; Estados UnidosFil: Wolf, Amy. University of California; Estados UnidosFil: Allen, Isabel Elaine. University of California; Estados UnidosFil: Salloway, Stephen. Brown University; Estados UnidosFil: Chhatwal, Jasmeer. Harvard Medical School; Estados UnidosFil: Brickman, Adam M.. Columbia University; Estados UnidosFil: Reyes Dumeyer, Dolly. Columbia University; Estados UnidosFil: Bateman, Randal J.. University of Washington; Estados UnidosFil: Benzinger, Tammie L.S.. University of Washington; Estados UnidosFil: Morris, John C.. University of Washington; Estados UnidosFil: Ances, Beau M.. University of Washington; Estados UnidosFil: Joseph Mathurin, Nelly. University of Washington; Estados UnidosFil: Perrin, Richard J.. University of Washington; Estados UnidosFil: Gordon, Brian A.. University of Washington; Estados UnidosFil: Levin, Johannes. German Center for Neurodegenerative Diseases; Alemania. Ludwig Maximilians Universitat; AlemaniaFil: Vöglein, Jonathan. Ludwig Maximilians Universitat; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Jucker, Mathias. German Center for Neurodegenerative Diseases; Alemania. Eberhard Karls Universität Tübingen; AlemaniaFil: la Fougère, Christian. Eberhard Karls Universität Tübingen; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Martins, Ralph N.. Cooperative Research Centres Australia; Australia. University of Western Australia; Australia. Edith Cowan University; Australia. Australian Alzheimer's Research Foundation; Australia. Macquarie University; AustraliaFil: Sohrabi, Hamid R.. University of Western Australia; Australia. Macquarie University; Australia. Australian Alzheimer's Research Foundation; Australia. Cooperative Research Centres Australia; Australia. Edith Cowan University; AustraliaFil: Taddei, Kevin. Australian Alzheimer's Research Foundation; Australia. Edith Cowan University; AustraliaFil: Villemagne, Victor L.. Austin Health; AustraliaFil: Schofield, Peter R.. Neuroscience Research Australia; Australia. Unsw Medicine; AustraliaFil: Brooks, William S.. Neuroscience Research Australia; Australia. Unsw Medicine; AustraliaFil: Fulham, Michael. Royal Prince Alfred Hospital; AustraliaFil: Masters, Colin L.. University of Melbourne; AustraliaFil: Allegri, Ricardo Francisco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; Argentin

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease

BackgroundBrain-predicted age estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology.MethodsWe modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-beta-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE epsilon 4 carrier status, sex, and education.ResultsAdvanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG.ConclusionsWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI

Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer\u27s disease: Associations with Aβ-PET, neurodegeneration, and cognition

Background: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer\u27s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. Methods: We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Results: Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (A ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished A -positive from A -negative ADAD participants and showed a stronger relationship with A load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Conclusion: Our findings support a role for plasma GFAP as a clinical biomarker of A -related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. Highlights: Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer\u27s disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not