Blood-cell-free circulating micro-RNAs (miRNAs) have been proposed as potential accessible biomarkers for neurodegenerative diseases such as Parkinson's disease (PD). Here we analyzed the serum levels of 377 miRNAs in a discovery set of 10 idiopathic Parkinson's disease (IPD) patients, 10 PD patients carriers of the LRRK2 G2019S mutation (LRRK2 PD), and 10 controls by using real-time quantitative PCR-based TaqMan MicroRNA arrays. We detected candidate differentially expressed miRNAs, which were further tested in a first validation set consisting of 20 IPD, 20 LRRK2 PD, and 20 control samples. We found four statistically significant miRNAs that were downregulated in either LRRK2 or IPD (miR-29a, miR-29c, miR-19a, and miR-19b). Subsequently, we validated these findings in a third set of samples consisting of 65 IPD and 65 controls and confirmed the association of downregulated levels of miR-29c, miR-29a, and miR-19b in IPD. Differentially expressed miRNAs are predicted to target genes belonging to pathways related to ECM-receptor interaction, focal adhesion, MAPK, Wnt, mTOR, adipocytokine, and neuron projection. Results from our exploratory study indicate that downregulated levels of specific circulating serum miRNAs are associated with PD and suggest their potential use as noninvasive biomarkers for PD. Future studies should further confirm the association of these miRNAs with PD.

Introduction: Synaptic damage, axonal neurodegeneration, and neuroinflammation are common features in Alzheimer's disease (AD), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD). Methods: Unicentric cohort of 353 participants included healthy control (HC) subjects, AD continuum stages, genetic AD and FTD, and FTD and CJD. We measured cerebrospinal fluid neurofilament light (NF-L), neurogranin (Ng), 14-3-3, and YKL-40 proteins.Results: Biomarkers showed differences in HC subjects versus AD, FTD, and CJD. Disease groups differed between them except AD versus FTD for YKL-40. Only NF-L differed between all stages within the AD continuum. AD and FTD symptomatic mutation carriers presented differences with respect to HC subjects. Applying the AT(N) system, 96% subjects were positive for neurodegeneration if 14-3-3 was used, 94% if NF-L was used, 62% if Ng was used, and 53% if YKL-40 was used.

IMPORTANCESleep disturbance is common among patients with neurodegenerative diseases. Examining the subcortical neuronal correlates of sleep disturbances is important to understanding the early-stage sleep neurodegenerative phenomena.OBJECTIVES To examine the correlation between the number of important subcortical wake-promoting neurons and clinical sleep phenotypes in patients with Alzheimer disease (AD) or progressive supranuclear palsy (PSP).

Background and purpose Several diagnostic biomarkers are currently available for clinical use in early‐onset cognitive impairment. The decision on which biomarker is used in each patient depends on several factors such as its predictive value or tolerability. Methods There were a total of 40 subjects with early‐onset cognitive complaints (<65 years of age): 26 with Alzheimer's disease (AD), five with frontotemporal dementia and nine with diagnostic suspicion of non‐neurodegenerative disorder. Clinical and neuropsychological evaluation, lumbar puncture for cerebrospinal fluid (CSF) AD core biochemical marker determination, medial temporal atrophy evaluation on magnetic resonance imaging, amyloid‐positron emission tomography (PET) and 18F‐fluorodeoxyglucose‐PET were performed. Neurologists provided pre‐ and post‐biomarker diagnosis, together with diagnostic confidence and clinical/therapeutic management. Patients scored the tolerability of each procedure. Results Cerebrospinal fluid biomarkers and amyloid‐PET increased diagnostic confidence in AD (77.4%–86.2% after CSF, 92.4% after amyloid‐PET, P < 0.01) and non‐neurodegenerative conditions (53.6%–75% after CSF, 95% after amyloid‐PET, P < 0.05). Biomarker results led to diagnostic (32.5%) and treatment (32.5%) changes. All tests were well tolerated. Conclusions Biomarker procedures are well tolerated and have an important diagnostic/therapeutic impact on early‐onset cognitive impairment.

NIA-AA diagnostic criteria include volumetric or visual rating measures of hippocampal atrophy (HA) as a diagnostic biomarker of Alzheimer's disease (AD). We aimed to determine its utility as a diagnostic biomarker for early onset Alzheimer's disease (EOAD) by assessing Medial Temporal Atrophy (MTA) and hippocampal volume (HV) determination. MTA score and HV quantified by FreeSurfer were assessed in 140 (aged ≤65) subjects with biomarker supported diagnosis: 38 amnesic (A-EOAD), 20 non-amnesic (NA-EOAD), 30 late onset AD (LOAD), 20 fronto-temporal dementia (FTD) and 32 healthy controls (HC). The results showed that the proportion of MTA ≥ 1.5 was higher on LOAD and FTD than EOAD and HC but none of the MTA thresholds (≥1, ≥1.5 and ≥ 2) showed acceptable diagnostic accuracy. LOAD had lower HV than the other groups. A-EOAD HV was lower than NA-EOAD and HC but equal to FTD. The 6258 mm3 cut-off showed good diagnostic accuracy between A-EOAD and HC. Both tools showed a moderate inverse correlation. In conclusion, MTA has a limited diagnostic utility as an EOAD biomarker as it does not discriminate AD from FTD or HC in initial symptomatic stages. HV may discriminate A-EOAD from HC but not from FTD.

Highlights Posterior cortices, hippocampus and amygdala track atrophy in EOAD over two years. The medial temporal cortex is unaltered in EOAD at early stages. EOAD exhibited a posterior-to-anterior gradient of cortical loss after two years. EOAD subcortical volume loss extends beyond hippocampus and amygdala after two years. Cerebrospinal fluid biomarkers might predict atrophy rates in EOAD.

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early-onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid-long form of the amyloid-beta protein [Aβ42], total-tau protein [Ttau], neurofilament light chain [NfL], neurogranin [Ng], and 14-3-3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the "AD signature" and "FTLD signature." We tested multiple regression models to find which CSFbiomarkers better explained each disease neuroimaging signature. CTh and FA maps Neus Falgàs, Mariona Ruiz-Peris, Albert Lladó, and Raquel Sánchez-Valle authors contributed equally to this work.

Background and purpose The faster rates of cognitive decline and predominance of atypical forms in early‐onset Alzheimer's disease (EOAD) suggest that neuropsychiatric symptoms could be different in EOAD compared to late‐onset AD (LOAD); however, prior studies based on non‐biomarker‐diagnosed cohorts show discordant results. Our goal was to determine the profile of neuropsychiatric symptoms in EOAD and LOAD, in a cohort with biomarker/postmortem‐confirmed diagnoses. Additionally, the contribution of co‐pathologies was explored. Methods In all, 219 participants (135 EOAD, 84 LOAD) meeting National Institute on Aging and Alzheimer's Association criteria for AD (115 amyloid positron emission tomography/cerebrospinal fluid biomarkers, 104 postmortem diagnosis) at the University of California San Francisco were evaluated. The Neuropsychiatric Inventory—Questionnaire (NPI‐Q) was assessed at baseline and during follow‐up. The NPI‐Q mean comparisons and regression models adjusted by cognitive (Mini‐Mental State Examination) and functional status (Clinical Dementia Rating Sum of Boxes) were performed to determine the effect of EOAD/LOAD and amnestic/non‐amnestic diagnosis on NPI‐Q. Regression models assessing the effect of co‐pathologies on NPI‐Q were performed. Results At baseline, the NPI‐Q scores were higher in EOAD compared to LOAD (p < 0.05). Longitudinally, regression models showed a significant effect of diagnosis, where EOAD had higher NPI‐Q total, anxiety, motor disturbances and night‐time behavior scores (p < 0.05). No differences between amnestics/non‐amnestics were found. Argyrophilic grain disease co‐pathology predicted a higher severity of NPI‐Q scores in LOAD. Conclusions Anxiety, night‐time behaviors and motor disturbances are more severe in EOAD than LOAD across the disease course. The differential patterns of neuropsychiatric symptoms observed between EOAD/LOAD could suggest a pattern of selective vulnerability extending to the brain's subcortical structures. Further, co‐pathologies such as argyrophilic grain disease in LOAD may also play a role in increasing neuropsychiatric symptoms.