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 T‐tau, 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 CSF‐biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aβ and 14‐3‐3; whereas NfL and 14‐3‐3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD.
Synaptic damage, axonal neurodegeneration, and neuroinflammation are common features in Alzheimer's disease (AD), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD).
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.
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.
Biomarkers of synapse and neurodegeneration differentiate HC subjects from neurodegenerative dementias and between AD, FTD, and CJD. NF-L and 14-3-3 performed similar to total tau when AT(N) system was applied.
•Neurofilament light (NF-L) levels are increased in neurodegenerative dementias.•14-3-3 protein is increased in Alzheimer's disease (AD) and frontotemporal dementia (FTD).•Neurogranin is decreased in FTD and increased in AD and Creutzfeldt-Jakob disease.•NF-L and 14-3-3 are good neurodegeneration markers when applied in the AT(N) system.•Only cerebrospinal fluid NF-L levels tracked disease progression in AD.
Sex differences in early‐onset Alzheimer's disease Contador, José; Pérez‐Millan, Agnès; Guillén, Nuria ...
European journal of neurology,
December 2022, 2022-12-00, 20221201, Letnik:
29, Številka:
12
Journal Article
Recenzirano
Background and purpose
Sex is believed to drive heterogeneity in Alzheimer's disease (AD), although evidence in early‐onset AD (EOAD; <65 years) is scarce.
Methods
We included 62 EOAD patients and 44 ...healthy controls (HCs) with core AD cerebrospinal fluid (CSF) biomarkers, neurofilament light chain levels, neuropsychological assessment, and 3‐T magnetic resonance imaging. We measured cortical thickness (CTh) and hippocampal subfield volumes (HpS) using FreeSurfer. Adjusted linear models were used to analyze sex‐differences and the relationship between atrophy and cognition.
Results
Compared to same‐sex HCs, female EOAD subjects showed greater cognitive impairment and broader atrophy burden than male EOAD subjects. In a direct female‐EOAD versus male‐EOAD comparison, there were slight differences in temporal CTh, with no differences in cognition or HpS. CSF tau levels were higher in female EOAD than in male EOAD subjects. Greater atrophy was associated with worse cognition in female EOAD subjects.
Conclusions
At diagnosis, there are sex differences in the pattern of cognitive impairment, atrophy burden, and CSF tau in EOAD, suggesting there is an influence of sex on pathology spreading and susceptibility to the disease in EOAD.
Blood-based biomarkers have emerged as minimally invasive options for evaluating cognitive impairment. Most studies to date have assessed them in research cohorts, limiting their generalization to ...everyday clinical practice. We evaluated their diagnostic performance and clinical applicability in a prospective, real-world, memory clinic cohort.
All patients referred with suspected cognitive impairment between July 2019 and June 2021 were prospectively invited to participate. Five plasma biomarkers (tau phosphorylated at threonine 181 p-tau181, glial fibrillary acidic protein GFAP, neurofilament light chain NfL, total tau t-tau, and ubiquitin C-terminal hydrolase L1 UCH-L1) were determined with single-molecule array. Performance was assessed in comparison to clinical diagnosis (blinded to plasma results) and amyloid status (CSF/PET). A group of cognitively unimpaired (CU) controls was also included.
Three hundred forty-nine participants (mean age 68, SD 8.3 years) and 36 CU controls (mean age 61.7, SD 8.2 years) were included. In the subcohort with available Alzheimer disease (AD) biomarkers (n = 268), plasma p-tau181 and GFAP had a high diagnostic accuracy to differentiate AD from non-neurodegenerative causes (area under the receiver operating characteristic curve 0.94 and 0.92, respectively), with p-tau181 systematically outperforming GFAP. Plasma p-tau181 levels predicted amyloid status (85% sensitivity and specificity) with accurate individual prediction in approximately 60% of the patients. Plasma NfL differentiated frontotemporal dementia (FTD) syndromes from CU (0.90) and non-neurodegenerative causes (0.93), whereas the discriminative capacity with AD and between all neurodegenerative and non-neurodegenerative causes was less accurate. A combination of p-tau181 and NfL identified FTD with 82% sensitivity and 85% specificity and had a negative predictive value for neurodegenerative diagnosis of 86%, ruling out half of the non-neurodegenerative diagnoses. In the subcohort without AD biomarkers, similar results were obtained. T-tau and UCH-L1 did not offer added diagnostic value.
Plasma p-tau181 predicted amyloid status with high accuracy and could have potentially avoided CSF/amyloid PET testing in approximately 60% of subjects in a memory clinic setting. NfL was useful for identifying FTD from non-neurodegenerative causes but behaved worse than p-tau181 in all other comparisons. Combining p-tau181 and NfL improved diagnostic performance for FTD and non-neurodegenerative diagnoses. However, the 14% false-negative results suggest that further improvement is needed before implementation outside memory clinics.
This study provides Class I evidence that plasma p-tau181 correlates with the presence or absence of AD and a combination of plasma p-tau181 and NfL correlates moderately well with a diagnosis of FTD.
Background
The ongoing COVID‐19 pandemic and related care policies have affected dementia patients. The characteristics of early‐onset dementia (EOD, <65 years) patients in 2020 may provide insights ...on how to rearrange the provision of care.
Method
We retrospectively reviewed, from 2016 to 2020, the demographic and clinical data of the new referrals at our EOD clinic (Hospital Clínic Barcelona). We used Fisher’s Exact test and Mann–Whitney U test in R4.0.2 (http://www.R‐project.org/) to analyze differences between 2020 and the period 2016‐2019.
Result
In 2020, we did not visit any new referral from 15th march to 31th may. We evaluated 104 patients in 2020 and 392 patients in 2016‐2019 (mean=98(SD=11.8) patients/year). No differences were found in age at onset (AAO), sex, diagnostic delay and MMSE score (Table1). Significant differences were found in the diagnoses obtained in each period (p<0.000005, Figure1A). In 2020, 19.2% of the patients were diagnosed with neurodegenerative diseases (ND), 48.1% with non‐neurodegenerative diseases (NND) and 32.7% with subjective cognitive decline (SCD). On contrast, in 2016‐2019, 26% of the patients were diagnosed with ND, 22.2% with NND and 51.8% with SCD. Compared to 2016‐2019, ND, but not SCD or NND, presented longer diagnostic delay in 2020 (p<0.0005, Figure1B). ND, NND and SCD did not show differences between periods in AAO, sex or MMSE.
We did not find differences in the type of ND in each period (Figure1A). Compared to 2016‐2019, Frontotemporal Lobar Degeneration (FTLD) presented longer diagnostic delay in 2020 (p<0.005, Figure1B) while ND subgroups did not show differences in AAO, sex or MMSE. Cognitive disturbances in recovered COVID‐19 patients accounted for 16% of NND in 2020 N=8, AAO 50.63(12), 63% female, MMSE 26.8(2.3).
Conclusion
In 2020, albeit we were forced to stop our normal activity during 2.5 months, we visited a similar number of patients among which we observed an increase in NND, including cognitive disturbances in patients with recovered COVID‐19. On contrast, we found a reduction in SCD and, to a lesser extent, ND. ND showed a longer diagnostic delay in 2020 that mainly affected FTLD. Whether COVID‐19 pandemic entails a diagnostic delay in dementia patients must be confirmed in 2021.
Objectives
Early‐ and late‐onset Alzheimer's disease (EOAD and LOAD) share the same neuropathological traits but show distinct cognitive features. We aimed to explore baseline and longitudinal ...outcomes of global and domain‐specific cognitive function in a well characterized cohort of patients with a biomarker‐based diagnosis.
Methods
In this retrospective cohort study, 195 participants were included and classified according to their age, clinical status, and CSF AD biomarker profile: 89 EOAD, 37 LOAD, 46 young healthy controls (age ≤ 65 years), and 23 old healthy controls (>65 years). All subjects underwent clinical and neuropsychological assessment, neuroimaging, APOE genotyping and lumbar puncture.
Results
We found distinct neuropsychological profiles between EOAD and LOAD at the time of diagnosis. Both groups showed similar performances on memory and language domains, but the EOAD patients displayed worsened deficits in visual perception, praxis, and executive tasks (p < 0.05). Longitudinally, cognitive decline in EOAD was more pronounced than LOAD in the global outcomes at the expense of these non‐amnestic domains. We found that years of education significantly influenced the decline in most of the neuropsychological tests. Besides, the APOE ε4 status showed a significant effect on the decline of memory‐related tasks within the EOAD cohort (p < 0.05).
Interpretation
Age of onset is a main factor shaping the cognitive trajectories in AD patients, with younger age driving to a steeper decline of the non‐memory domains. Years of education are related to a transversal decline in all cognitive domains and APOE ε4 status to a specific decline in memory performance in EOAD.
Epigenetics, a potential underlying pathogenic mechanism of neurodegenerative diseases, has been in the scope of several studies performed so far. However, there is a gap in regard to analyzing ...different forms of early-onset dementia and the use of Lymphoblastoid cell lines (LCLs). We performed a genome-wide DNA methylation analysis on sixty-four samples (from the prefrontal cortex and LCLs) including those taken from patients with early-onset forms of Alzheimer's disease (AD) and frontotemporal dementia (FTD) and healthy controls. A beta regression model and adjusted
-values were used to obtain differentially methylated positions (DMPs) via pairwise comparisons. A correlation analysis of DMP levels with Clariom D array gene expression data from the same cohort was also performed. The results showed hypermethylation as the most frequent finding in both tissues studied in the patient groups. Biological significance analysis revealed common pathways altered in AD and FTD patients, affecting neuron development, metabolism, signal transduction, and immune system pathways. These alterations were also found in LCL samples, suggesting the epigenetic changes might not be limited to the central nervous system. In the brain, CpG methylation presented an inverse correlation with gene expression, while in LCLs, we observed mainly a positive correlation. This study enhances our understanding of the biological pathways that are associated with neurodegeneration, describes differential methylation patterns, and suggests LCLs are a potential cell model for studying neurodegenerative diseases in earlier clinical phases than brain tissue.
•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.
There is evidence of longitudinal atrophy in posterior brain areas in early-onset Alzheimer’s disease (EOAD; aged < 65 years), but no studies have been conducted in an EOAD cohort with fluid biomarkers characterization. We used 3T-MRI and Freesurfer 6.0 to investigate cortical and subcortical gray matter loss at two years in 12 EOAD patients (A + T + N + ) compared to 19 controls (A-T-N-) from the Hospital Clínic Barcelona cohort. We explored group differences in atrophy patterns and we correlated atrophy and baseline CSF-biomarkers levels in EOAD. We replicated the correlation analyses in 14 EOAD (A + T + N + ) and 55 late-onset AD (LOAD; aged ≥ 75 years; A + T + N + ) participants from the Alzheimer's disease Neuroimaging Initiative. We found that EOAD longitudinal atrophy spread with a posterior-to-anterior gradient and beyond hippocampus/amygdala. In EOAD, higher initial CSF NfL levels correlated with higher ventricular volumes at baseline. On the other hand, higher initial CSF Aβ42 levels (within pathological range) predicted higher rates of cortical loss in EOAD. In EOAD and LOAD subjects, higher CSF t-tau values at baseline predicted higher rates of subcortical atrophy. CSF p-tau did not show any significant correlation. In conclusion, posterior cortices, hippocampus and amygdala capture EOAD atrophy from early stages. CSF Aβ42 might predict cortical thinning and t-tau/NfL subcortical atrophy.
The diagnosis of incipient symptomatic stages of early-onset dementia is challenging. The magnetic resonance imaging (MRI) is an easy-access biomarker.
We aim to determine the distribution and ...diagnostic performance of the existing atrophy visual rating scales on MRI in initial stages of the most frequent neurodegenerative early onset dementias.
We evaluated the visual atrophy scales usefulness in two hundred subjects: seventy sporadic early onset Alzheimer's disease (AD) patients (48 amnestic and 22 non-amnestic), 14 patients with autosomal-dominant AD (ADAD), 25 sporadic frontotemporal dementia patients 11 with behavioral variant (bvFTD), nine with semantic variant of primary progressive aphasia (svPPA), and 5 with non-fluent primary progressive aphasia (nfvPPA), 7 with genetically determined FTD (genetic FTD), 25 mild cognitive impairment due to non-degenerative disorders, and 59 healthy controls. All had MMSE≥18, 3T-brain MRI, and biomarker-supported diagnosis. Two raters evaluated six frontal, temporal, and parietal scales. Inter-rater reliability and diagnostic performance in terms of area under the receiver-operator curves and balanced accuracy were analyzed.
Best scales to discriminate AD from controls were the anterior cingulate scale for amnestic and the posterior atrophy scale for sporadic non-amnestic AD and ADAD. The anterior temporal scale was the best for sporadic bvFTD and svPPA and the anterior cingulate scale was for nfvPPA. All scales performed well for the genetic FTD. However, no scale demonstrated good performance at discriminating AD from FTD or non-degenerative disorders.
The clinicians should interpret with caution atrophy scale assessment in subjects with early-onset cognitive impairment given that none of the evaluated scales met the requirements for being a diagnostic biomarker.
We analyzed Lewy body (LB) pathology in 18 autosomal dominant Alzheimer's disease (ADAD) brains via immunohistochemistry. Real-time quaking induced conversion was used to detect misfolded α-synuclein ...(α-syn) in 18 living ADAD cerebrospinal fluid (CSF) samples. Concomitant LB pathology was present in 44% ADAD brains. Only 6% CSF samples were positive for misfolded α-syn. In an additional AD sample, all patients with confirmed LB presented misfolded α-syn in postmortem CSF regardless of the LB staging. In conclusion, misfolded α-syn in CSF was scarce in symptomatic living ADAD individuals, in contrast to postmortem brain tissue. These results suggest late appearance of LB pathology in ADAD.
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