Publications by authors named "Juan Fortea"

164 Publications

The Clinical and Neuropathological Features of Sporadic (Late-Onset) and Genetic Forms of Alzheimer's Disease.

J Clin Med 2021 Oct 3;10(19). Epub 2021 Oct 3.

Cambridge Intellectual & Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Cambridge CB2 8PQ, UK.

The purpose of this review is to compare and highlight the clinical and pathological aspects of genetic versus acquired Alzheimer's disease: Down syndrome-associated Alzheimer's disease in (DSAD) and Autosomal Dominant Alzheimer's disease (ADAD) are compared with the late-onset form of the disease (LOAD). DSAD and ADAD present in a younger population and are more likely to manifest with non-amnestic (such as dysexecutive function features) in the prodromal phase or neurological features (such as seizures and paralysis) especially in ADAD. The very large variety of mutations associated with ADAD explains the wider range of phenotypes. In the LOAD, age-associated comorbidities explain many of the phenotypic differences.
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http://dx.doi.org/10.3390/jcm10194582DOI Listing
October 2021

Association of cortical microstructure with amyloid-β and tau: impact on cognitive decline, neurodegeneration, and clinical progression in older adults.

Mol Psychiatry 2021 Sep 29. Epub 2021 Sep 29.

Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer's disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-β and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, C-Pittsburgh compound-B-PET, F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-β, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-β, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-β, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-β and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-β, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.
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http://dx.doi.org/10.1038/s41380-021-01290-zDOI Listing
September 2021

Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain.

J Clin Med 2021 Aug 31;10(17). Epub 2021 Aug 31.

Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80208, USA.

Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) pathology at a young age, including amyloid plaques and neurofibrillary tangles (NFTs). Tau pathology can spread via extracellular vesicles, such as exosomes. The cargo of neuron-derived small extracellular vesicles (NDEVs) from individuals with DS contains p-Tau at an early age. The goal of the study was to investigate whether NDEVs isolated from the blood of individuals with DS can spread Tau pathology in the brain of wildtype mice. We purified NDEVs from the plasma of patients with DS-AD and controls and injected small quantities using stereotaxic surgery into the dorsal hippocampus of adult wildtype mice. Seeding competent Tau conformers were amplified in vitro from DS-AD NDEVs but not NDEVs from controls. One month or 4 months post-injection, we examined Tau pathology in mouse brains. We found abundant p-Tau immunostaining in the hippocampus of the mice injected with DS-AD NDEVs compared to injections of age-matched control NDEVs. Double labeling with neuronal and glial markers showed that p-Tau staining was largely found in neurons and, to a lesser extent, in glial cells and that p-Tau immunostaining was spreading along the corpus callosum and the medio-lateral axis of the hippocampus. These studies demonstrate that NDEVs from DS-AD patients exhibit Tau seeding capacity and give rise to tangle-like intracellular inclusions.
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http://dx.doi.org/10.3390/jcm10173931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432237PMC
August 2021

Regional grey matter microstructural changes and volume loss according to disease duration in multiple sclerosis patients.

Sci Rep 2021 Aug 19;11(1):16805. Epub 2021 Aug 19.

Center of Neuroimmunology, Laboratory of Advanced Imaging in Neuroimmunological Diseases, Hospital Clinic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Universitat de Barcelona, Barcelona, Spain.

The spatio-temporal characteristics of grey matter (GM) impairment in multiple sclerosis (MS) are poorly understood. We used a new surface-based diffusion MRI processing tool to investigate regional modifications of microstructure, and we quantified volume loss in GM in a cohort of patients with MS classified into three groups according to disease duration. Additionally, we investigated the relationship between GM changes with disease severity. We studied 54 healthy controls and 247 MS patients classified regarding disease duration: MS1 (less than 5 years, n = 67); MS2 (5-15 years, n = 107); and MS3 (more than15 years, n = 73). We compared GM mean diffusivity (MD), fractional anisotropy (FA) and volume between groups, and estimated their clinical associations. Regional modifications in diffusion measures (MD and FA) and volume did not overlap early in the disease, and became widespread in later phases. We found higher MD in MS1 group, mainly in the temporal cortex, and volume reduction in deep GM and left precuneus. Additional MD changes were evident in cingulate and occipital cortices in the MS2 group, coupled to volume reductions in deep GM and parietal and frontal poles. Changes in MD and volume extended to more than 80% of regions in MS3 group. Conversely, increments in FA, with very low effect size, were observed in the parietal cortex and thalamus in MS1 and MS2 groups, and extended to the frontal lobe in the later group. MD and GM changes were associated with white matter lesion load and with physical and cognitive disability. Microstructural integrity loss and atrophy present differential spatial predominance early in MS and accrual over time, probably due to distinct pathogenic mechanisms that underlie tissue damage.
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http://dx.doi.org/10.1038/s41598-021-96132-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376987PMC
August 2021

Metabolite Signature of Alzheimer's Disease in Adults with Down Syndrome.

Ann Neurol 2021 Sep 6;90(3):407-416. Epub 2021 Aug 6.

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Objective: The purpose of this study was to examine the Alzheimer's disease metabolite signature through magnetic resonance spectroscopy in adults with Down syndrome and its relation with Alzheimer's disease biomarkers and cortical thickness.

Methods: We included 118 adults with Down syndrome from the Down Alzheimer Barcelona Imaging Initiative and 71 euploid healthy controls from the Sant Pau Initiative on Neurodegeneration cohort. We measured the levels of myo-inositol (a marker of neuroinflammation) and N-acetyl-aspartate (a marker of neuronal integrity) in the precuneus using magnetic resonance spectroscopy. We investigated the changes with age and along the disease continuum (asymptomatic, prodromal Alzheimer's disease, and Alzheimer's disease dementia stages). We assessed the relationship between these metabolites and Aβ /Aβ ratio, phosphorylated tau-181, neurofilament light (NfL), and YKL-40 cerebrospinal fluid levels as well as amyloid positron emission tomography uptake using Spearman correlations controlling for multiple comparisons. Finally, we computed the relationship between cortical thickness and metabolite levels using Freesurfer.

Results: Asymptomatic adults with Down syndrome had a 27.5% increase in the levels of myo-inositol, but equal levels of N-acetyl-aspartate compared to euploid healthy controls. With disease progression, myo-inositol levels increased, whereas N-acetyl-aspartate levels decreased in symptomatic stages of the disease. Myo-inositol was associated with amyloid, tau, and neurodegeneration markers, mainly at symptomatic stages of the disease, whereas N-acetyl-aspartate was related to neurodegeneration biomarkers in symptomatic stages. Both metabolites were significantly associated with cortical thinning, mainly in symptomatic participants.

Interpretation: Magnetic resonance spectroscopy detects Alzheimer's disease related inflammation and neurodegeneration, and could be a good noninvasive disease-stage biomarker in Down syndrome. ANN NEUROL 2021;90:407-416.
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http://dx.doi.org/10.1002/ana.26178DOI Listing
September 2021

Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study.

Lancet Neurol 2021 08;20(8):605-614

Sant Pau Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain; Horizon 21 Consortium, Paris, France. Electronic address:

Background: Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome.

Methods: We did a multicentre cohort study, including adults with Down syndrome (≥18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively; NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses.

Findings: Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia; ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3·6 years (SD 1·6, range 0·6-9·2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0·83 (95% CI 0·76-0·91) in the prodromal group and 0·94 (0·90-0·97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1·04-fold risk of clinical progression (95% CI 1·01-1·07; p=0·0034). Plasma NfL concentrations showed an annual increase of 3·0% (95% CI 0·4-5·8) per year in the asymptomatic non-progressors group, 11·5% (4·9-18·5) per year in the asymptomatic progressors group, and 16·0% (8·4-24·0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24·3% (15·3-34·1).

Interpretation: Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials.

Funding: AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens und Umwelteinflüssen auf die menschliche Gesundheit, and NHS National Institute of Health Research Applied Research Collaborations East of England, UK.
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http://dx.doi.org/10.1016/S1474-4422(21)00129-0DOI Listing
August 2021

Sleep Disorders in Adults with Down Syndrome.

J Clin Med 2021 Jul 6;10(14). Epub 2021 Jul 6.

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain.

Sleep disorders, despite being very frequent in adults with Down syndrome (DS), are often overlooked due to a lack of awareness by families and physicians and the absence of specific clinical sleep guidelines. Untreated sleep disorders have a negative impact on physical and mental health, behavior, and cognitive performance. Growing evidence suggests that sleep disruption may also accelerate the progression to symptomatic Alzheimer's disease (AD) in this population. It is therefore imperative to have a better understanding of the sleep disorders associated with DS in order to treat them, and in doing so, improve cognition and quality of life, and prevent related comorbidities. This paper reviews the current knowledge of the main sleep disorders in adults with DS, including evaluation and management. It highlights the existing gaps in knowledge and discusses future directions to achieve earlier diagnosis and better treatment of sleep disorders most frequently found in this population.
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http://dx.doi.org/10.3390/jcm10143012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306783PMC
July 2021

Risk of intracranial haemorrhage and ischaemic stroke after convexity subarachnoid haemorrhage in cerebral amyloid angiopathy: international individual patient data pooled analysis.

J Neurol 2021 Jul 17. Epub 2021 Jul 17.

Department of Neurology, CHU Caen Normandie, Caen, France.

Objective: To investigate the frequency, time-course and predictors of intracerebral haemorrhage (ICH), recurrent convexity subarachnoid haemorrhage (cSAH), and ischemic stroke after cSAH associated with cerebral amyloid angiopathy (CAA).

Methods: We performed a systematic review and international individual patient-data pooled analysis in patients with cSAH associated with probable or possible CAA diagnosed on baseline MRI using the modified Boston criteria. We used Cox proportional hazards models with a frailty term to account for between-cohort differences.

Results: We included 190 patients (mean age 74.5 years; 45.3% female) from 13 centers with 385 patient-years of follow-up (median 1.4 years). The risks of each outcome (per patient-year) were: ICH 13.2% (95% CI 9.9-17.4); recurrent cSAH 11.1% (95% CI 7.9-15.2); combined ICH, cSAH, or both 21.4% (95% CI 16.7-26.9), ischemic stroke 5.1% (95% CI 3.1-8) and death 8.3% (95% CI 5.6-11.8). In multivariable models, there is evidence that patients with probable CAA (compared to possible CAA) had a higher risk of ICH (HR 8.45, 95% CI 1.13-75.5, p = 0.02) and cSAH (HR 3.66, 95% CI 0.84-15.9, p = 0.08) but not ischemic stroke (HR 0.56, 95% CI 0.17-1.82, p = 0.33) or mortality (HR 0.54, 95% CI 0.16-1.78, p = 0.31).

Conclusions: Patients with cSAH associated with probable or possible CAA have high risk of future ICH and recurrent cSAH. Convexity SAH associated with probable (vs possible) CAA is associated with increased risk of ICH, and cSAH but not ischemic stroke. Our data provide precise risk estimates for key vascular events after cSAH associated with CAA which can inform management decisions.
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http://dx.doi.org/10.1007/s00415-021-10706-3DOI Listing
July 2021

Opportunities, barriers, and recommendations in down syndrome research.

Transl Sci Rare Dis 2021 15;5(3-4):99-129. Epub 2021 Apr 15.

Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.

Background: Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community.

Objective: The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan.

Methods: NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS.

Results: This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade.

Conclusions: This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.
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http://dx.doi.org/10.3233/trd-200090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279178PMC
April 2021

Phosphorylated tau181 in plasma as a potential biomarker for Alzheimer's disease in adults with Down syndrome.

Nat Commun 2021 07 14;12(1):4304. Epub 2021 Jul 14.

Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer's disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73-0.87] and 0.92 [95% CI 0.89-0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS.
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http://dx.doi.org/10.1038/s41467-021-24319-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280160PMC
July 2021

Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome.

JAMA Neurol 2021 Aug;78(8):937-947

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Importance: Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ɛ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce.

Objective: To investigate the association of the APOE ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS.

Design, Setting, And Participants: This dual-center cohort study recruited adults with DS in Barcelona, Spain, and in Cambridge, UK, between June 1, 2009, and February 28, 2020. Included individuals had been genotyped for APOE and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either APOE ɛ4 allele carriers or noncarriers.

Main Outcomes And Measures: Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: Aβ1-42, Aβ1-40, phosphorylated tau 181 (pTau181) and neurofilament light chain (NfL) in cerebrospinal fluid (CSF), pTau181, and NfL in plasma; amyloid positron emission tomography (PET); fluorine 18-labeled-fluorodeoxyglucose PET; and/or magnetic resonance imaging. Age at symptom onset was compared between APOE ɛ4 allele carriers and noncarriers, and within-group local regression models were used to compare the association of biomarkers with age. Voxelwise analyses were performed to assess topographical differences in gray matter metabolism and volume.

Results: Of the 464 adults with DS included in the study, 97 (20.9%) were APOE ɛ4 allele carriers and 367 (79.1%) were noncarriers. No differences between the 2 groups were found by age (median [interquartile range], 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P = .56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]). APOE ɛ4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; P = .02) and showed earlier cognitive decline. Locally estimated scatterplot smoothing curves further showed between-group differences in biomarker trajectories with age as reflected by nonoverlapping CIs. Specifically, carriers showed lower levels of the CSF Aβ1-42 to Aβ1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma pTau181, and earlier loss of cortical metabolism and hippocampal volume. No differences were found in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE ɛ4 allele carriers.

Conclusions And Relevance: In this study, the APOE ɛ4 allele was associated with earlier clinical and biomarker changes of AD in DS. These results provide insights into the mechanisms by which APOE increases the risk of AD, emphasizing the importance of APOE genotype for future clinical trials in DS.
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http://dx.doi.org/10.1001/jamaneurol.2021.1893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261691PMC
August 2021

Epilepsy in Down Syndrome: A Highly Prevalent Comorbidity.

J Clin Med 2021 Jun 24;10(13). Epub 2021 Jun 24.

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain.

Individuals with Down syndrome (DS) have an increased risk for epilepsy during the whole lifespan, but especially after age 40 years. The increase in the number of individuals with DS living into late middle age due to improved health care is resulting in an increase in epilepsy prevalence in this population. However, these epileptic seizures are probably underdiagnosed and inadequately treated. This late onset epilepsy is linked to the development of symptomatic Alzheimer's disease (AD), which is the main comorbidity in adults with DS with a cumulative incidence of more than 90% of adults by the seventh decade. More than 50% of patients with DS and AD dementia will most likely develop epilepsy, which in this context has a specific clinical presentation in the form of generalized myoclonic epilepsy. This epilepsy, named late onset myoclonic epilepsy (LOMEDS) affects the quality of life, might be associated with worse cognitive and functional outcomes in patients with AD dementia and has an impact on mortality. This review aims to summarize the current knowledge about the clinical and electrophysiological characteristics, diagnosis and treatment of epileptic seizures in the DS population, with a special emphasis on LOMEDS. Raised awareness and a better understanding of epilepsy in DS from families, caregivers and clinicians could enable earlier diagnoses and better treatments for individuals with DS.
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http://dx.doi.org/10.3390/jcm10132776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268854PMC
June 2021

VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome.

Alzheimers Res Ther 2021 06 28;13(1):119. Epub 2021 Jun 28.

Memory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, c/Sant Quintí, 77-79, 08025, Barcelona, Spain.

Background: There is an urgent need for objective markers of Alzheimer's disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment.

Methods: We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aβ ratio, CSF Aβ, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing.

Results: In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aβ (adj.p = .0001), p-tau (adj.p < .0001), and NFL (adj.p < .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p < .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p < .002).

Conclusion: These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.
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http://dx.doi.org/10.1186/s13195-021-00861-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240298PMC
June 2021

Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias.

J Neurol Neurosurg Psychiatry 2021 Nov 8;92(11):1206-1214. Epub 2021 Jun 8.

Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Catalunya, Spain.

Objectives: All categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer's disease (AD) through an easy and minimally invasive approach.

Methods: We measured Aβ, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination.

Results: The plasma Aβ composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A-T- participants. There was a moderate correlation between plasma Aβ composite and CSF Aβ1-42/Aβ1-40 (Rho=-0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001).

Conclusions: Plasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach.
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http://dx.doi.org/10.1136/jnnp-2021-326603DOI Listing
November 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Markers of early changes in cognition across cohorts of adults with Down syndrome at risk of Alzheimer's disease.

Alzheimers Dement (Amst) 2021 2;13(1):e12184. Epub 2021 May 2.

Institute of Psychiatry, Psychology, and Neuroscience Department of Forensic and Neurodevelopmental Sciences King's College London London UK.

Introduction: Down syndrome (DS), a genetic variant of early onset Alzheimer's disease (AD), lacks a suitable outcome measure for prevention trials targeting pre-dementia stages.

Methods: We used cognitive test data collected in several longitudinal aging studies internationally from 312 participants with DS without dementia to identify composites that were sensitive to change over time. We then conducted additional analyses to provide support for the utility of the composites. The composites were presented to an expert panel to determine the most optimal cognitive battery based on predetermined criteria.

Results: There were common cognitive domains across site composites, which were sensitive to early decline. The final composite consisted of memory, language/executive functioning, selective attention, orientation, and praxis tests.

Discussion: We have identified a composite that is sensitive to early decline and thus may have utility as an outcome measure in trials to prevent or delay symptoms of AD in DS.
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http://dx.doi.org/10.1002/dad2.12184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088591PMC
May 2021

The Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS II): Optimization and Further Validation.

J Alzheimers Dis 2021 ;81(4):1505-1527

Department of Neurology and Alzheimer Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: People with Down syndrome (DS) are at high risk to develop Alzheimer's disease dementia (AD). Behavioral and psychological symptoms of dementia (BPSD) are common and may also serve as early signals for dementia. However, comprehensive evaluation scales for BPSD, adapted to DS, are lacking. Therefore, we previously developed the BPSD-DS scale to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior.

Objective: To optimize and further study the scale (discriminative ability and reliability) in a large representative DS study population.

Methods: Optimization was based on item irrelevance and clinical experiences obtained in the initial study. Using the shortened and refined BPSD-DS II, informant interviews were conducted to evaluate 524 individuals with DS grouped according to dementia status: no dementia (DS, N = 292), questionable dementia (DS + Q, N = 119), and clinically diagnosed dementia (DS + AD, N = 113).

Results: Comparing item change scores between groups revealed prominent changes in frequency and severity for anxious, sleep-related, irritable, restless/stereotypic, apathetic, depressive, and eating/drinking behavior. For most items, the proportion of individuals displaying an increased frequency was highest in DS + AD, intermediate in DS + Q, and lowest in DS. For various items within sections about anxious, sleep-related, irritable, apathetic, and depressive behaviors, the proportion of individuals showing an increased frequency was already substantial in DS + Q, suggesting that these changes may serve as early signals of AD in DS. Reliability data were promising.

Conclusion: The optimized scale yields largely similar results as obtained with the initial version. Systematically evaluating BPSD in DS may increase understanding of changes among caregivers and (timely) adaptation of care/treatment.
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http://dx.doi.org/10.3233/JAD-201427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293661PMC
September 2021

AMYQ: An index to standardize quantitative amyloid load across PET tracers.

Alzheimers Dement 2021 09 2;17(9):1499-1508. Epub 2021 Apr 2.

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Introduction: Positron emission tomography (PET) amyloid quantification methods require magnetic resonance imaging (MRI) for spatial registration and a priori reference region to scale the images. Furthermore, different tracers have distinct thresholds for positivity. We propose the AMYQ index, a new measure of amyloid burden, to overcome these limitations.

Methods: We selected 18F-amyloid scans from ADNI and Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) with the corresponding T1-MRI. A subset also had neuropathological data. PET images were normalized, and the AMYQ was calculated based on an adaptive template. We compared AMYQ with the Centiloid scale on clinical and neuropathological diagnostic performance.

Results: AMYQ was related with amyloid neuropathological burden and had excellent diagnostic performance to discriminate controls from patients with Alzheimer's disease (AD) (area under the curve [AUC] = 0.86). AMYQ had a high agreement with the Centiloid scale (intraclass correlation coefficient [ICC] = 0.88) and AUC between 0.94 and 0.99 to discriminate PET positivity when using different Centiloid cutoffs.

Discussion: AMYQ is a new MRI-independent index for standardizing and quantifying amyloid load across tracers.
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http://dx.doi.org/10.1002/alz.12317DOI Listing
September 2021

Accelerated long-term forgetting in individuals with subjective cognitive decline and amyloid-β positivity.

Int J Geriatr Psychiatry 2021 07 15;36(7):1037-1049. Epub 2021 Apr 15.

Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain.

Objectives: We studied a sample of cognitively unimpaired individuals, with and without subjective cognitive decline (SCD), in order to investigate accelerated long-term forgetting (ALF) and to explore the relationships between objective and subjective cognitive performance and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers.

Methods: Fifty-two individuals were included and SCD was quantified through the Subjective Cognitive Decline Questionnaire (SCD-Q), using its validated cutoff to classify participants as Low SCD-Q (n = 21) or High SCD-Q (n = 31). These groups were further subdivided according to the presence or absence of abnormal levels of CSF Aβ . Objective cognitive performance was assessed with the Ancient Farming Equipment Test (AFE-T), a new highly-demanding test that calls for acquisition and retention of novel object/name pairs and allows measuring ALF over a 6-month period.

Results: The High SCD-Q group showed a significantly higher free forgetting rate at 3 months compared to the Low SCD-Q (F [1,44] = 4.72; p < 0.05). When stratifying by amyloid status, High SCD-Q/Aβ+ showed a significantly lower performance than High SCD-Q/Aβ-on the final free and cued learning scores (F [1,27] = 6.44, p < 0.05 and F [1,27] = 7.51, p < 0.05, respectively), the 1-week free and cued recall (F [1,24] = 4.49; p < 0.05 and F [1,24] = 7.10; p < 0.01, respectively), the 1-week cued forgetting rate (F [1,24] = 5.13; p < 0.05), and the 3-month cued recall (F [1,24] = 4.27; p < 0.05). Linear regression analyses showed that higher SCD-Q scores were associated with higher forgetting rates on the AFE-T (β = -0.212; p < 0.05).

Conclusions: It is possible to detect ALF in individuals with high SCD ratings, appearing especially in those with abnormal CSF Aβ levels. Both in research and the clinical field, there is an increasing need of using more demanding cognitive measures, such as the AFE-T, for identifying and tracking the earliest cognitive changes in these populations.
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http://dx.doi.org/10.1002/gps.5539DOI Listing
July 2021

Atypical astroglial pTDP-43 pathology in astroglial predominant tauopathy.

Neuropathol Appl Neurobiol 2021 Mar 17. Epub 2021 Mar 17.

Department of Pathology and Experimental Therapeutics, University of Barcelona, Bellvitge University Hospital-IDIBELL, CIBERNED, Hospitalet de Llobregat, Spain.

We observed atypical astrocytic pTDP-43 pathology in astroglial predominant tauopathy.
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http://dx.doi.org/10.1111/nan.12707DOI Listing
March 2021

Diagnostic Utility of Measuring Cerebral Atrophy in the Behavioral Variant of Frontotemporal Dementia and Association With Clinical Deterioration.

JAMA Netw Open 2021 03 1;4(3):e211290. Epub 2021 Mar 1.

Memory and Aging Center, Department of Neurology, University of California, San Francisco.

Importance: The presence of atrophy on magnetic resonance imaging can support the diagnosis of the behavioral variant of frontotemporal dementia (bvFTD), but reproducible measurements are lacking.

Objective: To assess the diagnostic and prognostic utility of 6 visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index (MRPI).

Design, Setting, And Participants: In this diagnostic/prognostic study, data from 235 patients with bvFTD and 225 age- and magnetic resonance imaging-matched control individuals from 3 centers were collected from December 1, 1998, to September 30, 2019. One hundred twenty-one participants with bvFTD had high confidence of frontotemporal lobar degeneration (FTLD) (bvFTD-HC), and 19 had low confidence of FTLD (bvFTD-LC). Blinded clinicians applied 6 previously validated VAS, and the MRPI was calculated with a fully automated approach. Cortical thickness and subcortical volumes were also measured for comparison. Data were analyzed from February 1 to June 30, 2020.

Main Outcomes And Measures: The main outcomes of this study were bvFTD-HC or a neuropathological diagnosis of 4-repeat (4R) tauopathy and the clinical deterioration rate (assessed by longitudinal measurements of Clinical Dementia Rating Sum of Boxes). Measures of cerebral atrophy included VAS scores, the bvFTD atrophy score (sum of VAS scores in orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe, and frontal insula regions), the MRPI, and other computerized quantifications of cortical and subcortical volumes. The areas under the receiver operating characteristic curve (AUROC) were calculated for the differentiation of participants with bvFTD-HC and bvFTD-LC and controls. Linear mixed models were used to evaluate the ability of atrophy measures to estimate longitudinal clinical deterioration.

Results: Of the 460 included participants, 296 (64.3%) were men, and the mean (SD) age was 62.6 (11.4) years. The accuracy of the bvFTD atrophy score for the differentiation of bvFTD-HC from controls (AUROC, 0.930; 95% CI, 0.903-0.957) and bvFTD-HC from bvFTD-LC (AUROC, 0.880; 95% CI, 0.787-0.972) was comparable to computerized measures (AUROC, 0.973 [95% CI, 0.954-0.993] and 0.898 [95% CI, 0.834-0.962], respectively). The MRPI was increased in patients with bvFTD and underlying 4R tauopathies compared with other FTLD subtypes (14.1 [2.0] vs 11.2 [2.6] points; P < .001). Higher bvFTD atrophy scores were associated with faster clinical deterioration in bvFTD (1.86-point change in Clinical Dementia Rating Sum of Boxes score per bvFTD atrophy score increase per year; 95% CI, 0.99-2.73; P < .001).

Conclusions And Relevance: Based on these study findings, in bvFTD, VAS increased the diagnostic certainty of underlying FTLD, and the MRPI showed potential for the detection of participants with underlying 4R tauopathies. These widely available measures of atrophy can also be useful to estimate longitudinal clinical deterioration.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.1290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953307PMC
March 2021

Distinctive Oculomotor Behaviors in Alzheimer's Disease and Frontotemporal Dementia.

Front Aging Neurosci 2020 4;12:603790. Epub 2021 Feb 4.

Institute for Research Marqués de Valdecilla (IDIVAL), University of Cantabria and Department of Neurology, Marqués de Valdecilla University Hospital, Santander, Spain.

Oculomotor behavior can provide insight into the integrity of widespread cortical networks, which may contribute to the differential diagnosis between Alzheimer's disease and frontotemporal dementia. Three groups of patients with Alzheimer's disease, behavioral variant of frontotemporal dementia (bvFTD) and semantic variant of primary progressive aphasia (svPPA) and a sample of cognitively unimpaired elders underwent an eye-tracking evaluation. All participants in the discovery sample, including controls, had a biomarker-supported diagnosis. Oculomotor correlates of neuropsychology and brain metabolism evaluated with 18F-FDG PET were explored. Machine-learning classification algorithms were trained for the differentiation between Alzheimer's disease, bvFTD and controls. A total of 93 subjects (33 Alzheimer's disease, 24 bvFTD, seven svPPA, and 29 controls) were included in the study. Alzheimer's disease was the most impaired group in all tests and displayed specific abnormalities in some visually-guided saccade parameters, as pursuit error and horizontal prosaccade latency, which are theoretically closely linked to posterior brain regions. BvFTD patients showed deficits especially in the most cognitively demanding tasks, the antisaccade and memory saccade tests, which require a fine control from frontal lobe regions. SvPPA patients performed similarly to controls in most parameters except for a lower number of correct memory saccades. Pursuit error was significantly correlated with cognitive measures of constructional praxis and executive function and metabolism in right posterior middle temporal gyrus. The classification algorithms yielded an area under the curve of 97.5% for the differentiation of Alzheimer's disease vs. controls, 96.7% for bvFTD vs. controls, and 92.5% for Alzheimer's disease vs. bvFTD. In conclusion, patients with Alzheimer's disease, bvFTD and svPPA exhibit differentiating oculomotor patterns which reflect the characteristic neuroanatomical distribution of pathology of each disease, and therefore its assessment can be useful in their diagnostic work-up. Machine learning approaches can facilitate the applicability of eye-tracking in clinical practice.
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http://dx.doi.org/10.3389/fnagi.2020.603790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891179PMC
February 2021

Sex differences in the behavioral variant of frontotemporal dementia: A new window to executive and behavioral reserve.

Alzheimers Dement 2021 08 16;17(8):1329-1341. Epub 2021 Feb 16.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA.

Introduction: Biological sex is an increasingly recognized factor driving clinical and structural heterogeneity in Alzheimer's disease, but its role in the behavioral variant of frontotemporal dementia (bvFTD) is unknown.

Methods: We included 216 patients with bvFTD and 235 controls with magnetic resonance imaging (MRI) from a large multicenter cohort. We compared the clinical characteristics and cortical thickness between men and women with bvFTD and controls. We followed the residuals approach to study behavioral and cognitive reserve.

Results: At diagnosis, women with bvFTD showed greater atrophy burden in the frontotemporal regions compared to men despite similar clinical characteristics. For a similar amount of atrophy, women demonstrated better-than-expected scores on executive function and fewer changes in apathy, sleep, and appetite than men.

Discussion: Our findings suggest that women might have greater behavioral and executive reserve than men, and neurodegeneration must be more severe in women to produce symptoms similar in severity to those in men.
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http://dx.doi.org/10.1002/alz.12299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364861PMC
August 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Accelerated long-term forgetting over three months in asymptomatic APOE ɛ4 carriers.

Ann Clin Transl Neurol 2021 02 25;8(2):477-484. Epub 2020 Dec 25.

Institute of Neurosciences, University of Barcelona, Barcelona, Spain.

Accelerated long-term forgetting (ALF) refers to a rapid loss of information over days or weeks despite normal acquisition/encoding. Notwithstanding its potential relevance as a presymptomatic marker of cognitive dysfunction, no study has addressed the relationship between ALF and Alzheimer's disease (AD) biomarkers. We examined ALF in APOE ɛ4 carriers versus noncarriers, and its relationships with AD cerebrospinal fluid (CSF) biomarkers. We found ALF over three months in APOE ɛ4 carriers (F(1,19) = 5.60; P < 0.05; Cohen's d = 1.08), and this performance was associated with abnormal levels of the CSF Aβ /ptau ratio (r = -.614; P < 0.01). Our findings indicate that ALF is detectable in at-risk individuals, and that there is a relationship between ALF and the pathophysiological processes underlying AD.
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http://dx.doi.org/10.1002/acn3.51245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886043PMC
February 2021

Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer's Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome.

J Alzheimers Dis 2021 ;79(2):671-681

University of North Texas Health Science Center, Institute for Translational Research and Department of Pharmacology and Neuroscience, Fort Worth, TX, USA.

Background: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population.

Objective: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults.

Methods: Plasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome.

Results: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS.

Conclusion: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.
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http://dx.doi.org/10.3233/JAD-201167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273927PMC
September 2021

White Matter Hyperintensities Are No Major Confounder for Alzheimer's Disease Cerebrospinal Fluid Biomarkers.

J Alzheimers Dis 2021 ;79(1):163-175

Department of Geriatrics, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer's disease (AD). However, CSF biomarker levels can be affected by confounding factors.

Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels.

Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis.

Results: A small, negative association of CSF Aβ42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2 = 0.084, p = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2 = 0.105, p = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group.

Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.
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http://dx.doi.org/10.3233/JAD-200496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902951PMC
September 2021

Nerve growth factor (NGF) pathway biomarkers in Down syndrome prior to and after the onset of clinical Alzheimer's disease: A paired CSF and plasma study.

Alzheimers Dement 2021 04 23;17(4):605-617. Epub 2020 Nov 23.

Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.

Background: The discovery that nerve growth factor (NGF) metabolism is altered in Down syndrome (DS) and Alzheimer's disease (AD) brains offered a framework for the identification of novel biomarkers signalling NGF deregulation in AD pathology.

Methods: We examined levels of NGF pathway proteins (proNGF, neuroserpin, tissue plasminogen activator [tPA], and metalloproteases [MMP]) in matched cerebrospinal fluid (CSF)/plasma samples from AD-symptomatic (DSAD) and AD-asymptomatic (aDS) individuals with DS, as well as controls (HC).

Results: ProNGF and MMP-3 were elevated while tPA was decreased in plasma from individuals with DS. CSF from individuals with DS showed elevated proNGF, neuroserpin, MMP-3, and MMP-9. ProNGF and MMP-9 in CSF differentiated DSAD from aDS (area under the curve = 0.86, 0.87). NGF pathway markers associated with CSF amyloid beta and tau and differed by sex.

Discussion: Brain NGF metabolism changes can be monitored in plasma and CSF, supporting relevance in AD pathology. These markers could assist staging, subtyping, or precision medicine for AD in DS.
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http://dx.doi.org/10.1002/alz.12229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043977PMC
April 2021

Biphasic cortical macro- and microstructural changes in autosomal dominant Alzheimer's disease.

Alzheimers Dement 2021 04 16;17(4):618-628. Epub 2020 Nov 16.

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Introduction: A biphasic model for brain structural changes in preclinical Alzheimer's disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti-amyloid clinical trials.

Methods: In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity-a novel marker of cortical microstructure-changes in 389 participants from the Dominantly Inherited Alzheimer Network.

Results: In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations.

Discussion: These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials.
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http://dx.doi.org/10.1002/alz.12224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043974PMC
April 2021
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