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Nat Commun 2021 06 7;12(1):3400. Epub 2021 Jun 7.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. Read More

Mol Cell Neurosci 2021 Jun 4;114:103641. Epub 2021 Jun 4.

BioArctic AB, Warfvinges väg 35, SE-112 51 Stockholm, Sweden; Dept. of Public Health/Geriatrics, Uppsala University, SE-751 22 Uppsala, Sweden.

Down syndrome (DS) is caused by trisomy of chromosome 21, which leads to a propensity to develop amyloid β (Aβ) brain pathology in early adulthood followed later by cognitive and behavioral deterioration. Characterization of the Aβ pathology is important to better understand the clinical deterioration of DS individuals and to identify interventive strategies. Brain samples from people with DS and Alzheimer's disease (AD), as well as non-demented controls (NDC), were analyzed with respect to different Aβ species. Read More

Alzheimers Dement (Amst) 2021 20;13(1):e12105. Epub 2021 May 20.

Department of Neurology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA.

Introduction: Most individuals with Down syndrome (DS) have the neuropathological changes of Alzheimer's disease (AD) by age 40 and will have developed dementia by age 60. Alterations of the intrinsic connectivity of the default mode network (DMN) are associated with AD in the neurotypical population. In this study, we sought to determine whether, and how, connectivity between the hubs of the DMN were altered in cognitively stable adults with DS who did not have evidence of either mild cognitive impairment or AD. Read More

Nat Commun 2021 05 10;12(1):2603. Epub 2021 May 10.

Department of Neurology, Mitchell Center for Neurodegenerative Diseases. School of Medicine, University of Texas Medical Branch at Galveston, Galveston, USA.

Synaptic disturbances in excitatory to inhibitory (E/I) balance in forebrain circuits are thought to contribute to the progression of Alzheimer's disease (AD) and dementia, although direct evidence for such imbalance in humans is lacking. We assessed anatomical and electrophysiological synaptic E/I ratios in post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography and microtransplantation of synaptic membranes. Both approaches revealed significantly elevated E/I ratios for AD, but not DS, versus controls. Read More

J Alzheimers Dis 2021 May 4. Epub 2021 May 4.

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. Read More

Brain Connect 2021 Jun 1. Epub 2021 Jun 1.

Laboratory of Cognitive and Computational Neuroscience (UCM-UPM), Center for Biomedical Technology, Technical University of Madrid, Madrid, Spain.

The majority of individuals with Down syndrome (DS) show signs of Alzheimer's disease (AD) neuropathology in their fourth decade. However, there is a lack of specific markers for characterizing the disease stages while considering this population's differential features. Forty-one DS individuals participated in the study, and were classified into three groups according to their clinical status: Alzheimer's disease (AD-DS), mild cognitive impairment (MCI-DS), and controls (CN-DS). Read More

Neuromolecular Med 2021 Mar 4. Epub 2021 Mar 4.

The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, 5290002, Ramat-Gan, Israel.

The current SARS-CoV-2 outbreak, which causes COVID-19, is particularly devastating for individuals with chronic medical conditions, in particular those with Down Syndrome (DS) who often exhibit a higher prevalence of respiratory tract infections, immune dysregulation and potential complications. The incidence of Alzheimer's disease (AD) is much higher in DS than in the general population, possibly increasing further the risk of COVID-19 infection and its complications. Here we provide a biological overview with regard to specific susceptibility of individuals with DS to SARS-CoV-2 infection as well as data from a recent survey on the prevalence of COVID-19 among them. Read More

Neurol India 2021 Jan-Feb;69(1):32-41

Genetics and Molecular Biology Research Unit (UPGEM), Department of Molecular Biology, São José do Rio Preto Medical School (FAMERP), São José do Rio Preto - SP, Brazil.

The overexpression of the amyloid precursor protein (APP) gene, encoded on chromosome 21, has been associated in Down syndrome (DS) with the development of early-onset Alzheimer's disease (EOAD). The increase in APP levels leads to an overproduction of amyloid-β (Aβ) peptide that accumulates in the brain. In response to this deposition, microglial cells are active and generate cascade events that include release cytokines and chemokine. Read More

F1000Res 2020 5;9:1299. Epub 2020 Nov 5.

BioScience Project, PO Box 352, Wakefield, MA, 01880, USA.

People with Down Syndrome (DS) are born with an extra copy of Chromosome (Chr) 21 and many of these individuals develop Alzheimer's Disease (AD) when they age. This is due at least in part to the extra copy of the gene located on Chr 21. By 40 years, most people with DS have amyloid plaques which disrupt brain cell function and increase their risk for AD. Read More

Neurobiol Stress 2021 May 5;14:100305. Epub 2021 Feb 5.

Univ. Limoges, Peripheral Neuropathies, EA6309, F-87000, Limoges, France.

The relationships between psychological stress and cognitive functions are still to be defined despite some recent progress. Clinically, we noticed that patients with Down syndrome (DS) may develop rapid neurocognitive decline and Alzheimer's disease (AD) earlier than expected, often shortly after a traumatic life event (bereavement over the leave of a primary caregiver, an assault, modification of lifestyle, or the loss of parents). Of course, individuals with DS are naturally prone to develop AD, given the triplication of chromosome 21. Read More

Neuroimage 2021 03 7;228:117728. Epub 2021 Jan 7.

University of Wisconsin-Madison, Waisman Center, 1500 Highland Avenue, Madison, WI 53705, United States. Electronic address:

Introduction: Adults with Down syndrome (DS) are predisposed to Alzheimer's disease (AD) and reveal early amyloid beta (Aβ) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of Aβ throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of Aβ to better characterize the natural history of Aβ accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention. Read More

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. Read More

Brain 2020 12;143(12):3653-3671

Department of Anatomy and Cell Biology, McGill University, Montreal, Canada.

Epidemiological and experimental studies suggest that a disease-aggravating neuroinflammatory process is present at preclinical stages of Alzheimer's disease. Given that individuals with Down syndrome are at increased genetic risk of Alzheimer's disease and therefore develop the spectrum of Alzheimer's neuropathology in a uniform manner, they constitute an important population to study the evolution of neuroinflammation across the Alzheimer's continuum. Therefore, in this cross-sectional study, we characterized the brain inflammatory profile across the lifespan of individuals with Down syndrome. Read More

Alzheimers Dement (Amst) 2020 11;12(1):e12126. Epub 2020 Nov 11.

Department of Pediatrics Irvine Medical Center University of California Orange California USA.

Introduction: Down syndrome (DS) is associated with elevated risk for Alzheimer's disease (AD) due to amyloid beta (Aβ) lifelong accumulation. We hypothesized that the spatial distribution of brain Aβ predicts future dementia conversion in individuals with DS.

Methods: We acquired F-florbetapir positron emission tomography scans from 19 nondemented individuals with DS at baseline and monitored them for 4 years, with five individuals transitioning to dementia. Read More

Alzheimers Dement (N Y) 2020 31;6(1):e12096. Epub 2020 Oct 31.

Department of Psychiatry University of Pittsburgh Pittsburgh Pennsylvania USA.

Importance: Adults with Down syndrome (DS) are at high-risk of revealing Alzheimer's disease (AD) pathology, in part due to the triplication of chromosome 21 encoding the amyloid precursor protein. Adults with DS are uniformly affected by AD pathology by their 30's and have a 70% to 80% chance of clinical dementia by their 60's. Our previous studies have assessed longitudinal changes in amyloid beta (Aβ) accumulation in DS. Read More

Alzheimers Dement (Amst) 2020 27;12(1):e12062. Epub 2020 Oct 27.

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

The National Institute on Aging in conjunction with the Alzheimer's Association (NIA-AA) recently proposed a biological framework for defining the Alzheimer's disease (AD) continuum. This new framework is based upon the key AD biomarkers (amyloid, tau, neurodegeneration, AT[N]) instead of clinical symptoms and represents the latest understanding that the pathological processes underlying AD begin decades before the manifestation of symptoms. By using these same biomarkers, individuals with Down syndrome (DS), who are genetically predisposed to developing AD, can also be placed more precisely along the AD continuum. Read More

JAMA 2020 10;324(15):1543-1556

Global Down Syndrome Foundation, Denver, Colorado.

Importance: Down syndrome is the most common chromosomal condition, and average life expectancy has increased substantially, from 25 years in 1983 to 60 years in 2020. Despite the unique clinical comorbidities among adults with Down syndrome, there are no clinical guidelines for the care of these patients.

Objective: To develop an evidence-based clinical practice guideline for adults with Down syndrome. Read More

J Intellect Disabil Res 2020 12 30;64(12):934-945. Epub 2020 Sep 30.

Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.

Background: People with Down syndrome (DS) develop Alzheimer's disease (AD) at an earlier age of onset than those with sporadic AD. AD neuropathology is typically present in DS by 40 years of age with an onset of dementia approximately 10 years later. This early onset is due to the overexpression of amyloid precursor protein from the third copy of chromosome 21. Read More

JAMA Netw Open 2020 09 1;3(9):e2018221. Epub 2020 Sep 1.

Centre for Brain and Cognitive Development, Birkbeck, University of London, London, United Kingdom.

Importance: Risk of Alzheimer disease (AD) is particularly high for individuals with Down syndrome (DS). The ε4 allele of the apolipoprotein E gene (APOE ε4) is associated with an additional risk for AD. In typical development, there is evidence that the APOE ε4 genotype is associated with an early cognitive advantage. Read More

Int J Mol Sci 2020 Sep 20;21(18). Epub 2020 Sep 20.

Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, 39011 Santander, Spain.

Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer's disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. Read More

Ann Phys Rehabil Med 2021 Jan 15;64(1):101430. Epub 2020 Oct 15.

Memory and Aging Center, Global Brain Health Institute, University of California San Francisco, San Francisco, CA, USA; Department of neurology, Memory and Aging center, Sandler Neurosciences Center, University of California San Francisco, San Francisco, CA, USA.

Background: Aging individuals with Down syndrome (DS) are at increased risk of dementia due to trisomy of chromosome 21 on which the amyloid precursor protein gene is located and with increased life expectancy. Yet, little is known about the costs associated with DS dementia and how this compares to Alzheimer's disease (AD).

Objective: To better understand direct healthcare costs and care consumption in DS dementia, we compared the total cost of care to US Medicare and the drivers of these medical expenditures in individuals with DS with and without dementia, and in those with AD without DS. Read More

Prog Neurobiol 2021 01 11;196:101892. Epub 2020 Aug 11.

Department of Biochemical Sciences "A. Rossi Fanelli", Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy. Electronic address:

A major challenge in neurobiology is the identification of the mechanisms by which protein misfolding leads to cellular toxicity. Many neurodegenerative disorders, in which aberrant protein conformers aggregate into pathological inclusions, present the chronic activation of the PERK branch of the unfolded protein response. The adaptive effects of the PERK pathway include reduction of translation by transient inhibition of eIF2α and antioxidant protein production via induction of Nrf2 transcription factor. Read More

Alzheimers Dement (Amst) 2020 3;12(1):e12065. Epub 2020 Aug 3.

Irvine School of Medicine Department of Pediatrics University of California Orange California USA.

Introduction: Adults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments.

Methods: We describe the development of a multi-center, longitudinal study of biomarkers of AD in DS. Read More

Alzheimers Dement (Amst) 2020 9;12(1):e12057. Epub 2020 Jul 9.

Department of Neurology Washington University in St. Louis School of Medicine St. Louis Missouri USA.

Introduction: Virtually all individuals with Down syndrome (DS) will develop Alzheimer's disease (AD) pathology by age 40. Cerebrospinal fluid (CSF) biomarkers have characterized AD pathology in cohorts of late-onset AD (LOAD) and autosomal-dominant AD (ADAD). Few studies have evaluated such biomarkers in adults with DS. Read More

Alzheimers Dement (Amst) 2020 5;12(1):e12044. Epub 2020 Jul 5.

Department of Epidemiology School of Public Health Columbia University New York New York USA.

Introduction: Adults with Down syndrome (DS) are at high risk for developing Alzheimer's disease (AD) and its associated dementia, warranting the development of strategies to improve early detection when prevention is possible.

Methods: Using a broad battery of neuropsychological assessments, informant interviews, and clinical record review, we evaluated the psychometrics of measures in a large sample of 561 adults with DS. We tracked longitudinal stability or decline in functioning in a subsample of 269 participants over a period of 3 years, all initially without indications of clinically significant aging-related decline. Read More

Contemp Clin Trials Commun 2020 Sep 30;19:100607. Epub 2020 Jun 30.

Department of Internal Medicine, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.

Nearly all individuals with Down Syndrome (DS) display pathology associated with Alzheimer's disease (AD) beginning as early as age 30. Previous research in typically developed adults suggests that increased moderate-to-vigorous physical activity (MVPA) may improve cognitive function and protect against age-related structural and functional changes in the brain; however, the potential impact of increased MVPA on the development of AD in adults with DS has not been evaluated. Despite the potential positive impact of MVPA on cognition and AD risk, participation in MVPA among young adults with DS is low. Read More

AIMS Neurosci 2020 22;7(2):168-193. Epub 2020 Jun 22.

University of Liège, Cognitive Sciences, Building 32, Sart Tilman, Liège 4000, Belgium.

Experimental work regarding corrective actions on chromosomes and genes, and control of gene products is yielding promising results. It opens the way to advances in dealing with the etiological aspects of Down syndrome and may lead to important changes in the life of individuals affected with this condition. A small number of molecules are being investigated in pharmacological research that may have positive effects on intellectual functioning. Read More

Lancet 2020 06;395(10242):1988-1997

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; Center of Biomedical Investigation Network for Neurodegenerative Diseases, Madrid, Spain.

Background: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. Read More

Alzheimers Dement 2020 07 16;16(7):1065-1077. Epub 2020 Jun 16.

Alzheimer's Therapeutics Research Institute and Department of Neurology, University of Southern California, Los Angeles, California, USA.

Improved medical care of individuals with Down syndrome (DS) has led to an increase in life expectancy to over the age of 60 years. In conjunction, there has been an increase in age-related co-occurring conditions including Alzheimer's disease (AD). Understanding the factors that underlie symptom and age of clinical presentation of dementia in people with DS may provide insights into the mechanisms of sporadic and DS-associated AD (DS-AD). Read More

Alzheimers Dement (Amst) 2020 16;12(1):e12020. Epub 2020 Apr 16.

University of Wisconsin-Madison Waisman Center Madison Wisconsin.

Introduction: Individuals with Down syndrome (DS) show enhanced amyloid beta (Aβ) deposition in the brain. A new positron emission tomography (PET) index of amyloid load ( ) was recently developed as an alternative to standardized uptake value ratios (SUVrs) to quantify Aβ burden with high sensitivity for detecting and tracking Aβ change.. Read More