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J Neurochem 2017 10 15;143(1):11-29. Epub 2017 Aug 15.

Laboratorio de Neuropatología Experimental, Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina.

The amyloid precursor protein (APP) is a type I transmembrane glycoprotein better known for its participation in the physiopathology of Alzheimer disease as the source of the beta amyloid fragment. However, the physiological functions of the full length protein and its proteolytic fragments have remained elusive. APP was first described as a cell-surface receptor; nevertheless, increasing evidence highlighted APP as a cell adhesion molecule. Read More

Neurobiol Dis 2017 Oct 21;106:76-88. Epub 2017 Jun 21.

Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain. Electronic address:

The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Read More

Alzheimers Dement (Amst) 2017 23;9:1-9. Epub 2017 May 23.

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

Introduction: Down syndrome (DS) arises from a triplication of chromosome 21, causing overproduction of the amyloid precursor protein and predisposes individuals to early Alzheimer's disease (AD).

Methods: Fifty-two nondemented adults with DS underwent two cycles of carbon 11-labeled Pittsburgh compound B ([C]PiB) and T1 weighted magnetic resonance imaging (MRI) scans 3.0 ± 0. Read More

Sci Rep 2017 05 30;7(1):2477. Epub 2017 May 30.

Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, 03550, Sant Joan d'Alacant, Alicante, España.

This study assesses whether C-terminal fragments (CTF) of the amyloid precursor protein (APP) are present in cerebrospinal fluid (CSF) and their potential as biomarkers for Alzheimer's disease (AD). Immunoprecipitation and simultaneous assay by Western blotting using multiplex fluorescence imaging with specific antibodies against particular domains served to characterize CTFs of APP in human CSF. We demonstrate that APP-CTFs are detectable in human CSF, being the most abundant a 25-kDa fragment, probably resulting from proteolytic processing by η-secretase. Read More

Neurobiol Aging 2017 08 3;56:150-158. Epub 2017 May 3.

Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Taub Institute, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA.

Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g. Read More

Alzheimers Dement 2017 Nov 29;13(11):1251-1260. Epub 2017 Apr 29.

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

Introduction: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]).

Methods: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid β (Aβ) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68).

Results: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. Read More

Neuropathol Appl Neurobiol 2018 04 25;44(3):314-327. Epub 2017 May 25.

Institute of Neurology, Neurodegeneration Research Group, Medical University of Vienna, Vienna, Austria.

Aims: Down syndrome (DS) is a common cause of mental retardation accompanied by cognitive impairment. Comprehensive studies suggested a link between development and ageing, as nearly all individuals with DS develop Alzheimer disease (AD)-like pathology. However, there is still a paucity of data on tau in early DS to support this notion. Read More

Alzheimers Dement (Amst) 2017 20;8:1-10. Epub 2017 Mar 20.

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

Down syndrome (DS), present in nearly six million people, is associated with an extremely high risk to develop Alzheimer's disease (AD). Amyloid-β and tau pathology are omnipresent from age 40 years onward, but clinical symptoms do not appear in all DS individuals. Dementia diagnostics is complex in this population, illustrating the great need for predictive biomarkers. Read More

J Appl Res Intellect Disabil 2017 Dec 23;30 Suppl 1:49-57. Epub 2017 Mar 23.

Faculty of Social Work, Ostfalia University of Applied Sciences, Wolfenbüttel, Germany.

Background: This study investigated the application of a newly developed neuropsychological assessment, the Wolfenbütteler Dementia Test for Individuals with Intellectual Disabilities (WDTIM) in combination with the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID).

Methods: The instruments were evaluated in a prospective 2-year follow-up study. A total of 102 people with an intellectual disability were assessed at 6-month intervals. Read More

Curr Alzheimer Res 2017 ;14(7):709-721

Dementia Program, Local Health District, Modena. Italy.

Background: The USA National Task Group (NTG) guidelines advocate the use of an adapted version of Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID) for dementia screening of individuals with Down syndrome (DS) and with other forms of ID (non-DS).

Objective: In order to meet these guidelines, this study verifies the psychometric properties of an Italian version of the original DSQIID in a population composed of adults aged 40 years and over with DS and non-DS ID.

Methods: Internal consistency, inter-rater and intra-rater reliabilities, structural validity, convergent validity and known group differences of DSQIID-I were assessed with 200 individuals with ID (mean of 55. Read More

Curr Opin Psychiatry 2017 Mar;30(2):102-107

Division of Psychiatry, University College London, London, United Kingdom.

Purpose Of Review: Alzheimer's disease is most likely universal in older individuals with Down syndrome, due to having three copies of the amyloid precursor protein gene, resulting in amyloid-beta plaque deposition. Down syndrome is an important population in which to consider clinical trials of treatments to prevent or delay the development of dementia. However, assessment of subtler cognitive changes is challenging due to the presence of intellectual disability. Read More

Cold Spring Harb Perspect Med 2017 Jun 1;7(6). Epub 2017 Jun 1.

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029.

Alzheimer's disease (AD) is characterized neuropathologically by neuronal cell loss, extracellular neuritic plaques composed of β-amyloid (Aβ), and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Aβ is generated by proteolytic processing of the β-amyloid precursor protein (APP). Most individuals with Down syndrome (DS) have three copies of , leading to elevated APP expression, increased Aβ deposition, and characteristic AD neuropathology. Read More

J Alzheimers Dis 2017 ;56(2):459-470

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

Overexpression of the amyloid precursor protein (APP) gene on chromosome 21 in Down syndrome (DS) has been linked to increased brain amyloid levels and early-onset Alzheimer's disease (AD). An elderly man with phenotypic DS and partial trisomy of chromosome 21 (PT21) lacked triplication of APP affording an opportunity to study the role of this gene in the pathogenesis of dementia. Multidisciplinary studies between ages 66-72 years comprised neuropsychological testing, independent neurological exams, amyloid PET imaging with 11C-Pittsburgh compound-B (PiB), plasma amyloid-β (Aβ) measurements, and a brain autopsy examination. Read More

J Biol Chem 2016 Dec 2;291(51):26399-26409. Epub 2016 Nov 2.

From the Brain Research Institute,

DYRK1A, located on the Down syndrome (DS) critical region of chromosome 21, was found to be overexpressed in brains of DS and Alzheimer's disease individuals. DYRK1A was considered to play important roles in the pathogenesis of DS and Alzheimer's disease; however, the degradation mechanism of DYRK1A was still unclear. In this study, we found that DYRK1A was degraded through the ubiquitin-proteasome pathway in HEK293 cells. Read More

Alzheimers Dement 2017 May 15;13(5):541-549. Epub 2016 Oct 15.

Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, USA; The Center on Aging, Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA; Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden. Electronic address:

Introduction: Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) neuropathology and dementia early in life. Blood biomarkers of AD neuropathology would be valuable, as non-AD intellectual disabilities of DS and AD dementia overlap clinically. We hypothesized that elevations of amyloid β (Aβ) peptides and phosphorylated-tau in neuronal exosomes may document preclinical AD. Read More

Trials 2016 07 29;17:370. Epub 2016 Jul 29.

Gordon F Cheesbrough Research Chair and Director of UTOPIAN, University of Toronto, North York General Hospital, 4001 Leslie Street, Toronto, ON, M2K 1E1, Canada.

Background: Dementia is very common in Down syndrome (trisomy 21) adults. Statins may slow brain amyloid β (Aβ, coded on chromosome 21) deposition and, therefore, delay Alzheimer disease onset. One prospective cohort study with Down syndrome adults found participants on statins had reduced risk of incident dementia, but there are no randomised controlled trials (RCTs) on this issue. Read More

Alzheimers Dement 2016 11 21;12(11):1132-1148. Epub 2016 Jul 21.

Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Canada. Electronic address:

Introduction: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need.

Methods: We investigated the plasma levels of Aβ, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline. Read More

CNS Drugs 2016 07;30(7):567-73

Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive #0949, La Jolla, CA, 92093-0949, USA.

Down syndrome (DS), often due to trisomy 21, is the most common genetic cause of intellectual disability (ID). In addition, virtually all individuals with DS develop the neuropathology of Alzheimer's disease (AD) by the age of 40 years and almost 60 % will manifest symptoms of AD dementia by the age of 65 years. Currently, there are no pharmacological treatments available for ID in individuals with DS and only limited symptomatic treatments for AD dementia. Read More

Neurology 2016 May 4;86(22):2071-6. Epub 2016 May 4.

From the Department of Psychiatry (M.S.), Alzheimer Disease Research Center, Icahn School of Medicine at Mount Sinai, New York; James J. Peters VAMC (M.S.), Bronx, NY; Alzheimer's Therapeutic Research Institute (P.S.A.), University of Southern California, San Diego; Data Coordinating Center (H.F.A.), New York State Psychiatric Institute; Department of Psychiatry (H.F.A.) and Division of Biostatistics (W.-Y.T.), Columbia University College of Physicians and Surgeons, New York, NY; Department of Neurology (F.L.), McLean Hospital, Belmont; Harvard Medical School (F.L.), Boston, MA; and Center for Aging Studies (A.J.D.), George Jervis Clinic, New York State Institute for Basic Research in Developmental Disabilities, Staten Island.

Objective: To determine whether vitamin E would slow the progression of cognitive deterioration and dementia in aging persons with Down syndrome (DS).

Methods: A randomized, double-blind controlled clinical trial was conducted at 21 clinical sites, and researchers trained in research procedures recruited adults with DS older than 50 years to participate. Participants were randomly assigned to receive 1,000 IU of vitamin E orally twice daily for 3 years or identical placebo. Read More

CNS Neurol Disord Drug Targets 2016 ;15(4):434-47

Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, 3655 Sir- William-Osler Promenade, Room 1210, Montreal, QC, H3G 1Y6, Canada.

In Alzheimer's disease and Down syndrome, cholinergic neurons of the basal forebrain progressively degenerate. This neurotransmitter system is the main source of acetylcholine to the cortex and hippocampus. In the mature and fully differentiated central nervous system, the phenotype of forebrain cholinergic neurons and their nerve terminals in cortex and hippocampus depend on the continuous endogenous supply of nerve growth factor (NGF). Read More

Brain Cogn 2016 Apr 27;104:48-57. Epub 2016 Feb 27.

University of Florida College of Medicine, Department of Neurology, Room L3-100, McKnight Brain Institute, 1149 Newell Drive, Gainesville, FL 32611, United States. Electronic address:

Down syndrome (DS) is the most common genetic cause of intellectual disability in children. With aging, DS is associated with an increased risk for Alzheimer's disease (AD). The development of AD neuropathology in individuals with DS can result in further disturbances in cognition and behavior and may significantly exacerbate caregiver burden. Read More

Dement Geriatr Cogn Disord 2016 19;41(3-4):123-36. Epub 2016 Feb 19.

Old Age Research Group (PROTER), University of Sx00E3;o Paulo School of Medicine, Sx00E3;o Paulo, Brazil.

Background: There is a proven link between Down syndrome and the early development of the neuropathological features of Alzheimer's disease (AD). Changes in the personality and behavior of adults with Down syndrome might indicate the early stages of dementia or of frontotemporal lobar degeneration. The objective of this study was to investigate the executive functions and changes in behavior associated with frontal lobe degeneration in individuals with Down syndrome who develop AD. Read More

Exp Neurol 2016 May 24;279:40-56. Epub 2016 Feb 24.

Department of Anatomy and Neurobiology, Boston University School of Medicine, 72 East Concord Street, L-1004, Boston, MA 02118, United States. Electronic address:

Mouse models have provided insights into adult changes in learning and memory in Down syndrome, but an in-depth assessment of how these abnormalities develop over time has never been conducted. To address this shortcoming, we conducted a longitudinal behavioral study from birth until late adulthood in the Ts65Dn mouse model to measure the emergence and continuity of learning and memory deficits in individuals with a broad array of tests. Our results demonstrate for the first time that the pace at which neonatal and perinatal milestones are acquired is correlated with later cognitive performance as an adult. Read More

PLoS One 2016 5;11(1):e0146486. Epub 2016 Jan 5.

Department of Neurological and Movement Sciences, Anatomy and Histology Section, University of Verona, Verona, Italy.

Background: Down syndrome (DS) shows neuropathology similar to Alzheimer disease, which presents olfactory impairment. Previous work showed olfactory impairment in DS, but a comprehensive evaluation of olfactory function in DS is lacking.

Methods: We investigated a large number (n = 56; M = 31, F = 25) DS participants (age range18-57y) using the "Sniffin' Sticks" Extended test. Read More

Alzheimer Dis Assoc Disord 2016 Jul-Sep;30(3):251-7

*Alzheimer's Disease Research Center, Institute for Memory Impairments and Neurological Disorders (MIND) Departments of †Pediatrics §Department of Neurology, School of Medicine ‡Department of Statistics, University of California, Irvine (UCI), Irvine, CA.

Previous research has revealed similarities in the neuropathology, clinical presentation, and risk factors between persons with Alzheimer disease from the general population (GP-AD) and those with Down syndrome (DS-AD). Less is known, however, about the extent of similarities and differences in the cognitive profiles of these 2 populations. Fifty-one moderate to severely demented GP-AD and 59 DS-AD individuals participated in this study which compared the cognitive profiles of these 2 populations on the Severe Impairment Battery (SIB), controlling for sex as well as level of functional ability using a modified version of the Bristol Activities of Daily Living Scale. Read More