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Neurobiological Elements of Cognitive Dysfunction in Down Syndrome: Exploring the Role of APP

  • Martha Millan Sanchez
    Affiliations
    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, and the Sierra-Pacific Mental Illness Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California
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  • Sietske N. Heyn
    Affiliations
    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, and the Sierra-Pacific Mental Illness Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California
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  • Devsmita Das
    Affiliations
    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, and the Sierra-Pacific Mental Illness Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California
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  • Sarah Moghadam
    Affiliations
    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, and the Sierra-Pacific Mental Illness Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California
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  • Kara J. Martin
    Affiliations
    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, and the Sierra-Pacific Mental Illness Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California
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  • Ahmad Salehi
    Correspondence
    Address correspondence to Ahmad Salehi, M.D., Ph.D., VA Palo Alto Health Care System, 3801 Miranda Avenue, Y 151, Palo Alto, CA 94304
    Affiliations
    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, and the Sierra-Pacific Mental Illness Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California
    Search for articles by this author
Published:September 27, 2011DOI:https://doi.org/10.1016/j.biopsych.2011.08.016
      Down syndrome (DS) is the most common cause of cognitive dysfunction in children. Additionally, most adults with DS will eventually show both clinical and neuropathologic hallmarks of Alzheimer's disease (AD). The hippocampal formation constitutes the primary target for degeneration in both AD and DS. Over the past few years, we have studied the molecular mechanisms behind degeneration of this region and its major inputs in mouse models of DS. Our investigation has suggested that the loss of hippocampal inputs, particularly cholinergic and noradrenergic terminals, leads to de-afferentation of this region in the Ts65Dn mouse model of DS. Interestingly, we were able to link the overexpression of amyloid precursor protein (App) gene to degeneration of cholinergic and noradrenergic neurons in DS mouse models. We examined the underlying mechanisms of degeneration of multiple systems with extensive projections to the hippocampus in DS and its mouse models and the role of App overexpression in neurodegeneration. Understanding mechanisms behind hippocampal dysfunction has helped us to test several therapeutic strategies successfully in mouse models of DS. Here we review these strategies and mechanisms and discuss ways to translate our findings into possible interventions in humans.

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      References

        • Salehi A.
        • Pohlman B.
        • Mobley W.C.
        Down Syndrome/Trisomy 21.
        in: Squire L.R. The New Encyclopedia of Neuroscience. Elsevier, San Diego2008
        • Wisniewski K.E.
        • Wisniewski H.M.
        • Wen G.Y.
        Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome.
        Ann Neurol. 1985; 17: 278-282
        • Lai F.
        • Williams R.S.
        A prospective study of Alzheimer disease in Down syndrome.
        Arch Neurol. 1989; 46: 849-853
        • Melyn M.A.
        • White D.T.
        Mental and developmental milestones of noninstitutionalized Down's syndrome children.
        Pediatrics. 1973; 52: 542-545
        • Shanks A.
        • Odibo A.
        Nasal bone in prenatal trisomy 21 screening.
        Obstet Gynecol Surv. 2010; 65: 46-52
        • Kanamori G.
        • Witter M.
        • Brown J.
        • Williams-Smith L.
        Otolaryngologic manifestations of Down syndrome.
        Otolaryngol Clin North Am. 2000; 33: 1285-1292
        • Siegel M.S.
        • Smith W.E.
        Psychiatric features in children with genetic syndromes: Toward functional phenotypes.
        Child Adolesc Psychiatr Clin N Am. 2010; 19 (viii): 229-261
        • Kallen B.
        • Mastroiacovo P.
        • Robert E.
        Major congenital malformations in Down syndrome.
        Am J Med Genet. 1996; 65: 160-166
        • Roizen N.J.
        • Mets M.B.
        • Blondis T.A.
        Ophthalmic disorders in children with Down syndrome.
        Dev Med Child Neurol. 1994; 36: 594-600
        • Freeman S.B.
        • Bean L.H.
        • Allen E.G.
        • Tinker S.W.
        • Locke A.E.
        • Druschel C.
        • et al.
        Ethnicity, sex, and the incidence of congenital heart defects: A report from the National Down Syndrome Project.
        Genet Med. 2008; 10: 173-180
        • Morrison R.A.
        • McGrath A.
        • Davidson G.
        • Brown J.J.
        • Murray G.D.
        • Lever A.F.
        Low blood pressure in Down's syndrome, A link with Alzheimer's disease?.
        Hypertension. 1996; 28: 569-575
        • Fong C.T.
        • Brodeur G.M.
        Down's syndrome and leukemia: Epidemiology, genetics, cytogenetics and mechanisms of leukemogenesis.
        Cancer Genet Cytogenet. 1987; 28: 55-76
        • Rowley J.D.
        Down Syndrome and acute leukaemia: Increased risk may be due to trisomy 21.
        Lancet. 1981; 2: 1020-1022
        • Cohen W.I.
        Current dilemmas in Down syndrome clinical care: Celiac disease, thyroid disorders, and atlanto-axial instability.
        Am J Med Genet C Semin Med Genet. 2006; 142C: 141-148
        • Hankinson T.C.
        • Anderson R.C.
        Craniovertebral junction abnormalities in Down syndrome.
        Neurosurgery. 2010; 66: 32-38
        • Hawli Y.
        • Nasrallah M.El-Hajj Fuleihan G.
        Endocrine and musculoskeletal abnormalities in patients with Down syndrome.
        Nat Rev Endocrinol. 2009; 5: 327-334
        • Goldberg-Stern H.
        • Strawsburg R.H.
        • Patterson B.
        • Hickey F.
        • Bare M.
        • Gadoth N.
        • et al.
        Seizure frequency and characteristics in children with Down syndrome.
        Brain Dev. 2001; 23: 375-378
        • Dyken M.E.
        • Lin-Dyken D.C.
        • Poulton S.
        • Zimmerman M.B.
        • Sedars E.
        Prospective polysomnographic analysis of obstructive sleep apnea in down syndrome.
        Arch Pediatr Adolesc Med. 2003; 157: 655-660
        • Ng D.K.
        • Hui H.N.
        • Chan C.H.
        • Kwok K.L.
        • Chow P.Y.
        • Cheung J.M.
        • et al.
        Obstructive sleep apnoea in children with Down syndrome.
        Singapore Med J. 2006; 47: 774-779
        • Shott S.R.
        Down syndrome: Common otolaryngologic manifestations.
        Am J Med Genet C Semin Med Genet. 2006; 142C: 131-140
        • Schupf N.
        • Kapell D.
        • Lee J.H.
        • Zigman W.
        • Canto B.
        • Tycko B.
        • et al.
        Onset of dementia is associated with apolipoprotein E epsilon4 in Down's syndrome.
        Ann Neurol. 1996; 40: 799-801
        • Krmpotic-Nemanic J.
        Down's syndrome and presbyacousis.
        Lancet. 1970; 2: 670-671
        • Roizen N.J.
        • Wolters C.
        • Nicol T.
        • Blondis T.A.
        Hearing loss in children with Down syndrome.
        J Pediatr. 1993; 123: S9-S12
        • Miolo G.
        • Chapman R.S.
        • Sindberg H.A.
        Sentence comprehension in adolescents with Down syndrome and typically developing children: Role of sentence voice, visual context, and auditory-verbal short-term memory.
        J Speech Lang Hear Res. 2005; 48: 172-188
        • Bhagyalakshmi G.
        • Renukarya A.J.
        • Rajangam S.
        Metric analysis of the hard palate in children with Down syndrome: A comparative study.
        Downs Syndr Res Pract. 2007; 12: 55-59
        • Chapman R.S.
        • Hesketh L.J.
        Behavioral phenotype of individuals with Down syndrome.
        Ment Retard Dev Disabil Res Rev. 2000; 6: 84-95
        • Hesketh L.J.
        • Chapman R.S.
        Verb use by individuals with Down syndrome.
        Am J Ment Retard. 1998; 103: 288-304
        • Jarrold C.
        • Baddeley A.D.
        Short-term memory in Down syndrome: Applying the working memory model.
        Downs Syndr Res Pract. 2001; 7: 17-23
        • Edgin J.O.
        • Pennington B.F.
        • Mervis C.B.
        Neuropsychological components of intellectual disability: The contributions of immediate, working, and associative memory.
        J Intellect Disabil Res. 2010; 54: 406-417
        • Myers B.A.
        • Pueschel S.M.
        Psychiatric disorders in persons with Down syndrome.
        J Nerv Ment Dis. 1991; 179: 609-613
        • Gath A.
        • Gumley D.
        Behaviour problems in retarded children with special reference to Down's syndrome.
        Br J Psychiatry. 1986; 149: 156-161
        • Kent L.
        • Evans J.
        • Paul M.
        • Sharp M.
        Comorbidity of autistic spectrum disorders in children with Down syndrome.
        Dev Med Child Neurol. 1999; 41: 153-158
        • Tyrer F.
        • McGrother C.W.
        • Thorp C.F.
        • Donaldson M.
        • Bhaumik S.
        • Watson J.M.
        • et al.
        Physical aggression towards others in adults with learning disabilities: Prevalence and associated factors.
        J Intellect Disabil Res. 2006; 50: 295-304
        • Collacott R.A.
        • Cooper S.A.
        • McGrother C.
        Differential rates of psychiatric disorders in adults with Down's syndrome compared with other mentally handicapped adults.
        Br J Psychiatry. 1992; 161: 671-674
        • Maatta T.
        • Tervo-Maatta T.
        • Taanila A.
        • Kaski M.
        • Iivanainen M.
        Mental health, behaviour and intellectual abilities of people with Down syndrome.
        Downs Syndr Res Pract. 2006; 11: 37-43
        • Mann D.M.
        • Esiri M.M.
        The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome.
        J Neurol Sci. 1989; 89: 169-179
        • Schupf N.
        • Sergievsky G.H.
        Genetic and host factors for dementia in Down's syndrome.
        Br J Psychiatry. 2002; 180: 405-410
        • Pinter J.D.
        • Eliez S.
        • Schmitt J.E.
        • Capone G.T.
        • Reiss A.L.
        Neuroanatomy of Down's syndrome: A high-resolution MRI study.
        Am J Psychiatry. 2001; 158: 1659-1665
        • Pinter J.D.
        • Brown W.E.
        • Eliez S.
        • Schmitt J.E.
        • Capone G.T.
        • Reiss A.L.
        Amygdala and hippocampal volumes in children with Down syndrome: A high-resolution MRI study.
        Neurology. 2001; 56: 972-974
        • White N.S.
        • Alkire M.T.
        • Haier R.J.
        A voxel-based morphometric study of nondemented adults with Down Syndrome.
        Neuroimage. 2003; 20: 393-403
        • Teipel S.J.
        • Alexander G.E.
        • Schapiro M.B.
        • Moller H.J.
        • Rapoport S.I.
        • Hampel H.
        Age-related cortical grey matter reductions in non-demented Down's syndrome adults determined by MRI with voxel-based morphometry.
        Brain. 2004; 127: 811-824
        • Weitzdoerfer R.
        • Dierssen M.
        • Fountoulakis M.
        • Lubec G.
        Fetal life in Down syndrome starts with normal neuronal density but impaired dendritic spines and synaptosomal structure.
        J Neural Transm Suppl. 2001; : 59-70
        • Marin-Padilla M.
        Pyramidal cell abnormalities in the motor cortex of a child with Down's syndrome.
        J Comp Neurol. 1976; 167: 63-81
        • Takashima S.
        • Ieshima A.
        • Nakamura H.
        • Becker L.E.
        Dendrites, dementia and the Down syndrome.
        Brain Dev. 1989; 11: 131-133
        • Ferrer I.
        • Gullotta F.
        Down's syndrome and Alzheimer's disease: Dendritic spine counts in the hippocampus.
        Acta Neuropathol. 1990; 79: 680-685
        • Downes E.C.
        • Robson J.
        • Grailly E.
        • Abdel-All Z.
        • Xuereb J.
        • Brayne C.
        • et al.
        Loss of synaptophysin and synaptosomal-associated protein 25-kDa (SNAP-25) in elderly Down syndrome individuals.
        Neuropathol Appl Neurobiol. 2008; 34: 12-22
        • Sadowski M.
        • Wisniewski H.M.
        • Tarnawski M.
        • Kozlowski P.B.
        • Lach B.
        • Wegiel J.
        Entorhinal cortex of aged subjects with Down's syndrome shows severe neuronal loss caused by neurofibrillary pathology.
        Acta Neuropathol. 1999; 97: 156-164
        • Hof P.R.
        • Bouras C.
        • Perl D.P.
        • Sparks D.L.
        • Mehta N.
        • Morrison J.H.
        Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down's syndrome.
        Arch Neurol. 1995; 52: 379-391
        • Goate A.
        • Chartier-Harlin M.C.
        • Mullan M.
        • Brown J.
        • Crawford F.
        • Fidani L.
        • et al.
        Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
        Nature. 1991; 349: 704-706
        • Rovelet-Lecrux A.
        • Hannequin D.
        • Raux G.
        • Le Meur N.
        • Laquerriere A.
        • Vital A.
        • et al.
        APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy.
        Nat Genet. 2006; 38: 24-26
        • Prasher V.P.
        • Farrer M.J.
        • Kessling A.M.
        • Fisher E.M.
        • West R.J.
        • Barber P.C.
        • et al.
        Molecular mapping of Alzheimer-type dementia in Down's syndrome.
        Ann Neurol. 1998; 43: 380-383
        • Salehi A.
        • Delcroix J.D.
        • Belichenko P.V.
        • Zhan K.
        • Wu C.
        • Valletta J.S.
        • et al.
        Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration.
        Neuron. 2006; 51: 29-42
        • Acquati F.
        • Accarino M.
        • Nucci C.
        • Fumagalli P.
        • Jovine L.
        • Ottolenghi S.
        • et al.
        The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region.
        FEBS Lett. 2000; 468: 59-64
        • Liu K.
        • Solano I.
        • Mann D.
        • Lemere C.
        • Mercken M.
        • Trojanowski J.Q.
        • et al.
        Characterization of Abeta11-40/42 peptide deposition in Alzheimer's disease and young Down's syndrome brains: Implication of N-terminally truncated Abeta species in the pathogenesis of Alzheimer's disease.
        Acta Neuropathol. 2006; 112: 163-174
        • Sun X.
        • He G.
        • Song W.
        BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome.
        FASEB J. 2006; 20: 1369-1376
        • Salehi A.
        • Faizi M.
        • Colas D.
        • Valletta J.
        • Laguna J.
        • Takimoto-Kimura R.
        • et al.
        Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome.
        Sci Transl Med. 2009; 1 (7ra17)
        • Hunter C.L.
        • Bimonte H.A.
        • Granholm A.C.
        Behavioral comparison of 4 and 6 month-old Ts65Dn mice: Age-related impairments in working and reference memory.
        Behav Brain Res. 2003; 138: 121-131
        • Fernandez F.
        • Morishita W.
        • Zuniga E.
        • Nguyen J.
        • Blank M.
        • Malenka R.C.
        • et al.
        Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome.
        Nat Neurosci. 2007; 10: 411-413
        • Lorenzi H.A.
        • Reeves R.H.
        Hippocampal hypocellularity in the Ts65Dn mouse originates early in development.
        Brain Res. 2006; 1104: 153-159
        • Hanson J.E.
        • Blank M.
        • Valenzuela R.A.
        • Garner C.C.
        • Madison D.V.
        The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down's syndrome.
        J Physiol. 2007; 579: 53-67
        • Belichenko P.V.
        • Masliah E.
        • Kleschevnikov A.M.
        • Villar A.J.
        • Epstein C.J.
        • Salehi A.
        • et al.
        Synaptic structural abnormalities in the Ts65Dn mouse model of Down Syndrome.
        J Comp Neurol. 2004; 480: 281-298
        • Belichenko P.V.
        • Kleschevnikov A.M.
        • Masliah E.
        • Wu C.
        • Takimoto-Kimura R.
        • Salehi A.
        • et al.
        Excitatory-inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of Down syndrome.
        J Comp Neurol. 2009; 512: 453-466
        • Easton A.
        • Fitchett A.E.
        • Eacott M.J.
        • Baxter M.G.
        Medial septal cholinergic neurons are necessary for context-place memory but not episodic-like memory.
        Hippocampus. 2010; 21: 1021-1027
        • McGeer E.G.
        • Norman M.
        • Boyes B.
        • O'Kusky J.
        • Suzuki J.
        • McGeer P.L.
        Acetylcholine and aromatic amine systems in postmortem brain of an infant with Down's syndrome.
        Exp Neurol. 1985; 87: 557-570
        • Casanova M.F.
        • Walker L.C.
        • Whitehouse P.J.
        • Price D.L.
        Abnormalities of the nucleus basalis in Down's syndrome.
        Ann Neurol. 1985; 18: 310-313
        • Mann D.M.
        • Yates P.O.
        • Marcyniuk B.
        Alzheimer's presenile dementia, senile dementia of Alzheimer type and Down's syndrome in middle age form an age related continuum of pathological changes.
        Neuropathol Appl Neurobiol. 1984; 10: 185-207
        • Lott I.T.
        • Osann K.
        • Doran E.
        • Nelson L.
        Down syndrome and Alzheimer disease: Response to donepezil.
        Arch Neurol. 2002; 59: 1133-1136
        • Heller J.H.
        • Spiridigliozzi G.A.
        • Sullivan J.A.
        • Doraiswamy P.M.
        • Krishnan R.R.
        • Kishnani P.S.
        Donepezil for the treatment of language deficits in adults with Down syndrome: A preliminary 24-week open trial.
        Am J Med Genet A. 2003; 116A: 111-116
        • Kondoh T.
        • Kanno A.
        • Itoh H.
        • Nakashima M.
        • Honda R.
        • Kojima M.
        • et al.
        Donepezil significantly improves abilities in daily lives of female Down syndrome patients with severe cognitive impairment: A 24-week randomized, double-blind, placebo-controlled trial.
        Int J Psychiatry Med. 2011; 41: 71-89
        • Cooper J.D.
        • Salehi A.
        • Delcroix J.D.
        • Howe C.L.
        • Belichenko P.V.
        • Chua-Couzens J.
        • et al.
        Failed retrograde transport of NGF in a mouse model of Down's syndrome: Reversal of cholinergic neurodegenerative phenotypes following NGF infusion.
        Proc Natl Acad Sci U S A. 2001; 98: 10439-10444
        • Salehi A.
        • Delcroix J.D.
        • Swaab D.F.
        Alzheimer's disease and NGF signaling.
        J Neural Transm. 2004; 111: 323-345
        • Salehi A.
        • Delcroix J.D.
        • Mobley W.C.
        Traffic at the intersection of neurotrophic factor signaling and neurodegeneration.
        Trends Neurosci. 2003; 26: 73-80
        • Sendera T.J.
        • Ma S.Y.
        • Jaffar S.
        • Kozlowski P.B.
        • Kordower J.H.
        • Mawal Y.
        • et al.
        Reduction in TrkA-immunoreactive neurons is not associated with an overexpression of galaninergic fibers within the nucleus basalis in Down's syndrome.
        J Neurochem. 2000; 74: 1185-1196
        • Jiang Y.
        • Mullaney K.A.
        • Peterhoff C.M.
        • Che S.
        • Schmidt S.D.
        • Boyer-Boiteau A.
        • et al.
        Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition.
        Proc Natl Acad Sci U S A. 2010; 107: 1630-1635
        • Nixon R.A.
        Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases.
        Neurobiol Aging. 2005; 26: 373-382
        • Kaasinen S.K.
        • Harvey L.
        • Reynolds A.J.
        • Hendry I.A.
        Autophagy generates retrogradely transported organelles: A hypothesis.
        Int J Dev Neurosci. 2008; 26: 625-634
        • Berridge C.W.
        • Waterhouse B.D.
        The locus coeruleus-noradrenergic system: Modulation of behavioral state and state-dependent cognitive processes.
        Brain Res Brain Res Rev. 2003; 42: 33-84
        • German D.C.
        • Manaye K.F.
        • White 3rd, C.L.
        • Woodward D.J.
        • McIntire D.D.
        • Smith W.K.
        • et al.
        Disease-specific patterns of locus coeruleus cell loss.
        Ann Neurol. 1992; 32: 667-676
        • Murchison C.F.
        • Zhang X.Y.
        • Zhang W.P.
        • Ouyang M.
        • Lee A.
        • Thomas S.A.
        A distinct role for norepinephrine in memory retrieval.
        Cell. 2004; 117: 131-143
        • Yates C.M.
        • Ritchie I.M.
        • Simpson J.
        • Maloney A.F.
        • Gordon A.
        Noradrenaline in Alzheimer-type dementia and Down syndrome.
        Lancet. 1981; 2: 39-40
        • Godridge H.
        • Reynolds G.P.
        • Czudek C.
        • Calcutt N.A.
        • Benton M.
        Alzheimer-like neurotransmitter deficits in adult Down's syndrome brain tissue.
        J Neurol Neurosurg Psychiatry. 1987; 50: 775-778
        • Goldstein M.
        • Freedman L.S.
        • Ebstein R.P.
        • Park D.H.
        Studies on dopamine-beta-hydroxylase in mental disorders.
        J Psychiatr Res. 1974; 11: 205-210
        • Dierssen M.
        • Vallina I.F.
        • Baamonde C.
        • Garcia-Calatayud S.
        • Lumbreras M.A.
        • Florez J.
        Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome.
        Brain Res. 1997; 749: 238-244
        • Khakpour-Taleghani B.
        • Lashgari R.
        • Motamedi F.
        • Naghdi N.
        Effect of reversible inactivation of locus ceruleus on spatial reference and working memory.
        Neuroscience. 2009; 158: 1284-1291
        • Deacon R.M.
        • Croucher A.
        • Rawlins J.N.
        Hippocampal cytotoxic lesion effects on species-typical behaviours in mice.
        Behav Brain Res. 2002; 132: 203-213
        • Lockrow J.
        • Boger H.
        • Gerhardt G.
        • Aston-Jones G.
        • Bachman D.
        • Granholm A.C.
        A noradrenergic lesion exacerbates neurodegeneration in a Down syndrome mouse model.
        J Alzheimers Dis. 2011; 23: 471-489
        • Goldstein D.S.
        • Holmes C.
        • Kaufmann H.
        • Freeman R.
        Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure.
        Clin Auton Res. 2004; 14: 363-368
        • Kaufmann H.
        • Saadia D.
        • Voustianiouk A.
        • Goldstein D.S.
        • Holmes C.
        • Yahr M.D.
        • et al.
        Norepinephrine precursor therapy in neurogenic orthostatic hypotension.
        Circulation. 2003; 108: 724-728
        • Goldstein D.S.
        • Holmes C.
        • Sewell L.
        • Pechnik S.
        • Kopin I.J.
        Effects of carbidopa and entacapone on the metabolic fate of the norepinephrine prodrug L-DOPS.
        J Clin Pharmacol. 2011; 51: 66-74
        • Herrmann N.
        • Lanctot K.L.
        • Khan L.R.
        The role of norepinephrine in the behavioral and psychological symptoms of dementia.
        J Neuropsychiatry Clin Neurosci. 2004; 16: 261-276
        • Heneka M.T.
        • Nadrigny F.
        • Regen T.
        • Martinez-Hernandez A.
        • Dumitrescu-Ozimek L.
        • Terwel D.
        • et al.
        Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine.
        Proc Natl Acad Sci U S A. 2010; 107: 6058-6063
        • Oeseburg B.
        • Dijkstra G.J.
        • Groothoff J.W.
        • Reijneveld S.A.
        • Jansen D.E.
        Prevalence of chronic health conditions in children with intellectual disability: A systematic literature review.
        Intellect Dev Disabil. 2011; 49: 59-85
        • Randall A.D.
        • Witton J.
        • Booth C.
        • Hynes-Allen A.
        • Brown J.T.
        The functional neurophysiology of the amyloid precursor protein (APP) processing pathway.
        Neuropharmacology. 2010; 59: 243-267
        • Kaplan G.
        • Newcorn J.H.
        Pharmacotherapy for child and adolescent attention-deficit hyperactivity disorder.
        Pediatr Clin North Am. 2011; 58 (xi): 99-120