Bradley T Hyman

Harvard Medical School, Boston, Massachusetts, United States

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Publications (742)5004.17 Total impact

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    ABSTRACT: Amyloid β-protein oligomers play a key role in Alzheimer's disease (AD), but well-validated assays that routinely detect them in cerebrospinal fluid (CSF) are just emerging. We sought to confirm and extend a recent study using the Singulex Erenna platform that reported increased mean CSF oligomer levels in AD. We tested four antibody pairs and chose one pair that was particularly sensitive, using 1C22, our new oligomer-selective monoclonal antibody, for capture. We applied this new assay to extracts of human brain and CSF. A combination of 1C22 for capture and 3D6 for detection yielded an Erenna immunoassay with a lower limit of quantification of approximately 0.15 pg/ml that was highly selective for oligomers over monomers and detected a wide size-range of oligomers. Most CSFs we tested had detectable oligomer levels but with a large overlap between AD and controls and a trend for higher mean levels in mild cognitive impairment (MCI) than controls. Aβ oligomers are detectable in most human CSFs, but AD and controls overlap. MCI CSFs may have a modest elevation in mean value by this assay.
    Alzheimer's Research and Therapy 12/2015; 7(1). DOI:10.1186/s13195-015-0100-y · 3.98 Impact Factor
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    ABSTRACT: In early stages of Alzheimer's disease (AD), neurofibrillary tangles (NFT) are largely restricted to the entorhinal cortex and medial temporal lobe. At later stages, when clinical symptoms generally occur, NFT involve widespread limbic and association cortices. At this point in the disease, amyloid plaques are also abundantly distributed in the cortex. This observation from human neuropathological studies led us to pose two alternative hypotheses: that amyloid in the cortex is permissive for the spread of tangles from the medial temporal lobe, or that these are co-occurring but not causally related events simply reflecting progression of AD pathology. We now directly test the hypothesis that cortical amyloid acts as an accelerant for spreading of tangles beyond the medial temporal lobe. We crossed rTgTauEC transgenic mice that demonstrate spread of tau from entorhinal cortex to other brain structures at advanced age with APP/PS1 mice, and examined mice with either NFTs, amyloid pathology, or both. We show that concurrent amyloid deposition in the cortex 1) leads to a dramatic increase in the speed of tau propagation and an extraordinary increase in the spread of tau to distal brain regions, and 2) significantly increases tau-induced neuronal loss. These data strongly support the hypothesis that cortical amyloid accelerates the spread of tangles throughout the cortex and amplifies tangle-associated neural system failure in AD.
    12/2015; 3(1):14. DOI:10.1186/s40478-015-0199-x
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    ABSTRACT: Alzheimer's disease (AD) therapeutics based on the amyloid hypothesis have shown minimal efficacy in patients, suggesting that the activity of amyloid beta (Aβ) represents only one aspect of AD pathogenesis. Since neuroinflammation is thought to play an important role in AD, we hypothesized that cytokines may play a direct role in promoting neuronal death. Here, we profiled cytokine expression in a small cohort of human AD and control brain tissues. We identified AD-associated cytokines using partial least squares regression to correlate cytokine expression with quantified pathologic disease state and then used neuron cultures to test whether cytokines up-regulated in AD tissues could affect neuronal viability. This analysis identified cytokines that were associated with the pathological severity. Of the top correlates, only TNF-α reduced viability in neuron culture when applied alone. VEGF also reduced viability when applied together with Aβ, which was surprising because VEGF has been viewed as a neuro-protective protein. We found that this synthetic pro-death effect of VEGF in the context of Aβ was commensurate with VEGFR-dependent changes in multiple signaling pathways that govern cell fate. Our findings suggest that profiling of tissues combined with a culture-based screening approach can successfully identify new mechanisms driving neuronal death.
    Scientific Reports 11/2015; 5:16622. DOI:10.1038/srep16622 · 5.58 Impact Factor
  • Alberto Serrano-Pozo · Bradley T Hyman ·

    Nature Reviews Neurology 11/2015; DOI:10.1038/nrneurol.2015.221 · 15.36 Impact Factor
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    ABSTRACT: In Alzheimer's disease and tauopathies, tau protein aggregates into neurofibrillary tangles that progressively spread to synaptically connected brain regions. A prion-like mechanism has been suggested: misfolded tau propagating through the brain seeds neurotoxic aggregation of soluble tau in recipient neurons. We use transgenic mice and viral tau expression to test the hypotheses that trans-synaptic tau propagation, aggregation, and toxicity rely on the presence of endogenous soluble tau. Surprisingly, mice expressing human P301Ltau in the entorhinal cortex showed equivalent tau propagation and accumulation in recipient neurons even in the absence of endogenous tau. We then tested whether the lack of endogenous tau protects against misfolded tau aggregation and toxicity, a second prion model paradigm for tau, using P301Ltau-overexpressing mice with severe tangle pathology and neurodegeneration. Crossed onto tau-null background, these mice had similar tangle numbers but were protected against neurotoxicity. Therefore, misfolded tau can propagate across neural systems without requisite templated misfolding, but the absence of endogenous tau markedly blunts toxicity. These results show that tau does not strictly classify as a prion protein.
    The EMBO Journal 11/2015; DOI:10.15252/embj.201592748 · 10.43 Impact Factor
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    ABSTRACT: Objective: Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer's disease (AD), staging and monitoring of disease progression, and development of disease modifying therapies. Methods: We acquired tau positron emission tomography (PET) using (18) F T807 (AV1451), and amyloid-β PET using (11) C Pittsburgh Compound B (PIB) in older clinically normal individuals, and symptomatic patients with mild cognitive impairment or mild AD dementia. Results: We found abnormally high cortical (18) F T807 binding in patients with mild cognitive impairment and AD dementia compared to clinically normal controls. Consistent with the neuropathology literature, the presence of elevated neocortical (18) F T807 binding particularly in the inferior temporal gyrus was associated with clinical impairment. The association of cognitive impairment was stronger with inferior temporal (18) F T807 than with mean cortical (11) C PIB. Regional (18) F T807 was correlated with mean cortical (11) C PiB among both impaired and control subjects. Interpretation: These findings suggest that (18) F T807 PET could have value as a biomarker that reflects both the progression of AD tauopathy and the emergence of clinical impairment. This article is protected by copyright. All rights reserved.
    Annals of Neurology 10/2015; DOI:10.1002/ana.24546 · 9.98 Impact Factor
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    ABSTRACT: Tau pathology is known to spread in a hierarchical pattern in Alzheimer's disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.
    Nature Communications 10/2015; 6. DOI:10.1038/ncomms9490 · 11.47 Impact Factor
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    ABSTRACT: Objective: To examine region and substrate-specific autoradiographic and in vitro binding patterns of PET tracer [F-18]-AV-1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament tau-containing lesions, and to determine whether there is off-target binding to other amyloid/non-amyloid proteins. Methods: We applied [F-18]-AV-1451 phosphor screen autoradiography, [F-18]-AV-1451 nuclear emulsion autoradiography and [H-3]-AV-1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer's disease, frontotemporal lobar degeneration-tau, frontotemporal lobar degeneration-TDP-43, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology. Results: Our data suggest that AV-1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer's brains e.g. intra and extraneuronal tangles and dystrophic neurites, but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non-Alzheimer tauopathy brains or to β-amyloid, α-synuclein or TDP-43-containing lesions. AV-1451 off-target binding to neuromelanin- and melanin-containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified. Interpretation: Our data suggest that AV-1451 holds promise as surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament-tau-containing neurites in Alzheimer's brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non-Alzheimer tauopathy cases and to the existence of some AV-1451 off-target binding. These findings provide important insights for interpreting in vivo patterns of [F-18]-AV-1451 retention. This article is protected by copyright. All rights reserved.
    Annals of Neurology 09/2015; DOI:10.1002/ana.24517 · 9.98 Impact Factor

  • Alzheimer's & dementia: the journal of the Alzheimer's Association 08/2015; DOI:10.1016/j.jalz.2015.06.1887 · 12.41 Impact Factor
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    ABSTRACT: Neuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used. Fifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change. Current practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77-0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable. AD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 08/2015; DOI:10.1016/j.jalz.2015.07.492 · 12.41 Impact Factor
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    ABSTRACT: There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 07/2015; 138(Pt 9). DOI:10.1093/brain/awv202 · 9.20 Impact Factor
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    ABSTRACT: In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 07/2015; 138(Pt 9). DOI:10.1093/brain/awv199 · 9.20 Impact Factor
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    ABSTRACT: Human cerebrospinal fluid (CSF) contains diverse lipid particles, including lipoproteins that are distinct from their plasma counterparts and contain apolipoprotein (apo) E isoforms, apoJ, and apoAI, and extracellular vesicles, which can be detected by annexin V binding. The aim of this study was to develop a method to quantify CSF particles and evaluate their relationship to aging and neurodegenerative diseases. We used a flow cytometric assay to detect annexin V-, apoE-, apoAI-, apoJ-, and amyloid (A) β42-positive particles in CSF from 131 research volunteers who were neurologically normal or had mild cognitive impairment (MCI), Alzheimer disease (AD) dementia, or Parkinson disease. APOE ε4/ε4 participants had CSF apoE-positive particles that were more frequently larger but at an 88% lower level versus those in APOE ε3/ε3 or APOE ε3/ε4 patients; this finding was reproduced in conditioned medium from mouse primary glial cell cultures with targeted replacement of apoE. Cerebrospinal fluid apoE-positive and β-amyloid (Aβ42)-positive particle concentrations were persistently reduced one-third to one-half in middle and older age subjects; apoAI-positive particle concentration progressively increased approximately 2-fold with age. Both apoAI-positive and annexin V-positive CSF particle levels were reduced one-third to one-half in CSF of MCI and/or AD dementia patients versus age-matched controls. Our approach provides new methods to investigate CNS lipid biology in relation to neurodegeneration and perhaps develop new biomarkers for diagnosis or treatment monitoring.
    07/2015; 74(7):672-87. DOI:10.1097/NEN.0000000000000207
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    ABSTRACT: Amyloid-β (Aβ) plaques and α-synuclein (α-syn)-rich Lewy bodies are the major neuropathological hallmarks of Alzheimer's disease (AD) and Parkinson's disease, respectively. An overlap of pathologies is found in most individuals with dementia with Lewy bodies (DLB) and in more than 50% of AD cases. Their brains display substantial α-syn accumulation not only in Lewy bodies, but also in dystrophic neurites decorating Aβ plaques. Several studies report binding and coaggregation of Aβ and α-syn, yet the precise role of α-syn in amyloid plaque formation remains elusive. Here we performed intracerebral injections of α-syn-containing preparations into amyloid precursor protein (APP) transgenic mice (expressing APP695(KM670/671NL) and PSEN1(L166P) under the control of the neuron-specific Thy-1 promoter; referred to here as 'APPPS1'). Unexpectedly, α-syn failed to cross-seed Aβ plaques in vivo, but rather it inhibited plaque formation in APPPS1 mice coexpressing SNCA(A30P) (referred to here as 'APPPS1 × [A30P]aSYN' double-transgenic mice). This was accompanied by increased Aβ levels in cerebrospinal fluid despite unchanged overall Aβ levels. Notably, the seeding activity of Aβ-containing brain homogenates was considerably reduced by α-syn, and Aβ deposition was suppressed in grafted tissue from [A30P]aSYN transgenic mice. Thus, we conclude that an interaction between Aβ and α-syn leads to inhibition of Aβ deposition and to reduced plaque formation.
    Nature medicine 06/2015; 21(7). DOI:10.1038/nm.3885 · 27.36 Impact Factor
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    ABSTRACT: Oxidative stress is a common feature of the aging process and of many neurodegenerative disorders, including Alzheimer's disease. Understanding the direct causative relationship between oxidative stress and amyloid pathology, and determining the underlying molecular mechanisms is crucial for the development of more effective therapeutics for the disease. By employing microdialysis technique, we report local increase in the amyloid-β42 levels and elevated amyloid-β42/40 ratio in the interstitial fluid within 6h of direct infusion of oxidizing agents into the hippocampus of living and awake wild type mice. The increase in the amyloid-β42/40 ratio correlated with the pathogenic conformational change of the amyloid precursor protein-cleaving enzyme, presenilin1/γ-secretase. Furthermore, we found that the product of lipid peroxidation 4-hydroxynonenal, binds to both nicastrin and BACE, differentially affecting γ- and β-secretase activity, respectively. The present study demonstrates a direct cause-and-effect correlation between oxidative stress and altered amyloid-β production, and provides a molecular mechanism by which naturally occurring product of lipid peroxidation may trigger generation of toxic amyloid-β42 species. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 06/2015; DOI:10.1016/j.nbd.2015.06.013 · 5.08 Impact Factor
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    ABSTRACT: Proteolytic processing of amyloid-β precursor protein (APP) by beta-site APP cleaving enzyme 1 (BACE1) is the initial step in the production of amyloid beta (Aβ), which accumulates in senile plaques in Alzheimer's disease (AD). Essential for this cleavage is the transport and sorting of both proteins through endosomal/Golgi compartments. Golgi-localized γ-ear-containing ARF-binding (GGA) proteins have striking cargo-sorting functions in these pathways. Recently, GGA1 and GGA3 were shown to interact with BACE1, to be expressed in neurons, and to be decreased in AD brain, whereas little is known about GGA2. Since GGA1 impacts Aβ generation by confining APP to the Golgi and perinuclear compartments, we tested whether all GGAs modulate BACE1 and APP transport and processing. We observed decreased levels of secreted APP alpha (sAPPα), sAPPβ, and Aβ upon GGA overexpression, which could be reverted by knockdown. GGA-BACE1 co-immunoprecipitation was impaired upon GGA-GAE but not VHS domain deletion. Autoinhibition of the GGA1-VHS domain was irrelevant for BACE1 interaction. Our data suggest that all three GGAs affect APP processing via the GGA-GAE domain.
    PLoS ONE 06/2015; 10(6). DOI:10.1371/journal.pone.0129047 · 3.23 Impact Factor
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    ABSTRACT: Human APOE ϵ4 allele is a strong genetic risk factor of Alzheimer disease (AD). Neuropathological and genetic studies suggested that apolipoprotein E4 (apoE4) protein facilitates deposition of amyloid β peptide (Aβ) in the brain, although the mechanism whereby apoE4 increases amyloid aggregates remains elusive. Here we show that injection of Aβ protofibrils induced Aβ deposition in the brain of APP transgenic mice, suggesting that Aβ protofibrils acted as a seed for aggregation and deposition of Aβ in vivo. Injection of Aβ protofibrils together with apoE3 significantly attenuated Aβ deposition, whereas apoE4 did not have this effect. In vitro assays revealed that the conversion of Aβ protofibrils to fibrils progressed slower upon co-incubation with apoE2 or apoE3 compared to that with apoE4. Aβ protofibrils complexed with apoE4 were less stable than those with apoE2 or apoE3. These data suggest that the suppression effect of apoE2 or apoE3 on the structural conversion of Aβ protofibrils to fibrils is stronger than those of apoE4, thereby impeding β-amyloid deposition. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 04/2015; 290(24). DOI:10.1074/jbc.M114.622209 · 4.57 Impact Factor
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    ABSTRACT: -Epidemiological findings suggest a relationship between Alzheimer's disease (AD), inflammation and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. -Using summary statistics (p-values and odds ratios) from genome-wide association studies of over 200,000 individuals, we investigated overlap in single nucleotide polymorphisms (SNPs) associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides (TG), high- (HDL) and low-density lipoprotein (LDL) levels. We found up to 50-fold enrichment of AD SNPs for different levels of association with CRP, LDL, HDL and TG SNPs using an FDR threshold < 0.05. By conditioning on polymorphisms associated with the four phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across four independent AD cohorts (total n = 29,054 AD cases and 114,824 healthy controls) and discovered two genome-wide significant variants on chromosome 4 (rs13113697, closest gene HS3ST1, odds ratio (OR) = 1.07, 95% confidence interval (CI) = 1.05-1.11, p = 2.86 x 10(-8)) and chromosome 10 (rs7920721, closest gene ECHDC3, OR = 1.07, 95% CI = 1.04-1.11, p = 3.38 x 10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. -We demonstrate genetic overlap between AD, CRP, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci including two genome-wide significant variants conferring increased risk for Alzheimer's disease.
    Circulation 04/2015; 131(23). DOI:10.1161/CIRCULATIONAHA.115.015489 · 14.43 Impact Factor
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    Gilbert T. Feke · Bradley T. Hyman · Robert A. Stern · Louis R. Pasquale ·
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    ABSTRACT: Background: Patients with Alzheimer's disease (AD) demonstrate the narrowing of retinal veins and decreased retinal venous blood flow compared with control subjects. We assessed whether these abnormalities are present in patients with mild cognitive impairment (MCI). Methods: After the determination of the global clinical dementia rating, 52 subjects (10 AD, 21 MCI, and 21 normal controls) underwent retinal hemodynamic profiling. Blood column diameter, blood speed, and blood flow were measured in a major temporal retinal vein using retinal laser Doppler flowmetry. In addition, peripapillary retinal nerve fiber layer (RNFL) thickness was measured using optical coherence tomography. Results: Blood column diameter in AD was narrower than in both MCI (P=.004) and controls (P=.002). However, blood speed in both AD (P=.024) and MCI (P=.005) was lower than in controls. As a result, the differences in blood flow between AD and MCI (P=.036), AD and controls (P<.0001), and MCI and controls (P=.009) were significant. Although there were no differences in RNFL thickness among the groups, blood flow was correlated (P=.047) with superior RNFL thickness in the AD group, but not in the MCI (P=.40) or control (P=.84) groups. Conclusions: Retinal blood flow in MCI is intermediate between what is measured in control subjects and in AD patients. Our findings suggest that blood flow abnormalities may precede the neurodegeneration in AD.
    04/2015; 1(2). DOI:10.1016/j.dadm.2015.01.004
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    ABSTRACT: The relationship between primary age-related tauopathy (PART) and Alzheimer’s disease (AD) is currently a matter of discussion. Recently the term PART was referred to cases characterized by mainly allocortical neurofibrillary (NF) pathology (Braak stages 0-IV) with only few or no amyloid (Aβ) deposits (Thal Aβ phases 0-2) [49]. In addition, no elevated soluble Aβ was detected in this disorder [9, 46]. PART cases that lack any Aβ do not meet formal criteria for sporadic AD according to the NIA-AA guidelines [35]. These neurofibrillary tangle (NFT)+/Aβ-brains are commonly observed in extreme old age [9, 15, 19]. When associated with a high density of NFTs in the same distribution and some cognitive deficits, the disorder has been referred to as tangle-predominant senile dementia (TPSD) [27] or “tangle-only dementia” [55].The new neuropathologic criteria recommend subdividing PART cases into “definite” (Braak stage ≤IV, Thal Aβ phase 0) and “possible” (Braak stage ≤IV, Thal Aβ phase 1-2) ...
    Acta Neuropathologica 03/2015; 129(5). DOI:10.1007/s00401-015-1407-2 · 10.76 Impact Factor

Publication Stats

61k Citations
5,004.17 Total Impact Points


  • 1991-2015
    • Harvard Medical School
      • Department of Neurology
      Boston, Massachusetts, United States
  • 1990-2015
    • Massachusetts General Hospital
      • • Department of Neurology
      • • Alzheimer Research Unit
      Boston, Massachusetts, United States
  • 1990-2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2013
    • University of Massachusetts Amherst
      • Division of Biostatistics and Epidemiology
      Amherst Center, Massachusetts, United States
  • 2009-2011
    • Partners HealthCare
      • Department of Neurology
      Boston, MA, United States
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States
  • 2006-2011
    • McLaughlin Research Institute
      Great Falls, Montana, United States
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 2010
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2004-2010
    • Institute for Neurodegenerative Disorders
      New Haven, Connecticut, United States
    • American University Washington D.C.
      Washington, Washington, D.C., United States
  • 2007
    • University of Pittsburgh
      • Department of Psychiatry
      Pittsburgh, Pennsylvania, United States
  • 2005
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States
  • 1997-2004
    • Massachusetts Institute of Technology
      • Department of Brain and Cognitive Sciences
      Cambridge, Massachusetts, United States
    • The Rockefeller University
      New York City, New York, United States
  • 2000
    • Nathan Kline Institute
      Orangeburg, New York, United States
    • George Washington University
      Washington, Washington, D.C., United States
  • 1999
    • Cardiff University
      Cardiff, Wales, United Kingdom
  • 1998-1999
    • Cornell University
      Итак, New York, United States
    • University of Illinois, Urbana-Champaign
      Urbana, Illinois, United States
  • 1996
    • Mass General Hospital
      Charlestown, Rhode Island, United States
  • 1995
    • Boston University
      • Center for Polymer Studies
      Boston, Massachusetts, United States
  • 1992
    • University of Toronto
      • Department of Psychiatry
      Toronto, Ontario, Canada
  • 1987-1991
    • University of Iowa
      • Department of Neurology
      Iowa City, Iowa, United States
  • 1985
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States