Elsevier

Neurobiology of Disease

Volume 125, May 2019, Pages 67-76
Neurobiology of Disease

TDP-43 proteinopathy in aging: Associations with risk-associated gene variants and with brain parenchymal thyroid hormone levels

https://doi.org/10.1016/j.nbd.2019.01.013Get rights and content

Highlights

  • Clinical, pathological, genetic, and biochemical parameters were analyzed from 136 subjects.

  • ABCC9 and SLCO1A2 genes are near human brain thyroid hormone receptor gene.

  • Cases with ABCC9 and SLCO1A2 trended toward lower brain T3/T4 (thyroid hormone) ratio.

  • Cases with lowest brain T3/T4 ratios had elevated risk for hippocampal sclerosis pathology.

  • Thyroid hormone dysregulation is implicated in HS/TDP-43 pathology but more work is required.

Abstract

TDP-43 proteinopathy is very prevalent among the elderly (affecting at least 25% of individuals over 85 years of age) and is associated with substantial cognitive impairment. Risk factors implicated in age-related TDP-43 proteinopathy include commonly inherited gene variants, comorbid Alzheimer's disease pathology, and thyroid hormone dysfunction. To test parameters that are associated with aging-related TDP-43 pathology, we performed exploratory analyses of pathologic, genetic, and biochemical data derived from research volunteers in the University of Kentucky Alzheimer's Disease Center autopsy cohort (n = 136 subjects). Digital pathologic methods were used to discriminate and quantify both neuritic and intracytoplasmic TDP-43 pathology in the hippocampal formation. Overall, 46.4% of the cases were positive for TDP-43 intracellular inclusions, which is consistent with results in other prior community-based cohorts. The pathologies were correlated with hippocampal sclerosis of aging (HS-Aging) linked genotypes. We also assayed brain parenchymal thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) levels. In cases with SLCO1A2/IAPP or ABCC9 risk associated genotypes, the T3/T4 ratio tended to be reduced (p = .051 using 2-tailed statistical test), and in cases with low T3/T4 ratios (bottom quintile), there was a higher likelihood of HS-Aging pathology (p = .025 using 2-tailed statistical test). This is intriguing because the SLCO1A2/IAPP and ABCC9 risk associated genotypes have been associated with altered expression of the astrocytic thyroid hormone receptor (protein product of the nearby gene SLCO1C1). These data indicate that dysregulation of thyroid hormone signaling may play a role in age-related TDP-43 proteinopathy.

Introduction

Hippocampal sclerosis of aging (HS-Aging) is a neurodegenerative disease, distinct from Alzheimer's disease (AD) (Montine et al., 2012; Nelson et al., 2013), yet often mimicking AD clinically (Brenowitz et al., 2014; Murray et al., 2014; Nelson et al., 2013; Pao et al., 2011; Zarow et al., 2012). HS-Aging is a very prevalent condition, affecting 10–25% of persons over age 85 (Brenowitz et al., 2014; Kero et al., 2018; Leverenz et al., 2002; Nelson et al., 2011; Zarow et al., 2012). The defining characteristics of HS-Aging are neuronal loss, astrocytosis, and transactive response DNA binding protein of 43 kDa (TDP-43) pathology in the hippocampus (Amador-Ortiz and Dickson, 2008; Nelson et al., 2011), and these pathologic features are specifically associated with cognitive impairment (Brenowitz et al., 2014; Murray et al., 2014; Nag et al., 2017; Nelson et al., 2010). “TDP-43 pathology” refers to phosphorylated TDP-43 detected via immunohistochemistry, and localized in cytoplasmic, nuclear, perivascular, and/or neurite-like structures. Currently, the upstream disease-driving mechanisms associated with TDP-43 pathology and HS-Aging are not well understood. Thyroid hormone (TH) signaling, and/or comorbid AD-type plaques and tangles, may affect persons' vulnerability to HS-Aging pathology, and disease susceptibility factors may also overlap with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) (Dickson et al., 1994; Josephs et al., 2008; Katsumata et al., 2018; Nelson et al., 2013, Nelson et al., 2016a; Zarow et al., 2008, Zarow et al., 2012).

The identification of genetic risk factors for HS-Aging has provided insights into disease mechanisms. Specific variants in genes (GRN and TMEM106B) that previously were associated with risk for FTLD-TDP, were later also linked with risk for HS-Aging pathology and age-related TDP-43 pathology, which probably represent a disease continuum previously referred to together as cerebral age-related TDP-43 pathology with sclerosis (Cykowski et al., 2017; Dickson et al., 2010, Dickson et al., 2015; Murray et al., 2014; Nelson et al., 2016b; Rutherford et al., 2012; Van Langenhove et al., 2012). These prior studies support the hypothesis that GRN and TMEM106B gene variants influence the brain's vulnerability to developing TDP-43 pathology. There also is compelling evidence that TDP-43 pathology is comorbid with advanced AD-type plaques and tangles in the medial temporal lobe structures in many persons (Davidson et al., 2011; Josephs et al., 2008, Josephs et al., 2016; Nelson et al., 2018). However, the associations between GRN/TMEM106B gene variants, AD-type pathology, and TDP-43 pathology are inconsistent, so other factors must also be relevant.

The only genome-wide association study published to date that focused exclusively on autopsy-confirmed HS-Aging pathology as the endophenotype identified a single nucleotide polymorphism (SNP) in ABCC9 that was associated with risk for HS-Aging pathology (Nelson et al., 2014). In a non-overlapping group of autopsied subjects, the association between the same ABCC9 SNP and HS-Aging pathology was replicated (Nelson et al., 2015b). These same gene variants in ABCC9 were associated with brain atrophy (Nho et al., 2016), and nearby polymorphisms were also linked to dementia risk in APOE ε4(-) individuals (D'Introno et al., 2006; Mayeux et al., 2002; Pericak-Vance et al., 1997; Scott et al., 1999).

Approximately one million base-pairs away on Chr. 12p12 from ABCC9 is SLCO1C1 (Jansen et al., 2005), which encodes the brain's main thyroid hormone (TH) importing protein. Importantly, Roostaei et al. discovered a novel Chr. 12p12 SNP based on its association with non-Aβ neurodegeneration (Roostaei et al., 2016), and this SNP status also was shown to be associated with variability in SLCO1C1 expression in human brain (Nelson et al., 2016a). Both ABCC9 and SLCO1C1 transcripts are highly expressed in human astrocytes (Nelson et al., 2016a), and their functions appear interconnected. Astrocytes import TH from blood into brain, process blood-borne thyroxine (T4) hormone into the biologically active triiodothyronine (T3), and deliver T3 to neurons (Heuer and Visser, 2009; Morte and Bernal, 2014). The ABCC9 polypeptide (also known as SUR2) serves as a metabolic sensor that helps couple energy needs with blood flow and intracellular signaling (Nelson et al., 2015a; Nichols, 2006; Nichols et al., 2013), whereas the TH importing SLCO1C1 polypeptide is also known as OATP1C1 and Thyroxine transporter (Bernal et al., 2015; Jansen et al., 2005). TH is a potent metabolic regulating agent (McAninch and Bianco, 2014; Mullur et al., 2014; Trentin, 2006; van der Deure et al., 2008), whereas TH dysregulation has been previously associated with dementia risk (Chaker et al., 2016; Mafrica and Fodale, 2008; Sampaolo et al., 2005; Tan and Vasan, 2009) and HS-Aging specifically (Nelson et al., 2016a; Trieu, 2018). Together, these observations provide the basis for a plausible mechanistic hypothesis: gene variants that affect TH levels in the brain appear to be relevant to TDP-43/HS-Aging pathology. Much remains unknown about the biochemical landscape of the aged brain, and the impact of genetics. For example, a separate GWAS found that a SNP (rs9637454) in a gene encoding a distinct K+ channel modifying protein – KCNMB2 – was also linked to HS-Aging risk (Beecham et al., 2014).

The main objectives of the present study were to analyze the pathologic, genetic, and biochemical parameters that can be correlated with TDP-43/HS-Aging pathology in the aged human hippocampus. We tested whether gene variants associated with altered HS-Aging risk also are associated with variation in brain TH processing. The data were gathered from research volunteers followed to autopsy in the University of Kentucky Alzheimer's Disease Center (UK-ADC) cohort. Results of these analyses provide support of the hypothesis that TH related pathways in the brain may alter vulnerability to TDP-43 pathology and HS-Aging.

Section snippets

UK-ADC autopsy cohort

Details of UK-ADC research volunteers' recruitment, the overall cohort inclusion/exclusion criteria, and clinical assessments were described previously (Jicha et al., 2012; Schmitt et al., 2012). Briefly, older adult volunteers (most recruited while cognitively normal) agreed to be followed annually for cognitive, physical, and neurological examination and to donate their brain at the time of death, with a provision to allow genetic testing for research purposes. Protocols and informed consent

Results

An underlying a priori hypothesis for the current study is shown in Fig. 1, and the workflow is depicted in Supplemental Fig. 1. The overall goals were to analyze genetic, clinical, pathologic, and biochemical (related to TH) variables, in order to test hypotheses related to pathogenesis of TDP-43 pathology and HS-Aging. The data analyzed derived from a convenience sample based on availability of brain tissue for biochemistry, with the goal of including a relatively broad range of ages,

Discussion

To explore evidence of disease-associated mechanisms relevant to TDP-43 proteinopathy in aged human brains, a multimodal (clinical, pathologic, genetic, and biochemical) data set was generated and analyzed from volunteers participating in a well-characterized autopsy cohort. As in another high-quality community-based cohort (Nag et al., 2018), slightly under 50% of the cases in the present study were positive for TDP-43 inclusions. A focal point of the present study was T3 and T4 levels in

Competing interests

The authors report no competing interests.

Funding support

Funding included grants P30 AG028383, R01 AG057187, and R01 AG042475 from the National Institute on Aging (NIA)/National Institutes of Health (NIH).

Acknowledgements

We are deeply grateful to all of the study participants, clinical workers, and researchers that made this study possible. Special thanks to Sonya Anderson and Ela Patel for work in biobanking and neurohistology.

References (98)

  • M.M. Kaplan

    Prevalence of abnormal thyroid function test results in patients with acute medical illnesses

    Am. J. Med.

    (1982)
  • Y. Katsumata

    Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2

    Neurobiol. Aging

    (May 2017)
  • Y.Y. Liu et al.

    Thyroid hormone and the brain: mechanisms of action in development and role in protection and promotion of recovery after brain injury

    Pharmacol. Ther.

    (2018)
  • R. Mayeux

    Chromosome-12 mapping of late-onset Alzheimer disease among Caribbean Hispanics

    Am. J. Hum. Genet.

    (2002)
  • P.T. Nelson

    ABCC9/SUR2 in the brain: implications for hippocampal sclerosis of aging and a potential therapeutic target

    Ageing Res. Rev.

    (2015)
  • P. Sadana

    Anti-edema action of thyroid hormone in MCAO model of ischemic brain stroke: possible association with AQP4 modulation

    J. Neurol. Sci.

    (2015)
  • S. Suda

    Low free triiodothyronine predicts poor functional outcome after acute ischemic stroke

    J. Neurol. Sci.

    (2016)
  • E. Taylor et al.

    Evolution of thyroid hormone signaling in animals: Non-genomic and genomic modes of action

    Mol. Cell. Endocrinol.

    (2017)
  • Y. Wang

    Low T3 levels as a predictor marker predict the prognosis of patients with acute ischemic stroke

    Int. J. Neurosci.

    (2017)
  • E.L. Abner

    Diffuse amyloid-beta plaques, neurofibrillary tangles, and the impact of APOE in elderly persons' brains lacking neuritic amyloid plaques

    J. Alzheimers Dis.

    (2018)
  • A.A. Akintola

    Subclinical hypothyroidism and cognitive function in people over 60 years: a systematic review and meta-analysis

    Front. Aging Neurosci.

    (2015)
  • J. Attems

    Quantitative neuropathological assessment to investigate cerebral multi-morbidity

    Alzheimers Res. Ther.

    (2014)
  • A.D. Bachstetter

    Disease-related microglia heterogeneity in the hippocampus of Alzheimer's disease, dementia with Lewy bodies, and hippocampal sclerosis of aging

    Acta Neuropathol. Commun.

    (2015)
  • G.W. Beecham

    Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias

    PLoS Genet.

    (2014)
  • J. Bernal

    Thyroid hormone transporters--functions and clinical implications

    Nat. Rev. Endocrinol.

    (2015)
  • W.D. Brenowitz

    Hippocampal sclerosis of aging is a key Alzheimer's disease mimic: clinical-pathologic correlations and comparisons with both alzheimer's disease and non-tauopathic frontotemporal lobar degeneration

    J. Alzheimers Dis.

    (2014)
  • L. Chaker

    Thyroid function and the risk of dementia: the Rotterdam Study

    Neurology

    (2016)
  • S.J. Crockford

    Evolutionary roots of iodine and thyroid hormones in cell-cell signaling

    Integr. Comp. Biol.

    (2009)
  • M.D. Cykowski

    Hippocampal Sclerosis in older patients: practical examples and guidance with a focus on cerebral age-related TDP-43 with sclerosis

    Arch. Pathol. Lab. Med.

    (2017)
  • Y.S. Davidson

    TDP-43 pathological changes in early onset familial and sporadic Alzheimer's disease, late onset Alzheimer's disease and Down's syndrome: association with age, hippocampal sclerosis and clinical phenotype

    Acta Neuropathol.

    (2011)
  • J.D. Davis

    Thyroid hormone levels in the prefrontal cortex of post-mortem brains of Alzheimer's disease patients

    Curr. Aging Sci.

    (2008)
  • F. Despa et al.

    Amylin: what might be its role in Alzheimer's disease and how could this affect therapy?

    Expert Rev. Proteomics.

    (2013)
  • D.W. Dickson

    Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans

    Acta Neuropathol.

    (1994)
  • D.W. Dickson

    Common variant in GRN is a genetic risk factor for hippocampal sclerosis in the elderly

    Neurodegener. Dis.

    (2010)
  • D.W. Dickson

    The TMEM106B locus and TDP-43 pathology in older persons without FTLD

    Neurology

    (2015)
  • J. Gal

    Detergent insoluble proteins and inclusion body-like structures immunoreactive for PRKDC/DNA-PK/DNA-PKcs, FTL, NNT, and AIFM1 in the amygdala of cognitively impaired elderly persons

    J. Neuropathol. Exp. Neurol.

    (2018)
  • H. Heuer et al.

    Minireview: pathophysiological importance of thyroid hormone transporters

    Endocrinology

    (2009)
  • E.T. Ighodaro

    Challenges and considerations related to studying dementia in Blacks/African Americans

    J. Alzheimers Dis.

    (2017)
  • J. Jansen

    Thyroid hormone transporters in health and disease

    Thyroid

    (2005)
  • K.A. Josephs

    Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype

    Neurology

    (2008)
  • K.A. Josephs

    Updated TDP-43 in Alzheimer's disease staging scheme

    Acta Neuropathol.

    (2016)
  • Y. Katsumata

    Dichotomous scoring of TDP-43 proteinopathy from specific brain regions in 27 academic research centers: associations with Alzheimer's disease and cerebrovascular disease pathologies

    Acta Neuropathol. Commun.

    (2018)
  • M. Kero

    Hippocampal sclerosis in the oldest old: a finnish population-based study

    J. Alzheimers Dis.

    (2018)
  • M. Leino

    Transactive DNA binding protein 43 rather than other misfolded proteins in the brain is associated with islet amyloid polypeptide in pancreas in aged subjects with diabetes mellitus

    J. Alzheimers Dis.

    (2017)
  • J.B. Leverenz

    Clinical and neuropathological characteristics of hippocampal sclerosis: a community-based study

    Arch. Neurol.

    (2002)
  • W.L. Lin

    Transactivation response DNA-binding protein 43 microvasculopathy in frontotemporal degeneration and familial Lewy body disease

    J. Neuropathol. Exp. Neurol.

    (2009)
  • R.C. Lu

    TMEM106B and APOE polymorphisms interact to confer risk for late-onset Alzheimer's disease in Han Chinese

    J. Neural Transm. (Vienna)

    (2014)
  • M.J. Machiela et al.

    LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants

    Bioinformatics

    (2015)
  • F. Mafrica et al.

    Thyroid function, Alzheimer's disease and postoperative cognitive dysfunction: a tale of dangerous liaisons?

    J. Alzheimers Dis.

    (2008)
  • Cited by (0)

    View full text