Restricted accessResearch articleFirst published online 2023-06-13
Comparison of Clinical,Genetic,and Pathologic Features of Limbic and Diffuse Transactive Response DNA-Binding Protein 43 Pathology in Alzheimer’s Disease Neuropathologic Spectrum
Increasing evidence suggests that TAR DNA-binding protein 43 (TDP-43) pathology in Alzheimer’s disease (AD), or AD-TDP, can be diffuse or limbic-predominant. Understanding whether diffuse AD-TDP has genetic, clinical, and pathological features that differ from limbic AD-TDP could have clinical and research implications.
Objective:
To better characterize the clinical and pathologic features of diffuse AD-TDP and differentiate it from limbic AD-TDP.
Methods:
363 participants from the Mayo Clinic Study of Aging, Alzheimer’s Disease Research Center, and Neurodegenerative Research Group with autopsy confirmed AD and TDP-43 pathology were included. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. AD-TDP pathology distribution was assessed using the Josephs 6-stage scale. Stages 1–3 were classified as Limbic, those 4–6 as Diffuse. Multivariable logistic regression was used to identify clinicopathologic features that independently predicted diffuse pathology.
Results:
The cohort was 61% female and old at onset (median: 76 years [IQR:70–82]) and death (median: 88 years [IQR:82–92]). Fifty-four percent were Limbic and 46% Diffuse. Clinically, ∼10–20% increases in odds of being Diffuse associated with 5-year increments in age at onset (p = 0.04), 1-year longer disease duration (p = 0.02), and higher Neuropsychiatric Inventory scores (p = 0.03), while 15-second longer Trailmaking Test-B times (p = 0.02) and higher Block Design Test scores (p = 0.02) independently decreased the odds by ~ 10–15%. There was evidence for association of APOEɛ4 allele with limbic AD-TDP and of TMEM106B rs3173615 C allele with diffuse AD-TDP. Pathologically, widespread amyloid-β plaques (Thal phases: 3–5) decreased the odds of diffuse TDP-43 pathology by 80–90%, while hippocampal sclerosis increased it sixfold (p < 0.001).
Conclusion:
Diffuse AD-TDP shows clinicopathologic and genetic features different from limbic AD-TDP.
WilsonAC, DuggerBN, DicksonDW, WangDS (2011) TDP-43 in aging and Alzheimer’s disease - a review. Int J Clin Exp Pathol4, 147–155.
5.
ArnoldSJ, DuggerBN, BeachTG (2013) TDP-43 deposition in prospectively followed, cognitively normal elderly individuals: Correlation with argyrophilic grains but not other concomitant pathologies. Acta Neuropathol126, 51–57.
6.
NagS, YuL, WilsonRS, ChenEY, BennettDA, SchneiderJA (2017) TDP-43 pathology and memory impairment in elders without pathologic diagnoses of AD or FTLD. Neurology88, 653–660.
7.
Amador-OrtizC, LinWL, AhmedZ, PersonettD, DaviesP, DuaraR, Graff-RadfordNR, HuttonML, DicksonDW (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol61, 435–445.
8.
HigashiS, IsekiE, YamamotoR, MinegishiM, HinoH, FujisawaK, TogoT, KatsuseO, UchikadoH, FurukawaY, KosakaK, AraiH (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res1184, 284–294.
WennbergAM, TosakulwongN, LesnickTG, MurrayME, WhitwellJL, LiesingerAM, PetrucelliL, BoeveBF, ParisiJE, KnopmanDS, PetersenRC, DicksonDW, JosephsKA (2018) Association of apolipoprotein E ɛ4 with transactive response DNA-binding protein 43. JAMA Neurol75, 1347–1354.
11.
GauthreauxKM, TeylanMA, KatsumataY, MockC, CulhaneJE, ChenYC, ChanKCG, FardoDW, DuganAJ, CykowskiMD, JichaGA, KukullWA, NelsonPT (2022) Limbic-predominant age-related TDP-43 encephalopathy: Medical and pathologic factors associated with comorbid hippocampal sclerosis. Neurology98, e1422–e1433.
12.
SpinaS, La JoieR, PetersenC, NolanAL, CuevasD, CosmeC, HepkerM, HwangJH, MillerZA, HuangEJ, KarydasAM, GrantH, BoxerAL, Gorno-TempiniML, RosenHJ, KramerJH, MillerBL, SeeleyWW, RabinoviciGD, GrinbergLT (2021) Comorbid neuropathological diagnoses in early versus late-onset Alzheimer’s disease. Brain144, 2186–2198.
13.
JosephsKA, WhitwellJL, WeigandSD, MurrayME, TosakulwongN, LiesingerAM, PetrucelliL, SenjemML, KnopmanDS, BoeveBF, IvnikRJ, SmithGE, JackCRJr, ParisiJE, PetersenRC, DicksonDW (2014) TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol127, 811–824.
JosephsKA, MurrayME, TosakulwongN, WeigandSD, SerieAM, PerkersonRB, MatchettBJ, JackCRJr., KnopmanDS, PetersenRC, ParisiJE, PetrucelliL, BakerM, RademakersR, WhitwellJL, DicksonDW (2019) Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains. Acta Neuropathol137, 227–238.
18.
BuciucM, WhitwellJL, TosakulwongN, WeigandSD, MurrayME, BoeveBF, KnopmanDS, ParisiJE, PetersenRC, DicksonDW, JosephsKA (2020) Association between transactive response DNA-binding protein of 43 kDa type and cognitive resilience to Alzheimer’s disease: A case-control study. Neurobiol Aging92, 92–97.
19.
CarlosAF, TosakulwongN, WeigandSD, BoeveBF, KnopmanDS, PetersenRC, NguyenA, ReichardRR, MurrayME, DicksonDW, JosephsKA (2022) Frequency and distribution of TAR DNA-binding protein 43 (TDP-43) pathology increase linearly with age in a large cohort of older adults with and without dementia. Acta Neuropathol144, 159–160.
20.
CairnsNJ, BigioEH, MackenzieIRA, NeumannM, LeeVMY, HatanpaaKJ, WhiteCL, SchneiderJA, GrinbergLT, HallidayG, DuyckaertsC, LoweJS, HolmIE, TolnayM, OkamotoK, YokooH, MurayamaS, WoulfeJ, MunozDG, DicksonDW, IncePG, TrojanowskiJQ, MannDMA (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: Consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol114, 5–22.
21.
FolsteinMF, FolsteinSE, McHughPR (1975) “Mini-mental state”. A practical method for grading the cognitivestate of patients for the clinician. J Psychiatr Res12, 189–198.
22.
HughesCP, BergL, DanzigerWL, CobenLA, MartinRL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry140, 566–572.
RobertsRO, GedaYE, KnopmanDS, ChaRH, PankratzVS, BoeveBF, IvnikRJ, TangalosEG, PetersenRC, RoccaWA (2008) The Mayo Clinic Study of Aging: Design and sampling, participation, baseline measures and sample characteristics. Neuroepidemiology30, 58–69.
JosephsKA, TsuboiY, CooksonN, WattH, DicksonDW (2004) Apolipoprotein E ɛ4 is a determinant for Alzheimer-type pathologic features in tauopathies, synucleinopathies, and frontotemporal degeneration. Arch Neurol61, 1579–1584.
34.
JosephsKA, DuffyJR, ClarkHM, UtianskiRL, StrandEA, MachuldaMM, BothaH, MartinPR, PhamNTT, StierwaltJ, AliF, BuciucM, BakerM, Fernandez De CastroCH, SpychallaAJ, SchwarzCG, ReidRI, SenjemML, JackCRJr, LoweVJ, BigioEH, ReichardRR, PolleyEJ, Ertekin-TanerN, RademakersR, DeTureMA, RossOA, DicksonDW, WhitwellJL (2021) A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech. Nat Commun12, 3452.
(1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging18, S1–S2.
37.
MontineTJ, PhelpsCH, BeachTG, BigioEH, CairnsNJ, DicksonDW, DuyckaertsC, FroschMP, MasliahE, MirraSS, NelsonPT, SchneiderJA, ThalDR, TrojanowskiJQ, VintersHV, HymanBT (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: A practical approach. Acta Neuropathol123, 1–11.
MirraSS, HeymanA, McKeelD, SumiSM, CrainBJ, BrownleeLM, VogelFS, HughesJP, van BelleG, BergL (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology41, 479–486.
40.
ThalDR, RübU, OrantesM, BraakH (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology58, 1791–1800.
41.
BeachTG, AdlerCH, LueL, SueLI, BachalakuriJ, Henry-WatsonJ, SasseJ, BoyerS, ShirohiS, BrooksR, EschbacherJ, WhiteCL3rd, AkiyamaH, CavinessJ, ShillHA, ConnorDJ, SabbaghMN, WalkerDG (2009) Unified staging system for Lewy body disorders: Correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol117, 613–634.
42.
DicksonDW, DaviesP, BevonaC, Van HoevenKH, FactorSM, GroberE, AronsonMK, CrystalHA (1994) Hippocampal sclerosis: A common pathological feature of dementia in very old (>or=80 years of age) humans. Acta Neuropathol88, 212–221.
43.
JosephsKA, MartinPR, WeigandSD, TosakulwongN, BuciucM, MurrayME, PetrucelliL, SenjemML, SpychallaAJ, KnopmanDS, BoeveBF, PetersenRC, ParisiJE, DicksonDW, JackCR, WhitwellJL (2020) Protein contributions to brain atrophy acceleration in Alzheimer’s disease and primary age-related tauopathy. Brain143, 3463–3476.
McDonaldCR, GharapetianL, McEvoyLK, Fennema-NotestineC, HaglerDJJr, HollandD, DaleAM (2012) Relationship between regional atrophy rates and cognitive decline in mild cognitive impairment. Neurobiol Aging33, 242–253.
46.
ZakzanisKK, MrazR, GrahamSJ (2005) An fMRI study of the Trail Making Test. Neuropsychologia43, 1878–1886.
47.
HazlettKE, FigueroaCM, NielsonKA (2015) Executive functioning and risk for Alzheimer’s disease in the cognitively intact: Family history predicts Wisconsin Card Sorting Test performance. Neuropsychology29, 582–591.
48.
PerryRJ, HodgesJR (1999) Attention and executive deficits in Alzheimer’s disease. A critical review. Brain122(Pt 3), 383–404.
49.
Duarte-AbrittaB, SánchezSM, AbulafiaC, GustafsonDR, VázquezS, SevleverG, CastroMN, FiorentiniL, VillarrealMF, GuinjoanSM (2021) Amyloid and anatomical correlates of executive functioning in middle-agedoffspring of patients with late-onset Alzheimer’s disease. Psychiatry Res Neuroimaging316, 111342.
50.
KangSH, ParkYH, LeeD, KimJP, ChinJ, AhnY, ParkSB, KimHJ, JangH, JungYH, KimJ, LeeJ, KimJS, CheonBK, HahnA, LeeH, NaDL, KimYJ, SeoSW (2019) The cortical neuroanatomy related to specific neuropsychological deficits in Alzheimer’s continuum. Dement Neurocogn Disord18, 77–95.
51.
ChaseTN, FedioP, FosterNL, BrooksR, Di ChiroG, MansiL (1984) Wechsler Adult Intelligence Scale performance. Cortical localization by fluorodeoxyglucose F 18-positron emission tomography. Arch Neurol41, 1244–1247.
NelsonPT, AbnerEL, SchmittFA, KryscioRJ, JichaGA, SantacruzK, SmithCD, PatelE, MarkesberyWR (2009) Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer disease. J Neuropathol Exp Neurol68, 774–784.
59.
BraakH, Del TrediciK (2014) Are cases with tau pathology occurring in the absence of Aβ deposits part of the AD-related pathological process?Acta Neuropathol128, 767–772.
60.
HermanAM, KhandelwalPJ, StanczykBB, RebeckGW, MoussaCE (2011) β-amyloid triggers ALS-associatedTDP-43 pathology in AD models. Brain Res1386, 191–199.
61.
JamerlanA, AnSSA (2020) The influence of Aβ-dependent and independent pathways on TDP-43 proteinopathy in Alzheimer’s disease: A possible connection to LATE-NC. Neurobiol Aging95, 161–167.
62.
ChangXL, TanMS, TanL, YuJT (2016) The role of TDP-43 in Alzheimer’s disease. Mol Neurobiol53, 3349–3359.
63.
CohenTJ, LeeVM, TrojanowskiJQ (2011) TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies. Trends Mol Med17, 659–667.
64.
PaolicelliRC, JawaidA, HenstridgeCM, ValeriA, MerliniM, RobinsonJL, LeeEB, RoseJ, AppelS, LeeVM, TrojanowskiJQ, Spires-JonesT, SchulzPE, RajendranL (2017) TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron95, 297–308.e296.
65.
MackenzieIR, NeumannM, BaborieA, SampathuDM, Du PlessisD, JarosE, PerryRH, TrojanowskiJQ, MannDM, LeeVM (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol122, 111–113.
66.
LeeEB, PortaS, Michael BaerG, XuY, SuhE, KwongLK, ElmanL, GrossmanM, LeeVM, IrwinDJ, Van DeerlinVM, TrojanowskiJQ (2017) Expansion of the classification of FTLD-TDP: Distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol134, 65–78.
67.
JosephsKA, StrohA, DuggerB, DicksonDW (2009) Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes. Acta Neuropathol118, 349–358.
Nakashima-YasudaH, UryuK, RobinsonJ, XieSX, HurtigH, DudaJE, ArnoldSE, SiderowfA, GrossmanM, LeverenzJB, WoltjerR, LopezOL, HamiltonR, TsuangDW, GalaskoD, MasliahE, KayeJ, ClarkCM, MontineTJ, LeeVM, TrojanowskiJQ (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol114, 221–229.
71.
AgrawalS, YuL, NagS, ArfanakisK, BarnesLL, BennettDA, SchneiderJA (2021) The association of Lewy bodies with limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes and their role in cognition and Alzheimer’s dementia in older persons. Acta Neuropathol Commun9, 156.
72.
KogaS, LinWL, WaltonRL, RossOA, DicksonDW (2018) TDP-43 pathology in multiple system atrophy: Colocalization of TDP-43 and α-synuclein in glial cytoplasmic inclusions. Neuropathol Appl Neurobiol44, 707–721.
73.
FarrerLA, CupplesLA, HainesJL, HymanB, KukullWA, MayeuxR, MyersRH, Pericak-VanceMA, RischN, van DuijnCM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA278, 1349–1356.
74.
CorderEH, SaundersAM, StrittmatterWJ, SchmechelDE, GaskellPC, SmallGW, RosesAD, HainesJL, Pericak-VanceMA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science261, 921–923.
75.
SandoSB, MelquistS, CannonA, HuttonML, SletvoldO, SaltvedtI, WhiteLR, LydersenS, AaslyJO (2008) APOE epsilon 4 lowers age at onset and is a high risk factor for Alzheimer’s disease; a case control study from central Norway. BMC Neurol8, 9.
76.
KokE, HaikonenS, LuotoT, HuhtalaH, GoebelerS, HaapasaloH, KarhunenPJ (2009) Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol65, 650–657.
77.
PolvikoskiT, SulkavaR, HaltiaM, KainulainenK, VuorioA, VerkkoniemiA, NiinistöL, HalonenP, KontulaK (1995) Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med333, 1242–1247.
78.
NicholsonAM, RademakersR (2016) What we know about TMEM106B in neurodegeneration. Acta Neuropathol132, 639–651.
