There is an urgent need to identify the earliest biological changes within the neuropathological cascade of Alzheimer’s disease (AD) processes. Recent findings in a murine model of AD showed significant preclinical loss of dopaminergic neurons in the ventral tegmental area (VTA), accompanied by reduced hippocampal innervation and declining memory. It is unknown if these observations can be translated in humans.
Objective:
We tested the hypothesis that VTA volume is associated with the typical clinical markers of AD in a cohort of patients and healthy controls.
Methods:
Structural and resting state functional MRI scans, and neuropsychological scores were acquired for 51 healthy adults, 30 patients with a diagnosis of mild cognitive impairment, and 29 patients with a diagnosis of AD dementia. VTA volume was quantified together with other control nuclei. The association between nuclei volume, hippocampal size, memory performance, and linguistic-executive skills was tested. The effect of VTA functional connectivity was also tested.
Results:
VTA size, but not of control nuclei, yielded a strong association with both hippocampal size and memory competence (but not linguistic-executive performance), and this was particularly strong in healthy adults. In addition, functional connectivity between the VTA and hippocampus was significantly associated with both markers of AD.
Conclusion:
Diminished dopaminergic VTA activity may be crucial for the earliest pathological features of AD and might suggest new strategies for early treatment. Memory encoding processes may represent cognitive operations susceptible to VTA neurodegeneration.
FiestKM, RobertsJI, MaxwellCJ, HoganDB, SmithEE, FrolkisA, CohenA, KirkA, PearsonD, PringsheimT, Venegas-TorresA, JettéN (2016) The prevalence and incidence of dementia due to Alzheimer’s disease: A systematic review and meta-analysis.. Can J Neurol Sci43, S51–S82.
2.
SelkoeDJ, HardyJ (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med8, 595–608.
3.
HerrupK (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci18, 794–799.
4.
SnowdonDA, GreinerLH, MarkesberyWR (2000) Linguistic ability in early life and the neuropathology of Alzheimer’s disease and cerebrovascular disease. Findings from the nun study. Ann N Y Acad Sci903, 34–38.
5.
BraakH, Del TrediciK (2012) Where, when, and in what form does sporadic Alzheimer’s disease begin?Curr Opin Neurol25, 708–714.
6.
NobiliA, LatagliataEC, ViscomiMT, CavallucciV, CutuliD, GiacovazzoG, KrashiaP, RizzoFR, MarinoR, FedericiM, De BartoloP, AversaD, Dell’AcquaMC, CordellaA, SancandiM, KellerF, PetrosiniL, Puglisi-AllegraS, MercuriNB, CoccurelloR, BerrettaN, D’AmelioM (2017) Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat Commun8, 14727.
7.
WinbladB, PalmerK, KivipeltoM, JelicV, FratiglioniL, WahlundLO, NordbergA, BäckmanL, AlbertM, AlmkvistO, AraiH, BasunH, BlennowK, de LeonM, DeCarliC, ErkinjunttiT, GiacobiniE, GraffC, HardyJ, JackC, JormA, RitchieK, van DuijnC, VisserP, PetersenRC (2004) Mild cognitive impairment-beyond controversies, towards a consensus: Report of the International Working Group on Mild Cognitive Impairment. J Intern Med256, 240–246.
8.
AlbertMS, DeKoskyST, DicksonD, DuboisB, FeldmanHH, FoxNC, GamstA, HoltzmanDM, JagustWJ, PetersenRC, SnyderPJ, CarrilloMC, ThiesB, PhelpsCH (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 270–279.
9.
HornerMD, TeichnerG, KortteKB, HarveyRT (2002) Construct validity of the Babcock Story Recall Test. Appl Neuropsychol9, 114–116.
10.
MeinzerM, FlaischT, WilserL, EulitzC, RockstrohB, ConwayT, Gonzalez-RothiL, CrossonB (2009) Neural signatures of semantic and phonemic fluency in young and old adults. J Cogn Neurosci21, 2007–2018
.
11.
FolsteinMF, FolsteinSE, McHughPR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res12, 189–198.
MaldjianJA, LaurientiPJ, KraftRA, BurdetteJH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage19, 1233–1239.
14.
GuH, SalmeronBJ, RossTJ, GengX, ZhanW, SteinEA, YangY (2010) Mesocorticolimbic circuits are impaired in chronic cocaine users as demonstrated by resting-state functional connectivity. Neuroimage53, 593–601.
15.
ZhangJT, MaSS, YipSW, WangLJ, ChenC, YanCG, LiuL, LiuB, DengLY, LiuQX, FangXY (2015) Decreased functional connectivity between ventral tegmental area and nucleus accumbens in Internet gaming disorder: Evidence from resting state functional magnetic resonance imaging. Behav Brain Funct11, 37.
16.
BrettM, AntonJL, ValabregueR, PolineJB (2002) Region of interest analysis using an SPM toolbox [abstract]. Neuroimage16, abstract497.
17.
SchulteT, Müller-OehringEM, ChanraudS, RosenbloomMJ, PfefferbaumA, SullivanEV (2011) Age-related reorganization of functional networks for successful conflict resolution: A combined functional and structural MRI study. Neurobiol Aging32, 2075–2090.
18.
CardosoMJ, LeungK, ModatM, KeihaninejadS, CashD, BarnesJ, FoxNC, OurselinS, Alzheimer’s Disease NeuroimagingInitiative (2013) STEPS: Similarity and Truth Estimation for Propagated Segmentations and its application to hippocampal segmentation and brain parcelation. Med Image Anal17, 671–684.
19.
De MarcoM, MeneghelloF, DuzziD, RigonJ, PilosioC, VenneriA (2016) Cognitive stimulation of the default-mode network modulates functional connectivity in healthy aging. Brain Res Bull121, 26–41.
20.
ColemanPD, MastroeniD (2017) A call for new approaches to Alzheimer’s disease research. Neurobiol Aging57, iii–iv.
21.
HallidayGM, TörkI (1986) Comparative anatomy of the ventromedial mesencephalic tegmentum in the rat, cat, monkey and human. J Comp Neurol252, 423–445.
22.
MargolisEB, LockH, HjelmstadGO, FieldsHL (2006) The ventral tegmental area revisited: Is there an electrophysiological marker for dopaminergic neurons?J Physiol577, 907–924.
23.
BourdyR, BarrotM (2012) A new control center for dopaminergic systems: Pulling the VTA by the tail. Trends Neurosci35, 681–690.
BariselliS, GlangetasC, TzanoulinouS, BelloneC (2016) Ventral tegmental area subcircuits process rewarding and aversive experiences. J Neurochem139, 1071–1080.
26.
ChaJ, CarlsonJM, DedoraDJ, GreenbergT, ProudfitGH, Mujica-ParodiLR (2014) Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder. J Neurosci34, 5855–5860.
27.
YamashitaF, SasakiM, FukumotoK, OtsukaK, UwanoI, KamedaH, EndohJ, SakaiA (2016) Detection of changes in the ventral tegmental area of patients with schizophrenia using neuromelanin-sensitive MRI. Neuroreport27, 289–294.
28.
KahnI, ShohamyD (2013) Intrinsic connectivity between the hippocampus, nucleus accumbens, and ventral tegmental area in humans. Hippocampus23, 187–192.
29.
MurtyVP, ShermohammedM, SmithDV, CarterRM, HuettelSA, AdcockRA (2014) Resting state networks distinguish human ventral tegmental area from substantia nigra. Neuroimage100, 580–589.
30.
HymanBT, Van HoesenGW, DamasioAR, BarnesCL (1984) Alzheimer’s disease: Cell-specific pathology isolates the hippocampal formation. Science225, 1168–1170.
31.
EustonDR, GruberAJ, McNaughtonBL (2012) The role of medial prefrontal cortex in memory and decision making. Neuron76, 1057–1070.
32.
ArendtT, BrücknerMK, MorawskiM, JägerC, GertzHJ (2015) Early neurone loss in Alzheimer’s disease: Cortical or subcortical?Acta Neuropathol Commun3, 10.
33.
LismanJE, GraceAA (2005) The hippocampal-VTA loop: Controlling the entry of information into long-term memory. Neuron46, 703–713.
34.
ShohamyD, WagnerAD (2008) Integrating memories in the human brain: Hiocampal-midbrain encoding of overlapping events. Neuron60, 378–389.
35.
TulvingE, ThomsonDM (1973) Encoding specificity and retrieval processes in episodic memory. Psychol Rev80, 352–373.
36.
SchindlerSE, JasielecMS, WengH, HassenstabJJ, GroberE, McCueLM, MorrisJC, HoltzmanDM, XiongC, FaganAM (2017) Neuropsychological measures that detect early impairment and decline in preclinical Alzheimer disease. Neurobiol Aging56, 25–32.
37.
PihlajamäkiM, TanilaH, HänninenT, KönönenM, MikkonenM, JalkanenV, PartanenK, AronenHJ, SoininenH (2003) Encoding of novel picture pairs activates the perirhinal cortex: An fMRI study. Hippocampus13, 67–80.
38.
StrangeBA, OttenLJ, JosephsO, RuggMD, DolanRJ (2002) Dissociable human perirhinal, hippocampal, and parahippocampal roles during verbal encoding. J Neurosci22, 523–528.
39.
MarksSM, LockhartSN, BakerSL, JagustWJ (2017) Tau and β-Amyloid are associated with medial temporal lobe structure, function, and memory encoding in normal aging. J Neurosci37, 3192–3201.
40.
TomparyA, DuncanK, DavachiL (2015) Consolidation of associative and item memory is related to post-encoding functional connectivity between the ventral tegmental area and different medial temporal lobe subregions during an unrelated task. J Neurosci35, 7326–7331.
41.
HeckersS, WeissAP, AlpertNM, SchacterDL (2002) Hippocampal and brain stem activation during word retrieval after repeated and semantic encoding. Cereb Cortex12, 900–907
.
42.
IvanoiuA, CooperJM, ShanksMF, VenneriA (2006) Patterns of impairment in autobiographical memory in the degenerative dementias constrain models of memory. Neuropsychologia44, 1936–1955.
43.
LeyheT, MüllerS, MilianM, EschweilerGW, SaurR (2009) Impairment of episodic and semantic autobiographical memory in patients with mild cognitive impairment and early Alzheimer’s disease. Neuropsychologia47, 2464–2469
.
44.
PrakashJ, RyaliV, SrivastavaK, BhatPS, ShashikumarR (2011) Cognitive reserve: The warehouse within. Ind Psychiatry J20, 79–82.
45.
WilcockGK, BirksJ, WhiteheadA, EvansSJ (2002) The effect of selegiline in the treatment of people with Alzheimer’s disease: A meta-analysis of published trials. Int J Geriatr Psychiatry17, 175–183.
46.
WeinrebO, AmitT, Bar-AmO, YoudimMB (2012) Ladostigil: A novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer’s disease treatment. Curr Drug Targets13, 483–494.
47.
YangHL, CaiP, LiuQH, YangXL, LiF, WangJ, WuJJ, WangXB, KongLY (2017) Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of Alzheimer’s disease. Eur J Med Chem138, 715–728.
48.
ZhengH, AmitT, Bar-AmO, FridkinM, YoudimMB, MandelSA (2012) From anti-Parkinson’s drug rasagiline to novel multitarget iron chelators with acetylcholinesterase and monoamine oxidase inhibitory and neuroprotective properties for Alzheimer’s disease. J Alzheimers Dis30, 1–16.
