Familial Alzheimer’s disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel’s time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function.
WanngrenJ, LaraP, ÖjemalmK, MaioliS, MoradiN, ChenL, TjernbergLO, LundkvistJ, NilssonI, KarlströmH (2014) Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations. FEBS Open Bio4, 393–406.
6.
BatemanRJ, AisenPS, StrooperB De, FoxNC, LemereCA, RingmanJM (2011) Autosomal-dominant Alzheimer’s disease: A review and proposal for the prevention of Alzheimer’s disease. Alzheimers Res Ther3, 1–13.
7.
ShepherdC, McCannH, HallidayGM (2009) Variations in the neuropathology of familial Alzheimer’s disease. Acta Neuropathol118, 37–52.
8.
SelkoeDJ (2002) Alzheimer’s disease is a synaptic failure. Science298, 789–791.
9.
LogothetisNK, PaulsJ, AugathM, TrinathT, OeltermannA (2001) Neurophysiological investigation of the basis of the fMRI signal. Nature412, 150–157.
10.
NielsenAN, LauritzenM (2001) Coupling and uncoupling of activity-dependent increases of neuronal activity and blood flow in rat somatosensory cortex. J Physiol533, 773–785.
11.
RaichleME, MacLeodAM, SnyderAZ, PowersWJ, GusnardDA, ShulmanGL (2001) A default mode of brain function. Proc Natl Acad Sci U S A98, 676–682.
12.
BucknerRL, Andrews-HannaJR, SchacterDL (2008) The brain’s default network: Anatomy, function, and relevance to disease. Ann N Y Acad Sci1124, 1–38.
13.
BraakH, ThalDR, GhebremedhinE, TrediciKD (2011) Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years. J Neuropathol Exp Neurol70, 960–969.
14.
GreiciusMD, SrivastavaG, ReissAL, MenonV (2004) Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: Evidence from functional MRI. Proc Natl Acad Sci U S A101, 4637–4642.
15.
ShelineYI, RaichleME (2013) Resting state functional connectivity in preclinical Alzheimer’s disease. Biol Psychiatry74, 340–347.
16.
BinnewijzendMAA, SchoonheimMM, Sanz-ArigitaE, WinkAM, van der FlierWM, TolboomN, AdriaanseSM, DamoiseauxJS, ScheltensP, van BerckelBNM, BarkhofF (2012) Resting-state fMRI changes in Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging33, 2018–2028.
17.
PetrellaJR, SheldonFC, PrinceSE, CalhounVD, DoraiswamyPM (2011) Default mode network connectivity in stable vs progressive mild cognitive impairment. Neurology76, 511–517.
18.
ZhangHY, WangSJ, LiuB, MaZL, YangM, ZhangZJ, TengGJ (2010) Resting brain connectivity: Changes during the progress of Alzheimer disease. Radiology256, 598–606.
19.
LiX, LiT-Q, AndreasenN, WibergMK, WestmanE, WahlundL-O (2013) Ratio of Aβ42/P-tau(181p) in CSF is associated with aberrant default mode network in AD. Sci Rep3, 1339.
MullanM, CrawfordF, AxelmanK (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet1, 345–347.
ClarkR, HuttonM, FuldnerR, FroelichS, KarranC (1995) The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Alzheimer’s Disease Collaborative Group. Nat Genet11, 219–222.
25.
KellerL, WelanderH, ChiangH-H, TjernbergLO, NennesmoI, WallinAK, GraffC (2010) The PSEN1 I143T mutation in a Swedish family with Alzheimer’s disease: Clinical report and quantification of Aβ in different brain regions. Eur J Hum Genet18, 1202–1208.
26.
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.
27.
WinbladB, PalmerK, KivipeltoM, JelicV, FratiglioniL, WahlundL-O, 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.
BlennowK, WallinA, AgrenH, SpengerC, SiegfriedJ, VanmechelenE (1995) Tau protein in cerebrospinal fluid: A biochemical marker for axonal degeneration in Alzheimer disease?Mol Chem Neuropathol26, 231–245.
30.
VanmechelenE, VandersticheleH, DavidssonP, KerschaverE Van, AndreasenN, BlennowK (2000) Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: A sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci Lett285, 49–52.
31.
SchöllM, AlmkvistO, BogdanovicN, WallA, LångströmB, ViitanenM, NordbergA (2011) Time course of glucose metabolism in relation to cognitive performance and postmortem neuropathology in Met146Val PSEN1 mutation carriers. J Alzheimers Dis24, 495–506.
32.
SchöllM, WallA, ThordardottirS, FerreiraD, BogdanovicN, LångströmB, AlmkvistO, GraffC, NordbergA (2012) Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers. Neurology79, 229–236.
33.
ArendtT (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol118, 167–179.
34.
BrinkmalmA, BrinkmalmG, HonerWG, FrölichL, HausnerL, MinthonL, HanssonO, WallinA, ZetterbergH, BlennowK, ÖhrfeltA (2014) SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer’s disease. Mol Neurodegener9, 53.
35.
KvartsbergH, DuitsFH, IngelssonM, AndreasenN, ÖhrfeltA, AnderssonK, BrinkmalmG, LannfeltL, MinthonL, HanssonO, AndreassonU, TeunissenCE, ScheltensP, Van der FlierWM, ZetterbergH, PorteliusE, BlennowK (2015) Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer’s disease. Alzheimers Dement11, 1180–1190.
36.
PorteliusE, ZetterbergH, SkillbäckT, TörnqvistU, AndreassonU, TrojanowskiJQ, WeinerMW, ShawLM, MattssonN (2015) Cerebrospinal fluid neurogranin: Relation to cognition and neurodegeneration in Alzheimer’s disease. Brain138, 3373–3385.
37.
ShelineYI, RaichleME, SnyderAZ, MorrisJC, HeadD, WangS, MintunMA (2010) Amyloid plaques disrupt resting state default mode network connectivity in cognitively normal elderly. Biol Psychiatry67, 584–587.
38.
BucknerRL, SnyderAZ, ShannonBJ, LaRossaG, SachsR, FotenosAF, ShelineYI, KlunkWE, MathisC a, MorrisJC, MintunMA (2005) Molecular, structural, and functional characterization of Alzheimer’s disease: Evidence for a relationship between default activity, amyloid, and memory. J Neurosci25, 7709–7717.
39.
BlennowK, HampelH, WeinerM, ZetterbergH (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol6, 131–144.
40.
GunhildNR, JørgenW, NielsenE, SimonsenAH, RostgaardN (2015) Cerebrospinal fluid biomarkers in familial forms of Alzheimer’s disease and frontotemporal dementia. Dement Geriatr Cogn Disord40, 54–62.
