Brain Connectivity in Neurodegenerative Diseases--from Phenotype to Proteinopathy

Overview

Journal Nat Rev Neurol

Specialty Neurology

Date 2014 Oct 8

PMID 25287597

Citations 136

Authors

Michela Pievani

Nicola Filippini

Martijn P van den Heuvel

Stefano F Cappa

Giovanni B Frisoni

Affiliations

Soon will be listed here.

Abstract

Functional and structural connectivity measures, as assessed by means of functional and diffusion MRI, are emerging as potential intermediate biomarkers for Alzheimer disease (AD) and other disorders. This Review aims to summarize current evidence that connectivity biomarkers are associated with upstream and downstream disease processes (molecular pathology and clinical symptoms, respectively) in the major neurodegenerative diseases. The vast majority of studies have addressed functional and structural connectivity correlates of clinical phenotypes, confirming the predictable correlation with topography and disease severity in AD and frontotemporal dementia. In neurodegenerative diseases with motor symptoms, structural--but, to date, not functional--connectivity has been consistently found to be associated with clinical phenotype and disease severity. In the latest studies, the focus has moved towards the investigation of connectivity correlates of molecular pathology. Studies in cognitively healthy individuals with brain amyloidosis or genetic risk factors for AD have shown functional connectivity abnormalities in preclinical disease stages that are reminiscent of abnormalities observed in symptomatic AD. This shift in approach is promising, and may aid identification of early disease markers, establish a paradigm for other neurodegenerative disorders, shed light on the molecular neurobiology of connectivity disruption and, ultimately, clarify the pathophysiology of neurodegenerative diseases.

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References

Verstraete E, van den Heuvel M, Veldink J, Blanken N, Mandl R, Hulshoff Pol H . Motor network degeneration in amyotrophic lateral sclerosis: a structural and functional connectivity study. PLoS One. 2010; 5(10):e13664. PMC: 2965124. DOI: 10.1371/journal.pone.0013664. View

Honey C, Sporns O, Cammoun L, Gigandet X, Thiran J, Meuli R . Predicting human resting-state functional connectivity from structural connectivity. Proc Natl Acad Sci U S A. 2009; 106(6):2035-40. PMC: 2634800. DOI: 10.1073/pnas.0811168106. View

Gour N, Felician O, Didic M, Koric L, Gueriot C, Chanoine V . Functional connectivity changes differ in early and late-onset Alzheimer's disease. Hum Brain Mapp. 2013; 35(7):2978-94. PMC: 6869697. DOI: 10.1002/hbm.22379. View

Choe I, Yeo S, Chung K, Kim S, Lim S . Decreased and increased cerebral regional homogeneity in early Parkinson's disease. Brain Res. 2013; 1527:230-7. DOI: 10.1016/j.brainres.2013.06.027. View

Zhou J, Gennatas E, Kramer J, Miller B, Seeley W . Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron. 2012; 73(6):1216-27. PMC: 3361461. DOI: 10.1016/j.neuron.2012.03.004. View

Zhou F, Xu R, Dowd E, Zang Y, Gong H, Wang Z . Alterations in regional functional coherence within the sensory-motor network in amyotrophic lateral sclerosis. Neurosci Lett. 2013; 558:192-6. DOI: 10.1016/j.neulet.2013.11.022. View

Petrella J, Sheldon F, Prince S, Calhoun V, Doraiswamy P . Default mode network connectivity in stable vs progressive mild cognitive impairment. Neurology. 2011; 76(6):511-7. PMC: 3053179. DOI: 10.1212/WNL.0b013e31820af94e. View

Crespi C, Cerami C, Dodich A, Canessa N, Arpone M, Iannaccone S . Microstructural white matter correlates of emotion recognition impairment in Amyotrophic Lateral Sclerosis. Cortex. 2014; 53:1-8. DOI: 10.1016/j.cortex.2014.01.002. View

Douaud G, Filippini N, Knight S, Talbot K, Turner M . Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis. Brain. 2011; 134(Pt 12):3470-9. DOI: 10.1093/brain/awr279. View

10.

Agosta F, Pagani E, Petrolini M, Caputo D, Perini M, Prelle A . Assessment of white matter tract damage in patients with amyotrophic lateral sclerosis: a diffusion tensor MR imaging tractography study. AJNR Am J Neuroradiol. 2010; 31(8):1457-61. PMC: 7966122. DOI: 10.3174/ajnr.A2105. View

11.

Whitwell J, Master A, Avula R, Kantarci K, Eggers S, Edmonson H . Clinical correlates of white matter tract degeneration in progressive supranuclear palsy. Arch Neurol. 2011; 68(6):753-60. PMC: 3401587. DOI: 10.1001/archneurol.2011.107. View

12.

Alexander A, Lee J, Lazar M, Field A . Diffusion tensor imaging of the brain. Neurotherapeutics. 2007; 4(3):316-29. PMC: 2041910. DOI: 10.1016/j.nurt.2007.05.011. View

13.

Fukunaga M, Horovitz S, de Zwart J, van Gelderen P, Balkin T, Braun A . Metabolic origin of BOLD signal fluctuations in the absence of stimuli. J Cereb Blood Flow Metab. 2008; 28(7):1377-87. DOI: 10.1038/jcbfm.2008.25. View

14.

Collin G, Sporns O, Mandl R, van den Heuvel M . Structural and functional aspects relating to cost and benefit of rich club organization in the human cerebral cortex. Cereb Cortex. 2013; 24(9):2258-67. PMC: 4128699. DOI: 10.1093/cercor/bht064. View

15.

Verstraete E, Veldink J, van den Berg L, van den Heuvel M . Structural brain network imaging shows expanding disconnection of the motor system in amyotrophic lateral sclerosis. Hum Brain Mapp. 2013; 35(4):1351-61. PMC: 6869230. DOI: 10.1002/hbm.22258. View

16.

Stanton B, Shinhmar D, Turner M, Williams V, Williams S, Blain C . Diffusion tensor imaging in sporadic and familial (D90A SOD1) forms of amyotrophic lateral sclerosis. Arch Neurol. 2009; 66(1):109-15. DOI: 10.1001/archneurol.2008.527. View

17.

Zamboni G, Wilcock G, Douaud G, Drazich E, McCulloch E, Filippini N . Resting functional connectivity reveals residual functional activity in Alzheimer's disease. Biol Psychiatry. 2013; 74(5):375-83. DOI: 10.1016/j.biopsych.2013.04.015. View

18.

Melzer T, Watts R, MacAskill M, Pitcher T, Livingston L, Keenan R . White matter microstructure deteriorates across cognitive stages in Parkinson disease. Neurology. 2013; 80(20):1841-9. DOI: 10.1212/WNL.0b013e3182929f62. View

19.

Sajjadi S, Acosta-Cabronero J, Patterson K, Diaz-de-Grenu L, Williams G, Nestor P . Diffusion tensor magnetic resonance imaging for single subject diagnosis in neurodegenerative diseases. Brain. 2013; 136(Pt 7):2253-61. DOI: 10.1093/brain/awt118. View

20.

Lu H, Zou Q, Gu H, Raichle M, Stein E, Yang Y . Rat brains also have a default mode network. Proc Natl Acad Sci U S A. 2012; 109(10):3979-84. PMC: 3309754. DOI: 10.1073/pnas.1200506109. View