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  • Review Article
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Brain connectivity in neurodegenerative diseases—from phenotype to proteinopathy

Nature Reviews Neurology volume 10, pages 620–633 (2014)Cite this article

Subjects

Key Points

  • Abnormal functional and structural connectivity are candidate biomarkers for Alzheimer disease (AD) and other neurodegenerative diseases

  • The topography of abnormal functional and structural connectivity maps onto the clinical phenotype, and its severity correlates with clinical disease severity in AD and frontotemporal dementia

  • Structural—but, as yet, not functional—connectivity signatures of neurodegenerative diseases with a primary motor phenotype (for example, amyotrophic lateral sclerosis, Parkinson disease and Huntington disease) have been consistently identified

  • Functional connectivity signatures are related to specific molecular pathology in preclinical AD, and could serve as early disease markers

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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Figure 1: Upstream determinants (genes and molecular pathology) and downstream effects (clinical phenotypes) for the main neurodegenerative disorders.
Figure 2: Spatial patterns of task-free networks commonly investigated in neurodegenerative disorders.
Figure 3: Brain connectivity signatures for major neurodegenerative disorders.
Figure 4: Correspondence between structural and functional connectivity findings in four neurodegenerative diseases.

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Acknowledgements

N.F. is funded by the HDH Wills 1965 Charitable Trust. M.P.v.d.H. is supported by a Fellowship from the Brain Center Rudolf Magnus and a VENI grant from the Dutch Council for Research (NWO).

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Authors and Affiliations

  1. Laboratory of Epidemiology, Neuroimaging and Telemedicine (LENITEM), Istituto Centro San Giovanni di Dio, Fatebenefratelli, via Pilastroni 4, Brescia, 25125, Italy

    Michela Pievani

  2. University Department of Psychiatry, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, UK

    Nicola Filippini

  3. Brain Center Rudolf Magnus, University Medical Center, Heidelberglaan 100, Utrecht, 85500 3908, GA, Netherlands

    Martijn P. van den Heuvel

  4. Istituto Universitario di Studi Superiori (IUSS), Piazza della Vittoria 15, Pavia, 27100, Italy

    Stefano F. Cappa

  5. Memory Clinic and LANVIE—Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Chemin du Petit Bel-Air 2 (Bâtiment Voirons), Genève, CH-1225, Chêne-Bourg, Switzerland

    Giovanni B. Frisoni

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  1. Michela Pievani
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  4. Stefano F. Cappa
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Contributions

M.P. and G.B.F. developed the architecture of the manuscript. M.P. wrote the initial draft, which was completed, edited and reviewed for important intellectual content by N.F., M.P.v.d.H., S.F.C. and G.B.F. M.P. and G.B.F. prepared Figure 1, Figure 3 and Figure 4, and N.F. prepared Figure 2. All the authors have seen and approved the final version.

Corresponding author

Correspondence to Giovanni B. Frisoni.

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Competing interests

G.B.F. has served on the advisory boards for Lilly, BMS, Bayer, Lundbeck, Elan, AstraZeneca, Pfizer, Baxter, Taurx and Wyeth, and has received research support from Wyeth, Lilly and Lundbeck Italia. The other authors declare no competing interests.

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Supplementary Table 1

Technical variability (magnetic field strength and post-processing method) across studies on resting-state functional connectivity MRI (PDF 157 kb)

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Pievani, M., Filippini, N., van den Heuvel, M. et al. Brain connectivity in neurodegenerative diseases—from phenotype to proteinopathy. Nat Rev Neurol 10, 620–633 (2014). https://doi.org/10.1038/nrneurol.2014.178

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