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Review
. 2022 Feb 3:12:788168.
doi: 10.3389/fneur.2021.788168. eCollection 2021.

Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development

Spyros Papapetropoulos  1   2 , Angela Pontius  1 , Elizabeth Finger  3 , Virginija Karrenbauer  4   5 , David S Lynch  6 , Matthew Brennan  1 , Samantha Zappia  1 , Wolfgang Koehler  7 , Ludger Schoels  8   9 , Stefanie N Hayer  8   9 , Takuya Konno  10 , Takeshi Ikeuchi  10 , Troy Lund  11 , Jennifer Orthmann-Murphy  12 , Florian Eichler  2 , Zbigniew K Wszolek  13
Affiliations
Review

Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development

Spyros Papapetropoulos et al. Front Neurol. .

Abstract

A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.

Keywords: ALSP; CSF1R; HDLS; adult-onset; axonal spheroids; leukodystrophy; leukoencephalopathy; pigmented glia.

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Conflict of interest statement

Unrelated to this study, EF received personal compensation for serving on a PSP Scientific Advisory or Data Safety Monitoring board for Biogen, Vigil Neuroscience, Inc., and Denali Therapeutics, as a section editor for NeuroImage Clinical and as a course director for the AAN Annual Meeting. EF has received research support paid to her institution (UWO) from CIHR and the Weston Foundation to conduct an ongoing study of oxytocin in FTD, from Alzheimer Society of Canada and the Physicians and Services Incorporated Foundation, the Ministry of Research and Innovation of Ontario for research and for site participation in clinical trials sponsored by Alector, Biogen, and TauRx. VK was funded by the Stockholm County Council. WK received consulting honoraria from Vigil Neuroscience. LS was funded by the German Research council (DFG grant SCHO754/6-2), German Ministryof Health (BMG grant ZMVI1-2520DAT94E to LeukoExpert), German Ministry of Education and Research (BMBF grant 01GM1905A to Treat HSP and grant 01GM1907A to Treat ION), European Commission (EU grant 947588 to the ERNRND registry and JPND grant 01ED16028 to ESMI). LS was a member of the European Reference Network for Rare Neurological Diseases (Project No 739510). SH was funded by the Hertie Network of Excellence in Clinical Neuroscience (GHST grant P1200021). TK and TI are funded by AMED JP21dk0207045, a public grant from the Japanese government to support research on ALSP. JO-M was funded by the Conrad N. Hilton Foundation, the Institute for Translational Medicine and Therapeutics Transdisciplinary (ITMAT) and serves as a principal investigator on Vigil Neuroscience, Inc. sponsored clinical studies (VGL101-01.001; VGL101-01.002). FE is the principal investigator of Bluebird Bio and Minoryx Therapeutics clinical trials; consultant to Ionis, Alnylam, Sanofi Genzyme, Minoryx, and SwanBio Therapeutics; director of the Third Rock MGH Neuroscience Fellowship; and founder of SwanBio Therapeutics. ZW was partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, gifts from the Sol Goldman Charitable Trust and Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and the Albertson Parkinson's Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301), Neuraly, Inc. (NLY01-PD-1), and Vigil Neuroscience, Inc. (VGL101-01.001) clinical studies. He serves as an external advisory board member for Vigil Neuroscience, Inc. SP, AP, MB, and SZ are employed by Vigil Neuroscience, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic graph of the CSF1R protein and overview of CSF1R mutations identified in patients with CSF1R-related leukoencephalopathy. CSF1R, colony-stimulating factor 1 receptor; Ig, immunoglobulin domain. Revised/updated version reprinted with permission from (31).
Figure 2
Figure 2
Pathologic light microscopic findings from cases with Colony-Stimulating Factor 1 receptor (CSF1R)-related leukoencephalopathy. (A–H) A 78-year-old man with CSF1R p.M875T. At 71 years of age, he developed cognitive impairment followed by personality and behavior change, depression, executive dysfunction, apraxia, parkinsonism, and pyramidal weakness. He died after 7 years of disease duration. (A) Luxol fast blue stain shows severe myelinated fiber loss in the superior frontal and cingulate white matter, whereas the U-fibers are relatively spared. Note the thinning of the corpus callosum (arrow). (B) The axonal spheroids in the affected white matter are stained with amyloid precursor protein (APP). (C) Numerous axonal spheroids (arrows) are seen within the frontal white matter (hematoxylin and eosin). (D) 68-immunopositive macrophages in the frontal white matter. (E,F) An axonal spheroid in the white matter depicted by phosphorylated neurofilament (SMI31) (E) and APP (F). (G) A bizarre astrocyte in the white matter (αB-crystallin). (H) A ballooned neuron in the superior frontal cortex (αB-crystallin). (I,J) A 55-year-old woman with autopsy-confirmed adult-onset leukodystrophy with neuroaxonal spheroids and pigmented glia, but genetic testing was not performed because DNA was unavailable. (I) Note the small, calcified lesion (arrow) located in the pericallosal region. An arrowhead indicates the paper-like atrophy of the corpus callosum. (J) An enlarged image of the calcification. Bars in A, B, and I = 5 mm; C and D = 100 μm; E, F, G, and H = 50 μm; and J = 400 μm. Reprinted with permission from (6).
Figure 3
Figure 3
Brain magnetic resonance imaging (MRI)/computed tomography (CT) findings from cases of Colony-Stimulating Factor-1 Receptor (CSF1R)-related leukoencephalopathy. (A–D,F,H) A 44-year-old woman with CSF1R p.G589R. (E) A 27-year-old woman with CSF1R c.2442 + 5 G > A. (G) A 31-year-old woman with CSF1R p.A652P. (A,B), Bilateral diffuse white matter hyperintensity with pyramidal tract involvement (arrows in A), cortical atrophy, and enlarged lateral ventricles on fluid-attenuated inversion recovery MRI. (C) Longitudinal pyramidal tract involvement (arrows) on coronal T2-weighted image. (D) Thinning of the corpus callosum with hyperintensity on sagittal fluid-attenuated inversion recovery image. (E) Hyperintensity lesions in the subcortical white matter on diffusion-weighted image. (F) Small calcifications located bilaterally near the anterior horns of the lateral ventricles on brain CT image. (G) Calcifications in parietal subcortical white matter. (H) Stepping-stone appearance of calcifications (arrows) in the frontal pericallosal region on sagittal CT image. Reprinted with permission from (6).
Figure 4
Figure 4
TREM2 signaling cascade and convergence with CSF1R signaling. Schematic representation of TREM2/DAP12 signaling in microglia. Ligands and downstream signaling of TREM2/DAP12. Of the known TREM2 ligands, only ligands that highly correlate with neural diseases are shown. Upon ligand binding to TREM2, two tyrosine residues within the ITAM motif of DAP12 are phosphorylated, which recruits Syk kinase to activate downstream signaling molecules, such as ERK, PI3K, PLCγ, and Vav. Src, the main effector of CSF1R, is a kinase supposed to phosphorylate the ITAM tyrosine residues. Reprinted with permission form (94).
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