Looking ALS in the Eye

In 2012, ophthalmologist Amani Fawzi moved into the lab across the hall from ALS neurologist Teepu Siddique at the Feinberg School of Medicine of Northwestern University in Chicago, Illinois. Fawzi, a retinal disease specialist, speculated that some signs of ALS might show up in the eye. Siddique was skeptical—after all, people with ALS never told him about difficulty seeing. But he gave her an eye that had been donated by one of his patients post-mortem. There, in the retina, Fawzi found p62-positive inclusions, just as can be seen in the CNS of people with ALS (Fawzi et al., 2014; Mizuno et al., 2006).

See change? More than 50 types of neurons can be found in the retina, a structure in the eye needed to process visual images. But in people with ALS, studies indicate that some of these neurons might be are lost, and may be a key sign of the disease. [Courtesy of Wellcome Images under CC BY 4.0 license.]

Although the motor neurons that control eye movement are rarely affected in ALS and FTD (see Sep 2017 news), scientists are increasingly seeing signs that some of the neurons in the retina of the eye may be lost. Therefore, the measurement of the thickness of the retina, determined in part by the size of those neural populations, is beginning to emerge as a potentially convenient, non-invasive though as-yet unproven, biomarker for FTD and perhaps ALS, too.

“The retina is really a forward outcropping of the brain. It’s not covered by skull, so we can easily look at it,” said neuro-ophthalmologist Ari Green, at the University of California, San Francisco (UCSF). “That’s the major advantage.”

Eying ALS

Ophthalmologists use a suite of tools to check the eyes for signs of disease. One of these tests increasingly ordered by neurologists is optical coherence tomography (OCT). It uses light to take a cross-sectional image of the retina, allowing doctors to measure its overall thickness and the widths of its various parts. “There are many aspects of OCT testing that make it ideal as a biomarker test,” noted ophthalmologist Benjamin Kim of the Hospital of the University of Pennsylvania in Philadelphia. “It is non-invasive, has no known risks, and takes only minutes to acquire.” Kim recently used OCT to analyze people with FTD, and reported on October 10, in the journal Neurology, that thinning of the retina correlates with cognitive test scores.

He’s not the only one eyeing the retina as a potential biomarker of neurodegenerative disease. On September 25 in the journal PLoS One, Duke University Medical Center physicians in Durham, North Carolina, confirmed previous reports that retinal thinning could be detected in people with ALS. And in addition to the thinning, the retinas of people with progranulin-deficient FTD also accumulate deposits of lipofuscin, Green and colleagues reported July 25 in Science Translational Medicine (see April 2017 news; Ward et al., 2017).

“It’s really a hot area,” said Fawzi.

The hope is that the simple eye test might help identify people with ALS or FTD, forecast their prognosis, or evaluate the potential efficacy of drugs in clinical trials. But scientists say there are still plenty of questions to answer first, including which subgroups of patients exhibit retinal phenotypes, when these changes first occur, and if and how these phenotypes change over time.

Neurologists Eye OCT Test

Ophthalmologists first turned to OCT to detect eye diseases such as macular degeneration and glaucoma. Then, neurologists started to use these devices to follow the ocular manifestations of diseases in the central nervous system, explained neurologist Michael Ward, who collaborated with Green at UCSF and is now at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.

In Your Eyes. OCT produces a cross-sectional view of the retina. The eye test is routinely used in ophthalmology clinics to diagnose and develop treatment plans for eye diseases such as glaucoma and macular degeneration. [Image: Maskim, Wikimedia Commons, under a CC By 2.0 license.]

Multiple sclerosis specialists were among the first to take note of OCT (Sepulcre et al., 2007). In that disease, changes in the eye occur early, explained Green, and visual tests can even be used as outcome measures for clinical trials (for review, see Moccia et al., 2017).

As multiple sclerosis doctors began to purchase OCT machines for their clinics, other neurologists took note, and began trying the test on their own patients, Ward said. The resolution and analysis software for the machines has since greatly improved, he added. “The field has really moved forward over the last couple years,” said Ward.

This has led to recognition of noticeable retinal defects in a broad range of neurological conditions, even ones previously thought to leave vision untouched. Retinal thinning occurs in neurodegenerative diseases including Alzheimer’s and Parkinson’s disease (Kesler et al., 2011; Garcia-Martin et al., 2012). And, structural changes can also be detected in the retina in atypical parkinsonism syndromes including corticobasal syndrome and progressive supranuclear palsy (Albrecht et al., 2012).

Looking FTD in the Eye

UCSF scientists Michael Ward, Li Gan and Ari Green knew that the complete loss of progranulin leads to neuronal ceroid lipofuscinosis (NCL), a fatal condition with a host of symptoms including vision loss, and build up of lipofuscin in retina of the eye (Smith et al., 2012). They therefore wondered if these same yellowish pigments, known as lipofuscin, could also be detected in people with progranulin-deficient FTD. Previously, the team detected retinal thinning in these people before symptoms suggesting that the eye is affected by the disease (Ward et al., 2014).

Keeping an eye out for FTD? Researchers found that people at risk of developing progranulin-deficient FTD built up more lipofuscin in the retina. [Courtesy of Michael Ward and Robert Chen. Science Translational Medicine, AAAS.]

Peering into the eyes of 11 people with progranulin deficiency, the USCF team found the same increase in abnormal, yellowish lipofuscin deposits as in the eyes of people with NCL. This was twice the number of deposits detected, on average, in 22 controls. In some cases, the lipofuscin deposits appeared before symptoms of dementia.

“It is much more similar to this disease, neuronal ceroid lipofuscinosis, than I think anyone would have guessed,” said Green. (see Apr 2017 news, Ward et al., 2017).

And, these changes in the shape and size of the retina can be detected in other forms of FTD, according to a new study led in part by Benjamin Kim. The University of Pennsylvania team analyzed the eyes of 38 people with any form of the condition in their study. They found, using OCT, the same total retinal thickness in patients as in 44 controls, but specific parts of the retina—the outer retina, outer nuclear layer and ellipsoid zone—were thinner in people with FTD. The outer retina thickness correlated with cognitive challenges. The relationship between retinal thinning and FTD was especially apparent in the subgroup of patients categorized as “likely tauopathy” based on their symptoms or their genetics. (Kim et al., 2017)

Now, the team is planning to determine how these changes in the structure of the retina compare between people with different types of FTD such as FTLD-tau versus FTLD-TDP, and Alzheimer’s to determine whether these tests can help distinguish these diseases.

What About ALS?

Despite these findings, people with FTD do not report first to the eye clinic. Nor do people with ALS typically notice changes in their eyesight. That does not surprise ophthalmologist Amani Fawzi. “It’s a few microns difference in the retina,” said Fawzi. “The vision effects of such subtle structural changes are very mild…this is the least of their worries.”

Through Thick and Thin University of Pennsylvania scientists found, using optical coherence tomography, that patients with FTD tend to have thinner-than-average retinas. The results for a healthy 61-year-old woman (control, left), and a 60-year-old woman with MAPT-linked FTD, are shown. The green lines and red asterisks indicate the locations of the cross-sections and point measurements, respectively. [Courtesy of Kim et al., 2017, Neurology.]

But genetic studies nevertheless give reason to suspect a link between structural changes in the retina and ALS. ALS-associated genes are increasingly linked to glaucoma, which occurs due to the loss of key neurons known as retinal ganglion cells in the retina. Mutations in optineurin cause either ALS or glaucoma, depending on the location of the genetic defect (see May 2010 news). The ALS gene TBK1 (see Mar 2015 news), which encodes a protein that interacts with optineurin, has also been linked to the glaucoma (Kawase et al., 2012). And, the ALS gene ataxin-2 (see Aug 2010 news) was recently linked to glaucoma in a genome-wide association screen (Bailey et al., 2016).

These tantalizing genetic clues led researchers to look for changes in the eyes in people with the ALS. A group at the Charité-Universitätsmedizin Berlin reported no significant differences in the shape and size of the retina, on OCT, between people with ALS and controls (Roth et al., 2013). But that might be because they included patients who were not definitely diagnosed with ALS, suggested Philipp Albrecht, a consultant neurologist at University Hospital Düsseldorf in Germany. His group and another team at Ulm University, also in Germany, found evidence of retinal thinning associated with ALS (Ringelstein et al., 2014; Hübers et al., 2016). In Chicago, Fawzi and Siddique found thinning of the macular retinal nerve fiber layer, and this correlated with lung function in patients (Simonett et al., 2016).

Doing such studies correctly requires great care, and collaboration between ophthalmologists and neurologists is crucial, Fawzi said. Neurologists can distinguish the ALS subtypes, and ophthalmologists must differentiate retinal phenotypes due to ALS from those that arise from other, age-related eye diseases such as glaucoma.

No Correlation. Duke University researchers found no link between retinal thinning and progression rate in people with ALS who did not have glaucoma-linked mutations. [Courtesy of Mukherjee et al., 2017, PLoS One under a CC BY 4.0 license.]

Physicians at Duke University Medical Center recently used this approach to further evaluate whether there is a link between ALS and retinal thinning. Ophthalmologist Henry Tseng, in collaboration with ALS neurologist Richard Bedlack, worked with 21 patients who had a confirmed ALS diagnosis, made by a specialist. They checked each eye for problems such as glaucoma, neuropathy, or hemorrhage, and discounted two eyes (of different people) due to history of retinal detachment or macular hole.worked with 21 patients who had a confirmed ALS diagnosis, made by a specialist.

The researchers found clear signs of neuronal loss in the retina of people with ALS. They measured an average retinal nerve fiber layer thickness of 89 microns, significantly lower than the average value in a standard database, 96 microns. However, they found no correlation between that thickness and several other disease measures, such as forced vital capacity and the ALS Functional Rating Scale. (Mukherjee et al., 2017)

“ALS is not as specific to motor neurons as we once thought,” said Bedlack. But according to Bedlack, there are plenty more questions to answer about this retinal phenotype before it can be determined whether this eye test could be helpful to neurologists in the clinic. “A larger, longer duration study is needed to determine if retinal thickness might be a useful way to follow progression, and whether patients with different genetic mutations causing their ALS have more severe retinal involvement.”

Larger Studies Needed

Why would ALS, a disease of motor neurons, show up in the retina? “Our hypothesis—many peoples’ hypothesis—is that retinal neurons are very vulnerable to lysosomal dysfunction,” said Ward. Should lysosome defects occur in ALS or FTD, then the retina should show the signs, he suggested. Buoying the theory, several genes linked to these diseases do seem to have roles in the lysosome. Missense mutations in CHMP2B, associated with FTD (Skibinski et al., 2005), cause a holdup in protein degradation (see September 2015 news; Han et al., 2012; Clayton et al., 2015). FTD-linked progranulin may be needed to keep lysosomes from clogging up (see August 2017, September 2017 news; Evers et al., 2017). VCP, associated with ALS (see December 2010 news; Johnson et al., 2010) and FTD (Guinto et al., 2007), helps remove damaged lysosomes (Papadapoulos et al., 2017). And C9orf72, also linked to ALS and FTD, works at the lysosome as well (March 2016 news; for review, see Amick and Ferguson, 2017).

Alternatively, these structural signs in the retina could simply be evidence of changes in the brain overall, suggested Albrecht. “In a lot of degenerative diseases, what is seen in the brain on volumetric imaging, in different areas of the brain, can also be found in layers of the retina,” he said.

Waste not? Lysosomes help keep neurons clutter free. But in people with ALS/FTD, these intracellular recycling centers may malfunction and contribute to the disease. [Sullivan et al., 2017 under a CC BY 3.0 license.]

Key questions about the potential of such an eye test as a biomarker for ALS and FTD remain. “Is [the retina] vulnerable in everybody, or just in certain people?” asked Ward. “Are there second hits that make it vulnerable?”

For example, it might be that certain genotypes, such as C9orf72 expansion carriers, might be more likely to have an eye phenotype. Bedlack and colleagues noted that none of their participants happened to carry mutations in optineurin, TBK1, or ataxin; such folks might offer different results.

Another outstanding question is whether these retinal changes occur before other ALS symptoms, as seen in FTD—for example, in carriers of C9 expansions. Also unanswered is whether this phenotype changes over the course of either disease, setting it up as a potential biomarker of drug efficacy. Thus far, no one has performed such longitudinal studies. One challenge is that as people with ALS progress, it becomes more difficult for them to travel to an ophthalmology clinic and sit for the test, though handheld devices may make it somewhat easier for them.

“We do not think this would be useful as a ‘diagnostic’ biomarker because it is not a specific finding in ALS,” Bedlack said. “We are hoping it might be useful as an ‘evaluative’ marker that allows us to more accurately measure progression.”

But a screening eye test might serve as a way to identify people at risk for FTD and in need of further testing, Green speculated. The test, according to Fawzi and Green, may also find a place as one of a set of assays that provide information together to track disease. For example, Fawzi suggested, doctors might combine OCT and other biomarker tests to make a diagnosis or prognosis.

As for clinical trials, Green doubts that this eye test would serve as a primary phase 3 outcome measure for a new medication’s approval, but suggested it might help speed up results in phase 2 studies.

Albrecht, however, is skeptical. “I’m doubtful that OCT will be helpful for ALS,” he said. “They’re not huge changes [and] there’s a pretty big overlap between the controls and the ALS patients.”

What is needed now, Green said, are large studies to determine how these changes in the retina vary between people and subclasses of the disease, and how these phenotypes change over the course of the disease. The best way to achieve that is for multiple institutions to collaborate, Green suggested. However, such collaborations raise their own set of challenges. It will be crucial, he added, to ensure that collaborators use the same equipment in the same way, with the same protocols, so results are comparable.

Despite these challenges, Ward said, “There’s enough rationale, I think, to pursue this.”

Featured Papers

Kim BJ, Irwin DJ, Song D, Daniel E, Leveque JD, Raquib AR, Pan W, Ying GS, Aleman TS, Dunaief JL, Grossman M. Optical coherence tomography identifies outer retina thinning in frontotemporal degeneration. Neurology. 2017 Oct 10;89(15):1604-1611. [PubMed]

Mukherjee N, McBurney-Lin S, Kuo A, Bedlack R, Tseng H. Retinal thinning in amyotrophic lateral sclerosis patients without ophthalmic disease. PLoS One. 2017 Sep 25;12(9):e0185242. [PubMed]

Ward ME, Chen R, Huang HY, Ludwig C, Telpoukhovskaia M, Taubes A, Boudin H, Minami SS, Reichert M, Albrecht P, Gelfand JM, Cruz-Herranz A, Cordano C, Alavi MV, Leslie S, Seeley WW, Miller BL, Bigio E, Mesulam MM, Bogyo MS, Mackenzie IR, Staropoli JF, Cotman SL, Huang EJ, Gan L, Green AJ. Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis. Sci Transl Med. 2017 Apr 12;9(385). [PubMed]


Fawzi AA, Simonett JM, Purta P, Moss HE, Lowry JL, Deng HX, Siddique N, Sufit R, Bigio EH, Volpe NJ, Siddique T. Clinicopathologic report of ocular involvement in ALS patients with C9orf72 mutation. Amyotroph lateral schler frontotemporal degener. 2014 Dec;15(7-8):569-80. [PubMed]

Mizuno Y, Amari M, Takatama M, Aizawa H, Mihara B, Okamoto K. Immunoreactivities of p62, an ubiquitin-binding protein, in the spinal anterior horn cells of patients with amyotrophic lateral sclerosis. J Neurol Sci. 2006 Nov 1;249(1):13-8. [PubMed]

Sepulcre J, Murie-Fernandez M, Salinas-Alaman A, García-Layana A, Bejarano B, Villoslada P. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology. 2007 May 1;68(18):1488-94. [PubMed]

Moccia M, de Stefano N, Barkhof F. Mult Scler. 2017 Oct;23(12):1614-1626. [PubMed]

Kesler A, Vakhapova V, Korczyn AD, Naftaliev E, Neudorfer M. Retinal thickness in patients with mild cognitive impairment and Alzheimer’s disease. Clin Neurol Neurosurg. 2011 Sep;113(7):523-6. [PubMed]

Garcia-Martin E, Satue M, Fuertes I, Otin S, Alarcia R, Herrero R, Bambo MP, Fernandez J, Pablo LE. Ability and reproducibility of Fourier-domain optical coherence tomography to detect retinal nerve fiber layer atrophy in Parkinson’s disease. Ophthalmology. 2012 Oct;119(10):2161-7. [PubMed]

Albrecht P, Müller AK, Südmeyer M, Ferrea S, Ringelstein M, Cohn E, Aktas O, Dietlein T, Lappas A, Foerster A, Hartung HP, Schnitzler A, Methner A. Optical coherence tomography in parkinsonian syndromes. PLoS One. 2012;7(4):e34891. [PubMed]

Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, Rossi G, Pareyson D, Mole SE, Staropoli JF, Sims KB, Lewis J, Lin WL, Dickson DW, Dahl HH, Bahlo M, Berkovic SF. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am J Hum Genet. 2012 Jun 8;90(6):1102-7. [PubMed]

Ward ME, Taubes A, Chen R, Miller BL, Sephton CF, Gelfand JM, Minami S, Boscardin J, Martens LH, Seeley WW, Yu G, Herz J, Filiano AJ, Arrant AE, Roberson ED, Kraft TW, Farese RV Jr, Green A, Gan L. Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD. J Exp Med. 2014 Sep 22;211(10):1937-45. [PubMed]

Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010 May 13;465(7295):223-6. [PubMed]

Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, Couthouis J, Lu YF, Wang Q, Krueger BJ, Ren Z, Keebler J, Han Y, Levy SE, Boone BE, Wimbish JR, Waite LL, Jones AL, Carulli JP, Day-Williams AG, Strapoli JF, Xin WW, Chesi A, Raphael AR, McKenna-Yasek D, Cady J, Vianney de Jong JM, Kenna KP, Smith BN, Topp S, Miller J, Gkazi A, FALS Sequencing Consortium, Al-Chalabi A, van den Berg LH, Veldink J, Silani V, Ticozzi N, Shaw CE, Baloh RH, Appel S, Simpson E, Lagier-Tourenne C, Pulst SM, Gibson S, Trojanowski JQ, Elman L, McCluskey L, Grossman M, Schneider NA, Chung WK, Ravits JM, Glass JD, Sims KB, Van Deerlin VM, Maniatis T, Hayes SD, Ordureau A, Swarup S, Landers J, Baas F, Allen AS, Bedlack RS, Harper JW, Gitler AD, Rouleau GA, Brown R, Harms MB, Cooper GM, Harris T, Myers RM, Goldstein DB. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015 Mar 27;347(6229):1436-41. [PubMed]

Kawase K, Allingham RR, Meguro A, Mizuki N, Roos B, Solivan-Timpe FM, Robin AL, Ritch R, Fingert JH. Confirmation of TBK1 duplication in normal tension glaucoma. Exp Eye Res. 2012 Mar;96(1):178-80. [PubMed]

Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, Padmanabhan A, Clay-Falcone D, McCluskey L, Elman L, Juhr D, Gruber PJ, Rüb U, Auburger G, Trojanowski JQ, Lee VM, Van Deerlin VM, Bonini NM, Gitler AD. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010 Aug 26;466(7310):1069-75. [PubMed]

Bailey JN, Loomis SJ, Kang JH, Allingham RR, Gharahkhani P, Khor CC, Burdon KP, aschard H, Chasman DI, Igo RP Jr, Hysi PG, Glastonbury CA, Ashley-Koch A, Brilliant M, Brown AA, Budenz DL, Buil A, Cheng CY, Choi H, Christen WG, Curhan G, De Vivo I, Fingert JH, Foster PJ, Fuchs C, Gaasterland D, Gaasterland T, Hewitt AW, Hu F, Hunger DJ, Khawwaja AP, Lee RK, Li Z, Lichter PR, Mackey DA, McGuffin P, Mitchell P, Moroi SE, Perera SA, Pepper KW, Qi Q, Realini T, Richards JE, Ridker PM, Rimm E, Ritch R, Ritchie M, Schuman JS, Scott WK, Singh K, Sit AJ, Song YE, Tamimi RM, Topouzis F, Viswanathan AC, Verma SS, Vollrath D, Wang JJ, Weisschuh N, Wissinger B, Wollstein G, Wong TY, Yaspan BL, Zack DJ, Zhang K, Study EN, ANZRAG Consortium, Weinreb RN, Pericak-Vance MA, Small K, Hammond CJ, Aung T, Liu Y, Vithana EN, MacGregor S, Craig JE, Kraft P, Howell G, Hauser MA, Pasquale LR, Haines JL, Wiggs JL. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet. 2016 Feb;28(2):189-94. [PubMed]

Roth NM, Saidha S, Zimmermann H, Brandt AU, Oberwahrenbrock T, Maragakis NJ, Tumani H, Ludolph AC, Meyer T, Calabresi PA, Paul F. Optical coherence tomography does not support optic nerve involvement in amyotrophic lateral sclerosis. Eur J Neurol. 2013 Aug;20(8):1170-6. [PubMed]

Ringelstein M, Albrecht P, Südmeyer M, Harmel J, Müller AK, Keser N, Finis D, Ferrea S, Guthoff R, Schnitzler A, Hartung HP, Methner A, Aktas O. Subtle retinal pathology in amyotrophic lateral sclerosis. Ann Clin Transl Neurol. 2014 Apr;1(4):290-7. [PubMed]

Hübers A, Müller HP, Dreyhaupt J, Böhm K, Lauda F, Tumani H, Kassubek J, Ludolph AC, Pinkhardt EH. Retinal involvement in amyotrophic lateral sclerosis: a study with optical coherence tomography and diffusion tensor imaging. J Neural Transm (Vienna). 2016 Mar;123(3):281-7. [PubMed]

Simonett JM, Huang R, Siddique N, Farsiu S, Siddique T, Volpe NJ, Fawzi AA. Macular sub-layer thinning and association with pulmonary function tests in Amyotrophic Lateral Sclerosis. Sci Rep. 2016 Jul 7;6:29187. [PubMed]

Skibinski G, Parkinson NJ, Brown JM, Chakrabarti L, Lloyd SL, Hummerich H, Nielsen JE, Hodges JR, Spillantini MG, Thusgaard T, Brandner S, Brun A, Rossor MN, Gade A, Johannsen P, Sørensen SA, Gydesen S, Fisher EM, Collinge J. Mutations in the endisomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet. 2005 Aug;37*8):806-8. [PubMed]

Clayton EL, Mizielinska S, Edgar JR, Nielsen TT, Marshall S, Norona FE, Robbins M, Damirji H, Holm IE, Johannsen P, Nielsen JE, Asante EA, Collinge J, FReJA consortium, Isaacs AM. Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology. Acta Neuropathol. 2015 Oct;130(4):511-23. [PubMed]

Han JH, Ryu HH, Jun MH, Jang DJ, Lee JA. The functional analysis of the CHMP2B missense mutation associated with neurodegenerative diseases in the endo-lysosomal pathway. Biochem Biophys Res Commun. 2012 May 11;421(3):544-9. [PubMed]

Evers BM, Rodriguez-Navas C, Tesla RJ, Prange-Kiel J, Wasser CR, Yoo KS, McDonald J, Cenik B, Ravenscroft TA, Plattner F, Rademakers R, Yu G, White CL 3rd, Herz J. Lipidomic and transcriptomic basis of lysosomal dysfunction in progranulin deficiency. Cell Rep. 2017 Sep 12;20(11):2565-2574. [PubMed]

Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ, Gibbs JR, Brunetti M, Gronka S, Wuu J, Ding J, McCluskey L, Martinez-Lage M, Falcone D, Hernandez DG, Arepalli S, Chong S, Schymick JC, Rothstein J, Landi F, Wang YD, Calvo A, Mora G, Sabatelli M, Monsurrò MR, Battistini S, Salvi F, Spataro R, Sola P, Borghero G, ITALSGEN Consortium, Galassi G, Scholz SW, Taylor JP, Restagno G, Chiò A, Traynor BJ. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron. 2010 Dec 9;68(5):857-64. [PubMed]

Guinto JB, Ritson GP, Taylor JP, Forman MS. Valosin-containing protein and the pathogenesis of frontotemporal dementia associated with inclusion body myopathy. Acta Neuropathol. 2007 Jul;114(1):55-61. [PubMed]

Papadopoulos C, Kirchner P, Bug M, Grum D, Koerver L, Schulze N, Poehler R, Dressler A, Fengler S, Arhzaouy K, Lux V, Ehrmann M, Weihl CC, Meyer H. VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J. 2017 Jan 17;36(2):135-150. [PubMed]

Amick J, Ferguson SM. C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease. Traffic. 2017 May;18(5):267-276. [PubMed]


clinical trial diagnosis disease-als disease-ftd eye OCT optical coherence tomography prognosis retina topic-biomarkers topic-clinical topic-newmethods
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