Adult-onset Leukoencephalopathy Research Articles

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): Estimation of pathological lesion stage from brain images

BackgroundAdult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a disease responsible for cognitive impairment in adult humans. It is caused by mutations in the colony stimulating factor 1 receptor gene (CSF1R) or alanyl-transfer (t) RNA synthetase 2 (AARS2) gene and affects brain white matter. Settlement of stages of the pathological brain lesions (Oyanagi et al. 2017) from the findings of brain imaging will be inevitably essential for prognostication. MethodsMRI images of eight patients with ALSP were analyzed semiquantitatively. White matter degeneration was assessed on a scale of 0 to 4 (none, patchy, large patchy, confluent, and diffuse) at six anatomical points, and brain atrophy on a scale 0 to 4 (none, slight, mild, moderate, and severe) in four anatomical areas. The scores of the two assessments were then summed to give total MRI scores of 0–40 points. Based on the scores, the MRI features were classified as Grades (0–4). Regression analysis was applied to mutual association between mRS, white matter degeneration score, brain atrophy score, the total MRI score and disease duration. ResultsWhite matter degeneration score, brain atrophy score, and the total MRI score were significantly correlated with the disease duration. MRI Grades (2–4) based on the total MRI scores and the features of the images were well correlated with the pathological lesion stages (II - IV); i.e., ‘large patchy’ white matter degeneration in the frontal and parietal lobes (MRI Grade 2) corresponded to pathological Stage II, ‘confluent’ degeneration (Grade 3) to Stage III, and ‘diffuse’ degeneration (Grade 4) to Stage IV. ConclusionMRI Grades (2–4) resulted from the total MRI scores were well correlated with the pathological lesion Stages (II - IV).

Iluzanebart Phase 2, IGNITE Study: First Interventional Study in Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP)

Iluzanebart Phase 2, IGNITE Study: First Interventional Study in Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP)

Findings from the ILLUMINATE Prospective Natural History Study (NHS) in Individuals with Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (P3-9.001)

Findings from the ILLUMINATE Prospective Natural History Study (NHS) in Individuals with Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (P3-9.001)

Interim Results on VGL101 from IGNITE: First Interventional Phase 2 Study in Patients with Adultonset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (S28.005)

Interim Results on VGL101 from IGNITE: First Interventional Phase 2 Study in Patients with Adultonset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (S28.005)

VGL101: An Immunotherapy that Enhances Microglial Survival for Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (P9-9.013)

VGL101: An Immunotherapy that Enhances Microglial Survival for Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (P9-9.013)

An adapted protocol to derive microglia from stem cells and its application in the study of CSF1R-related disorders

BackgroundInduced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R.MethodsSerial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c.2350G > A (p.V784M) CSF1R variant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL.ResultsThe newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to cultured primary human microglia and with higher scavenging and inflammatory competence at ~ threefold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 (P2RY12) expression, a heightened capacity to internalize myelin, as well as heightened inflammatory response to Pam3CSK4. Poor P2RY12 expression was confirmed to be a consequence of CSF1R haploinsufficiency, as this feature was also observed following CSF1R knockdown or inhibition in mature control iMGL, and in CSF1RWT/KO and CSF1RWT/E633K iMGL compared to their respective isogenic controls.ConclusionsWe optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenic CSF1R variant, with preliminary characterization pointing toward functional alterations in migratory, phagocytic and inflammatory activities.Graphical

Clinical presentation and diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: a literature analysis of case studies.

Because adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, rapidly progressive, debilitating, and ultimately fatal neurodegenerative disease, a rapid and accurate diagnosis is critical. This analysis examined the frequency of initial misdiagnosis of ALSP via comprehensive review of peer-reviewed published cases. Data were extracted from a MEDLINE search via PubMed (January 1, 1980, through March 22, 2022) from eligible published case reports/series for patients with an ALSP diagnosis that had been confirmed by testing for the colony-stimulating factor-1 receptor gene (CSF1R) mutation. Patient demographics, clinical symptoms, brain imaging, and initial diagnosis data were summarized descriptively. Categorical data for patient demographics, symptoms, and brain imaging were stratified by initial diagnosis category to test for differences in initial diagnosis based on each variable. Data were extracted from a cohort of 291 patients with ALSP from 93 published case reports and case series. Mean (standard deviation) age of symptom onset was 43.2 (11.6) years. A family history of ALSP was observed in 59.1% of patients. Cognitive impairment (47.1%) and behavioral and psychiatric abnormalities (26.8%) were the most frequently reported initial symptoms. Of 291 total cases, an accurate initial diagnosis of ALSP was made in 72 cases (24.7%) and the most frequent initial misdiagnosis categories were frontotemporal dementia (28 [9.6%]) and multiple sclerosis (21 [7.2%]). Of the 219 cases (75.3%) that were initially mis- or undiagnosed, 206 cases (94.1%) were later confirmed as ALSP by immunohistology, imaging, and/or genetic testing; for the remaining 13 cases, no final diagnosis was reported. Initial diagnosis category varied based on age, family history, geographic region, mode of inheritance, and presenting symptoms of pyramidal or extrapyramidal motor dysfunction, behavioral and psychiatric abnormalities, cognitive impairment, and speech difficulty. Brain imaging abnormalities were common, and initial diagnosis category was significantly associated with white matter hyperintensities, white matter calcifications, and ventricular enlargement. In this literature analysis, ALSP was frequently misdiagnosed. Improving awareness of this condition and distinguishing it from other conditions with overlapping presenting symptoms is important for timely management of a rapidly progressive disease such as ALSP.

A - 117 Neuropsychological Profile of CSF1R-Related Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rapidly progressive neurodegenerative disorder caused by mutations in the CSF1R gene and is characterized by white matter disease, seizures, motor and cognitive impairment, and personality change. However, the existing neuropsychological literature on ALSP is limited. This exploratory study describes the cognitive profile of patients diagnosed with CSF1R-related ALSP. 7 patients with genetically confirmed CSF1R-related ALSP (Mage = 43.71, SD = 1.6; Meducation = 15.71, SD = 1.89; 71% female; 100% white) underwent neuropsychological examination as part of a pre-bone-marrow transplant work-up. Patients completed tests assessing all standard cognitive domains. Given variability in tests between evaluations, domain means were calculated for each patient and used to calculate frequencies of poor (below average and exceptionally low range) cognitive performance by domain. Two patients were asymptomatic at the time of the evaluation and performed in the low average to exceptionally high range across domains. Of the remaining patients, the average time between symptom onset and the neuropsychological evaluation was 1.6years (SD = 0.55). Below average to exceptionally low range performances were most often observed in executive functioning (80%) and processing speed (80%) domains. 60% of symptomatic patients showed poor performances in attention, verbal skills, visual skills, and fine motor functioning domains. Consistent with prior research, results suggest primarily frontal and subcortical system dysfunction. Neuropsychologists may be uniquely qualified to aid in detecting subtle cognitive changes in ALSP patients that may be critical for early detection of symptoms and treatment planning. Future studies should evaluate these findings in large and more diverse samples.

Case 317: Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia.

A 44-year-old previously healthy man with a 9-month history of progressive cognitive decline, depression, urinary incontinence, and inability to perform tasks of daily living presented to the emergency department with worsening cognitive and neuropsychiatric symptoms. He had become more distressed, and his family noticed him departing the house without closing doors, leaving water faucets running, and sending his children to school on Sundays. History taken from the patient's wife revealed that his brother had passed away in his late 30s after a slowly progressing functional and cognitive decline over the course of 5 years. No further detailed family history could be obtained. The review of systems was negative; he had no prior medical, psychiatric, or surgical history; and he denied any history of recent travel, camping, hiking, or vaccination. The patient was not taking any dietary supplements, nor was he taking any over-the-counter or prescription medication. Examination revealed vital signs were within normal limits. Neurocognitive assessment revealed a conscious, coherent, and alert patient with impaired memory and concentration. He showed poor attention, depressed mood, and restricted affect. He was unable to spell the word world forward, nor was he able to understand a request to spell it backward. The rest of the physical and neurologic examination revealed no abnormalities. Extensive laboratory work-up was conducted and included the following: toxicology screening; screening for HIV-1, HIV-2, and syphilis treponemal antibodies; COVID-19 polymerase chain reaction; and measurement of B1 and B12 levels. The results of screening were negative. Cerebrospinal fluid (CSF) assays, including CSF oligoclonal bands and CSF flow cytometry, revealed values within normal limits. CT of the brain without intravenous contrast material was performed in the emergency department to rule out acute intracranial abnormality. Multiplanar multisequence MRI of the brain without and with intravenous contrast material was ordered for further assessment. CT images of chest, abdomen, and pelvis were unremarkable (images not shown).

Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)

BackgroundMutations in colony-stimulating factor 1 receptor (CSF1R) are known to cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), which has been recently demonstrated as a primary microgliopathy characterized by cognitive impairment. Although the molecular mechanism underlying CSF1R-mediated microgliopathy remains unclear, therapeutic strategies have generally targeted modulation of microglial function. In particular, the microglial inhibitor, minocycline, has been shown to attenuate learning and memory deficits in several neurodegenerative diseases. The objectives of this study were to investigate the pathogenic mechanisms underlying ALSP and to explore the therapeutic effects of minocycline in an in vivo model of ALSP. We hypothesized that inhibiting microglial activation via minocycline could reverse the behavior and pathological defects in ALSP model mice.MethodsWe generated a Csf1r haploinsufficiency mouse model of ALSP using CRISPR/Cas9 genome editing and conducted electrophysiological recordings of long-term potentiation (LTP) and behavioral tests to validate the recapitulation of clinical ALSP characteristics in 8- to 11-month-old mice. RNA-sequencing was used to explore enriched gene expression in the molecular pathogenesis of ALSP. Microglial activation was assessed by immunofluorescent detection of Iba1 and CD68 in brain sections of male ALSP mice and pro-inflammatory activation and phagocytosis were assessed in Csf1r+/− microglia. Therapeutic effects were assessed by behavioral tests, histological analysis, and morphological examination after four weeks of intraperitoneal injection with minocycline or vehicle control in Csf1r+/− mice and wild-type control littermates.ResultsWe found that synaptic function was reduced in LTP recordings of neurons in the hippocampal CA1 region, while behavioral tests showed impaired spatial and cognitive memory specifically in male Csf1r+/− mice. Increased activation, pro-inflammatory cytokine production, and enhanced phagocytic capacity were also observed in Csf1r+/− microglia. Treatment with minocycline could suppress the activation of Csf1r+/− microglia both in vitro and in vivo. Notably, the behavioral and pathological deficits in Csf1r+/− mice were partially rescued by minocycline administration, potentially due to inhibition of microglial inflammation and phagocytosis in Csf1r+/− mice.ConclusionsOur study shows that CSF1R deficiency results in aberrant microglial activation, characterized by a pro-inflammatory phenotype and enhanced phagocytosis of myelin. Our results also indicate that microglial inhibition by minocycline can ameliorate behavioral impairment and ALSP pathogenesis in CSF1R-deficient male mice, suggesting a potential therapeutic target for CSF1R-related leukoencephalopathy. Collectively, these data support that minocycline confers protective effects against CSF1R-related microgliopathy in male ALSP model mice.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is commonly misdiagnosed as Frontotemporal Dementia (FTD), Multiple Sclerosis (MS,) Alzheimer’s disease (AD), or other adult-onset leukodystrophies (P12-4.003)

<h3>Objective:</h3> Characterize the misdiagnosis of ALSP <h3>Background:</h3> ALSP is a progressive, fatal autosomal dominant neurodegenerative disease caused by <i>CSF1R</i> gene mutations resulting in microglial dysfunction and profound white matter changes. ALSP prevalence is estimated at 10,000 in the US alone. The phenotype associated with ALSP is cognitive and motor impairment and can be misdiagnosed as FTD, MS or AD. Diagnostic accuracy of ALSP has modestly improved due to published diagnostic criteria. However, the rate of initial ALSP misdiagnosis remains high and involves a spectrum of neurodegenerative and neuroimmune disorders. <h3>Design/Methods:</h3> A systematic literature review of ALSP clinical and genetic features was conducted with published case studies (1/1/1980–3/22/2022). Data were extracted for 292 ALSP patients from 90 published case reports. Categorical variables were stratified by initial diagnosis, dichotomized by ALSP versus misdiagnosis categories and presented as frequency distribution. P-values for differences in frequency distribution between stratification factors were generated by Chi-square test. <h3>Results:</h3> Demographic data revealed the mean (SD) age (years) of patients was 43.2 (11.6), median (minimum, maximum) of 42.0 (18.0, 86.0). Family history of ALSP was identified in 58.9% of patients. Due to phenotypic heterogeneity at disease onset, accurate initial diagnosis was detected in only 31.5% of ALSP patients. FTD (11.6%), MS (7.9%), AD (4.5%), adult-onset leukodystrophy (6.8%), and familial leukoencephalopathy (6.8%) were common misdiagnoses. Cognitive impairment (45.9%) and behavioral and psychiatric dysfunction (26.4%) were the most common initial symptoms. <h3>Conclusions:</h3> This review confirms ALSP is commonly misdiagnosed as a cognitive disorder, AD/FTD, MS or other leukodystrophy. The presenting symptoms of ALSP family history, white matter MRI lesions and early-onset cognitive impairment with behavioral and/or motor dysfunction should trigger suspicion for ALSP and initiate genetic testing. To avoid misdiagnosis, screening patients for ALSP should be considered. Accurate diagnosis can allow for early intervention with investigational therapies currently in development. <b>Disclosure:</b> Dr. Meier has received personal compensation for serving as an employee of Vigil Neuroscience. Dr. Meier has received personal compensation for serving as an employee of Voyager Therapeutics. Dr. Meier has stock in Vigil Neuroscience. Dr. Meier has stock in Voyager Therapeutics. Dr. Leahy has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Vigil Neuroscience. Dr. Leahy has stock in Ovid Therapeutics. Mrs. Pontius has received personal compensation for serving as an employee of Vigil Neuroscience, Inc. Mrs. Zappia has received personal compensation for serving as an employee of Vigil Neuroscience, Inc.. Mr. Brennan has received personal compensation for serving as an employee of Vigil Neuroscience. Dr. Papapetropoulos has received personal compensation for serving as an employee of Vigil Neuroscience . Dr. Papapetropoulos has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Acadia. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Ventus Therapeutics Inc. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Adamas Pharmaceuticals. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Lipocine Inc. Dr. Papapetropoulos has stock in Vigil Neuroscience. Dr. Papapetropoulos has stock in Adamas. Dr. Papapetropoulos has stock in Lipocine. Dr. Wszolek has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Polish Neurological Society/Via Medica.

A Prospective Natural History Study of Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (S49.008)

A Prospective Natural History Study of Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (S49.008)

Refining the phenotype of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a commonly misdiagnosed autosomal dominant neurodegenerative disease (S49.010)

<h3>Objective:</h3> Characterize the clinical phenotype of ALSP through a comprehensive chart review study. <h3>Background:</h3> ALSP is a fatal, rare genetic disease characterized by neuronal and glial cell pathology and rapidly progressive neurological symptoms (executive dysfunction, motor impairment, neuropsychiatric complications). ALSP is underrecognized with an estimated prevalence of 10,000 in the U.S. alone and frequently misdiagnosed for atypical forms of common CNS disorders i.e., multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. <h3>Design/Methods:</h3> We conducted an IRB-approved, multicenter (3 North American sites), retrospective study of patients with clinically or neuropathologically confirmed diagnosis of ALSP. Data were acquired through medical review of EHRs/medical records. Data collected included demographics, medical/family history, disease manifestations at onset, symptom progression, and therapeutic interventions. <h3>Results:</h3> EHR/medical records from 57 patients were included in the analysis population (F:34/M:23). Mean age at diagnosis was 47.4±12.6 yrs. Initial consultation occurred in various settings: movement disorders, dementia, leukodystrophy, and multiple sclerosis clinics. 59.6% of patients had a family history of ALSP. Cognitive impairment (n=52, 91.9%) was the most frequent initial manifestation, followed by psychiatric symptoms (n=47, 82.5%). Cognitive symptoms included executive dysfunction (77.2%), word finding difficulty (64.4%), confusion (57.9%), and memory loss (52.6%). The most common psychiatric symptoms included depression (54.4%), agitation (31.6%), and insomnia (28.1%). Almost all patients had at least one abnormality on MRI (mostly white matter lesions and brain atrophy). Thirty-five deaths were reported with a mean interval of 5.2±7.0 years after diagnosis. <h3>Conclusions:</h3> This study confirms that ALSP has a diverse phenotype and can be easily misdiagnosed. To avoid misdiagnosis, screening patients for family history, pattern of MRI abnormalities consistent with ALSP, early-onset cognitive impairment with behavioral and/or motor dysfunction should be considered. This combination of symptoms should generate suspicion for ALSP and genetic testing. Increased disease awareness and genetic testing is expected to improve diagnostic accuracy. <b>Disclosure:</b> Dr. Papapetropoulos has received personal compensation for serving as an employee of Vigil Neuroscience . Dr. Papapetropoulos has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Acadia. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Ventus Therapeutics Inc. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Adamas Pharmaceuticals. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Lipocine Inc. Dr. Papapetropoulos has stock in Vigil Neuroscience. Dr. Papapetropoulos has stock in Adamas. Dr. Papapetropoulos has stock in Lipocine. Mr. Marsh has received personal compensation for serving as an employee of Vigil Neuroscience, Inc.. Mr. Marsh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Vigil Neuroscience, Inc.. Andreas Meier has received personal compensation for serving as an employee of Voyager Therapeutics. Andreas Meier has received personal compensation for serving as an employee of Biogen. Dr. Rajagovindan has received personal compensation for serving as an employee of Biogen. Dr. Rajagovindan has received personal compensation for serving as an employee of Vigil. Dr. Rajagovindan has stock in Biogen. Dr. Rajagovindan has stock in Vigil . Dr. Leahy has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Vigil Neuroscience. Dr. Leahy has stock in Ovid Therapeutics. Mr. O’Mara has received personal compensation for serving as an employee of VIgil Neuroscience, LLC. Dr. Wszolek has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Polish Neurological Society/Via Medica.

Radiological features of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its longitudinal progression (P8-4.003)

Radiological features of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its longitudinal progression (P8-4.003)

A Phase 1, First-in-human, Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Intravenous Dose Study of a novel TREM2 agonist (VGL101) in Healthy Volunteers (HVs) (S14.004)

<h3>Objective:</h3> To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VGL101 in healthy adult participants after both single- (SAD) and multiple-ascending dose (MAD) administration. <h3>Background:</h3> VGL101 is a fully human monoclonal antibody targeting TREM2, in development for the treatment of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, progressive, debilitating neurodegenerative disorder. TREM2, a receptor expressed on microglia in the brain is critical to microglial function in health and in disease. The activation of TREM2 by VGL101 is expected to enhance microglia function and neural tissue repair mechanisms regulated by microglia thereby slowing disease progression in ALSP. <h3>Design/Methods:</h3> The Phase 1 study has enrolled 74 HVs in several cohorts at doses up to 40mg/kg SAD and 20mg/kg MAD or placebo. Safety was assessed by the incidence of adverse events (AEs), changes in vital signs, laboratory tests, ECGs, and clinical evaluations. VGL101 serum and CSF PK and the PD of CSF soluble TREM2 (a marker of microglia target engagement) were characterized across single and multiple doses. <h3>Results:</h3> VGL101 demonstrated a favorable safety and tolerability profile at studied doses. Adverse events were mild, did not require intervention and resolved spontaneously. To date, there are no reports of SAEs or clinically meaningful abnormalities in vital signs, laboratory parameters or ECGs. VGL101 demonstrated approximately dose proportional peripheral pharmacokinetics with half-life supporting monthly dosing and brain penetration typical of IgG1 monoclonal antibodies. Dose and time dependent reduction in sTREM2 levels in the CSF was observed demonstrating CNS target engagement for VGL101. <h3>Conclusions:</h3> VGL101 demonstrated a favorable safety, PK profile and confirmation of CNS target engagement in healthy volunteers. The Phase 1 data supports further clinical development of VGL101 in ALSP. <b>Disclosure:</b> Dr. Papapetropoulos has received personal compensation for serving as an employee of Vigil Neuroscience . Dr. Papapetropoulos has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Acadia. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Ventus Therapeutics Inc. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Adamas Pharmaceuticals. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Lipocine Inc. Dr. Papapetropoulos has stock in Vigil Neuroscience. Dr. Papapetropoulos has stock in Adamas. Dr. Papapetropoulos has stock in Lipocine. Andreas Meier has received personal compensation for serving as an employee of Voyager Therapeutics. Andreas Meier has received personal compensation for serving as an employee of Biogen. Mr. O’Mara has received personal compensation for serving as an employee of VIgil Neuroscience, LLC. Mr. Marsh has received personal compensation for serving as an employee of Vigil Neuroscience, Inc.. Mr. Marsh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Vigil Neuroscience, Inc.. Dr. Neelon has received personal compensation for serving as an employee of BridgeBio. Dr. Neelon has received personal compensation for serving as an employee of Vigil NeuroScience. An immediate family member of Dr. Neelon has received personal compensation for serving as an employee of Crisper Therapeutics. An immediate family member of Dr. Neelon has received personal compensation for serving as an employee of Mana Therapeutics. Dr. Neelon has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for BridgeBio. Dr. Neelon has stock in BridgeBio. Dr. Neelon has stock in VigilNeuro Science. An immediate family member of Dr. Neelon has stock in Cripser Therapeutics. An immediate family member of Dr. Neelon has stock in Mana Therapeutics. Dr. Neelon has received intellectual property interests from a discovery or technology relating to health care. Dr. Rajagovindan has received personal compensation for serving as an employee of Biogen. Dr. Rajagovindan has received personal compensation for serving as an employee of Vigil. Dr. Rajagovindan has stock in Biogen. Dr. Rajagovindan has stock in Vigil . Dr. Thackaberry has received personal compensation for serving as an employee of Vigil Neuroscience. Dr. Thackaberry has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Samsara Biocapital. Dr. Thackaberry has stock in Vigil Neurosciences. Dr. Stiles has received personal compensation for serving as an employee of Vigil Neuroscience. Dr. Stiles has received personal compensation for serving as an employee of Vertex Pharmaceuticals.

Novel partial deletions, frameshift and missense mutations of CSF1R in patents with CSF1R-related leukoencephalopathy.

Colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is an adult-onset leukoencephalopathy caused by mutations in CSF1R. The present study aimed to explore the broader genetic spectrum of CSF1R-related leukoencephalopathy in association with clinical and imaging features. Mutational analysis of CSF1R was performed for 100 consecutive patients with adult-onset leukoencephalopathy. Sequence and copy number variation (CNV) analyses of CSF1R were performed. The genomic ranges of the deletions were determined by long-read sequencing. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing the CSF1R mutants identified in this study. CSF1R mutations were identified in 15 patients, accounting for 15% of the adult-onset leukoencephalopathy cases. Seven novel and five previously reported CSF1R mutations were identified. The novel mutations, including three missense and one in-frame 3 bp deletion, were located in the tyrosine kinase domain (TKD) of CSF1R. Functional assays revealed that none of the novel mutations in the TKD showed autophosphorylation of CSF1R. Two partial deletions of CSF1R were identified that resulted in lack of the C-terminal region, including the distal TKD, in two patients. Various clinical features including cognitive impairment, psychiatric symptoms and gait disturbance were observed. Various degrees of the white matter lesions and corpus callosum abnormalities on magnetic resonance imaging and characteristic calcifications on computed tomography were observed as imaging features. Our results highlight the importance of examining the CNV of CSF1R even when Sanger or exome sequencing reveals no CSF1R mutations. Genetic examination of sequences and CNV analyses of CSF1R are recommended for an accurate diagnosis of CSF1R-related leukoencephalopathy.

Generation of a heterozygous and a homozygous CSF1R knockout line from iPSC using CRISPR/Cas9

Mutations in Colony-stimulating factor 1 receptor (CSF1R) lead to CSF1R-related leukoencephalopathy, also known as Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rapidly progressing neurodegenerative disease with severe cognitive and motor impairment. In this study, a homozygous and a heterozygous CSF1R knockout induced pluripotent stem cell (iPSC) line were generated by CRISPR/Cas9-based gene editing. These in vitro models will provide a helpful tool for investigating the still largely unknown pathophysiology of CSF1R-related leukoencephalopathy.

Adult-Onset Leukoencephalopathy with Axonal Spheroid and Pigmented Glia: Different Histological Spectrums Presented in Autopsy Cases of Siblings and a Surgical Case of Stereotactic Biopsy

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia encompasses hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented orthochromatic leukodystrophy. We describe the clinicopathological and genetic findings of three patients with this disorder. All patients presented with dysarthria, with or without cognitive decline. The first and second patients were siblings who died of the disease at ages 42 and 54, respectively, while the third patient has been bedridden. Brain magnetic resonance imaging revealed T2 hyperintensities in the subcortical and periventricular white matter. Pathological diagnosis was established by brain autopsy in cases 1 and 2, and a stereotactic brain biopsy in case 3, followed by genetic analysis of colony stimulating factor-1 receptor gene. A heterozygous c.2345G > A (p.R782H) variant was identified in the autopsy-proven cases, and a c.1765G > A (p.G589R) variant in the biopsy-proven case. Postmortem examination revealed severe white matter degeneration involving the bilateral frontoparietal lobes, but sparing the subcortical U-fibers. All cases revealed widespread loss of myelinated axons in the white matter lesions; however, axonal spheroids and pigmented macrophages were abundant in cases 1 and 3 and much less in case 2. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia should be considered in patients with presenile dementia and diffuse white matter lesions.

Expanding the DARS phenotype: Late-adult onset myelopathy and leukoencephalopathy

A significant proportion of adult-onset neurological disorders remain diagnostic odysseys despite extensive evaluation. Hypomyelination with Brainstem and Spinal Cord Involvement and Leg Spasticity (HBSL) is an autosomal recessive disorder caused by mutations in the cytoplasmic aspartyl-tRNA synthetase (DARS) gene involved in mRNA translation. Clinical features of patients with DARS mutations include developmental delay, leg spasticity, cerebellar dysfunction, cognitive impairment and epilepsy. Most reported cases have been infantile-onset with severe neurological disability and neuroimaging abnormalities. To our knowledge, late- or adult-onset cases have never been reported in the literature. Here, we report for the first time, with video documentation and six-year clinical follow-up, an ethnic Malay patient with onset of spasticity and ataxia in late-adulthood, carrying a pathogenic DARS mutation discovered via whole-genome sequencing. His clinical and radiological findings were consistent with HBSL, but this diagnosis was not considered as, up until now, HBSL has only been reported with childhood/adolescent-onset. This case highlights that HBSL/DARS mutations should now be considered in the differential diagnosis of adult-onset spastic paraplegia and/or leukoencephalopathy.

A case of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia presenting with alien hand syndrome.

A case of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia presenting with alien hand syndrome.