Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) is a rare, fatal, autosomal-dominant neurodegenerative disorder caused by pathogenic CSF1R variants and characterized by progressive cognitive, neuropsychiatric, and motor dysfunction, white matter lesions on brain imaging, and white matter demyelination, swollen axons, and pigmented glial cells on pathology. Limited data regarding clinical, biofluid or radiological biomarkers of disease severity are available, and no clinical trial endpoints have yet been validated. The objectives of this first-of-its-kind, prospective, observational natural history study were to characterize the clinical trajectory of CSF1R-ALSP and to identify and evaluate key biomarkers and clinical endpoints indicative of disease severity and progression. ILLUMINATE (NCT05020743) was a multicentre, noninterventional natural history study of adults with CSF1R-ALSP and prodromal carriers of CSF1R variants. Participants were followed for up to 36 months, with clinical assessments, fluid biomarkers and volumetric MRI assessments of brain atrophy collected at screening and every 6 months. This study was terminated early (4 June 2025). The analyses reported here include data collected through 19 February 2025. Of 53 participants, 19 were prodromal and 34 were symptomatic (11 of whom had a history of haematopoietic stem cell transplant and 23 who did not). Mean participant age was 47.8 (standard deviation, 4.5) years, and 36.4% were female. Prodromal participants remained relatively stable over 36 months, with little change in neurological function, neurodegeneration biomarkers or radiological disease burden. Impaired neurological function, MRI characteristics of CSF1R-ALSP, and elevated NfL (neurofilament light chain; neurodegeneration biomarker) and GFAP (glial fibrillary acidic protein; astrogliosis biomarker) levels were more pronounced at baseline and often showed progression over time among symptomatic participants who had not previously received haematopoietic stem cell transplant compared with participants who had previously received haematopoietic stem cell transplant. Significant correlations were observed at baseline and longitudinally between MRI measures of brain atrophy and clinical outcome measures. Based on the fluid biomarkers, MRI measures, and clinical outcome assessments evaluated here, active neurodegeneration, widespread changes visualized on brain MRI, and impaired cognitive and motor function were observed in symptomatic patients with CSF1R-ALSP. The neurological impairment can be assessed using the Montreal Cognitive Assessment and Cortical Basal ganglia Functional Scale. Our data suggest that quantification of brain atrophy using MRI volumetry is a potential biomarker of disease severity and progression in CSF1R-ALSP. It is hoped that this report will contribute to the understanding of disease progression in CSF1R-ALSP and inform future drug development.

Patients with metachromatic leukodystrophy (MLD) show variable motor and cognitive decline. The ARSA variants c.256C>T, p.(Arg86Trp), c.257G>A, p.(Arg86Gln) and c.542T>G, p.(Ile181Ser) are associated with predominantly cognitive decline. This multinational study analyzed MLD onset type, presenting signs/symptoms, cognitive function, gross motor function, central motor tract involvement, MRI severity score, peripheral neuropathy, and survival of 47 patients (three homozygous for c.256C>T and five, twelve and 27 compound heterozygous for c.256C>T, c.257G>A, or c.542T>G and another ARSA variant, respectively). Eleven underwent hematopoietic stem cell transplantation (HSCT). Onset was late-juvenile (46.8%) or adult (44.7%) with predominantly cognitive decline (n = 40/41 symptomatic patients). At diagnosis, untreated patients typically retained independent walking (100%), sparing of central motor tracts (87.5%), and absence of demyelinating neuropathy (95.5%), which persisted in follow-up for most (76.5%, 71.4%, and 64.7%, respectively). Early-juvenile onset and rapid motor decline occurred only in patients compound heterozygous for c.256C>T and a severe second variant (n = 4), showing central motor tract involvement at diagnosis. One untreated and one treated patient died of disease progression, and another from HSCT complications. All other treated patients retained independent walking, and four of five tested normal cognitive function. Median MRI severity score remained lower in treated (13) than untreated patients (25). The phenotype of c.256C>T carriers depends on the severity of the second ARSA variant. Patients harboring c.257G>A or c.542T>G show late-juvenile or adult onset with cognitive decline and preserved motor function, usually associated with sparing of central motor tracts. In these patients, cognitive function and MRI severity score should be preferred treatment outcomes.

BACKGROUND:Colony stimulating factor-1 receptor (CSF1R)-related disorder (CSF1R-RD) is an autosomal dominant, rapidly progressive, demyelinating disease leading to death usually within a few years. Because of the central role of CSF1R in microglia functions, allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a therapy for CSF1R-RD. OBJECTIVES:To report multicenter clinical (Expanded Disability Scoring Scale [EDSS]), neurocognitive), neuroimaging (Sundal score), and biological (neurofilament light chain [NfL]) outcomes after HSCT in CSF1R-RD. METHODS:We report an international cohort of 17 adult patients (8 females/9 males, 43.3 ± 9.4 years) who were treated in seven transplant centers. Patients were evaluated for a median of 2.5 years post-HSCT, including one patient with follow-up of 8 years. We also report neurological outcomes of the first child transplanted to date with biallelic CSF1R variants. RESULTS:In the first 6 months post-HSCT, 2 patients died from early complications of myeloablative transplantation, and clinical and radiological severity scores worsened in most surviving adult patients. At 12 months post-HSCT, most patients completely stabilized or improved in certain clinical domains. Radiological scores fully stabilized or slightly improved in all but one of the patients. Plasma/serum NfL sharply decreased in most patients after transplantation. Notably, 7/8 adult patients who received a reduced-intensity conditioning regimen displayed similar neurological outcomes as patients who underwent myeloablative transplantation. CONCLUSIONS:After an initial clinical and radiological deterioration in the first 6 months post-transplantation, HSCT can halt disease progression in patients with CSF1R-RD, regardless of their presenting clinical symptoms. The possibility of reduced conditioning regimens in CSF1R-RD opens the way to treat older patients. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The purpose of this letter to the editor is to illustrate the effect of tofacitinib on psoriatic skin lesions in a patient with Aicardi–Goutières syndrome (AGS) type 7/Singleton-Merten syndrome 1. AGS is characterized by an encephalopathy of variable severity and systemic autoinflammatory manifestations due to continuous type I interferon (IFN) induction. While traditional JAK 1/2 inhibitors like baricitinib and ruxolitinib have proven effectiveness for systemic inflammatory symptoms, they face reimbursement issues in some countries. Tofacitinib, a JAK 1/3 inhibitor, significantly improved psoriatic skin lesions in our patient without the need for additional immunosuppressive therapy. Within one month of starting tofacitinib, psoriatic rashes and ulcerative skin lesions markedly improved, in the absence of a reduction in the IFN-stimulated gene signature or CD169 expression on monocytes. The clinical benefits persisted until the treatment was discontinued, after which symptoms recurred. Resuming tofacitinib treatment again led to improvement. No adverse effects were observed. This case highlights the potential of tofacitinib as a clinically effective treatment for psoriatic skin lesions in AGS and offers a viable alternative for JAK 1/2 inhibitors for this target symptom. Further studies are needed to confirm the long-term safety of JAK 1/3 inhibitors in AGS as well as their possible efficacy and dosing to address other systemic symptoms or neurologic manifestations.

BACKGROUND:Treatment decisions in metachromatic leukodystrophy (MLD), a rare life-threatening neurological disease, are challenging. Hematopoietic stem cell transplantation or autologous stem-cell-based gene therapy can be life-changing but come with uncertainties, risks, and high costs. To address this, the international MLD treatment eligibility panel was established in collaboration with the European Reference Network on Rare Neurological Diseases. The panel reviews and discusses individual MLD cases and provides consensus-based recommendations on whether to treat and which treatment modality. The goal is to streamline international care and treatment counseling by providing uncomplicated access to expert opinion. METHODS:The panel operates according to a published standard operating procedure and was evaluated between September 2021-2024. Case data were recorded in a Castor EDC-based system and, with consent, included in the MLD Initiative (MLDi) patient registry. Physicians' experiences were assessed via EUsurvey, and patients' feedback was collected through an MLDi registry survey. FINDINGS:The panel discussed 43 cases, recommending treatment in 20, abstaining in 19, and reaching no consensus in 4. Open questions regarding cognitive function and lack of outcome data caused challenges in treatment recommendations in late-onset MLD patients. All treatment recommendations were followed. Physicians reported positive experiences with the panel. INTERPRETATION:The MLD treatment eligibility panel demonstrates how international expert advice can be streamlined across Europe for a rare disease like MLD, where disease-specific guidelines are still in development. By balancing complex clinical, social, and ethical parameters, the panel aids in encouraging appropriate use of innovative and costly therapies and guarantees accessibility to expert advice irrespective of country of origin.

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by disease-causing variants in the gene coding for arylsulfatase A, leading to deficient enzyme activity and subsequent accumulation of sulfatides. MLD is characterized by demyelination and neurodegeneration of the central and peripheral nervous system, manifesting as progressive motor and cognitive defects in affected individuals. This review provides a comprehensive overview of the significant progress made in MLD research in the past decade, regarding natural history, disease and treatment mechanisms, and newborn screening (NBS). Traditionally, MLD has been classified according to age at onset (late-infantile, early-juvenile and late-juvenile, and adult MLD), with earlier forms leading to more rapid neurologic decline. New data show that the type of presenting symptoms further influences the dynamic of disease progression. Patients with a cognitive presentation have a much slower or even no motor decline than patients with a mixed motor and cognitive presentation. Research advancements have enabled improved understanding of the effects of allogeneic hematopoietic stem cell transplantation and the development of novel therapeutic approaches, including hematopoietic stem cell gene therapy, which is now authorized in the EU, United Kingdom, and United States as treatment for selected patients with early-onset forms of MLD. Both hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy are most effective when administered before disease onset. To identify presymptomatic patients, NBS for MLD is becoming available in several countries, resulting in new challenges. Decisions regarding patient eligibility for these treatments in already symptomatic individuals, as well as the timing of treatment for patients identified through NBS, require thorough understanding of disease progression. Biomarkers may be helpful for disease staging and prediction of disease evolution. Moreover, apart from timing, challenges remain regarding optimal treatment strategies across MLD subtypes, especially late-onset MLD, and management of the clinical heterogeneity and course of the disease. Another important issue is ensuring therapy accessibility, which forms a substantial barrier for equitable care. Continued research and international collaboration are essential to address these challenges, with the goal of improving care and outcomes for patients with MLD and their families.

Metachromatic leukodystrophy (MLD) is a neuro-metabolic disorder due to arylsulfatase A deficiency, causing demyelination of the central and peripheral nervous system. Hematopoietic cell transplantation (HCT) can provide a symptomatic and survival benefit for pre-symptomatic and early symptomatic patients by stabilizing CNS disease. This case series, however, illustrates the occurrence of severely progressive polyneuropathy shortly after HCT in two patients with late-infantile, one with late-juvenile, and one with adult MLD, leading to the inability to walk or sit without support. The patients had demyelinating polyneuropathy before HCT, performed at the ages of 2 years in the first two patients and at 14 and 23 years in the other two patients. The myeloablative conditioning regimen consisted of busulfan, fludarabine and, in one case, rituximab, with anti-thymocyte globulin, cyclosporine, steroids, and/or mycophenolate mofetil for GvHD prophylaxis. Polyneuropathy after HCT progressed parallel with tapering immunosuppression and paralleled bouts of infection and graft-versus-host disease (GvHD). Differential diagnoses included MLD progression, neurological GvHD or another (auto)inflammatory cause. Laboratory, electroneurography and pathology investigations were inconclusive. In two patients, treatment with immunomodulatory drugs led to temporary improvement, but not sustained stabilization of polyneuropathy. One patient showed recovery to pre-HCT functioning, except for a Holmes-like tremor, for which a peripheral origin cannot be excluded. One patient showed marginal response to immunosuppressive treatment and died ten months after HCT due to respiratory failure. The extensive diagnostic and therapeutic attempts highlight the challenge of characterizing and treating progressive polyneuropathy in patients with MLD shortly after HCT. We advise to consider repeat electro-neurography and possibly peripheral nerve biopsy in such patients. Nerve conduction blocks, evidence of the presence of T lymphocytes and macrophages in the neuronal and surrounding nerve tissue, and beneficial effects of immunomodulatory drugs may indicate a partially (auto)immune-mediated pathology. Polyneuropathy may cause major residual disease burden after HCT. MLD patients with progressive polyneuropathy could potentially benefit from a more intensified immunomodulatory drug regime following HCT, especially at times of immune activation.

This study aimed to evaluate the effect of intrathecal (IT) recombinant human arylsulfatase A (rhASA) on magnetic resonance imaging (MRI)-assessed brain tissue changes in children with metachromatic leukodystrophy (MLD). In total, 510 MRI scans were collected from 12 intravenous (IV) rhASA-treated children with MLD, 24 IT rhASA-treated children with MLD, 32 children with untreated MLD, and 156 normally developing children. Linear mixed models were fitted to analyze the time courses of gray matter (GM) volume and fractional anisotropy (FA) in the posterior limb of the internal capsule. Time courses for demyelination load and FA in the centrum semiovale were visualized using locally estimated scatterplot smoothing regression curves. All assessed imaging parameters demonstrated structural evidence of neurological deterioration in children with MLD. GM volume was significantly lower at follow-up (median duration, 104 weeks) in IV rhASA-treated versus IT rhASA-treated children. GM volume decline over time was steeper in children receiving low-dose (10 or 30 mg) versus high-dose (100 mg) IT rhASA. Similar effects were observed for demyelination. FA in the posterior limb of the internal capsule showed a higher trend over time in IT rhASA-treated versus children with untreated MLD, but FA parameters were not different between children receiving the low doses versus those receiving the high dose. GM volume in IT rhASA-treated children showed a strong positive correlation with 88-item Gross Motor Function Measure score over time. In some children with MLD, IT administration of high-dose rhASA may delay neurological deterioration (assessed using MRI), offering potential therapeutic benefit.

>Recently Zhang et al.(2024) published their study entitled “Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: A long-term follow-up pilot study.” The authors present three metachromatic leukodystrophy(MLD) patients treated with gene therapy and claim stabilization or even improvement, despite advanced symptomatic disease stage. The metachromatic leukodystrophy initiative(MLDi)(Schoenmakers et al., 2022), an international collaborative network and registry for MLD, urges caution in interpreting these results, as the evidence raises several critical concerns. These claims risk fostering false hope among MLD patients and their families, particularly given the significant gaps in the data provided(Fig. 1).

We report three siblings homozygous for CSF1R variant c.1969 + 115_1969 + 116del to expand the phenotype of “brain abnormalities, neurodegeneration, and dysosteosclerosis” (BANDDOS) and discuss its link with “adult leukoencephalopathy with axonal spheroids and pigmented glia” (ALSP), caused by heterozygous CSF1R variants. We evaluated medical, radiological, and laboratory findings and reviewed the literature. Patients presented with developmental delay, therapy-resistant epilepsy, dysmorphic features, and skeletal abnormalities. Secondary neurological decline occurred from 23 years in sibling one and from 20 years in sibling two. Brain imaging revealed multifocal white matter abnormalities and calcifications during initial disease in siblings two and three. Developmental brain anomalies, seen in all three, were most severe in sibling two. During neurological decline in siblings one and two, the leukoencephalopathy was progressive and had the MRI appearance of ALSP. Skeletal survey revealed osteosclerosis, most severe in sibling three. Blood markers, monocytes, dendritic cell subsets, and T-cell proliferation capacity were normal. Literature review revealed variable initial disease and secondary neurological decline. BANDDOS presents with variable dysmorphic features, skeletal dysplasia, developmental delay, and epilepsy with on neuro-imaging developmental brain anomalies, multifocal white matter abnormalities, and calcifications. Secondary neurological decline occurs with a progressive leukoencephalopathy, in line with early onset ALSP. Despite the role of CSF1R signaling in myeloid development, immune deficiency is absent. Phenotype varies within families; skeletal and neurological manifestations may be disparate.

We present the case of a patient with leukoencephalopathy with calcifications and cysts (LCC), who experienced progressive severe hemiparesis despite multiple neurosurgical interventions of a large contralateral cyst. Bevacizumab was proposed as an ultimate treatment option based on prior case reports. While awaiting reimbursement approval for bevacizumab, major improvement occurred in both clinical and radiological disease manifestations. The disease course of LCC is variable and unpredictable; neurosurgical treatment should be reserved for severe and progressive neurological deficits. Bevacizumab has been reported as a promising alternative treatment option. Importantly, in our case the observed clinical improvement would have been attributed to the effects of bevacizumab, if started when requested. Our case underscores the need for a natural history study for LCC and the necessity of validating treatment efficacy by systematic evaluation through appropriate clinical trials rather than relying on anecdotal evidence from published case reports.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive neuromuscular degeneration resulting from mutations in the survival motor neuron (SMN1) gene. The availability of disease-modifying therapies for SMA therapies highlights the pressing need for easily accessible and cost-effective blood biomarkers to monitor treatment response and for better disease management. Additionally, the wide implementation of newborn genetic screening programs in Western countries enables presymptomatic diagnosis of SMA and immediate treatment administration. However, the absence of monitoring and prognostic blood biomarkers for neurodegeneration in SMA hinders effective disease management. Neurofilament light protein (NfL) is a promising biomarker of neuroaxonal damage in SMA and reflects disease progression in children with SMA undergoing treatment. Recently, the European Medicines Agency issued a letter of support endorsing the potential utilization of NfL as a biomarker of pediatric neurological diseases, including SMA. Within this review, we comprehensively assess the potential applications of NfL as a monitoring biomarker for disease severity and treatment response in pediatric-onset SMA. We provide reference ranges for normal levels of serum based NfL in neurologically healthy children aged 0-18 years. These reference ranges enable accurate interpretation of NfL levels in children and can accelerate the implementation of NfL into clinical practice.

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder characterized by arylsulfatase A (ASA) deficiency, leading to sulfatide accumulation and myelin degeneration in the central nervous system. While primarily considered a white matter (WM) disease, gray matter (GM) is also affected in MLD, and hematopoietic stem cell transplantation (HSCT) may have limited effect on GM atrophy. We cross-sectionally and longitudinally studied GM volumes using volumetric MRI in a cohort of 36 (late-infantile, juvenile and adult type) MLD patients containing untreated and HSCT treated subjects. Cerebrum, cortical GM, (total) CSF, cerebellum, deep gray matter (DGM) (excluding thalamus) and thalamus volumes were analyzed. Longitudinal correlations with measures of cognitive and motor functioning were assessed. Cross-sectionally, juvenile and adult type patients (infantiles excluded based on limited numbers) were compared with controls at earliest scan, before possible treatment. Patients had lower cerebrum, cortical GM, DGM and thalamus volumes. Differences were most pronounced for adult type patients. Longitudinal analyses showed substantial and progressive atrophy of all regions and increase of CSF in untreated patients. Similar, albeit less pronounced, effects were seen in treated patients for cerebrum, cortical GM, CSF and thalamus volumes. Deterioration in motor performance (all patients) was related to atrophy, and increase of CSF, in all regions. Cognitive functioning (data available for treated patients) was related to cerebral, cortical GM and thalamus atrophy; and to CSF increase. Our findings illustrate the importance of recognizing GM pathology as a potentially substantial, clinically relevant part of MLD, apparently less amenable to treatment.

Colony stimulating factor 1 receptor (CSF1R) is an essential receptor for both colony stimulating factor 1 (CSF1) and interleukin (IL) 34 signaling expressed on monocyte precursors and myeloid cells, including monocytes, dendritic cells (DC), and microglia. In humans, dominant heterozygous pathogenic variants in CSF1R cause a neurological condition known as CSF1R-related disorder (CSF1R-RD), typically with late onset, previously referred to as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). CSF1R-RD is characterized by microglia reduction and altered monocyte function; however, the impact of pathogenic CSF1R variants on the human DC lineage remains largely unknown.We previously reported that cord blood CD34+ stem cell-derived DCs generated in vitro originate specifically from CSF1R expressing precursors. In this study, we examined the DC lineage of four unrelated patients with late-onset CSF1R-RD who carried heterozygous missense CSF1R variants (c.2330G>A, c.2375C>A, c.2329C>T, and c.2381T>C) affecting different amino acids in the protein tyrosine kinase domain of CSF1R. CD34+ stem cells and CD14+ monocytes were isolated from peripheral blood and subjected to an in vitro culture protocol to differentiate towards conventional DCs and monocyte-derived DCs, respectively. Flow cytometric analysis revealed that monocytes from patients with late-onset CSF1R-RD were still able to differentiate into monocyte-derived DCs in vitro, whereas the ability of CD34+ stem cells to differentiate into conventional DCs was impaired. Strikingly, the peripheral blood of patients contained all naturally occurring DC subsets. We conclude that the in vitro abrogation of DC-development in patients with heterozygous pathogenic missense CSF1R variants does not translate to an impairment in DC development in vivo and speculate that CSF1R signalling in vivo is compensated, which needs further study.

A brachial plexus lesion is a devastating injury often affecting young, male adults after traffic accidents. Therefore, surgical restoration of elbow flexion is critical for establishing antigravity movement of the upper extremity. We analyzed different methods for musculocutaneous reconstruction regarding outcome.We conducted a retrospective analysis of 146 brachial plexus surgeries with musculocutaneous reconstruction performed at our department from 2013 to 2017. Demographic data, surgical method, donor and graft nerve characteristics, body mass index (BMI) as well as functional outcome of biceps muscle based on medical research council (MRC) strength grades before and after surgery were analyzed. Multivariate analysis was performed using SPSS.Oberlin reconstruction was the procedure performed most often (34.2%, n = 50). Nerve transfer and autologous repair showed no significant differences regarding outcome (p = 0.599, OR 0.644 CI95% 0.126–3.307). In case of nerve transfers, we found no significant difference whether reconstruction was performed with or without a nerve graft (e.g. sural nerve) (p = 0.277, OR 0.619 CI95% 0.261–1.469). Multivariate analysis identifies patient age as a strong predictor for outcome, univariate analysis indicates that nerve graft length > 15 cm and BMI of > 25 could lead to inferior outcome. When patients with early recovery (n = 19) are included into final evaluation after 24 months, the general success rate of reconstructions is 62,7% (52/83).Reconstruction of musculocutaneous nerve after brachial plexus injury results in a high rate of clinical improvement. Nerve transfer and autologous reconstruction both show similar results. Young age was confirmed as an independent predictor for better clinical outcome. Prospective multicenter studies are needed to further clarify.

OBJECTIVE:Metachromatic leukodystrophy is a lysosomal storage disease caused by deficient arylsulfatase A. It is characterized by progressive demyelination and thus mainly affects the white matter. Hematopoietic stem cell transplantation may stabilize and improve white matter damage, yet some patients deteriorate despite successfully treated leukodystrophy. We hypothesized that post-treatment decline in metachromatic leukodystrophy might be caused by gray matter pathology. METHODS:Three metachromatic leukodystrophy patients treated with hematopoietic stem cell transplantation with a progressive clinical course despite stable white matter pathology were clinically and radiologically analyzed. Longitudinal volumetric MRI was used to quantify atrophy. We also examined histopathology in three other patients deceased after treatment and compared them with six untreated patients. RESULTS:The three clinically progressive patients developed cognitive and motor deterioration after transplantation, despite stable mild white matter abnormalities on MRI. Volumetric MRI identified cerebral and thalamus atrophy in these patients, and cerebellar atrophy in two. Histopathology showed that in brain tissue of transplanted patients, arylsulfatase A expressing macrophages were clearly present in the white matter, but absent in the cortex. Arylsulfatase A expression within patient thalamic neurons was lower than in controls, the same was found in transplanted patients. INTERPRETATION:Neurological deterioration may occur after hematopoietic stem cell transplantation in metachromatic leukodystrophy despite successfully treated leukodystrophy. MRI shows gray matter atrophy, and histological data demonstrate absence of donor cells in gray matter structures. These findings point to a clinically relevant gray matter component of metachromatic leukodystrophy, which does not seem sufficiently affected by transplantation.

Sexual well-being refers to the evaluation of one's sexuality. We examined the association of enjoyment of sexuality with longevity and the moderating role of perceived importance of sexuality in this association. In the population-based Longitudinal Ageing Study Amsterdam, the survival of initially 55-84-year-olds was followed during 27 years. Complete data were available for 1042 participants (45.3%). Analyses were adjusted for health-related and psychosocial covariates. 60% of the participants experienced their sexuality as enjoyable and 44% as important. Enjoyment of sexuality was weakly, positively associated with longevity (B[CI] = 0.29[-0.004;0.58]). Perceived importance modified this association: only in those who perceived sexuality as important, the association between enjoyment and longevity was statistically significant (B[CI] = 0.78[0.29;1.27]). Positive affect, functional limitations, emotional loneliness, self-rated health, sense of mastery and alcohol consumption accounted for 35% of the latter association. Interventions may target older adults who perceive sexuality as important but not enjoyable.

AbstractObjectivesMetachromatic leukodystrophy (MLD) has characteristic white matter (WM) changes on brain MRI, which often trigger biochemical and genetic confirmation of the diagnosis. In early or pre‐symptomatic disease stages, these typical MRI changes might be absent, hampering early diagnosis. This study aims to describe the characteristics of MRI WM abnormalities at diagnosis, related to clinical presentation.MethodsWe retrospectively reviewed brain MRIs of MLD patients followed in 2 centers at the time of diagnosis regarding MLD MRI score and presence of tigroid pattern. In addition, MLD subtype, symptom status, CNS/PNS phenotype, motor/cognitive/mixed phenotype, and the presence of CNS symptoms were evaluated.ResultsWe included 104 brain MRIs from patients with late‐infantile (n = 43), early‐juvenile (n = 24), late‐juvenile (n = 20) and adult (n = 17) onset. Involvement of the corpus callosum was a characteristic early MRI sign and was present in 71% of the symptomatic late‐infantile patients, 94% of the symptomatic early‐juvenile patients and 100% of the symptomatic late‐juvenile and adult patients. Symptomatic early‐juvenile, late‐juvenile and adult patients generally had WM abnormalities on MRI suggestive of MLD. By contrast, 47% of the early‐symptomatic late‐infantile patients had no or only mild WM abnormalities on MRI, even in the presence of CNS symptoms including pyramidal signs.InterpretationPatients with late‐infantile MLD may have no or only mild, nonspecific abnormalities at brain MRI, partly suggestive of ‘delayed myelination’, even with clear clinical symptoms. This may lead to significant diagnostic delay. Knowledge of these early MRI signs (or their absence) is important for fast diagnosis.

Tissue-resident macrophages of the brain, including microglia, are implicated in the pathogenesis of various CNS disorders and are possible therapeutic targets by their chemical depletion or replenishment by hematopoietic stem cell therapy. Nevertheless, a comprehensive understanding of microglial function and the consequences of microglial depletion in the human brain is lacking. In human disease, heterozygous variants in CSF1R, encoding the Colony-stimulating factor 1 receptor, can lead to adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) possibly caused by microglial depletion. Here, we investigate the effects of ALSP-causing CSF1R variants on microglia and explore the consequences of microglial depletion in the brain. In intermediate- and late-stage ALSP post-mortem brain, we establish that there is an overall loss of homeostatic microglia and that this is predominantly seen in the white matter. By introducing ALSP-causing missense variants into the zebrafish genomic csf1ra locus, we show that these variants act dominant negatively on the number of microglia in vertebrate brain development. Transcriptomics and proteomics on relatively spared ALSP brain tissue validated a downregulation of microglia-associated genes and revealed elevated astrocytic proteins, possibly suggesting involvement of astrocytes in early pathogenesis. Indeed, neuropathological analysis and in vivo imaging of csf1r zebrafish models showed an astrocytic phenotype associated with enhanced, possibly compensatory, endocytosis. Together, our findings indicate that microglial depletion in zebrafish and human disease, likely as a consequence of dominant-acting pathogenic CSF1R variants, correlates with altered astrocytes. These findings underscore the unique opportunity CSF1R variants provide to gain insight into the roles of microglia in the human brain, and the need to further investigate how microglia, astrocytes, and their interactions contribute to white matter homeostasis.