Gene and protein expression data provide useful resources for understanding brain function, but little is known about the lipid composition of the brain. Here, we perform quantitative shotgun ...lipidomics, which enables a cell-type-resolved assessment of the mouse brain lipid composition. We quantify around 700 lipid species and evaluate lipid features including fatty acyl chain length, hydroxylation, and number of acyl chain double bonds, thereby identifying cell-type- and brain-region-specific lipid profiles in adult mice, as well as in aged mice, in apolipoprotein-E-deficient mice, in a model of Alzheimer’s disease, and in mice fed different diets. We also integrate lipid with protein expression profiles to predict lipid pathways enriched in specific cell types, such as fatty acid β-oxidation in astrocytes and sphingolipid metabolism in microglia. This resource complements existing brain atlases of gene and protein expression and may be useful for understanding the role of lipids in brain function.
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•Brain-region- and cell-type-resolved lipidomic profiling•Definition of differences in lipid profiles of CNS cell types•Integration of lipid with protein expression profiles predicts lipid pathways•Aging alters brain lipid profiles with regional differences
Fitzner et al. perform extensive lipidome analyses on the mouse brain and its major cell types and integrate lipid with protein expression profiles to predict lipid pathways enriched in specific cells and brain regions. The study serves as a resource for better understanding of brain development and function.
Brain transcriptome and connectome maps are being generated, but an equivalent effort on the proteome is currently lacking. We performed high-resolution mass spectrometry-based proteomics for ...in-depth analysis of the mouse brain and its major brain regions and cell types. Comparisons of the 12,934 identified proteins in oligodendrocytes, astrocytes, microglia and cortical neurons with deep sequencing data of the transcriptome indicated deep coverage of the proteome. Cell type-specific proteins defined as tenfold more abundant than average expression represented about a tenth of the proteome, with an overrepresentation of cell surface proteins. To demonstrate the utility of our resource, we focused on this class of proteins and identified Lsamp, an adhesion molecule of the IgLON family, as a negative regulator of myelination. Our findings provide a framework for a system-level understanding of cell-type diversity in the CNS and serves as a rich resource for analyses of brain development and function.
Background
Up to 80% of women with X‐linked adrenoleukodystrophy (X‐ALD) develop symptoms of myelopathy and peripheral neuropathy during their lifetime. The study's objective was to compare ...symptomatic versus asymptomatic women with X‐ALD regarding their physical and mental well‐being and quality of life.
Methods
Data were obtained from a prospective, international, cross‐sectional cohort study of women with X‐ALD recruited both clinically and population based. Symptoms, quality of life, and physical and mental co‐morbidities were assessed by questionnaires. Women were considered symptomatic if they reported any sign of myelopathy or peripheral neuropathy. Group differences between symptomatic versus asymptomatic women and between age groups were examined using χ2 tests for categorical and independent sample t tests or analysis of variance for continuous variables.
Results
Complete data were available from N = 180 women (mean age: 51.2 ± 13.6 years, range: 18–85), of whom 71.7% were classified as symptomatic, with prevalence increasing with age. Symptomatic versus asymptomatic women reported poorer physical and mental health, with 26.4% meeting the criteria for a clinical depression, 73.6% reporting chronic pain, 80.6% sleeping disturbances, 38.2% sexual dysfunction, and 47.3% restless legs syndrome. Large group differences were found on the physical health, but not on the mental health component of quality of life, where symptomatic women only differed when controlling for having a boy affected by X‐ALD (small effect) and treatment frequency (medium effect).
Conclusions
Symptomatic women with X‐ALD present with physical and psychological co‐morbidities significantly reducing individuals’ quality of life. The findings emphasize the need to develop new multi‐disciplinary treatment options tailored to women's specific needs.
This currently largest cross‐sectional cohort study of women with X‐linked adrenoleukodystrophy (X‐ALD) found that symptomatic women with X‐ALD report physical and psychological comorbidities that significantly impact their quality of life. The findings highlight the need to develop new multi‐disciplinary treatment options tailored to the specific needs of symptomatic women with X‐ALD.
X‐linked adrenoleukodystrophy (X‐ALD) and metachromatic leukodystrophy (MLD) are two relatively common examples of hereditary demyelinating diseases caused by a dysfunction of peroxisomal or ...lysosomal lipid degradation. In both conditions, accumulation of nondegraded lipids leads to the destruction of cerebral white matter. Because of their high lipid content, oligodendrocytes are considered key to the pathophysiology of these leukodystrophies. However, the response to allogeneic stem cell transplantation points to the relevance of cells related to the hematopoietic lineage. In the present study, we aimed to better characterize the pathogenetic role of microglia in the above‐mentioned diseases. Applying recently established microglia markers to human autopsy cases of X‐ALD and MLD we were able to delineate distinct lesion stages in evolving demyelinating lesions. The immune‐phenotype of microglia was altered already early in lesion evolution, and microglia loss preceded full‐blown myelin degeneration both in X‐ALD and MLD. DNA fragmentation indicating phagocyte death was observed in areas showing microglia loss. The morphology and dynamics of phagocyte decay differed between the diseases and between lesion stages, hinting at distinct pathways of programmed cell death. In summary, the present study shows an early and severe damage to microglia in the pathogenesis of X‐ALD and MLD. This hints at a central pathophysiologic role of these cells in the diseases and provides evidence for an ongoing transfer of toxic substrates primarily enriched in myelinating cells to microglia.
Main Points
Immune‐phenotyping of microglia allows a more precise assessment of lesion evolution in leukodystrophies.
Microglia cell death is a seminal early feature in X‐ALD and MLD.
Cell death pathways differ according to the diseases and lesion stages.
Abstract
Although whisker-related perception is based predominantly on local, near-instantaneous coding, global, intensive coding, which integrates the vibrotactile signal over time, has also been ...shown to play a role given appropriate behavioral conditions. Here, we study global coding in isolation by studying head-fixed rats that identified pulsatile stimuli differing in pulse frequency but not in pulse waveforms, thus abolishing perception based on local coding. We quantified time locking and spike counts as likely variables underpinning the 2 coding schemes. Both neurometric variables contained substantial stimulus information, carried even by spikes of single barrel cortex neurons. To elucidate which type of information is actually used by the rats, we systematically compared psychometric with neurometric sensitivity based on the 2 coding schemes. Neurometric performance was calculated by using a population-encoding model incorporating the properties of our recorded neuron sample. We found that sensitivity calculated from spike counts sampled over long periods (>1 s) matched the performance of rats better than the one carried by spikes time-locked to the stimulus. We conclude that spike counts are more relevant to tactile perception when instantaneous kinematic parameters are not available.
Cerebral disease manifestation occurs in about two thirds of males with X‐linked adrenoleukodystrophy (CALD) and is fatally progressive if left untreated. Early histopathologic studies categorized ...CALD as an inflammatory demyelinating disease, which led to repeated comparisons to multiple sclerosis (MS). The aim of this study was to revisit the relationship between axonal damage and myelin loss in CALD. We applied novel immunohistochemical tools to investigate axonal damage, myelin loss and myelin repair in autopsy brain tissue of eight CALD and 25 MS patients. We found extensive and severe acute axonal damage in CALD already in prelesional areas defined by microglia loss and relative myelin preservation. In contrast to MS, we did not observe selective phagocytosis of myelin, but a concomitant decay of the entire axon‐myelin unit in all CALD lesion stages. Using a novel marker protein for actively remyelinating oligodendrocytes, breast carcinoma‐amplified sequence (BCAS) 1, we show that repair pathways are activated in oligodendrocytes in CALD. Regenerating cells, however, were affected by the ongoing disease process. We provide evidence that—in contrast to MS—selective myelin phagocytosis is not characteristic of CALD. On the contrary, our data indicate that acute axonal injury and permanent axonal loss are thus far underestimated features of the disease that must come into focus in our search for biomarkers and novel therapeutic approaches.
MAIN POINTS
This study characterizes CALD as an axonopathic disease.
Microglia cell death in CALD early lesion formation is associated with severe axonal damage.
Microglia homeostasis may be linked to axonal energy metabolism.
CSF1 receptor-related leukoencephalopathy is a rare genetic disorder presenting with severe, adult-onset white matter dementia as one of the leading symptoms. Within the central nervous system, the ...affected CSF1-receptor is expressed exclusively in microglia cells. Growing evidence implicates that replacing the defective microglia with healthy donor cells through hematopoietic stem cell transplant might halt disease progression. Early initiation of that treatment is crucial to limit persistent disability. However, which patients are suitable for this treatment is not clear, and imaging biomarkers that specifically depict lasting structural damage are lacking. In this study, we report on two patients with CSF1R-related leukoencephalopathy in whom allogenic hematopoietic stem cell transplant at advanced disease stages led to clinical stabilization. We compare their disease course with that of two patients admitted in the same timeframe to our hospital, considered too late for treatment, and place our cases in context with the respective literature. We propose that the rate of clinical progression might be a suitable stratification measure for treatment amenability in patients. Furthermore, for the first time we evaluate 18F florbetaben, a PET tracer known to bind to intact myelin, as a novel MRI-adjunct tool to image white matter damage in CSF1R-related leukoencephalopathy. In conclusion, our data add evidence for allogenic hematopoietic stem cell transplant as a promising treatment in CSF1R-related leukoencephalopathy patients with slow to moderate disease progression.
Understanding the neural code underlying perception requires the mapping of physical stimulus parameters to both psychophysical decisions and neuronal responses. Here, we employed a novel ...psychophysical task in head-fixed rats to measure discriminability of vibrotactile whisker deflections. Rats could discriminate 90 Hz from 60 Hz pulsatile stimuli if stimulus intensity covaried with frequency. To pin down the physical parameters used by the rats to discriminate these vibrations, we manipulated stimulus amplitude to arrive at pairs of nondiscriminable stimuli. We found that vibrations matched in intensity (measured as mean absolute velocity), but differing in frequency, were no longer discriminable. Recordings of trigeminal ganglion neurons revealed that the distribution of neurometric sensitivities based on spike counts, but not interspike intervals, matched the rats' inability to discriminate intensity-matched stimuli. In conclusion, we suggest that stimulus mean absolute velocity, encoded in primary afferent spike counts, plays a prominent role for whisker-mediated perception.
► Vibrotactile vibrissa stimuli are discriminated by rats using intensity cues ► The vibrissal system measures intensity as mean absolute velocity ► Spike counts rather than intervals are used as coding symbol in primary afferents
Retaining interns to work in the communities and settings in which they trained helps ensure a workforce that is well prepared to meet the needs of society. Psychology workforce data suggest that the ...supply of psychologists is not always sufficient in some areas, leading to unmet need. However, patterns of mobility in the psychology workforce are not well understood, nor are factors that might impact decisions to move away from a particular location or setting. This study surveyed early-career psychologists about the distance between their internship and other training and employment settings. Of the 2,206 respondents, individuals were significantly more likely to do their internship at a setting more than 75 miles from their doctoral program and take a first position less than 75 miles from their internship. Individuals were also significantly more likely to have their second position more than 75 miles from their internship (although 40% reported their second position was still less than 75 miles from their internship). Older individuals were less likely to take a first or second position more than 75 miles from their internship, whereas identifying as an ethnic minority was not related to location. Results also indicate that certain states are more likely to lose/gain interns as they pursue employment. Employment setting, job responsibilities, and opportunities for growth were early-career psychologists' top factors for selecting first and second positions. Compared with other settings, military medical centers, school districts/systems, and university counseling centers were significantly more likely to retain trainees in that setting as they advanced in their careers. Finally, about as many respondents stated that their internship site did bill for their services as those who said their site did not bill. Collectively, these results have implications for efforts to recruit and retain a sufficient psychology workforce.
Public Significance Statement
This article reports on the results of a survey intended to gather information about prevalence and reasons psychology interns take positions more than 75 miles from their internship. Findings can be used to guide efforts to better align needs for psychologists and the locations and settings where they work.
X-linked adrenoleukodystrophy (X-ALD) is highly variable, ranging from slowly progressive adrenomyeloneuropathy to severe brain demyelination and inflammation (cerebral ALD, CALD) affecting males ...with childhood peak onset. Risk models integrating blood-based biomarkers to indicate CALD onset, enabling timely interventions, are lacking. Therefore, we evaluated the prognostic value of blood biomarkers in addition to current neuroimaging predictors for early detection of CALD.
We measured blood biomarkers in a retrospective, male CALD risk-assessment cohort consisting of 134 X-ALD patients and 66 controls and in a phenotype-blinded validation set (25 X-ALD boys, 4–13 years) using Simoa®and Luminex® technologies.
Among 25 biomarkers indicating axonal damage, astrocye/microglia activation, or immune-cell recruitment, neurofilament light chain (NfL) had the highest prognostic value for early indication of childhood/adolescent CALD. A plasma NfL cut-off level of 8.33 pg/mL, determined in the assessment cohort, correctly discriminated CALD with an accuracy of 96% 95% CI: 80–100 in the validation group. Multivariable logistic regression models revealed that combining NfL with GFAP or cytokines/chemokines (IL-15, IL-12p40, CXCL8, CCL11, CCL22, and IL-4) that were significantly elevated in CALD vs healthy controls had no additional benefit for detecting neuroinflammation. Some cytokines/chemokines were elevated only in childhood/adolescent CALD and already upregulated in asymptomatic X-ALD children (IL-15, IL-12p40, and CCL7). In adults, NfL levels distinguished CALD but were lower than in childhood/adolescent CALD patients with similar (MRI) lesion severity. Blood GFAP did not differentiate CALD from non-inflammatory X-ALD.
Biomarker-based risk prediction with a plasma NfL cut-off value of 8.33 pg/mL, determined by ROC analysis, indicates CALD onset with high sensitivity and specificity in childhood X-ALD patients. A specific pro-inflammatory cytokine/chemokine profile in asymptomatic X-ALD boys may indicate a primed, immanent inflammatory state aligning with peak onset of CALD. Age-related differences in biomarker levels in adult vs childhood CALD patients warrants caution in predicting onset and progression of CALD in adults. Further evaluations are needed to assess clinical utility of the NfL cut-off for risk prognosis of CALD onset.
Austrian Science Fund, European Leukodystrophy Association.
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