Overlapping clusters of gray matter deficits in paranoid schizophrenia and psychotic bipolar mania with family history

The purpose of this study was to assess volumetric abnormalities of gray matter throughout the entire brain in patients with paranoid schizophrenia or with bipolar mania compared with control groups. We obtained weighted 3D T1 magnetic resonance images from 23 patients with paranoid schizophrenia, 24 patients with psychotic bipolar mania, and 36 healthy controls. Gray matter volume differences were assessed using optimized volumetric voxel-based morphometry (VBM). Both paranoid schizophrenia and bipolar mania group showed reduction of gray matter volume in the superior temporal gyrus (STG) (Brodmann Area, BA 22 areas), and the inferior parietal lobule, and enlargement of putamen, although different sides of the inferior parietal lobule and putamen were affected in the groups. Our findings showed the presence of overlapping clusters of gray matter deficits in paranoid-type schizophrenia and psychotic bipolar mania. The overlap in gray matter pathology between the two disorders may be attributed to risk factors common to both disorders.     

Olfaction evaluation and correlation with brain atrophy in Bardet‐Biedl syndrome

Bardet‐Biedl syndrome (BBS) is a well‐recognized ciliopathy characterized by cardinal features namely: early onset retinitis pigmentosa, polydactyly, obesity, hypogonadism, renal and cognitive impairment. Recently, disorders of olfaction (anosmia, hyposmia) have been also described in BBS patients. Moreover, morphological brain anomalies have been reported and prompt for further investigations to determine whether they are primary or secondary to peripheral organ involvement (i.e. visual or olfactory neuronal tissue). The objective of this article is to evaluate olfactory disorders in BBS patients and to investigate putative correlation with morphological cerebral anomalies. To this end, 20 BBS patients were recruited and evaluated for olfaction using the University of Pennsylvania Smell Identification Test (UPSIT). All of them underwent a structural magnetic resonance imaging (MRI) scan. We first investigated brain morphological differences between BBS subjects and 14 healthy volunteers. Then, we showed objective olfaction disorders in BBS patients and highlight correlation between gray matter volume reduction and olfaction dysfunction in several brain areas.     

Covarying structural alterations in laterality of the temporal lobe in schizophrenia: A case for source‐based laterality

The human brain is asymmetrically lateralized for certain functions (such as language processing) to regions in one hemisphere relative to the other. Asymmetries are measured with a laterality index (LI). However, traditional LI measures are limited by a lack of consensus on metrics used for its calculation. To address this limitation, source‐based laterality (SBL) leverages an independent component analysis for the identification of laterality‐specific alterations, identifying covarying components between hemispheres across subjects. SBL is successfully implemented with simulated data with inherent differences in laterality. SBL is then compared with a voxel‐wise analysis utilizing structural data from a sample of patients with schizophrenia and controls without schizophrenia. SBL group comparisons identified three distinct temporal regions and one cerebellar region with significantly altered laterality in patients with schizophrenia relative to controls. Previous work highlights reductions in laterality (ie, reduced left gray matter volume) in patients with schizophrenia compared with controls without schizophrenia. Results from this pilot SBL project are the first, to our knowledge, to identify covarying laterality differences within discrete temporal brain regions. The authors argue SBL provides a unique focus to detect covarying laterality differences in patients with schizophrenia, facilitating the discovery of laterality aspects undetected in previous work.     

Region‐specific insular volumetric decreases in drug‐naive,first‐episode schizophrenia and their unaffected siblings

Decreased insular volume may be one of the anatomical alterations caused by schizophrenia. The possibility of region‐specific insular volumetric reduction as an endophenotype and/or a possible treatment predictor is a critical issue with great implications for the diagnosis and prognosis of the disease. The sample of the current study comprised 44 drug‐naive and first‐episode patients, 42 unaffected siblings, and 44 healthy controls. A computational anatomy toolbox (CAT12) was applied to analyze the structural images with a fine‐grained, cross‐validated brainnetome atlas. Correlation analysis and support vector regression (SVR) were used to determine the relationship between insular deficits and symptomatic severity among patients. The gray matter volume (GMV) values in the left hypergranular insula (G) exhibited the following pattern: patients < siblings < controls. GMV values in the right ventral agranular insula (vIa) and baseline Positive and Negative Syndrome Scale negative symptoms subscale scores among patients showed a positive correlation (r = 0.384, p = .010). Further SVR analysis exhibited a significantly positive correlation between GMV values in the right vIa and negative symptomatic improvement among patients (r = 0.537, p < .001). Results suggested the presence of region‐specific insular volumetric decreases in first‐episode schizophrenia. Thus, volumetric decrease in left G might be a potential endophenotype for schizophrenia, and GMV values in right vIa might be used to predict negative symptomatic improvement in schizophrenia.     

Verbal working memory‐related neural network communication in schizophrenia

Impaired working memory (WM) in schizophrenia is associated with reduced hemodynamic and electromagnetic activity and altered network connectivity within and between memory‐associated neural networks. The present study sought to determine whether schizophrenia involves disruption of a frontal‐parietal network normally supporting WM and/or involvement of another brain network. Nineteen schizophrenia patients (SZ) and 19 healthy comparison subjects (HC) participated in a cued visual‐verbal Sternberg task while dense‐array EEG was recorded. A pair of item arrays each consisting of 2–4 consonants was presented bilaterally for 200 ms with a prior cue signaling the hemifield of the task‐relevant WM set. A central probe letter 2,000 ms later prompted a choice reaction time decision about match/mismatch with the target WM set. Group and WM load effects on time domain and time‐frequency domain 11–15 Hz alpha power were assessed for the cue‐to‐probe time window, and posterior 11–15 Hz alpha power and frontal 4–8 Hz theta power were assessed during the retention period. Directional connectivity was estimated via Granger causality, evaluating group differences in communication. SZ showed slower responding, lower accuracy, smaller overall time‐domain alpha power increase, and less load‐dependent alpha power increase. Midline frontal theta power increases did not vary by group or load. Network communication in SZ was characterized by temporal‐to‐posterior information flow, in contrast to bidirectional temporal‐posterior communication in HC. Results indicate aberrant WM network activity supporting WM in SZ that might facilitate normal load‐dependent and only marginally less accurate task performance, despite generally slower responding.     

BDNF gene variants and brain morphology in schizophrenia.

The objective was to investigate putative associations between brain-derived neurotrophic factor gene (BDNF) polymorphisms and brain morphology in patients with schizophrenia and healthy control subjects. Four BDNF polymorphisms were genotyped and analyzed versus 39 brain volume measures in 96 patients with schizophrenia or schizoaffective disorder and 104 healthy subjects. In all subjects, quantitative data on segmented gray, white, and cerebrospinal fluid (CSF) tissue class volumes of total brain and major cerebral lobes including ventricular CSF were obtained using magnetic resonance imaging (MRI). In a randomly selected subset of this population (n = 101-122), MR volumes from cerebellar tonsil, hemispheres, and vermis subregions, striatal structures, hippocampus, and corpus callosum were also measured. The BDNF 11757 G/C polymorphism was highly significantly associated with frontal gray matter volume variation in patients alone and in patients and control subjects combined. In patients only, the 270 C/T polymorphism was associated with total caudate volume. Significant associations were demonstrated between the BDNF 11757 G/C and Val66Met polymorphisms and a global haplotype estimate of four BDNF polymorphisms and the posterior superior cerebellar vermis volume in the controls as well as in the combined group, but not in the patients. The 11757 G/C polymorphism was associated with cerebellar hemisphere white and gray matter volumes in the combined group. The BDNF -633 T/A polymorphism was associated with gray matter of the putamen in the controls. Trends for associations between several polymorphisms/haplotype estimates and MRI volumes were found. BDNF gene variation may influence brain morphology. The effects may be different in patients with schizophrenia and healthy subjects.     

Simultaneous multi‐slice spin‐ and gradient‐echo dynamic susceptibility‐contrast perfusion‐weighted MRI of gliomas

Although combined spin‐ and gradient‐echo (SAGE) dynamic susceptibility‐contrast (DSC) MRI can provide perfusion quantification that is sensitive to both macrovessels and microvessels while correcting for T₁‐shortening effects, spatial coverage is often limited in order to maintain a high temporal resolution for DSC quantification. In this work, we combined a SAGE echo‐planar imaging (EPI) sequence with simultaneous multi‐slice (SMS) excitation and blipped controlled aliasing in parallel imaging (blipped CAIPI) at 3 T to achieve both high temporal resolution and whole brain coverage. Two protocols using this sequence with multi‐band (MB) acceleration factors of 2 and 3 were evaluated in 20 patients with treated gliomas to determine the optimal scan parameters for clinical use. ΔR₂*(t) and ΔR₂(t) curves were derived to calculate dynamic signal‐to‐noise ratio (dSNR), ΔR₂*‐ and ΔR₂‐based relative cerebral blood volume (rCBV), and mean vessel diameter (mVD) for each voxel. The resulting SAGE DSC images acquired using MB acceleration of 3 versus 2 appeared visually similar in terms of image distortion and contrast. The difference in the mean dSNR from normal‐appearing white matter (NAWM) and that in the mean dSNR between NAWM and normal‐appearing gray matter were not statistically significant between the two protocols. ΔR₂*‐ and ΔR₂‐rCBV maps and mVD maps provided unique contrast and spatial heterogeneity within tumors.     

Structural and functional abnormalities in migraine patients without aura

Migraine is a primary headache disorder characterized by recurrent attacks of throbbing pain associated with neurological, gastrointestinal and autonomic symptoms. Previous studies have detected structural deficits and functional impairments in migraine patients. However, researchers have failed to investigate the functional connectivity alterations of regions with structural deficits during the resting state. Twenty‐one migraine patients without aura and 21 age‐ and gender‐matched healthy controls participated in our study. Voxel‐based morphometric (VBM) analysis and functional connectivity were employed to investigate the abnormal structural and resting‐state properties, respectively, in migraine patients without aura. Relative to healthy comparison subjects, migraine patients showed significantly decreased gray matter volume in five brain regions: the left medial prefrontal cortex (MPFC), dorsal anterior cingulate cortex (dACC), right occipital lobe, cerebellum and brainstem. The gray matter volume of the dACC was correlated with the duration of disease in migraine patients, and thus we chose this region as the seeding area for resting‐state analysis. We found that migraine patients showed increased functional connectivity between several regions and the left dACC, i.e. the bilateral middle temporal lobe, orbitofrontal cortex (OFC) and left dorsolateral prefrontal cortex (DLPFC). Furthermore, the functional connectivity between the dACC and two regions (i.e. DLPFC and OFC) was correlated with the duration of disease in migraine patients. We suggest that frequent nociceptive input has modified the structural and functional patterns of the frontal cortex, and these changes may explain the functional impairments in migraine patients. Copyright © 2012 John Wiley & Sons, Ltd.     

Genome‐wide analysis of adolescent psychotic‐like experiences shows genetic overlap with psychiatric disorders

This study aimed to test for overlap in genetic influences between psychotic‐like experience traits shown by adolescents in the community, and clinically‐recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic‐like experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self‐ and parent‐ratings in three European community samples aged 15–19 years (Final N incl. siblings = 6,297–10,098). A mega‐genome‐wide association study (mega‐GWAS) for each psychotic‐like experience domain was performed. Single nucleotide polymorphism (SNP)‐heritability of each psychotic‐like experience domain was estimated using genomic‐relatedness‐based restricted maximum‐likelihood (GREML) and linkage disequilibrium‐ (LD‐) score regression. Genetic overlap between specific psychotic‐like experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk score (PRS) and LD‐score regression. GREML returned SNP‐heritability estimates of 3–9% for psychotic‐like experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent‐rated Negative Symptoms). Mega‐GWAS analysis identified one genome‐wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic‐like experience trait domains (Paranoia and Hallucinations only in non‐zero scorers). The major depression PRS significantly predicted Anhedonia and Parent‐rated Negative Symptoms in adolescence. Psychotic‐like experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically‐recognized psychiatric disorders, specifically schizophrenia and major depression.     

Morphometric and functional connectivity changes in the brain of patients with obstructive sleep apnea: A meta‐analysis

Existing evidence for brain morphometric changes and functional connectivity alterations in patients with obstructive sleep apnea is mixed. The current study aimed to meta‐analyse the neuroimaging data, and thus synthesize a brain map showing locations with morphometric and functional connectivity differences between patients with obstructive sleep apnea and controls. Published studies to 2018 were retrieved and included into the analysis if they reported such between‐group differences using voxel‐based morphometry or resting‐state functional magnetic resonance imaging, and reported the results in the form of brain coordinates based on whole‐brain analysis. Twelve voxel‐based morphometry and seven resting‐state functional magnetic resonance imaging studies that comprised a total of 1,113 participants fulfilled the inclusion criteria. Compared with healthy controls, patients with obstructive sleep apnea had reduced resting‐state connectivity in the right anterior cingulate and larger grey matter volume in the right insula. Patients with obstructive sleep apnea do have morphometric and resting‐state connectivity alterations in the brain. These neural correlates may help explain the effects of obstructive sleep apnea on the emotion, cognition and quality of life of patients, and may be used in future for evaluating its treatment outcome.     

Structural and resting‐state MRI detects regional brain differences in young and mid‐age healthy APOE‐e4 carriers compared with non‐APOE‐e4 carriers

The presence of the e4 allele of the apolipoprotein E (APOE) gene is the best‐known genetic risk factor for Alzheimer's disease. In this study, we investigated the link between functional and behavioural differences and regional brain volume and cortical thickness differences in those who carry the e4 allele (e4+) and those who only carry the e3 allele (e3/e3). We studied these genotype populations in two age groups: a young group (average age, 21 years) and a mid‐age group (average age, 50 years). High‐resolution T₁‐weighted MRI scans were analysed with Freesurfer to measure regional white matter brain volume and cortical thickness differences between genotype groups at each age. These data were correlated with behavioural findings in the same cohort. Resting‐state MRI was also conducted to identify differences in underlying brain functional connectivity. We found that there was a positive correlation between the thickness of the parahippocampal cortex in young e4+ individuals and performance on an episodic memory task. Young e4+ individuals also showed a positive correlation between white matter volume in the left anterior cingulate and performance on a covert attention task. At mid‐age, e4+ individuals had structural differences relative to e3/e3 individuals in these areas: the parahippocampal cortex was thicker and white matter volume in the left anterior cingulate was greater than in e3/e3 individuals. We discuss the possibility that an over‐engagement with these regions by e4+ individuals in youth may have a neurogenic effect that is observable later in life. The cuneus appears to be an important region for APOE‐driven differences in the brain, with greater functional connectivity among young e3/e3 individuals and greater white matter volume in young e4+ individuals. Copyright © 2016 John Wiley & Sons, Ltd.     

Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age × group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.     

WDR45B‐related intellectual disability,spastic quadriplegia,epilepsy, and cerebral hypoplasia: A consistent neurodevelopmental syndrome

The advancement in genomic sequencing has greatly improved the diagnostic yield for neurodevelopmental disorders and led to the discovery of large number of novel genes associated with these disorders. WDR45B has been identified as a potential intellectual disability gene through genomic sequencing of 2 large cohorts of affected individuals. In this report we present 6 individuals from 3 unrelated families with homozygous pathogenic variants in WDR45B: c.799C>T (p.Q267*) in 1 family and c.673C>T (p.R225*) in 2 families. These individuals shared a similar phenotype including profound development delay, early‐onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations. Neuroimaging showed ventriculomegaly, reduced cerebral white matter volume, and thinning of cerebral gray matter. The consistency in the phenotype strongly supports that WDR45B is associated with this disease.     

Influence of regional cerebral blood volume on voxel‐based morphometry

The investigation of structural brain alterations is one focus in research of brain diseases like depression. Voxel‐based morphometry (VBM) based on high‐resolution 3D MRI images is a widely used non‐invasive tool for such investigations. However, the result of VBM might be sensitive to local physiological parameters such as regional cerebral blood volume (rCBV) changes. In order to investigate whether rCBV changes may contribute to variation in VBM, we performed analyses in a study with the congenital learned helplessness (cLH) model for long‐term findings. The 3D structural and rCBV data were acquired with T₂‐weighted rapid acquisition with relaxation enhancement (RARE) pulse sequences. The group effects were determined by standard statistical parametric mapping (SPM) and biological parametric mapping (BPM) and examined further using atlas‐based regions. In our genetic animal model of depression, we found co‐occurrence of differences in gray matter volume and rCBV, while there was no evidence of significant interaction between both. However, the multimodal analysis showed similar gray matter differences compared with the standard VBM approach. Our data corroborate the idea that two group VBM differences might not be influenced by rCBV differences in genetically different strains. Copyright © 2016 John Wiley & Sons, Ltd.     

Alterations of regional spontaneous neuronal activity and corresponding brain circuit changes during resting state in migraine without aura

Although previous resting‐state studies have reported abnormal functional cerebral changes in patients with migraine without aura (MwoA), few have focused on alterations in both regional spontaneous neuronal activity and corresponding brain circuits in MwoA patients during rest. Eighteen MwoA patients and 18 age‐ and gender‐matched healthy controls (HC) were recruited in the current study. Baseline cerebral alterations were investigated using amplitude of low‐frequency fluctuation (ALFF) and region of interest (ROI)‐based functional connectivity (FC) analyses. Compared with HC, MwoA patients showed decreased ALFF values in the left rostral anterior cingulate cortex (rACC) and bilateral prefrontal cortex (PFC) as well as increased ALFF values in the right thalamus. FC analysis also revealed abnormal FCs associated with these ROIs. In addition, ALFF values of the left rACC correlated with duration of disease in MwoA. Our findings could lead to a better understanding of intrinsic functional architecture of baseline brain activity in MwoA, providing both regional and brain circuit spontaneous neuronal activity properties. Copyright © 2013 John Wiley & Sons, Ltd.     

Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study.

BACKGROUND. Data from postmortem, CT, and magnetic resonance imaging (MRI) studies indicate that patients with schizophrenia may have anatomical abnormalities of the left temporal lobe, but it is unclear whether these abnormalities are related to the thought disorder characteristic of schizophrenia. METHODS. We used new MRI neuroimaging techniques to derive (without knowledge of the diagnosis) volume measurements and three-dimensional reconstructions of temporal-lobe structures in vivo in 15 right-handed men with chronic schizophrenia and 15 matched controls. RESULTS. As compared with the controls, the patients had significant reductions in the volume of gray matter in the left anterior hippocampus-amygdala (by 19 percent [95 percent confidence interval, 3 to 36 percent]), the left parahippocampal gyrus (by 13 percent [95 percent confidence interval, 3 to 23 percent], vs. 8 percent on the right), and the left superior temporal gyrus (by 15 percent [95 percent confidence interval, 5 to 25 percent]). The volume of the left posterior superior temporal gyrus correlated with the score on the thought-disorder index in the 13 patients evaluated (r = -0.81, P = 0.001). None of these regional volume decreases was accompanied by a decrease in the volume of the overall brain or temporal lobe. The volume of gray matter in a control region (the superior frontal gyrus) was essentially the same in the patients and controls. CONCLUSIONS. Schizophrenia involves localized reductions in the gray matter of the left temporal lobe. The degree of thought disorder is related to the size of the reduction in volume of the left posterior superior temporal gyrus.     

Enhanced delineation of white matter structures of the fixed mouse brain using Gd‐DTPA in microscopic MRI

The purpose of this study was to investigate the effect of gadolinium (III) diethyltriaminepenta‐acetic acid (Gd‐DTPA) mixed with a fixative on the image contrast between the white and gray matter of the perfusion‐fixed mouse brain. A series of microscopic MRI (µMRI) studies using different concentrations of Gd‐DTPA were performed at multiple time points to determine the optimal Gd‐DTPA concentration and fixation time necessary to maximize the contrast‐to‐noise ratio between the white and gray matter with relatively short scan time using a three‐dimensional gradient‐echo pulse sequence. On the basis of the experimental results, high‐resolution (39 µm isotropic) images with excellent contrast‐to‐noise ratio (～50) were acquired in less than 2 h of scan time after the specimen had been soaked in 10 mM Gd‐DTPA for 4 days. Excellent correlation was noted between µMRI and histology in that the µMRI clearly depicted brain regions that were also observed by the Kluver–Barrera stain. The enhanced contrast between the white and gray matter obtained by the proposed µMRI method may facilitate the development of µMRI‐based morphological phenotyping methods for mouse models of neurological disorders. Copyright © 2008 John Wiley & Sons, Ltd.     

Neuroimaging of cortical development and brain connectivity in human newborns and animal models

Significant human brain growth occurs during the third trimester, with a doubling of whole brain volume and a fourfold increase of cortical gray matter volume. This is also the time period during which cortical folding and gyrification take place. Conditions such as intrauterine growth restriction, prematurity and cerebral white matter injury have been shown to affect brain growth including specific structures such as the hippocampus, with subsequent potentially permanent functional consequences. The use of 3D magnetic resonance imaging (MRI) and dedicated postprocessing tools to measure brain tissue volumes (cerebral cortical gray matter, white matter), surface and sulcation index can elucidate phenotypes associated with early behavior development. The use of diffusion tensor imaging can further help in assessing microstructural changes within the cerebral white matter and the establishment of brain connectivity. Finally, the use of functional MRI and resting-state functional MRI connectivity allows exploration of the impact of adverse conditions on functional brain connectivity in vivo. Results from studies using these methods have for the first time illustrated the structural impact of antenatal conditions and neonatal intensive care on the functional brain deficits observed after premature birth. In order to study the pathophysiology of these adverse conditions, MRI has also been used in conjunction with histology in animal models of injury in the immature brain. Understanding the histological substrate of brain injury seen on MRI provides new insights into the immature brain, mechanisms of injury and their imaging phenotype.     

Neuroanatomical correlates of trait anhedonia in patients with schizophrenia: A voxel-based morphometric study

The aim of this study was to characterize the association between trait anhedonia and regional gray matter volume in patients with schizophrenia. Forty-six patients with schizophrenia and 56 healthy controls underwent magnetic resonance imaging (MRI) to acquire high-resolution T1-weighted images. Trait anhedonia was measured using the Chapman Revised Physical Anhedonia Scale (PAS). Voxel-based morphometry was performed to investigate brain volume correlates of trait anhedonia. Several brain regions in the patient group, including the left precuneus and right posterior cingulate (PCC), were found to show significantly less correlation with PAS scores than those of the control group. Post-hoc analysis revealed that negative correlations between the regional gray matter volume and the PAS scores in the patient group were found at a trend level in the left precuneus and the right PCC. In conclusion, these findings suggest that trait anhedonia in patients with schizophrenia could possibly be associated with a volume deficit in brain regions related to default-mode, which reflects the impairment of self-referential processing and reward anticipation.     

Alpha‐mannosidosis: characterization of CNS pathology and correlation between CNS pathology and cognitive function

Alpha‐mannosidosis (AM) (OMIM 248500) is a rare lysosomal storage disease. The understanding of the central nervous system (CNS) pathology is limited. This study is the first describing the CNS pathology and the correlation between the CNS pathology and intellectual disabilities in human AM. Thirty‐four patients, aged 6–35 years, with AM were included. Data from 13 healthy controls were included in the analysis of the magnetic resonance spectroscopy (MRS). Measurements of CNS neurodegeneration biomarkers in cerebrospinal fluid (CSF), CSF‐oligosaccharides, and performance of cerebral magnetic resonance imaging (MRI) and MRS were carried out. On MRI, 5 of 10 patients had occipital white matter (WM) signal abnormalities, and 6 of 10 patients had age‐inappropriate myelination. MRS demonstrated significantly elevated mannose complex in gray matter and WM. We found elevated concentrations of tau‐protein, glial fibrillary acidic protein and neurofilament light protein in 97 patients, 74% and 41% of CSF samples, respectively. A negative correlation between CSF‐biomarkers and cognitive function and CSF‐oligosaccharides and cognitive function was found. The combination of MRS/MRI changes, elevated concentrations of CSF‐biomarkers and CSF‐oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM. Our data demonstrate early neuropathological changes, which may be taken into consideration when planning initiation of treatment.