White Matter Volume Reduction Research Articles

Focal Brain Lesions Causing Acquired Amusia Map to a Common Brain Network.

Music is a universal human attribute. The study of amusia, a neurologic music processing deficit, has increasingly elaborated our view on the neural organization of the musical brain. However, lesions causing amusia occur in multiple brain locations and often also cause aphasia, leaving the distinct neural networks for amusia unclear. Here, we utilized lesion network mapping to identify these networks. A systematic literature search was carried out to identify all published case reports of lesion-induced amusia. The reproducibility and specificity of the identified amusia network were then tested in an independent prospective cohort of 97 stroke patients (46 female and 51 male) with repeated structural brain imaging, specifically assessed for both music perception and language abilities. Lesion locations in the case reports were heterogeneous but connected to common brain regions, including bilateral temporoparietal and insular cortices, precentral gyrus, and cingulum. In the prospective cohort, lesions causing amusia mapped to a common brain network, centering on the right superior temporal cortex and clearly distinct from the network causally associated with aphasia. Lesion-induced longitudinal structural effects in the amusia circuit were confirmed as reduction of both gray and white matter volume, which correlated with the severity of amusia. We demonstrate that despite the heterogeneity of lesion locations disrupting music processing, there is a common brain network that is distinct from the language network. These results provide evidence for the distinct neural substrate of music processing, differentiating music-related functions from language, providing a testable target for noninvasive brain stimulation to treat amusia.

Glial cell changes in the corpus callosum in chronically-starved mice

Anorexia nervosa (AN) is characterized by emaciation, hyperactivity, and amenorrhea. Imaging studies in AN patients have revealed reductions in grey and white matter volume, which correlate with the severity of neuropsychological deficits. However, the cellular basis for the observed brain atrophy is poorly understood. Although distinct hypothalamic centers, including the arcuate nucleus (ARC) are critically involved in regulating feeding behavior, little is known about potential hypothalamic modifications in this disorder. Since glia e.g. astrocytes and microglia influence neuronal circuits, we investigated the glial changes underlying pathophysiology of starvation in the corpus callosum (CC) and hypothalamus. Female mice were given a limited amount of food once a day and had unlimited access to a running wheel until a 20% weight reduction was achieved (acute starvation). This weight reduction was maintained for two weeks to mimic chronic starvation. Immunohistochemistry was used to quantify the density of astrocytes, microglia, oligodendrocytes, and the staining intensity of neuropeptide Y (NPY), a potent orexigenic peptide. Chronic starvation induced a decreased density of OLIG2+ oligodendrocytes, GFAP+ astrocytes, and IBA1+ microglia in the CC. However, the densities of glial cells remained unchanged in the ARC following starvation. Additionally, the staining intensity of NPY increased after both acute and chronic starvation, indicating an increased orexigenic signaling. Chronic starvation induced glial cell changes in the CC in a mouse model of AN suggesting that glia pathophysiology may play a role in the disease.

Triangulating brain alterations in anorexia nervosa: a multimodal investigation of magnetic resonance spectroscopy, morphometry and blood-based biomarkers

The acute state of anorexia nervosa (AN) is associated with widespread reductions in cortical gray matter (GM) thickness and white matter (WM) volume, suspected changes in myelin content and elevated levels of the neuronal damage marker neurofilament light (NF-L), but the underlying mechanisms remain largely unclear. To gain a deeper understanding of brain changes in AN, we applied a multimodal approach combining advanced neuroimaging methods with analysis of blood-derived biomarkers. In addition to standard measures of cortical GM thickness and WM volume, we analyzed tissue-specific profiles of brain metabolites using multivoxel proton magnetic resonance spectroscopy, T1 relaxation time as a proxy of myelin content leveraging advanced quantitative MRI methods and serum NF-L concentrations in a sample of 30 female, predominately adolescent patients with AN and 30 age-matched female healthy control participants. In patients with AN, we found a reduction in GM cortical thickness and GM total N-acetyl aspartate. The latter predicted higher NF-L levels, which were elevated in AN. Furthermore, GM total choline was elevated. In WM, there were no group differences in either imaging markers, choline levels or N-acetyl aspartate levels. The current study provides evidence for neuronal damage processes as well as for increased membrane lipid catabolism and turnover in GM in acute AN but no evidence for WM pathology. Our results illustrate the potential of multimodal research including tissue-specific proton magnetic resonance spectroscopy analyses to shed light on brain changes in psychiatric and neurological conditions, which may ultimately lead to better treatments.

Neurodevelopmental Correlates of Brain Magnetic Resonance Imaging Abnormalities in Extremely Low-birth-weight Infants

To evaluate the relationship between impaired brain growth and structural brain abnormalities at term-equivalent age (TEA) and neurodevelopment in extremely low-birth-weight (ELBW) infants over the first 2years. ELBW infants born from 2009 through 2018 and undergoing brain magnetic resonance imaging (MRI) at TEA were enrolled in this retrospective cohort study. MRI scans were reviewed using a validated quali-quantitative score, including several white and gray matter items. Neurodevelopment was assessed at 6, 12, 18, and 24months using the Griffiths scales. The independent associations between MRI subscores and the trajectories of general and specific neurodevelopmental functions were analyzed by generalized estimating equations. One hundred-nine ELBW infants were included. White matter volume reduction and delayed myelination were associated with worse general development (b = -2.33, P=.040; b = -6.88, P=.049 respectively), social skills (b = -3.13, P=.019; b = -4.79, P=.049), and eye-hand coordination (b = -3.48, P=.009; b = -7.21, P=.045). Cystic white matter lesions were associated with poorer motor outcomes (b = -4.99, P=.027), while white matter signal abnormalities and corpus callosum thinning were associated with worse nonverbal cognitive performances (b = -6.42, P=.010; b = -6.72, P=.021, respectively). Deep gray matter volume reduction correlated with worse developmental trajectories. Distinctive MRI abnormalities correlate with specific later developmental skills. This finding may suggest that TEA brain MRI may assist with neurodevelopmental prediction, counseling of families, and development of targeted supportive interventions to improve neurodevelopment in ELBW neonates.

High sensitivity of asymmetric 18F-THK5351 PET abnormality in patients with corticobasal syndrome

Corticobasal syndrome (CBS) is characterized by symptoms related to the asymmetric involvement of the cerebral cortex and basal ganglia. However, early detection of asymmetric imaging abnormalities can be challenging. Previous studies reported asymmetric 18F-THK5351 PET abnormalities in CBS patients, but the sensitivity for detecting such abnormalities in larger patient samples, including early-stage cases, remains unclear. Patients clinically diagnosed with CBS were recruited. All patients displayed asymmetric symptoms in the cerebral cortex and basal ganglia. Asymmetric THK5351 PET abnormalities were determined through visual assessment. Brain MRI, perfusion SPECT, and dopamine transporter (DAT) SPECT results were retrospectively reviewed. The 15 patients had a median age of 72 years (59–86 years) and a disease duration of 2 years (0.5–7 years). Four patients met the probable and 11 met the possible CBS criteria according to Armstrong criteria at the time of PET examination. All patients, including early-stage cases, exhibited asymmetric tracer uptake contralateral to their symptom-dominant side in the cerebral cortex/subcortical white matter and striatum (100%). The sensitivity for detecting asymmetric imaging abnormalities contralateral to the symptom-dominant side was 86.7% for brain MRI, 81.8% for perfusion SPECT, and 90% for DAT SPECT. White matter volume reduction was observed in the subcortical region of the precentral gyrus with increased THK5351 uptake, occurring significantly more frequently than gray matter volume reduction. THK5351 PET may be a sensitive imaging technique for detecting asymmetric CBS pathologies, including those in early stages.

Brain structure-function coupling associated with cognitive impairment in cerebral small vessel disease.

Cerebral small vessel disease (CSVD) is a common chronic and progressive disease that can lead to mental and cognitive impairment. Damage to brain structure and function may play an important role in the neuropsychiatric disorders of patients with CSVD. Increasing evidence suggests that functional changes are accompanied by structural changes in corresponding brain regions. Thus, normal structure-function coupling is essential for optimal brain performance, and disrupted structure-function coupling can be found in many neurological and psychiatric disorders. To date, most studies on patients with CSVD have focused on separate structures or functions, including reductions in white matter volume and blood flow, which lead to cognitive dysfunction. However, there are few studies on brain structure-function coupling in patients with CSVD. In recent years, with the rapid development of multilevel (voxel-wise, neurovascular, regional level, and network level) brain structure-functional coupling analysis methods based on multimodal magnetic resonance imaging (MRI), new evidence has been provided to reveal the correlation between brain function and structural abnormalities and cognitive impairment. Therefore, studying brain structure-function coupling has a potential significance in the exploration and elucidation of the neurobiological mechanism of cognitive impairment in patients with CSVD. This article mainly describes the currently popular brain structure-function coupling analysis technology based on multimodal MRI and the important research progress of these coupling technologies on CSVD and cognitive impairment to provide a perspective for the study of the pathogenesis and early diagnosis of CSVD.

Unraveling the pathophysiology of schizophrenia: insights from structural magnetic resonance imaging studies.

Schizophrenia affects about 1% of the global population. In addition to the complex etiology, linking this illness to genetic, environmental, and neurobiological factors, the dynamic experiences associated with this disease, such as experiences of delusions, hallucinations, disorganized thinking, and abnormal behaviors, limit neurological consensuses regarding mechanisms underlying this disease. In this study, we recruited 72 patients with schizophrenia and 74 healthy individuals matched by age and sex to investigate the structural brain changes that may serve as prognostic biomarkers, indicating evidence of neural dysfunction underlying schizophrenia and subsequent cognitive and behavioral deficits. We used voxel-based morphometry (VBM) to determine these changes in the three tissue structures: the gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). For both image processing and statistical analysis, we used statistical parametric mapping (SPM). Our results show that patients with schizophrenia exhibited a significant volume reduction in both GM and WM. In particular, GM volume reductions were more evident in the frontal, temporal, limbic, and parietal lobe, similarly the WM volume reductions were predominantly in the frontal, temporal, and limbic lobe. In addition, patients with schizophrenia demonstrated a significant increase in the CSF volume in the left third and lateral ventricle regions. This VBM study supports existing research showing that schizophrenia is associated with alterations in brain structure, including gray and white matter, and cerebrospinal fluid volume. These findings provide insights into the neurobiology of schizophrenia and may inform the development of more effective diagnostic and therapeutic approaches.

A Multimodal Neuroimaging Feature Extraction Framework for Biomarker Discovery in Myotonic Dystrophies (P8-4.004)

<h3>Objective:</h3> Myotonic dystrophies (DM) are neuromuscular conditions that cause widespread effects throughout the body. New therapeutics are being developed that attack the RNA mechanism underlying DM. Here, we address the urgent need of identifying DM neuroimaging biomarkers that can be used in trials. <h3>Background:</h3> DTI shows decreased white matter connectivity in DM patients and MRI reveals decreased parietal, frontal, and temporal resting state metabolism. Additionally, DTI studies of DM have shown that the white matter abnormalities are diffuse as opposed to multi-focal. <h3>Design/Methods:</h3> Extracting important features from neuroimaging data is challenging due to the high feature dimension and low sample-size problem. This work utilizes a sparse matrix decomposition method and a manifold regularization approach to identify the most discriminative features and improves spatial and temporal resolutions of neuroimaging data. To this end, neuroimaging data of 46 DM1, 17 DM2 patients and 92 healthy controls were analyzed using a ten-fold-cross-validation technique. In addition to neuroimaging data, additional clinical assessments including Quebec Muscular Impairment Rating Scale and Quebec Daytime Sleepiness Scale were calculated for DM patients. Wavelet approximation and detailed coefficients were calculated to consider both long term and short-term fluctuations caused by the disease process. <h3>Results:</h3> Normalized sub-band energy calculated based on wavelet coefficients can characterize DM1 and DM2. Patients with DM1 have widespread white matter volume reductions that are correlated with distal to proximal progression of the muscular involvement in DM1. A significant difference can be seen between DM1 and healthy controls in terms of executive function, motor speed, processing speed, and memory. <h3>Conclusions:</h3> The proposed method can potentially be used to develop and validate key predictors of DM type, severity, and progression of DM central nervous system abnormalities using brain morphometry. Identified features can also potentially provide multidisciplinary biomarkers that help unravel our understanding of fatigue, sleepiness, and attention. <b>Disclosure:</b> Ms. Kamali has nothing to disclose. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Affinia Therapeutics. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis Gene Therapy. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avidity. Dr. Day 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 Muscular Dystrophy Association. The institution of Dr. Day has received research support from Audentes. The institution of Dr. Day has received research support from Novartis Gene Therapy. The institution of Dr. Day has received research support from Biogen. The institution of Dr. Day has received research support from Cytokinetics. The institution of Dr. Day has received research support from Roche/Genentech. The institution of Dr. Day has received research support from Sanofi/Genzyme. The institution of Dr. Day has received research support from Sarepta. The institution of Dr. Day has received research support from Scholar Rock. Dr. Day has received intellectual property interests from a discovery or technology relating to health care. Dr. Sampson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Dyne Therapeutics. Dr. Sampson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Expansion Therapeutics. Dr. Sampson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viking Therapeutics. Dr. Sampson has received research support from Marigold Foundation. Dr. Sampson has a non-compensated relationship as a Scientific Advisory Committee with Myotonic Dystrophy Foundation that is relevant to AAN interests or activities. Dr. Murad has received personal compensation for serving as an employee of UCB. Dr. Murad has received personal compensation for serving as an employee of Skyhawk Therapeutics. Dr. Murad has stock in Forma Therapeutics. Dr. Murad has stock in Skyhawk Therapeutics. Mr. Chaufty has received personal compensation for serving as an employee of UCB. Mr. Chaufty has stock in UCB. Mr. Chaufty has received intellectual property interests from a discovery or technology relating to health care.

Silent infarction in sickle cell disease is associated with brain volume loss in excess of infarct volume.

Sickle cell disease (SCD) increases cerebral infarct risk, but reported effects on brain volume have varied. More detailed information using larger cohorts and contemporary methods could motivate the use of longitudinal brain volume assessment in SCD as an automated marker of disease stability or future progression. The purpose of this study was to rigorously evaluate whether children and young adults with SCD have reduced gray matter volume (GMV) and white matter volume (WMV) compared to healthy controls using high-resolution MRI. We tested the hypotheses that (i) elevated CBF, a marker of cerebral hemodynamic compensation in SCD, is associated with global and regional brain atrophy, and (ii) silent cerebral infarct burden is associated with brain atrophy in excess of infarct volume. Healthy controls (n = 49) and SCD participants without overt stroke (n = 88) aged 7-32 years completed 3 T brain MRI; pseudocontinuous arterial spin labeling measured CBF. Multivariable linear regressions assessed associations of independent variables with GMV, WMV, and volumes of cortical/subcortical regions. Reduced hemoglobin was associated with reductions in both GMV (p = 0.032) and WMV (p = 0.005); reduced arterial oxygen content (CaO2) was also associated with reductions in GMV (p = 0.035) and WMV (p = 0.006). Elevated gray matter CBF was associated with reduced WMV (p = 0.018). Infarct burden was associated with reductions in WMV 30-fold greater than the infarct volume itself (p = 0.005). Increased GM CBF correlated with volumetric reductions of the insula and left and right caudate nuclei (p = 0.017, 0.017, 0.036, respectively). Infarct burden was associated with reduced left and right nucleus accumbens, right thalamus, and anterior corpus callosum volumes (p = 0.002, 0.002, 0.009, 0.002, respectively). We demonstrate that anemia and decreased CaO2 are associated with reductions in GMV and WMV in SCD. Increased CBF and infarct burden were also associated with reduced volume in subcortical structures. Global WMV deficits associated with infarct burden far exceed infarct volume itself. Hemodynamic compensation via increased cerebral blood flow in SCD seems inadequate to prevent brain volume loss. Our work highlights that silent cerebral infarcts are just a portion of the brain injury that occurs in SCD; brain volume is another potential biomarker of brain injury in SCD.

Sleep quality, perivascular spaces and brain health markers in ageing - A longitudinal study in the Lothian Birth Cohort 1936

BackgroundSleep is thought to play a major role in brain health and general wellbeing. However, few longitudinal studies have explored the relationship between sleep habits and imaging markers of brain health, particularly markers of brain waste clearance such as perivascular spaces (PVS), of neurodegeneration such as brain atrophy, and of vascular disease, such as white matter hyperintensities (WMH). We explore these associations using data collected over 6 years from a birth cohort of older community-dwelling adults in their 70s. MethodWe analysed brain MRI data from ages 73, 76 and 79 years, and self-reported sleep duration, sleep quality and vascular risk factors from community-dwelling participants in the Lothian Birth Cohort 1936 (LBC1936) study. We calculated sleep efficiency (at age 76), quantified PVS burden (at age 73), and WMH and brain volumes (age 73 to 79), calculated the white matter damage metric, and used structural equation modelling (SEM) to explore associations and potential causative pathways between indicators related to brain waste cleaning (i.e., sleep and PVS burden), brain and WMH volume changes during the 8th decade of life. ResultsLower sleep efficiency was associated with a reduction in normal-appearing white matter (NAWM) volume (β = 0.204, P = 0.009) from ages 73 to 79, but not concurrent volume (i.e. age 76). Increased daytime sleep correlated with less night-time sleep (r = −0.20, P < 0.001), and with increasing white matter damage metric (β = −0.122, P = 0.018) and faster WMH growth (β = 0.116, P = 0.026). Shorter night-time sleep duration was associated with steeper 6-year reduction of NAWM volumes (β = 0.160, P = 0.011). High burden of PVS at age 73 (volume, count, and visual scores), was associated with faster deterioration in white matter: reduction of NAWM volume (β = −0.16, P = 0.012) and increasing white matter damage metric (β = 0.37, P < 0.001) between ages 73 and 79. On SEM, centrum semiovale PVS burden mediated 5% of the associations between sleep parameters and brain changes. ConclusionSleep impairments, and higher PVS burden, a marker of impaired waste clearance, were associated with faster loss of healthy white matter and increasing WMH in the 8th decade of life. A small percentage of the effect of sleep in white matter health was mediated by the burden of PVS consistent with the proposed role for sleep in brain waste clearance.

Pervasive cortical and white matter anomalies in a mouse model for CHARGE syndrome.

CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth, Genital anomalies and Ear abnormalities) syndrome is a disorder caused by mutations in the gene encoding CHD7, an ATP dependent chromatin remodelling factor, and is characterised by a diverse array of congenital anomalies. These include a range of neuroanatomical comorbidities which likely underlie the varied neurodevelopmental disorders associated with CHARGE syndrome, which include intellectual disability, motor coordination deficits, executive dysfunction, and autism spectrum disorder. Cranial imaging studies are challenging in CHARGE syndrome patients, but high-throughput magnetic resonance imaging (MRI) techniques in mouse models allow for the unbiased identification of neuroanatomical defects. Here, we present a comprehensive neuroanatomical survey of a Chd7 haploinsufficient mouse model of CHARGE syndrome. Our study uncovered widespread brain hypoplasia and reductions in white matter volume across the brain. The severity of hypoplasia appeared more pronounced in posterior areas of the neocortex compared to anterior regions. We also perform the first assessment of white matter tract integrity in this model through diffusion tensor imaging (DTI) to assess the potential functional consequences of widespread reductions in myelin, which suggested the presence of white matter integrity defects. To determine if white matter alterations correspond to cellular changes, we quantified oligodendrocyte lineage cells in the postnatal corpus callosum, uncovering reduced numbers of mature oligodendrocytes. Together, these results present a range of promising avenues of focus for future cranial imaging studies in CHARGE syndrome patients.

Evolution of the intracranial features of congenital cytomegalovirus on MRI

To describe the evolution of the intracranial features of congenital cytomegalovirus (cCMV) on magnetic resonance imaging (MRI). Sixteen infants with polymerase chain reaction (PCR)-confirmed cCMV who had undergone at least two MRI examinations of the brain were identified. Two paediatric neuroradiologists reviewed the baseline studies retrospectively for intracranial features of cCMV, including white matter signal abnormalities, subependymal cysts, malformations of cortical development, and intracranial calcification. The subsequent MRI studies were then reviewed and directly compared to the baseline examinations. White matter signal abnormalities were seen on all 16 baseline studies (100%); these persisted on all subsequent examinations but were patchier, more focal, and associated with an interval reduction in white matter volume. Subependymal cysts were present on 11 (69%) of the baseline scans; these almost universally regressed (in 10 of the 11 cases [91%]), with no new cysts appreciable on subsequent imaging. Malformations of cortical development, exclusively in the form of polymicrogyria, were seen in six (38%) patients and persisted, unchanged, on subsequent imaging. Intracranial calcification was seen in a minority of baseline studies (4 [25%]) and remained stable on subsequent scans. Children with cCMV who present later in life without an established or suspected underlying pathology can pose a challenge to the assessing radiologist. The radiological sequelae of cCMV can be non-specific; in some cases, white matter signal abnormalities and focal loss of white matter volume may be the only intracranial features. It is therefore important that radiologists are aware of cCMV as a potential differential for these findings.

Association of long-term hyperglycaemia and insulin resistance with brain atrophy and cognitive decline: A longitudinal cohort study.

To investigate the longitudinal changes in brain volume and cognitive function associated with diabetes at midlife, and to examine whether long-term hyperglycaemia, insulin resistance or secretory function is associated with brain atrophy and cognitive decline. We used data from 2377 participants with both baseline and 4-year follow-up brain magnetic resonance images and neuropsychological measures from the Ansan cohort of the Korean Genome Epidemiology Study. Time-weighted mean glycaemic values were calculated using all measurements over an average duration of 10.6 years from cohort initiation to baseline visits. Type 2 diabetes was associated with greater white matter volume reduction (adjusted volume difference=-1.96 ml, 95% CI: -3.73, -0.18) and executive function decline (adjusted Z score difference=-0.14, 95% CI: -0.23, -0.05) during the follow-up period of 4.2 years. Decline of verbal and visual memory or verbal fluency was not associated with diabetes. Greater executive function decline was associated with higher time-weighted mean HbA1c level over the preceding 10.6 years (P < .001), but not with insulin resistance markers in the diabetes group. Participants with diabetes, whose time-weighted average HbA1c level was maintained above 6.5% over the previous decade, showed greater decline in executive function and global cognition than the normal glucose group. Long-term hyperglycaemia was a major independent factor associated with rapid cognitive decline in middle-aged adults with diabetes. Maintaining ideal glucose levels in diabetes at midlife might prevent later rapid cognitive decline.

Structural and microstructural neuroimaging signature of C9orf72-associated ALS: A multiparametric MRI study

BackgroundALS patients with hexanucleotide expansion in C9orf72 are characterized by a specific clinical phenotype, including more aggressive disease course and cognitive decline. Computerized multiparametric MRI with gray matter volumetry and diffusion tensor imaging (DTI) to analyze white matter structural connectivity is a potential in vivo biomarker. ObjectiveThe objective of this study was to develop a multiparametric MRI signature in a large cohort of ALS patients with C9orf72 mutations. The aim was to investigate how morphological features of C9orf72-associated ALS differ in structural MRI and DTI compared to healthy controls and ALS patients without C9orf72 mutations. MethodsAtlas-based volumetry (ABV) and whole brain-based DTI-based analyses were performed in a cohort of n = 51 ALS patients with C9orf72 mutations and compared with both n = 51 matched healthy controls and n = 51 C9orf72 negative ALS patients, respectively. Subsequently, Spearman correlation analysis of C9orf72 ALS patients‘ data with clinical parameters (age of onset, sex, ALS-FRS-R, progression rate, survival) as well as ECAS and p-NfH in CSF was performed. ResultsThe whole brain voxel-by-voxel comparison of fractional anisotropy (FA) maps between C9orf72 ALS patients and controls showed significant bilateral alterations in axonal structures of the white matter at group level, primarily along the corticospinal tracts and in fibers projecting to the frontal lobes. For the frontal lobes, these alterations were also significant between C9orf72 positive and C9orf72 negative ALS patients. In ABV, patients with C9orf72 mutations showed lower volumes of the frontal, temporal, and parietal lobe, with the lowest values in the gray matter of the superior frontal and the precentral gyrus, but also in hippocampi and amygdala. Compared to C9orf72 negative ALS, the differences were shown to be significant for cerebral gray matter (p = 0.04), especially in the frontal (p = 0.01) and parietal lobe (p = 0.01), and in the thalamus (p = 0.004). A correlation analysis between ECAS and averaged regional FA values revealed significant correlations between cognitive performance in ECAS and frontal association fibers. Lower FA values in the frontal lobes were associated with worse performance in all cognitive domains measured (language, verbal fluency, executive functions, memory and spatial perception). In addition, there were significant negative correlations between age of onset and atlas-based volumetry results for gray matter. ConclusionsThis study demonstrates a distinct pattern of DTI alterations of the white matter and ubiquitous volume reductions of the gray matter early in the disease course of C9orf72-associated ALS. Alterations were closely linked to a more aggressive cognitive phenotype. These results are in line with an expected pTDP43 propagation pattern of cortical affection and thus strengthen the hypothesis that an underlying developmental disorder is present in ALS with C9orf72 expansions. Thus, multiparametric MRI could contribute to the assessment of the disease as an in vivo biomarker even in the early phase of the disease.

Herpes Viruses in the Baltimore Longitudinal Study of Aging:Associations with Brain Volumes, Cognitive Performance and Plasma Biomarkers

AbstractBackgroundAlthough an infectious etiology of Alzheimer’s Disease (AD) has received renewed attention, the longitudinal effects of symptomatic herpes viruses (sHHV) infection on brain structure and cognition remain poorly understood, as does the effect of sHHV on AD/neurodegeneration biomarkers.MethodUsing data from the Baltimore Longitudinal Study of Aging (BLSA), we characterize the association of sHHV diagnoses – defined using ICD‐9 classification – with longitudinal changes in total and regional brain volumes obtained from 3T magnetic resonance imaging (MRI), and cognitive performance across five cognitive domains. Additionally, we relate sHHV to plasma biomarkers of AD (Ab42/40), astrogliosis (glial fibrillary acidic protein [GFAP]) and neurodegeneration (neurofilament light [NfL]). The study design is illustrated in Figure 1.ResultA total of 1,009 participants were included in the primary MRI analysis, 98% of whom were cognitively normal at baseline MRI. Having a sHHV diagnosis (N = 119) was associated with longitudinal reductions in white matter volume (annual additional rate of change ‐0.34 cm3; p = 0.035), particularly in the temporal cortex; however, there was no association between sHHV and change in total brain, total gray matter, or AD signature region volume (Table 1; Figure 2). Among the 119 participants with sHHV infection, exposure to antiviral treatment attenuated declines in occipital white matter (annual reduction in rate of change 0.10 cm3; p = 0.036). Although the sHHV group (N = 290) had higher cognitive scores on certain cognitive domains at baseline, sHHV diagnosis was associated with accelerated longitudinal declines in attention (annual additional rate of change ‐0.01 Z‐score; p = 0.008) (Figure 3). In cross‐sectional analyses, sHHV diagnosis (N = 83) was associated with elevated plasma GFAP (Figure 4). However, sHHV was unrelated to plasma Ab42/40 and NfL levels.ConclusionThese findings suggest an association of sHHV infection with white matter volume loss, attentional decline, and astrogliosis. Although the findings link sHHV to several neurocognitive features, the results do not support an association between sHHV and AD‐specific disease processes.

Herpes Viruses in the Baltimore Longitudinal Study of Aging: Associations With Brain Volumes, Cognitive Performance, and Plasma Biomarkers.

Although an infectious etiology of Alzheimer disease (AD) has received renewed attention with a particular focus on herpes viruses, the longitudinal effects of symptomatic herpes virus (sHHV) infection on brain structure and cognition remain poorly understood, as does the effect of sHHV on AD/neurodegeneration biomarkers. We used a longitudinal, community-based cohort to characterize the association of sHHV diagnoses with changes in 3 T MRI brain volume and cognitive performance. In addition, we related sHHV to cross-sectional differences in plasma biomarkers of AD (β-amyloid [Aβ]42/40), astrogliosis (glial fibrillary acidic protein [GFAP]), and neurodegeneration (neurofilament light [NfL]). Baltimore Longitudinal Study of Aging participants were recruited from the community and assessed with serial brain MRIs and cognitive examinations over an average of 3.4 (SD = 3.2) and 8.6 (SD = 7.7) years, respectively. sHHV classification used International Classification of Diseases, Ninth Revision codes documented at comprehensive health and functional screening evaluations at each study visit. Linear mixed-effects and multivariable linear regression models were used in analyses. A total of 1,009 participants were included in the primary MRI analysis, 98% of whom were cognitively normal at baseline MRI (mean age = 65.7 years; 54.8% female). Having a sHHV diagnosis (N = 119) was associated with longitudinal reductions in white matter volume (annual additional rate of change -0.34 cm3/y; p = 0.035), particularly in the temporal lobe. However, there was no association between sHHV and changes in total brain, total gray matter, or AD signature region volumes. Among the 119 participants with sHHV, exposure to antiviral treatment attenuated declines in occipital white matter (p = 0.04). Although the sHHV group had higher cognitive scores at baseline, sHHV diagnosis was associated with accelerated longitudinal declines in attention (annual additional rate of change -0.01 Z-score/year; p = 0.008). In addition, sHHV diagnosis was associated with elevated plasma GFAP, but not related to Aβ42/40 and NfL levels. These findings suggest an association of sHHV infection with white matter volume loss, attentional decline, and astrogliosis. Although the findings link sHHV to several neurocognitive features, the results do not support an association between sHHV and AD-specific disease processes.

HPDL mutations identified by exome sequencing are associated with infant neurodevelopmental disorders.

BackgroundRecent research found that biallelic HPDL variants can cause neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), with only a few reports. Clinical phenotypic information on individuals with damaging HPDL variants may also be incomplete. The phenotype of NEDSWMA is characterized by severe neurodevelopmental delay, brain atrophy, and spasticity in infancy.MethodsExome sequencing was used in the proband and his parents to identify the underlying genetic cause. Candidate mutations were validated by classic Sanger sequencing. The clinical presentation of the infant who carried HPDL variants was summarized.ResultsWe identified a novel compound heterozygous variants in HPDL, c.995delC (p.T332Mfs) and c.1051C>T (p.Q351*) in the patient a 6‐month‐old boy presenting with global developmental delay, seizures, hypertonia, and limb spasticity. Brain magnetic resonance imaging (MRI) showed thin corpus callosum, ventriculomegaly, white matter volume reduction, bilateral frontotemporal subarachnoid widening, and sulcus deeping.ConclusionOur results provided important information for the associations of variants in HPDL with the neurodevelopmental disorder in infants, and broaden the genetic spectrum of HPDL‐related disease. This is the second report of the HPDL mutation causing infant neurodevelopmental disorders in a Chinese population.

Alteration of the Oligodendrocyte Lineage Varies According to the Systemic Inflammatory Stimulus in Animal Models That Mimic the Encephalopathy of Prematurity.

Preterm birth before the gestational age of 32 weeks is associated with the occurrence of specific white matter damage (WMD) that can compromise the neurological outcome. These white matter abnormalities are embedded in more global brain damage defining the encephalopathy of prematurity (EoP). A global reduction in white matter volume that corresponds to chronic diffuse WMD is the most frequent form in contemporary cohorts of very preterm infants. This WMD partly results from alterations of the oligodendrocyte (OL) lineage during the vulnerability window preceding the beginning of brain myelination. The occurrence of prenatal, perinatal and postnatal events in addition to preterm birth is related to the intensity of WMD. Systemic inflammation is widely recognised as a risk factor of WMD in humans and in animal models. This review reports the OL lineage alterations associated with the WMD observed in infants suffering from EoP and emphasizes the role of systemic inflammation in inducing these alterations. This issue is addressed through data on human tissue and imaging, and through neonatal animal models that use systemic inflammation to induce WMD. Interestingly, the OL lineage damage varies according to the inflammatory stimulus, i.e., the liposaccharide portion of the E.Coli membrane (LPS) or the proinflammatory cytokine Interleukin-1β (IL-1β). This discrepancy reveals multiple cellular pathways inducible by inflammation that result in EoP. Variable long-term consequences on the white matter morphology and functioning may be speculated upon according to the intensity of the inflammatory challenge. This hypothesis emerges from this review and requires further exploration.

A unique cerebellar pattern of microglia activation in a mouse model of encephalopathy of prematurity.

Preterm infants often show pathologies of the cerebellum, which are associated with impaired motor performance, lower IQ and poor language skills at school ages. Using a mouse model of inflammation‐induced encephalopathy of prematurity driven by systemic administration of pro‐inflammatory IL‐1β, we sought to uncover causes of cerebellar damage. In this model, IL‐1β is administered between postnatal day (P) 1 to day 5, a timing equivalent to the last trimester for brain development in humans. Structural MRI analysis revealed that systemic IL‐1β treatment induced specific reductions in gray and white matter volumes of the mouse cerebellar lobules I and II (5% false discovery rate [FDR]) from P15 onwards. Preceding these MRI‐detectable cerebellar volume changes, we observed damage to oligodendroglia, with reduced proliferation of OLIG2+ cells at P10 and reduced levels of the myelin proteins myelin basic protein (MBP) and myelin‐associated glycoprotein (MAG) at P10 and P15. Increased density of IBA1+ cerebellar microglia were observed both at P5 and P45, with evidence for increased microglial proliferation at P5 and P10. Comparison of the transcriptome of microglia isolated from P5 cerebellums and cerebrums revealed significant enrichment of pro‐inflammatory markers in microglia from both regions, but cerebellar microglia displayed a unique type I interferon signaling dysregulation. Collectively, these data suggest that perinatal inflammation driven by systemic IL‐1β leads to specific cerebellar volume deficits, which likely reflect oligodendrocyte pathology downstream of microglial activation. Further studies are now required to confirm the potential of protective strategies aimed at preventing sustained type I interferon signaling driven by cerebellar microglia as an important therapeutic target.

Neuropsychological correlates of cerebellar volumes in multiple sclerosis: an MRI volumetric analysis study.

The hallmark of Multiple Sclerosis (MS) pathophysiology is the damage to the myelin sheath around axons. The cerebellum is a predilection site for demyelination with a well-recognized role in motor and a rather understudied contribution to cognitive functions. The aim of this study is to investigate patterns of cerebellar grey and white matter pathology, expressed as reduced volume, as well as cortical thickness and their potential contribution to cognitive performance and disability status of patients with MS. 24 patients with MS underwent extensive neuropsychological assessment using paper and pencil tests and the Brain Health Assessment (BHA) tablet-based battery. Cerebellar lobular volumes and thickness were calculated using a volumetric analysis with automated segmentation of the cerebellum and its lobules. The main findings are a reduction of cerebellar grey matter (CGMV) and white matter volumes (CWMV) in lobule X and a widespread cerebellar cortical thinning in patients. Overall disease severity and neurological disability, assessed with the Expanded Disability Status Severity Scale, was correlated with fatigue and information processing speed tasks, but not with CGMV and CWMV. CWMV and CGMV of lobule I-II was negatively correlated with information processing speed, as well as visuospatial memory tests and, finally, inverse cortical thinning associations were noted between the whole cerebellum, lobule I-II, lobule III, lobule VI, Crus I, lobule VIIIA and information processing speed and verbal fluency tasks. The inverse associations observed may represent a compensatory mechanism activated in MS engaging additional high-level cortical areas functionally interconnected with the damaged cerebellum, in order to cope with the cognitive demands of a task.