Progressive Brain Atrophy Research Articles

Noninvasive optical estimation of CSF thickness for brain-atrophy monitoring.

Dementia disorders are increasingly becoming sources of a broad range of problems, strongly interfering with the normal daily tasks of a growing number of individuals. Such neurodegenerative diseases are often accompanied with progressive brain atrophy that, at late stages, leads to drastically reduced brain dimensions. Currently, this structural change could be followed with X-ray computed tomography (XCT) or magnetic resonance imaging (MRI), but they share numerous disadvantages in terms of usability, invasiveness and costs. In this work, we aim to retrieve information concerning the brain-atrophy stage and its evolution, proposing a novel approach based on non-invasive time-resolved near infra-red (tr-NIR) measurements. For this purpose, we created a set of virtual human-head atlases in which we eroded the brain as it would happen in a clinical brain-atrophy progression. These realistic meshes were used to simulate a longitudinal tr-NIR study, investigating the effects of an increased amount of cerebral spinal fluid (CSF) in the photon diffusion. The analysis of late photons in the time-resolved reflectance curve–obtained via accurate Monte Carlo simulations–exhibited peculiar slope-changes upon CSF layer increase. The visibility of the effect under several measurement conditions suggested good sensitivity to CSF variation, even in the case of real measurement and under different geometrical models. The robustness of the results might promote the technique as a potential indicator of the dementia progression, relying only on fast and non-invasive optical observations.

Fingolimod's Impact on MRI Brain Volume Measures in Multiple Sclerosis: Results from MS-MRIUS.

Evidence is needed to understand the effect of fingolimod on slowing down brain atrophy progression in multiple sclerosis (MS) patients in clinical practice. We investigated the effect of fingolimod on brain atrophy in MS patients with active disease (clinically and/or magnetic resonance imaging [MRI]) versus no evidence of active disease (NEAD). MS and clinical outcome and MRI in the United States (MS-MRIUS) is a multicenter, retrospective study that included 590 relapsing-remitting MS patients, who initiated fingolimod, and were followed for a median of 16 months. Patients with active disease at baseline (245, 41.5%) were defined as those who had one or more relapses in the year previous starting fingolimod, and/or displayed gadolinium enhancing lesions(s) at baseline MRI scan, whereas patients with NEAD at baseline (345, 58.5%) did not fulfill these criteria. Annualized percentage brain volume change (PBVC) and percentage lateral ventricle volume change (PLVVC) over the follow-up were analyzed in both groups. Over the follow-up, the rate of PBVC was -.38% in active disease and -.25% in NEAD patients (P = .076), whereas PLLVC was 1.76% in active disease and .28% in NEAD patients (P = .046). No changes in timed 25-foot walk (P = .619) and Expanded Disability Status Scale (P = .275) scores or MRI lesion accumulation (P > 0.08) were detected, although the active disease group had a higher proportion of relapses during the follow-up period (P = .02). The study provides real-world evidence that rate of brain atrophy in MS patients with underlying active disease and NEAD in fingolimod treated patients is below the established pathological cutoff for loss of whole brain volume (>-.4%) or expansion of lateral ventricles (> 3.5%).

Effect of Antihypertensive Medication on Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis.

Hypertension is an important risk factor for cerebral small vessel disease. We aimed to study the effect of antihypertensive medication (AHM) on the progression of cerebral small vessel disease. We performed a systematic literature search of electronic databases up to January 30, 2017, for randomized controlled trials on the effect of AHM on ≥1 cerebral small vessel disease magnetic resonance imaging markers (ie, white matter hyperintensities, lacunes, microbleeds, enlarged perivascular spaces, acute small subcortical infarcts, and brain atrophy) after ≥1 year. We performed a random-effects meta-analysis using standardized mean difference. We included 4 trials, including patients with stroke, with diabetes mellitus, and people ≥70 years of age. Patients in the AHM group had less progression of white matter hyperintensity during 28 to 47 months (standardized mean difference, -0.19; 95% confidence interval, -0.32 to -0.06; I2=20%; n=1369). Two trials reported on progression of brain atrophy with conflicting results. None of the trials reported on other cerebral small vessel disease markers. AHM has a protective effect on the progression of white matter hyperintensities, but no effect on brain atrophy. There are no trials on the effect of AHM on lacunes, microbleeds, enlarged perivascular spaces, or acute small subcortical infarcts.

Kynurenine System and Multiple Sclerosis, Pathomechanism and Drug Targets with An Emphasis on Laquinimod.

Multiple sclerosis is a common chronic, disabling autoimmune neurological disease affecting mainly young adults. In its pathomechanism, neurodegenerative and acute inflammatory characteristics are both involved. Disease-modifying therapies aim to reduce relapse-rate and slow down the deterioration in neurological functions. The currently available therapies fail to exert neuroprotective effects and most of them are associated with potentially toxic side-effects, therefore, ongoing research aims to develop novel drug candidates to cover these therapeutic gaps. The kynurenine pathway has been implicated in both the physiological processes of the central nervous system and in the pathomechanism of several neurological disorders as well. Alterations of the kynurenine pathway metabolites have been detected in multiple sclerosis and a number of potential therapeutic targets related to this metabolic route have been already identified. Laquinimod is a quinoline carboxamide showing structural similarities with kynurenic acid, which proved to have beneficial effects on reduction of brain atrophy and disability progression. The kynurenine pathway is therefore a promising target for the development of future drugs for the treatment of autoimmune diseases such as multiple sclerosis.

Brain Atrophy and Cognitive Impairment in Chronic Kidney Disease.

There is an increasing prevalence of dementia associated with population aging, and anti-dementia measures have now become of increasing importance in Japan. Chronic kidney disease (CKD) is a risk factor for cognitive impairment. We previously demonstrated that hemodialysis patients have a higher prevalence of brain atrophy, even at younger age, than the general population, and also demonstrated the association between frontal lobe atrophy and frequency of rapid decline in blood pressure during the hemodialysis session. Recently, we demonstrated that decline in gray matter volume in CKD patients on peritoneal dialysis was significantly more rapid compared to non-dialysis-dependent CKD patients, and also showed a close association between gray matter atrophy and executive dysfunction in CKD patients, suggesting the importance of preventing brain atrophy for the prevention of cognitive impairment. Our recent epidemiological study demonstrated that both decreased kidney function and albuminuria were identified as independent risk factors for the development of dementia. In addition, it has been reported that possible contributing factors include anemia, oxidative stress, and the renin-angiotensin system (RAS). Previous reports have demonstrated that CKD patients with severe anemia show cognitive impairment, which was recovered by correction of anemia using erythropoiesis-stimulating agents. Then, we examined the role of oxidative stress and RAS using a mouse model of CKD-associated cognitive impairment, and demonstrated that the RAS inhibitor candesartan, as well as the antioxidant tempol, inhibited the development of cognitive impairment through inhibition of oxidative stress in the hippocampus. Key Messages: In CKD patients, progression of brain atrophy is more rapid and cognitive impairment is more common than in non-CKD subjects. Oxidative stress and RAS in the brain are associated with CKD-associated cognitive impairment.

Testing the Protein Propagation Hypothesis of Parkinson Disease.

One of the most exciting recent hypotheses in neurology is that most neurodegenerative diseases are caused by the neuron to neuron propagation of prion-like misfolded proteins. In Parkinson disease, the theory initially emerged from postmortem studies demonstrating a caudal-rostral progression of pathology from lower brainstem to neocortex. Later, animal studies showed that the hallmark protein of PD, α-synuclein, exhibited all the characteristics of a prion. Here, we describe our work using human neuroimaging to test the theory that PD pathology advances via a propagating process along the connectome. We found that the pattern and progression of brain atrophy follow neuronal connectivity, correlate with clinical features, and identify an epicenter in the brainstem.

Do 2-year changes in superior frontal gyrus and global brain atrophy affect cognition?

IntroductionMetabolic alterations to the superior frontal gyrus (SFG) have been linked to cognitive decline. Whether these indicate structural atrophy, which could be screened for at a larger scale using noninvasive structural imaging, is unknown. MethodsWe assessed annual structural magnetic resonance imaging scans and cognitive data from 3 consecutive years from 204 participants from the AD Neuroimaging Initiative database (mean age 72.24 [8.175] years). We evaluated associations between brain structural changes and performance in the Montreal Cognitive Assessment, Everyday Cognition Visuospatial subtest (ECog Visuospatial), and Functional Assessment Questionnaire. ResultsChanges in the surface area of the SFG were associated with changes in the outcome of the ECog Visuospatial test (P < .05), but an inconsistent pattern of association was found between the 2-year global brain atrophy progression and changes in the outcome from the three cognitive tests selected. DiscussionThe extent into which (and if) changes in the SFG influence cognition warrant further evaluation in a larger period in more heterogeneous population.

Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study.

BackgroundGM1-gangliosidosis and GM2-gangliosidosis (Tay-Sachs disease and Sandhoff disease) are unrelenting heritable neurodegenerative conditions of lysosomal ganglioside accumulation. Although progressive brain atrophy is characteristic, longitudinal quantification of specific brain structures has not been systematically studied.ObjectivesThe goal of this longitudinal study has been to quantify and track brain MRI volume changes, including specific structure volume changes, at different times in disease progression of childhood gangliosidoses, and to explore quantitative brain MRI volumetry (qMRI) as a non-invasive marker of disease progression for future treatment trials.MethodsBrain qMRI studies were performed in 14 patients with gangliosidoses (9 infantile, 5 juvenile) yearly. Cerebellar cortex and white matter, caudate, putamen, corpus callosum, ventricles, total brain, and intracranial volumes were measured, as well as total brain volume. Age-matched controls were available for the patients with the juvenile phenotype.ResultsThe infantile phenotype of all gangliosidoses showed a consistent pattern of macrocephaly and rapidly increasing intracranial MRI volume with both (a) brain tissue volume (cerebral cortex and other smaller structures) and (b) ventricular volume (P < 0.01 for all). In contrast to apparent enlargement of the total brain volume, and chiefly the enlarged cerebral cortex, a subset of smaller brain substructures generally decreased in size: the corpus callosum, caudate and putamen became smaller with time. The volume of cerebellar cortex also decreased in patients with infantile GM1-gangliosidosis and juvenile GM1- and GM2-gangliosidosis; however, infantile GM2-gangliosidosis cerebellar cortex was the exception, increasing in size. Elevated intracranial pressure (estimated by lumbar spinal pressure) was a common finding in infantile disease and showed continued increases as the disease progressed, yet lacked MRI signs of hydrocephalus except for increasing ventricular size. Notably, in patients with juvenile gangliosidosis, macrocephaly and elevated intracranial pressure were absent and total brain volume decreased with time compared to controls (P = 0.004).ConclusionsThe disease course of infantile versus juvenile gangliosidoses is clearly distinguished by the rate of brain disease progression as characterized by qMRI. Assessments by qMRI represent a robust non-invasive method for monitoring CNS changes in the clinical course of gangliosidoses and is ideally suited to monitor effects of novel CNS-directed therapies in future clinical trials.

Improved Precision of Automatic Brain Volume Measurements in Patients with Clinically Isolated Syndrome and Multiple Sclerosis Using Edema Correction.

The presence of edema will result in increased brain volume, which may obscure progressing brain atrophy. Similarly, treatment-induced edema reduction may appear as accelerated brain tissue loss (pseudoatrophy). The purpose of this study was to correlate brain tissue properties to brain volume, to investigate the possibilities for edema correction and the resulting improvement of the precision of automated brain volume measurements. A group of 38 patients with clinically isolated syndrome or newly diagnosed MS were imaged at inclusion and after 1, 2, and 4 years using an MR quantification sequence. Brain volume, relaxation rates (R1 and R2), and proton density were measured by automated software. The reduction of normalized brain volume with time after inclusion was 0.273%/year. The mean SDs were 0.508%, 0.526%, 0.454%, and 0.687% at baseline and 1, 2, and 4 years. Linear regression of the relative change of normalized brain volume and the relative change of R1, R2, and proton density showed slopes of -0.198 (P < .001), 0.156 (P = .04), and 0.488 (P < .001), respectively. After we applied the measured proton density as a correction factor, the mean SDs decreased to 24.2%, 4.8%, 33.3%, and 17.4%, respectively. The observed atrophy rate reduced from 0.273%/year to 0.238%/year. Correlations between volume and R1, R2, and proton density were observed in the brain, suggesting that a change of brain tissue properties can affect brain volume. Correction using these parameters decreased the variation of brain volume measurements and may have reduced the effect of pseudoatrophy.

Evidence of progressive tissue loss in the core of chronic MS lesions: A longitudinal DTI study.

ObjectiveUsing diffusion tensor imaging (DTI), we examined chronic stable MS lesions, peri-lesional white matter (PLWM) and normal appearing white matter (NAWM) in patients with relapsing-remitting multiple sclerosis (RRMS) for evidence of progressive tissue destruction and evaluated whether diffusivity change is associated with conventional MRI parameters and clinical findings.MethodPre- and post-gadolinium T1, T2 and DTI images were acquired from 55 consecutive RRMS patients at baseline and 42.3 ± 9.7 months later. Chronic stable T2 lesions of sufficient size were identified in 43 patients (total of 134 lesions). Diffusivity parameters such as axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA) were compared at baseline and follow-up. MRI was also performed in 20 normal subjects of similar age and gender.ResultsWithin the core of chronic MS lesions the diffusion of water molecules significantly increased over the follow-up period, while in NAWM all diffusivity indices remained stable. Since increase of AD and RD in lesional core was highly concordant, indicating isotropic nature of diffusivity change, and considering potential effect of crossing fibers on directionally-selective indices, only MD, a directionally-independent measure, was used for further analysis. The significant increase of MD in the lesion core during the follow-up period (1.29 ± 0.19 μm2/ms and 1.34 ± 0.20 μm2/ms at baseline and follow-up respectively, P < 0.0001) was independent of age or disease duration, total brain lesion volume or new lesion activity, lesion size or location and baseline tissue damage (T1 hypointensity). Change of MD in the lesion core, however, was associated with progressive brain atrophy (r = 0.47, P = 0.002). A significant gender difference was also observed: the MD change in male patients was almost twice that of female patients (0.030 ± 0.04 μm2/ms and 0.058 ± 0.03 μm2/ms in female and male respectively, P = 0.01). Sub-analysis of lesions with lesion-free surrounding revealed the largest MD increase in the lesion core, while MD progression gradually declined towards PLWM. MD in NAWM remained stable over the follow-up period.ConclusionThe significant increase of isotropic water diffusion in the core of chronic stable MS lesions likely reflects gradual, self-sustained tissue destruction in demyelinated white matter that is more aggressive in males.

Motor, cognitive, and functional declines contribute to a single progressive factor in early HD.

To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials. We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up. The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy. Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures.

Progress in developing transgenic monkey model for Huntington's disease.

Huntington's disease (HD) is a complex neurodegenerative disorder that has no cure. Although treatments can often be given to relieve symptoms, the neuropathology associated with HD cannot be stopped or reversed. HD is characterized by degeneration of the striatum and associated pathways that leads to impairment in motor and cognitive functions as well as psychiatric disturbances. Although cell and rodent models for HD exist, longitudinal study in a transgenic HD nonhuman primate (i.e., rhesus macaque; HD monkeys) shows high similarity in its progression with human patients. Progressive brain atrophy and changes in white matter integrity examined by magnetic resonance imaging are coherent with the decline in cognitive behaviors related to corticostriatal functions and neuropathology. HD monkeys also express higher anxiety and irritability/aggression similar to human HD patients that other model systems have not yet replicated. While a comparative model approach is critical for advancing our understanding of HD pathogenesis, HD monkeys could provide a unique platform for preclinical studies and long-term assessment of translatable outcome measures. This review summarizes the progress in the development of the transgenic HD monkey model and the opportunities for advancing HD preclinical research.

Brain Atrophy Estimated from Structural Magnetic Resonance Imaging as a Marker of Large-Scale Network-Based Neurodegeneration in Aging and Stroke.

Brain atrophy is a normal part of healthy aging, and stroke appears to have neurodegenerative effects, accelerating this atrophy to pathological levels. The distributed pattern of atrophy in healthy aging suggests that large-scale brain networks may be involved. At the same time, the network wide effects of stroke are beginning to be appreciated. There is now widespread use of network methods to understand the brain in terms of coordinated brain activity or white matter connectivity. Examining brain morphology on a network level presents a powerful method of understanding brain structure and has been successfully applied to charting the course of brain development. This review will introduce recent advances in structural magnetic resonance imaging (MRI) acquisition and analyses that have allowed for reliable and reproducible estimates of atrophy in large-scale brain networks in aging and after stroke. These methods are currently underutilized despite their ease of acquisition and potential to clarify the progression of brain atrophy as a normal part of healthy aging and in the context of stroke. Understanding brain atrophy at the network level may be key to clarifying healthy aging processes and the pathway to neurodegeneration after stroke.

Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years.

Current HIV treatments are successful at suppressing plasma HIV RNA to undetectable levels for most adherent patients. Yet, emerging evidence suggests that viral suppression will inadequately control inflammation and mitigate risk for progressive brain injury. We sought to quantify differences in longitudinal brain atrophy rates among older virally suppressed HIV-infected participants compared with that of healthy aging participants. We examined longitudinal structural brain magnetic resonance imaging atrophy rates using region of interest assessments and voxel-wise tensor-based morphometry in HIV-infected participants older than 60 years (n = 38) compared with age-matched HIV-uninfected healthy and cognitively normal controls (n = 24). The mean age of participants was 63 years, the mean estimated duration of infection was 21 years, and the median duration of documented viral suppression was 3.2 years. Average proximal and nadir CD4 counts were 550 and 166, respectively; 15/38 (39%) met criteria for HIV-associated neurocognitive disorder. In models adjusting for age and sex, HIV serostatus was associated with more rapid average annualized rates of atrophy in the cerebellum (0.42% vs. 0.02%, P = 0.016), caudate (0.74% vs. 0.03%, P = 0.012), frontal lobe (0.48% vs. 0.01%, P = 0.034), total cortical gray matter (0.65% vs. 0.16%, P = 0.027), brainstem (0.31% vs. 0.01%, P = 0.026), and pallidum (0.73% vs. 0.39%, P = 0.046). Among those with HIV, atrophy rates did not differ statistically by cognitive status. Despite persistent control of plasma viremia, these older HIV-infected participants demonstrate more rapid progressive brain atrophy when compared with healthy aging. Either HIV or other factors that differ between older HIV-infected participants and healthy controls could be responsible for these differences.

Brain atrophy and clinical severity in patients with Xeroderma Pigmentosum group A

Background: Xeroderma pigmentosum (XP) is an inherited congenital disease presenting with dermatological and neurological manifestations. In Japan, XP complementation group A (XP-A) is most frequently observed in eight clinical subtypes, suffer from severe manifestations including progressive brain atrophy since childhood.

Longitudinal changes in the brain in mild cognitive impairment: a magnetic resonance imaging study using the visual rating method and tensor-based morphometry.

Background Brain atrophy is associated with mild cognitive impairment (MCI), and by using volumetric and visual analyzing methods, it is possible to differentiate between individuals with progressive MCI (MCIp) and stable MCI (MCIs). Automated analysis methods detect degenerative changes in the brain earlier and more reliably than visual methods. Purpose To detect and evaluate structural brain changes between and within the MCIs, MCIp, and control groups during a two-year follow-up period. Material and Methods Brain magnetic resonance imaging (MRI) scans of 11 participants with MCIs, 18 participants with MCIp, and 84 controls were analyzed by the visual rating method (VRM) and tensor-based morphometry (TBM). Results At baseline, both VRM and TBM differentiated the whole MCI group (combined MCIs and MCIp) and the MCIp group from the control group, but they did not differentiate the MCIs group from the control group. At follow-up, both methods differentiated the MCIp group from the control group, but minor differences between the MCIs and control groups were only seen by TBM. Neuropsychological tests did not find differences between the MCIs and control groups at follow-up. Neither method revealed relevant signs of brain atrophy progression within or between MCI subgroups during the follow-up time. Conclusion Both methods are equally good in the evaluation of structural brain changes in MCI if the groups are sufficiently large and the disease progresses to AD. Only TBM disclosed minor atrophic changes in the MCIs group compared to controls at follow-up. The results need to be confirmed with a large patient group and longer follow-up time.

Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis.

Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up.

Severe cognitive decline following chemotherapy of breast cancer

Chemotherapy for different types of cancer is often life-saving. On the other hand, the spectrum of side effects may involve the central nervous system (CNS) and lead to severe emotional and cognitive disturbances, a syndrome often referred to as “The Chemo Brain”. Here we report on a then 43-year-old female patient who first presented to our clinic in 2013 and in whom breast cancer of the right breast had been diagnosed four years earlier. At that time she became a patient of the Comprehensive Cancer Center of the University of Ulm (CCCU) and underwent breast-conserving therapy starting with systemic chemotherapy according to the rules of the GeparQuinto Study. This was followed by breast-conserving operation including axillary lymphonodectomy. Histological examination of the excised material revealed an invasive ductal mammary carcinoma the exact staging of which will be reported in detail. Convalescence of the patient was protracted, and she continued complaining of difficulties to concentrate and to remember what she had been told or read shortly before. In addition, she complained of frequent mood swings. Therefore, she was referred to our department. Exploring her case history, we learned that she had worked as a manager of a car rental company which she had no longer been able to do after her cancer treatment because of her cognitive deficits. Beside clinical and psychiatric examination, our diagnostic procedures included electroencephalography (EEG), magnetic resonance tomography (MRT) of the brain using gadolinium enhancement, and extensive neuropsychological testing. In detail, components of the Wechsler Adult Intelligence Scale (WAIS), the Ray Auditory Verbal Learning Test (RAVLT), the Multiple Choice Vocabulary (“Mehrfachwahl-Wortschatztest”), the “Regensburger Wortflussigkeitstest” (Regensburg Word Fluency Test, RWT), and the “Testbatterie zur Aufmerksamkeitsprufung” (Test Battery for the Assessment of Attention, TAP) were applied. Whereas the EEG was unremarkable, the MRT performed in 2013 showed brain atrophy with frontotemporal accentuation. As an accessory finding, an arachnoid cyst was detected at the left temporal pole. No metastases were found. Interestingly, we had the opportunity to compare these findings with those of an earlier MRT performed in 2011. In the latter one, the arachnoid cyst was also visible, but there was no pronounced brain atrophy. These observations raise the question if progressive brain atrophy might be associated with the syndrome of “Chemo Brain”. Neuropsychological examination revealed severe cognitive deficits in this patient – details of which will be reported – apparently due to the chemotherapy she had undergone. Possible mechanisms of action, treatment options, and ethical implications will be discussed.

Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy.

De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303_Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/β spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. αII/βII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303_Leu2305dup) and p.(Arg2308_Met2309dup), all falling in the nucleation site of the α/β spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/β heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/β spectrin heterodimer formation and/or αII spectrin function.

Quantitative analysis of brain atrophy in patients with xeroderma pigmentosum group A carrying the founder mutation in Japan

IntroductionXeroderma pigmentosum (XP) is an inherited congenital disease presenting with dermatological and neurological manifestations. In Japan, XP complementation group A (XP-A) is most frequently observed in eight clinical subtypes, and the homozygous founder mutation, IVS3-1G>C in XPA, suffer from severe manifestations including progressive brain atrophy since childhood. In this study, we used magnetic resonance imaging (MRI) and applied volumetric analysis to elucidate the start and the progression of the brain atrophy in these patients. Material and methodsTwelve Japanese patients with XP-A carrying the founder mutation and seven controls were included. MRI was performed for each patient once or more. Three-dimensional T1 weighted images were segmented to gray matter, white matter, and cerebrospinal fluid, and each volume was calculated. ResultsConventional MRI demonstrated progressive whole brain atrophy in patients with XP-A. Moreover, volumetric analysis showed that reductions of total gray matter volumes (GMV) and total brain volumes (TBV) started at the age of five. The slope of reduction was similar in all cases. The GMV and TBV values in controls were higher than those in XP-A cases after the age of five. ConclusionsThis is the first quantitative report presenting with the progression of brain atrophy in patients with XP-A. It is revealed that the brain atrophy started from early childhood in Japanese patients with XP-A carrying the homozygous founder mutation.