Cerebral Cortical Atrophy Research Articles

A study of the correlation between gray matter atrophy in multiple sclerosis and impairment of cognitive function domains

Objective: To quantify cerebral cortical and deep gray matter atrophy in patients with multiple sclerosis (MS) and explore its correlation with impairment in domains of cognitive function. Methods: Twenty patients with MS and 16 healthy controls (HC) matched for age, sex, and education level were included. Using FreeSurfer software, based on 3D-MRI technology, the differences in cortical thickness and deep gray matter volume between the two groups were comparatively analyzed. A neuropsychological scale that included six domains of cognitive function was scored on both study groups to analyze the correlation between cortical thickness and volume of deep gray matter in MS patients with impairment in cognitive function domains. Results: Impairment in domains of cognitive function: cognitive impairment was present in 60% MS patients in this study, mainly manifesting as impairment of verbal memory, verbal fluency, visuospatial memory, and information processing speed function (all P<0.05). Of these, the majority had impaired visuospatial memory function (55.0%), and the least number of patients had impaired information processing speed (15.0%). Changes in cortical thickness: compared with the HC group, the MS group showed that cortical atrophy was mainly concentrated in the frontoparietal region, including significant thinning of cortical thickness in the left inferior parietal gyrus, right superior frontal gyrus, and the right superior parietal gyrus (all P<0.05). Among them, atrophy of the left inferior parietal gyrus was significantly positively correlated with the impairment of verbal memory, verbal fluency, and information processing speed (all P<0.05). There was a significant positive correlation between the right superior frontal gyrus atrophy and verbal memory, verbal fluency, and visuospatial memory impairment (all P<0.05). Changes in deep gray matter volume: compared with the HC group, deep gray matter volume in the MS group decreased significantly in the bilateral thalamus, bilateral putamen, bilateral pallidum (all P<0.01), and right nucleus accumbens (P<0.05). Among them, left thalamus atrophy was significantly positively correlated with visuospatial memory impairment (r=0.45, P=0.046), and left putamen atrophy was both significantly positively correlated with visuospatial memory (r=0.45, P=0.047) and information processing speed impairment (r=0.50, P=0.026). Conclusions: Early structural brain changes in MS are dominated by gray matter atrophy. Deep gray matter is more prominent than cortical atrophy.

WHEN LAUGHTER GAS NO LONGER BRINGS LAUGHTER

Introduction: Nitrous oxide (N2O), also dubbed the laughing gas or proto, is a gas used therapeutically in the medical field. However, a recreational trend has emerged, involving the inhalation of N2O from culinary capsules or canisters. Clinical Case: This involves a 23-year-old patient, Hospitalized for psychomotor agitation, the patient has a history of cardiac arrest following extensive inhalation of laughing gas. The patient presented with a manic syndrome that resolved within 2 days. Biological tests returned normal results, including vitamin B12. Brain MRI revealed bilateral bi-fronto-parietal cortical cerebral atrophy. The patient underwent a neurological etiological assessment, which came back normal. Discussion: The majority of literature reviews on the psychiatric complications of NO2 use have indicated that the most frequent symptoms are delirium, hallucinations, and confusion. The prognosis is often favorable, with symptoms typically resolving under antipsychotic treatment. Conclusion: The consumption of nitrous oxide is a recreational practice that is on the rise, and especially among young people. With easy access and low cost.Cases of intoxication are increasing with serious medical complications which can lead to death, regardless of the type of exposure.

Jansky-Bielschowsky Disease in 2 Moroccan Girls. Clinical Cases

Neuronal ceroid lipofuscinoses (NLCs) belong to the group of lysosomal diseases. Their transmission is autosomal recessive. They are characterized by progressive degenerative neurological damage of variable clinical expressions, and by ophthalmic damage. Jansky-Bieloschowsky disease is the classic late infantile form of CLNs or classic CLN2. The EEG tracing is characteristic. Visual and somaesthetic cortical evoked potentials are abnormal. Cerebral MRI shows cerebellar and then cerebral cortical atrophy associated with T2 hypersignal of the periventricular white matter. The diagnosis was confirmed by biochemical, histological, and molecular tests. Patient n°1 is 7 years old. She is bedridden and visually impaired. She was presented with psychomotor regression at the age of 3 and epilepsy 6 months later. Brain imaging and EEG were typical. TPP1 (tripeptidyl-peptidase1) enzyme activity was significantly reduced. Patient 2 is a 5-year-old girl who is also bedridden and visually impaired. She presented with psychomotor regression at the age of 3 years and 2 months, and epilepsy 11 months later. Brain imaging and EEG were typical, and TPP1 enzyme activity had collapsed. These two observations illustrate the diagnostic particularities of this very rare disease and current therapeutic perspectives.

Natural products for the treatment of neurodegenerative diseases

BackgroundNeurodegenerative diseases are among the most common diseases in older adults worldwide. Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases, and are accompanied by cerebral cortical atrophy, neuronal loss, protein accumulation, and excessive accumulation of metal ions. Natural products exhibit outstanding performance in improving cerebral circulatory disorders, promoting cerebral haematoma absorption, repairing damaged nerve tissue, and improving damaged nerve function. In recent years, studies have shown that neuroinflammatory mechanisms and signalling pathways closely related to the occurrence and development of neurological diseases include microglial activation, nuclear factor-κB (NF-κB) pathway, mitogen activated protein kinases (MAPK) pathway, reactive oxygen pathway, nucleotide binding oligomerisation domain-like receptor protein3 (NLRP3) inflammasomes, toll-like receptor4 (TLR4) pathway, nuclear factor erythroid 2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) pathway, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, and intestinal flora. Therefore, this study considered the mechanism of neurological diseases as the starting point to review the mechanism of action of natural products in the prevention and treatment of AD and PD in recent years to provide a theoretical basis for clinical prevention and treatment. AimNatural products are a promising source of novel lead structures that have long been used to treat various nervous system diseases. MethodologyThis review collected literature on neurological diseases and natural products from 2012 to 2022, which were mainly searched through databases such as ScienceDirect, Springer, PubMed, SciFinder, China National Knowledge Infrastructure (CNKI), Wanfang, Google Scholar, and Baidu Academic. The following keywords were searched: neurological disorders, natural products, signalling pathway, mechanism of action. ResultsThis review summarises the pathogenesis of degenerative neurological diseases, recent findings on natural products used in neurodegenerative diseases, and the molecular mechanisms underlying these effects.

A case of early‐onset familial Alzheimer’s disease caused by PSEN1 gene Y115C mutation in a Chinese pedigree

AbstractBackgroundAlzheimer’s disease is the most common cause of dementia, with approximately 0.9% associated with known genetic mutations. Presenilin 1(PSEN1) gene is one of the most common genes associated with early‐onset familial Alzheimer’s disease (EOFAD). We reported a case of EOFAD with Y115C mutation of PSEN1 gene which was the first report in China.MethodAn early‐onset Alzheimer’s patient from Beijing Tiantan Hospital, Capital Medical University and her family were enrolled as the research object. The clinical and imaging data of the proband were collected. The genomic DNA from peripheral venous blood of the proband was screened.ResultThere were 6 members with memory and working competence loss in this pedigree. The proband, whose age of onset was 42 years old, was manifested as memory loss for more than 1year. She became apathetic, lazy in housework but without abnormal mood and behavior. She was healthy in the past, denied smoking and drinking history. Her grandmother, mother, aunt, uncle and brother all showed memory loss. Her brother is now unable to complete the driver’s work. The physical examination showed poor memory, calculation, orientation, executive functions, slow reaction and poor comprehension. The MMSE score was 11, MoCA‐Beijing score was 5, ADL‐20 score was 28, HAMD score was 2, HAMA score was 1 and PSQI score was 5. Head MRI of the proband showed whole cerebral cortical atrophy and bilateral hippocampal atrophy, obviously on the left side. The arterial spin labeling finding showed significantly reduced blood perfusion in the left cortex and hippocampus. A c.344A &gt; G (p. Tyr115Cys) pathogenic mutation in the exon 5 of PSEN1 gene was found, proving the diagnosis.ConclusionWe reported this EOFAD case caused by Y115C mutation of PSEN1 gene in a Chinese family to enrich the genetic and clinical phenotypic characteristics in China. Gene detection plays an important role in the diagnosis of the early‐onset Alzheimer’s disease.

A large genetic screen in flies uncovers human modifiers of Aβ42 and tau toxicity

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by dementia and cognitive decline due to progressive cerebral cortical atrophy. Brains of AD patients are characterized by the accumulation of microscopic extracellular amyloid‐beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. The deposition of Aβ42, which is one of the fragments of amyloid precursor protein (APP), has been known to play a role in initiating the events leading to the formation of amyloid and subsequently hyperphosphorylation of tau. However, animal models expressing either Aβ42 or tau individually do not mimic the complexity of the human condition. Indeed, recent evidence suggests that Aβ42 and pathological tau interact synergistically to modulate neurotoxicity in AD.MethodTo shed light on their concerted roles in AD pathogenesis and to discover pathways mediating Aβ42 and tau interactions, we generated transgenic flies co‐expressing human Aβ42 fused to a signal peptide along with the longest wild‐type tau isoform.ResultOverexpression of Aβ42 or tau in Drosophila using the UAS‐Gal4 system causes mild to the moderate rough eye. In comparison, co‐expression of Aβ42 with tau causes severe roughening and reduction of the eye size. The level of neuronal cell death in eye tissues was also significantly enhanced in flies co‐expressing Aβ42 and tau. To identify pathways mediating Aβ42+tau interactions, we are currently using the Aβ42+tau eye phenotype as platform to screen 1,500 UAS lines expressing a variety of human genes.ConclusionWe have identified few enhancers and suppressors not previously known to be involved in AD pathogenesis, which will be helpful to uncover new molecular pathways and potential therapeutic targets. This work is supported by NIH grant R21AG069050 to DERL.

Association of Traumatic Brain Injury with Late Life Neuropathological Outcomes in a Community-Based Cohort.

Prior studies into the association of head trauma with neuropathology have been limited by incomplete lifetime neurotrauma exposure characterization. To investigate the neuropathological sequelae of traumatic brain injury (TBI) in an autopsy sample using three sources of TBI ascertainment, weighting findings to reflect associations in the larger, community-based cohort. Self-reported head trauma with loss of consciousness (LOC) exposure was collected in biennial clinic visits from 780 older adults from the Adult Changes in Thought study who later died and donated their brain for research. Self-report data were supplemented with medical record abstraction, and, for 244 people, structured interviews on lifetime head trauma. Neuropathology outcomes included Braak stage, CERAD neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral/cortical atrophy. Exposures were TBI with or without LOC. Modified Poisson regressions adjusting for age, sex, education, and APOE ɛ4 genotype were weighted back to the full cohort of 5,546 participants. TBI with LOC was associated with the presence of cerebral cortical atrophy (Relative Risk 1.22, 95% CI 1.02, 1.42). None of the other outcomes was associated with TBI with or without LOC. TBI with LOC was associated with increased risk of cerebral cortical atrophy. Despite our enhanced TBI ascertainment, we found no association with the Alzheimer's disease-related neuropathologic outcomes among people who survived to at least age 65 without dementia. This suggests the pathophysiological processes underlying post-traumatic neurodegeneration are distinct from the hallmark pathologies of Alzheimer's disease.

Neuroimaging biomarkers of cognitive recovery after ischemic stroke.

Post-stroke cognitive impairment affects more than one-third of patients after an ischemic stroke (IS). Identifying markers of potential cognitive recovery after ischemic stroke can guide patients' selection for treatments, enrollment in clinical trials, and cognitive rehabilitation methods to restore cognitive abilities in post-stroke patients. Despite the burden of post-stroke cognitive impairment, biomarkers of cognitive recovery are an understudied area of research. This narrative review summarizes and critically reviews the current literature on the use and utility of neuroimaging as a predictive biomarker of cognitive recovery after IS. Most studies included in this review utilized structural Magnetic Resonance Imaging (MRI) to predict cognitive recovery after IS; these studies highlighted baseline markers of cerebral small vessel disease and cortical atrophy as predictors of cognitive recovery. Functional Magnetic Resonance Imaging (fMRI) using resting-state functional connectivity and Diffusion Imaging are potential biomarkers of cognitive recovery after IS, although more precise predictive tools are needed. Comparison of these studies is limited by heterogeneity in cognitive assessments. For all modalities, current findings need replication in larger samples. Although no neuroimaging tool is ready for use as a biomarker at this stage, these studies suggest a clinically meaningful role for neuroimaging in predicting post-stroke cognitive recovery.

Clinical features, imaging characteristics, genetic investigation and histopathologic findings in a Chihuahua dog with Lafora disease

AbstractA nine‐year‐old female spayed Chihuahua dog had developed hypnic jerks and progressive myoclonic seizures three months before presentation. Neurological examination showed mental depression and spontaneous or reflex myoclonus. Magnetic resonance imaging findings were consistent with cerebral cortical atrophy and mild cranio‐cervical junction abnormalities. Genetic testing revealed a homozygous NHCLR1 gene mutation, consistent with Lafora disease. Antiepileptic treatment was unsuccessful. Postmortem brain histopathological examination showed a diffuse combination of perikaryal, axonal and/or dendritic accumulation of periodic acid Schiff‐positive cytoplasmic polyglucosan bodies (Lafora bodies), in particular, in the cerebellar cortex. Lafora disease should be considered in the differential diagnosis of late‐onset myoclonus seizures in Chihuahua dogs. Genetic testing of relatives of affected cases is recommended in order to identify carriers and dogs at the preclinical disease stage, to establish the frequency of the mutation in the Chihuahua population, and ultimately to decrease the frequency of this fatal disease.

A novel deletion variant in CLN3 with highly variable expressivity is responsible for juvenile neuronal ceroid lipofuscinoses.

Mutations in CLN3 (OMIM: 607042) are associated with juvenile neuronal ceroid lipofuscinoses (JNCL)-a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration. The study aimed to determine the underlying genetic factors justifying the NCL phenotype in a large Iraqi consanguineous family. Four affected individuals with an initial diagnosis of NCL were recruited. By doing neuroimaging and also pertinent clinical examinations, e.g. fundus examination, due to heterogeneity of neurodevelopmental disorders, the proband was subjected to the paired-end whole-exome sequencing to identify underlying genetic factors. The candidate variant was also confirmed by Sanger sequencing. Various in silico predictions were used to show the pathogenicity of the variant. This study revealed a novel homozygous frameshift variant-NM_000086.2: c.1127del; p.(Leu376Argfs*15)-in the exon 14 of the CLN3 gene as the most likely disease-causing variant. Three out of 4 patients showed bilateral vision loss (< 7years) and retinal degeneration with macular changes in both eyes. Electroencephalography demonstrated the loss of normal posterior alpha rhythm and also low amplitude multifocal slow waves. Brain magnetic resonance imaging of the patients with a high degree of deterioration showed mild cerebral and cerebellar cortical atrophy, mild ventriculomegaly, thinning of the corpus callosum and vermis, and non-specific periventricular white matter signal changes in the occipital area. The novel biallelic deletion variant of CLN3 was identified that most probably led to JNCL with variable expressivity of the phenotype. This study also expanded our understanding of the clinical and genetic spectrum of JNCL.

Sneddon Syndrome: Livedo Reticularis and Ischemic Stroke

Sneddon syndrome(SS) is a rare, progressive vasculopathy with recurrent ischemic attacks. There is no specified treatment recommendation, various treatment methods such as anticoagulants, antiaggregants, and immunosuppressions are recommended. A 44-years-old woman who applied with a temporary numbness on her right side and speech disorder. In her neurological examination, there was central facial asymmetry on the right and mild dysarthria in his speech. In cranial diffusion MR, there was an acute ischemic change in the left lentiform nucleus and at the head of the caudate nucleus. In cranial MR, there were perivascular ischemic gliotic changes and diffuse cerebral cortical atrophy. The patient underwent a skin biopsy to have livedo reticularis-like lesions on both legs. Skin biopsy was compatible with vasculopathy. Due to the ischemic attack, periventricular ischemic changes, and livedoreticularis, the patient was accepted as SS. Since the antiphospholipid antibodies (APL) were negative, that she was followed up with dual antiplatelet therapy. There was no new attack within a year with dual therapy. Dual antiplatelet therapy may be used in SS patients with recurrent ischemic events and negative APL.

Cortical Thinning in the Medial Temporal Lobe and Precuneus Is Related to Cognitive Deficits in Patients With Subcortical Ischemic Vascular Disease.

Subcortical ischemic vascular disease (SIVD) is a major cause of vascular cognitive impairment (CI) and features extensive atrophy in the cerebral cortex. We aimed to test the hypothesis that cognitive deficits in SIVD are linked to decreased cortical thickness in specific brain regions, which may constitute neuroimaging biomarkers of CI. Sixty-seven SIVD patients without (SIVD-NC, n = 35) and with (SIVD-CI, n = 32) CI and a group of healthy controls (HCs, n = 36) underwent structural magnetic resonance imaging (MRI) and cognitive functional assessments. FreeSurfer was used to preprocess structural MRI data and to calculate and compare cortical thickness. The correlation between cortical thickness and cognitive scores was examined in SIVD patients. Significantly altered cortical thickness in the bilateral insula, middle and inferior temporal lobes, precuneus, and medial temporal lobe (MTL) was identified among the three groups (p < 0.05, Monte Carlo simulation corrected). Post hoc results showed significantly decreased thickness in the bilateral insula and temporal lobe in SIVD-NC and SIVD-CI patients compared with HCs. However, the areas with reduced cortical thickness were larger in SIVD-CI than SIVD-NC patients. SIVD-CI patients had significantly reduced thickness in the bilateral precuneus and left MTL (Bonferroni corrected) compared with SIVD-NC patients when we extracted the mean thickness for each region of interest. In SIVD patients, the thicknesses of the left MTL and bilateral precuneus were positively correlated with immediate recall in the memory test. SIVD might lead to extensive cerebral cortical atrophy, while atrophy in the MTL and precuneus might be associated with memory deficits.

Regional Cerebral Cortical Atrophy is Related to Urinary Tract Symptoms in Parkinson's Disease.

Lower urinary tract symptoms (LUTS) are the most common nonmotor symptoms usually occurring mid-stage of Parkinson's disease (PD); however, its underlying mechanisms are unknown. We aimed to assess whether corticometry or volumetry can identify a pattern of cerebral cortical changes in PD patients with LUTS. We recruited 85 idiopathic PD patients and performed corticometry and volumetry on various cortical regions using each patient's magnetic resonance imaging. To identify a correlation between the cortical thickness/volume and nonmotor symptoms scale domain 7 scores, which represent the severity of LUTS, we performed general linear model and region of interest analyses. Significant regional thinning of the left precuneus, left temporal pole, left precentral, right precuneus, and right pars opercularis was correlated with nonmotor symptoms scale domain 7 scores. We also found that cortical volumes of left precuneus and left frontal pole were inversely correlated with the severity of urinary symptoms. This study showed that the thicknesses and volumes of several cortical regions were significantly correlated with the severity of LUTS in PD patients. The findings of regional atrophy and thinning of specific cortical regions in this study provide additional evidence that multiple cortical regions, especially the precuneus cortex, not only may be involved in urinary dysfunctions of PD patients but also may help to elucidate the exact underlying mechanisms for LUTS in PD patients.

Hereditary spastic paraplegia type 11: Clinicogenetic lessons from 339 patients

Hereditary spastic paraplegia type 11 (SPG11) is the most common subtype of autosomal recessive hereditary spastic paraplegia (HSP), to date, there are more than 181 different KIAA1840 gene mutations detected, and yet the genetic landscape of SPG11 is far from complete. To find the clinical and genetic characteristics of SPG11, we performed a reanalysis of the clinical features and genotype-phenotype correlations in all reported studies exhibiting SPG11 mutations. A total of 339 patients were collected, their mean age at onset was 13.10 ± 3.65 years, with initial symptoms like gait disturbance (107/195, 54.87%) and mental retardation (47/195, 24.10%). Cognitive decline (228/270, 84.44%) was the most common complex manifestation stepped by dysarthria (134/195, 68.72%), neuropathy (112/177, 63.28%), amyatrophy, sphincter disturbance (60/130, 46.15%) and ataxia (90/194, 46.39%). The most common brain MRI abnormality is thinning of the corpus callosum (TCC) (173/190, 91.05%), followed by periventricular white matter changes (130/158, 82.28%), cerebral or cerebellar cortical atrophy (55/107, 51.40%). The mutational spectrum associated with KIAA1840 gene is wide, and frameshift mutations are the most common type followed by nonsense mutations. Our reanalysis demonstrated that SPG11 exhibited significant clinical and genetic heterogeneity, and no clear genotype-phenotype correlation was observed. There is no mutational hot spot in the KIAA1840 gene, which emphasizes the need to analyse the whole gene in clinical practice. In addition to conventional genetic testing methods, further mRNA analysis should be conducted on some cases to yield a definitive diagnosis.

Glial Response and Neuroinflammation in Cerebrocortical Atrophy in a Young Irish Wolfhound Dog

Simple SummaryNeuroinflammation is considered a reaction of the nervous system itself to protect and repair structural changes developed in it. Despite its initial positive purpose, sometimes it can produce worse consequences for the tissue. In this article, we present a case of an Irish Wolfhound dog suffering a rare idiopathic neurodegenerative disease producing wide cerebral cortical damage with loss of neuronal bodies in a bilateral and symmetrical pattern. We have studied the glial components of the neuroinflammation developed describing how they have exacerbated the nervous tissue damage.A two-year-old, Irish Wolfhound dog presented with a history of progressive neurological signs. Neurological exam revealed disorientation, absence of menace response, reduction of right nasal sensation, hypermetria and ataxia with reduction of proprioception in all four limbs. MRI findings were compatible with laminar neuronal necrosis and possible bilateral cortical cerebral atrophy. Grossly, a severe bilateral reduction of the gray matter with flattening of gyri, mainly in frontal and parietal cerebral areas, was observed. Histologically, multiple, segmental, bilateral, and symmetric areas of neuronal loss, necrosis and degeneration, in a laminar pattern, associated with a reactive gliosis were observed. Immunohistochemical studies showed severe reduction of neuronal bodies, proliferation and hypertrophy of astrocytes and microglia. Few perivascular B and T cells were demonstrated. Based on these data, we show some of the neuroinflammatory events that occur during CNS repair in a chronic phase of this condition.

Association of traumatic brain injury with late life neuropathological outcomes in a community‐based cohort

AbstractBackgroundDespite extensive interest in risk for dementia following traumatic brain injury (TBI), there is scant research on neuropathological outcomes among community‐dwelling elders with TBI exposure. We previously reported an association of TBI resulting in loss of consciousness (LOC) with microinfarcts and Lewy body pathology, but TBI exposure data were limited to a single self‐report question. With expanded ascertainment data from medical records and structured interview on lifetime TBI exposure, we conducted a comprehensive investigation of neuropathological associations of TBI in a large autopsy cohort.Method780 older adults from the Adult Changes in Thought (ACT) study underwent brain autopsy (Table 1). Participants were members of Kaiser Permanente Washington who completed biennial clinic visits including self‐reported head trauma with LOC exposure. These data were supplemented with medical record abstraction, and, for 244 people, with structured interviews, increasing the sensitivity for TBI‐LOC in that sample from 16% to 20% (see Figure 1). Neuropathology outcomes included neurofibrillary tangle distribution (Braak), neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral cortical atrophy. Exposures of interest included TBI with or without LOC. We used Poisson regressions with robust standard errors adjusted for age, sex, education, and APOε4 genotype, weighted back to the full cohort (n=5546; Table 2) in a bootstrapping procedure accounting for errors in estimating weights.ResultTBI with LOC was associated with increased cortical atrophy (Table 3). In those with the structured interview (including TBI without LOC), the neuropathological associations of TBI were attenuated; no outcomes were statistically significant (Table 4). These findings apply to the full ACT cohort, not just people with TBI data in the autopsy sample.ConclusionCerebral cortical atrophy results from chronic brain parenchymal injury, potentially including vascular brain injury and tauopathy. Understanding mechanisms underlying associations of TBI with microvascular brain injury and pathological tau are poorly understood; future studies deploying new techniques to better quantify these lesions and differentiate between TBI‐related, age‐related, and ADRD‐related pathways are needed.

A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog.

Dogs provide highly valuable models of human disease due to the similarity in phenotype presentation and the ease of genetic analysis. Seven Saluki puppies were investigated for neurological abnormalities including seizures and altered behavior. Magnetic resonance imaging showed a diffuse, marked reduction in cerebral cortical thickness, and symmetrical T2 hyperintensity in specific brain regions. Cerebral cortical atrophy with vacuolation (status spongiosus) was noted on necropsy. Genome-wide association study of 7 affected and 28 normal Salukis revealed a genome-wide significantly associated region on CFA 35. Whole-genome sequencing of three confirmed cases from three different litters revealed a homozygous missense variant within the aldehyde dehydrogenase 5 family member A1 (ALDH5A1) gene (XM_014110599.2: c.866G>A; XP_013966074.2: p.(Gly288Asp). ALDH5A1 encodes a succinic semialdehyde dehydrogenase (SSADH) enzyme critical in the gamma-aminobutyric acid neurotransmitter (GABA) metabolic pathway. Metabolic screening of affected dogs showed markedly elevated gamma-hydroxybutyric acid in serum, cerebrospinal fluid (CSF) and brain, and elevated succinate semialdehyde in urine, CSF and brain. SSADH activity in the brain of affected dogs was low. Affected Saluki dogs had striking similarities to SSADH deficiency in humans although hydroxybutyric aciduria was absent in affected dogs. ALDH5A1-related SSADH deficiency in Salukis provides a unique translational large animal model for the development of novel therapeutic strategies.

Accuracy of radiologists, nonradiologists, and laypeople for identifying children with cerebral cortical atrophy from "Mercator map" curved reconstructions of MRIs of the brain.

Background:Using text reports to communicate bilateral, symmetric, and zonal cortical brain atrophy in children with term hypoxic ischemic injury (HII) to parents and legal professionals contesting compensation rights can be difficult. Using standard cross-sectional images for explaining bilateral, regional brain imaging to laypeople is also challenging. A single flattened image of the brain surface, much like a map of the earth is derived from a globe, can be generated from curved reconstruction of magnetic resonance imaging (MRI) scans, i.e., a Mercator map. Laypeople's ability to identify abnormal “Mercator brain maps,” without prior training, requires evaluation before use in nonmedical settings. Aim:To determine the sensitivity and specificity of laypeople in detecting abnormal pediatric Mercator flat-earth maps of the brain, without prior training. Methods and Materials:10 Mercator brain maps were provided to 111 participants individually. The maps comprised 5 HII, 1 cortical dysplasia, and 4 normal cases. Participants were required to identify the abnormal scans. Sensitivity and specificity overall and for participants’ subgroups were calculated. Results:Overall sensitivity and specificity were 67% and 80%, respectively. General radiologists (n = 12) had sensitivity and specificity of 91.2% and 94.6%, respectively. Laypeople (n = 54) had a sensitivity of 67% and specificity of 80%. Conclusion:The high specificity and sensitivity of radiologists validated the technique for distinguishing abnormal scans, regarding cortical pathology. High specificity of laypeople for identifying abnormal brains using Mercator maps indicates that this is a viable communication tool for demonstrating cortical MRI abnormalities of HII in children to laypersons.

MYORG-related disease is associated with central pontine calcifications and atypical parkinsonism.

ObjectiveTo identify the phenotypic, neuroimaging, and genotype-phenotype expression of MYORG mutations.MethodsUsing next-generation sequencing, we screened 86 patients with primary familial brain calcification (PFBC) from 60 families with autosomal recessive or absent family history that were negative for mutations in SLC20A2, PDGFRB, PDGBB, and XPR1. In-depth phenotyping and neuroimaging investigations were performed in all cases reported here.ResultsWe identified 12 distinct deleterious MYORG variants in 7 of the 60 families with PFBC. Overall, biallelic MYORG mutations accounted for 11.6% of PFBC families in our cohort. A heterogeneous phenotypic expression was identified within and between families with a median age at onset of 56.4 years, a variable combination of parkinsonism, cerebellar signs, and cognitive decline. Psychiatric disturbances were not a prominent feature. Cognitive assessment showed impaired cognitive function in 62.5% of cases. Parkinsonism associated with vertical nuclear gaze palsy was the initial clinical presentation in 1/3 of cases and was associated with central pontine calcifications. Cerebral cortical atrophy was present in 37% of cases.ConclusionsThis large, multicentric study shows that biallelic MYORG mutations represent a significant proportion of autosomal recessive PFBC. We recommend screening MYORG mutations in all patients with primary brain calcifications and autosomal recessive or negative family history, especially when presenting clinically as atypical parkinsonism and with pontine calcification on brain CT.

Muscle Strength Is Independently Related to Brain Atrophy in Patients with Alzheimer’s Disease

Background/Aims: Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Interestingly, muscle mass (MM) and muscle strength (MS) are related to AD. In addition to the muscle profile, brain atrophy is also a prominent feature of AD. There is substantial evidence showing an association between muscle profile and dementia, but the role of the muscle profile and cerebral cortical atrophy within this association is less well understood. The objective of this study was to determine if there is any association between muscle profile and brain regional volume in AD. A secondary objective was to determine whether this relationship continues as the clinical stage of AD progresses. Methods: We recruited 28 patients with probable AD without weakness. We assessed the patients’ basic demographic characteristics, Mini-Mental State Examination score, and brain magnetic resonance images. MM was measured using body dual-energy X-ray absorptiometry. MS was assessed in Nm/kg with an isokinetic knee extensor using an isokinetic device at an angular velocity of 60°/s. An automatic analysis program was used for brain regional volumetric measurements. Dementia was divided into two stages: mild and moderate. Results: MS was related to left hippocampal volume ratio. After adjusting for age and cognitive status, the relationship remained. MS did not demonstrate any relationship to any brain regional volume ratio in the mild stage; however, in the moderate stage, it was positively related to both the right and the left hippocampal volume ratio. Conclusions: Our findings imply a shared underlying pathology relating MS and brain volume and suggest cognitive functional declines through the muscle-brain axis. Further longitudinal studies are needed to find possible and related causes of reduced MS and cortical atrophy in patients with dementia.