Atrophy Of Cerebral Cortex Research Articles

Clinical application of sparse canonical correlation analysis to detect genetic associations with cortical thickness in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cerebral cortex atrophy. In this study, we used sparse canonical correlation analysis (SCCA) to identify associations between single nucleotide polymorphisms (SNPs) and cortical thickness in the Korean population. We also investigated the role of the SNPs in neurological outcomes, including neurodegeneration and cognitive dysfunction. We recruited 1125 Korean participants who underwent neuropsychological testing, brain magnetic resonance imaging, positron emission tomography, and microarray genotyping. We performed group-wise SCCA in Aβ negative (-) and Aβ positive (+) groups. In addition, we performed mediation, expression quantitative trait loci, and pathway analyses to determine the functional role of the SNPs. We identified SNPs related to cortical thickness using SCCA in Aβ negative and positive groups and identified SNPs that improve the prediction performance of cognitive impairments. Among them, rs9270580 was associated with cortical thickness by mediating Aβ uptake, and three SNPs (rs2271920, rs6859, rs9270580) were associated with the regulation of CHRNA2, NECTIN2, and HLA genes. Our findings suggest that SNPs potentially contribute to cortical thickness in AD, which in turn leads to worse clinical outcomes. Our findings contribute to the understanding of the genetic architecture underlying cortical atrophy and its relationship with AD.

Association of gabapentin and neuropathological hallmarks in an autopsy cohort of older adults

AbstractBackgroundPrevious studies of the association between gabapentin use and neurocognitive change have shown conflicting results. We examined the association between end‐of‐life gabapentin use and neuropathological features in older adults using National Alzheimer’s Coordinating Center Uniform Data Set and Neuropathology Data Set (9/2005‐3/2022).MethodsWe conducted a cross‐sectional study including participants with at least one visit within two years before autopsy and age at visit 65+ years. Gabapentin use was determined based on the two‐year window. Outcomes of interest included burden of tau (Braak stage), amyloid (Thal stage, diffuse plaques, and neuritic plaques), α‐synuclein (Lewy bodies), cerebrovascular disease (infarcts, microinfarcts, and arteriosclerosis), hippocampal sclerosis, cerebral amyloid angiopathy, TDP‐43, and atrophy (cerebral cortex and hippocampus). Collection of Thal stage, TDP‐43, and atrophy information occurred after January 2014; these outcomes were assessed in the subset with data. For each dependent neuropathological hallmark, two models were constructed (M1: adjusted for age, sex, APOE, center, and cognitive status; M2: adjusted for M1 confounders, agitation, depression, antiseizure drug, and use of opioids). To mitigate bias, joint stabilized inverse probability of treatment and censoring weights were used.ResultsWe included 213 gabapentin‐users (mean age[SD]: 80.9[8.7]; male 53.5%) and 4107 non‐users (82.0[8.7]; 54.7%). Gabapentin use was associated with reduced odds of Braak stage IV‐VI vs. 0‐III, moderate/frequent vs. non/sparse diffuse plaques, presence of Lewy bodies, infarct, and cerebral amyloid angiopathy in M1 and M2, and hippocampal sclerosis in M1 (Figures 1A and 1B). For the subset outcomes, 116 gabapentin‐users (mean age [SD]: 81.0 [8.6]; male 50.9%) and 1919 non‐users (81.8 [8.9]; 54.3%) were included. Gabapentin use was associated with increased odds of Thal phase 3‐5 vs. 0‐2 in M1 and M2, and amygdala TDP‐43, hippocampus TDP‐43, and cerebral cortex atrophy in M2; whereas gabapentin use was associated with decreased odds of hippocampus atrophy in M1 and M2, and amygdala TDP‐43, hippocampus TDP‐43, and cerebral cortex atrophy in M1 (Figures 1C and 1D).ConclusionEnd‐of‐life gabapentin use was not significantly associated with burden of neuropathologic features and there were no clear patterns. Further studies with increased sample sizes and better measurement of gabapentin use are needed.

Diffusion tensor imaging (DTI) Analysis Based on Tract-based spatial statistics (TBSS) and Classification Using Multi-Metric in Alzheimer's Disease.

Alzheimer's disease (AD) is a brain disorder characterized by atrophy of cerebral cortex and neurofibrillary tangles. Accurate identification of individuals at high risk of developing AD is key to early intervention. Combining neuroimaging markers derived from diffusion tensor images with machine learning techniques, unique anatomical patterns can be identified and further distinguished between AD and healthy control (HC). In this study, 37 AD patients (ADs) and 36 healthy controls (HCs) from the Alzheimer's Disease Neuroimaging Initiative were applied to tract-based spatial statistics (TBSS) analysis and multi-metric classification research. The TBSS results showed that the corona radiata, corpus callosum and superior longitudinal fasciculus were the white matter fiber tracts which mainly suffered the severe damage in ADs. Using support vector machine recursive feature elimination (SVM-RFE) method, the classification performance received a decent improvement. In addition, the integration of fractional anisotropy (FA) + mean diffusivity (MD) + radial diffusivity (RD) into multi-metric could effectively separate ADs from HCs. The rank of significance of diffusion metrics was FA > axial diffusivity (DA) > MD > RD in our research. Our findings suggested that the TBSS and machine learning method could play a guidance role on clinical diagnosis.

Neuroprotection in Cerebral Cortex Induced by the Pregnancy Hormone Estriol

In multiple sclerosis (MS), demyelination occurs in the cerebral cortex, and cerebral cortex atrophy correlates with clinical disabilities. Treatments are needed in MS to induce remyelination. Pregnancy is protective in MS. Estriol is made by the fetoplacental unit, and maternal serum estriol levels temporally align with fetal myelination. Here, we determined the effect of estriol treatment on the cerebral cortex in the preclinical model of MS, experimental autoimmune encephalomyelitis (EAE). Estriol treatment initiated after disease onset decreased cerebral cortex atrophy. Neuropathology of the cerebral cortex showed increased cholesterol synthesis proteins in oligodendrocytes, more newly formed remyelinating oligodendrocytes, and increased myelin in estriol-treated EAE mice. Estriol treatment also decreased the loss of cortical layer V pyramidal neurons and their apical dendrites and preserved synapses. Together, estriol treatment after EAE onset reduced atrophy and was neuroprotective in the cerebral cortex.

Intranasal delivery of insulin for the restoration of memory signaling in Alzheimer's disease

Alzheimer's disease(AD), is progressive, degenerative brain disease characterized by marked atrophy of cerebral cortex and loss of cortical and sub-cortical neurons. Weakening of insulin receptor signaling is involved in ageing-related brain degeneration like AD. Objective of this study is to develop delivery-system to overcome BBB by employing novel, non-invasive approach via nasal route i.e. delivery of antibody appended Insulin encapsulated carrier, PEGylated nanoparticle coated with chitosan to facilitate nasal absorption for efficient transfer to brain.

Prevention of Diabetes-Associated Cognitive Dysfunction Through Oral Administration of Lipopolysaccharide Derived From Pantoea agglomerans.

Diabetes-related cognitive dysfunction (DRCD) is a serious complication induced by diabetes. However, there are currently no specific remedies for DRCD. Here, we show that streptozotocin-induced DRCD can be prevented without causing side effects through oral administration of lipopolysaccharide (LPS) derived from Pantoea agglomerans. Oral administration of LPS (OAL) prevented the cerebral cortex atrophy and tau phosphorylation induced by DRCD. Moreover, we observed that neuroprotective transformation of microglia (brain tissue-resident macrophages) is important for preventing DRCD through OAL. These findings are contrary to the general recognition of LPS as an inflammatory agent when injected systemically. Furthermore, our results strongly suggest that OAL promotes membrane-bound colony stimulating factor 1 (CSF1) expression on peripheral leukocytes, which activates the CSF1 receptor on microglia, leading to their transformation to the neuroprotective phenotype. Taken together, the present study indicates that controlling innate immune modulation through the simple and safe strategy of OAL can be an innovative prophylaxis for intractable neurological diseases such as DRCD. In a sense, for modern people living in an LPS-depleted environment, OAL is like a time machine that returns microglia to the good old LPS-abundant era.

FAF-DRVFL: Fuzzy activation function based deep random vector functional links network for early diagnosis of Alzheimer disease

Alzheimer’s disease (AD) is a degenerative neural condition marked by gradual memory loss and cognitive impairment. It is irreversible in nature and leads to progressive cerebral cortex atrophy. Therefore, structural Magnetic Resonance Imaging (sMRI) is an important tool that can be used for early-stage prediction of AD. Currently, deep learning networks are used for the diagnosis of AD, but it suffers from the limitations of gradient descent training of deep networks like local minima, slow learning speed, and overfitting. Also, there is a need to select hyperparameters like learning rate, momentum, number of epochs, and regularization coefficient. This paper proposes a deep non-iterative random vector functional link (RVFL) neural network. First, the MRI images’ features are extracted using transfer learning, and the classification of the extracted features is done using a non-iterative random vector initialized RVFL network. At the hidden layer of the RVFL classifier, the fuzzy activation function (FAF), is used to calculate the hidden layer’s output. The proposed algorithm has been evaluated and compared with the state-of-the-art methods on the ADNI dataset consisting of Cognitive Normal (CN), AD, converter Mild Cognitive Impairment (cMCI) and non-converter Mild Cognitive Impairment (ncMCI) MRI images. The performance achieved for CN vs AD diagnosis includes accuracy (86.67%), sensitivity (83.33%), specificity (88.89%), precision (83.33%), recall (83.33%) and F-score(86.07%) as well as Receiver Operating Characteristics shows that proposed method outperforms over several compared methods.

Voxel-Based Meta-Analysis of Gray Matter Abnormalities in Multiple System Atrophy

Purpose: This study aimed to identify consistent gray matter volume (GMV) changes in the two subtypes of multiple system atrophy (MSA), including parkinsonism subtype (MSA-P), and cerebellar subtype (MSA-C), by conducting a voxel-wise meta-analysis of whole brain voxel-based morphometry (VBM) studies.Method: VBM studies comparing MSA-P or MSA-C and healthy controls (HCs) were systematically searched in the PubMed, Embase, and Web of Science published from 1974 to 20 October 2020. A quantitative meta-analysis of VBM studies on MSA-P or MSA-C was performed using the effect size-based signed differential mapping (ES-SDM) method separately. A complementary analysis was conducted using the Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) method, which allows a familywise error rate (FWE) correction for multiple comparisons of the results, for further validation of the results.Results: Ten studies were included in the meta-analysis of MSA-P subtype, comprising 136 MSA-P patients and 211 HCs. Five studies were included in the meta-analysis of MSA-C subtype, comprising 89 MSA-C patients and 134 HCs. Cerebellum atrophy was detected in both MSA-P and MSA-C, whereas basal ganglia atrophy was only detected in MSA-P. Cerebral cortex atrophy was detected in both subtypes, with predominant impairment of the superior temporal gyrus, inferior frontal gyrus, temporal pole, insula, and amygdala in MSA-P and predominant impairment of the superior temporal gyrus, middle temporal gyrus, fusiform gyrus, and lingual gyrus in MSA-C. Most of these results survived the FWE correction in the complementary analysis, except for the bilateral amygdala and the left caudate nucleus in MSA-P, and the right superior temporal gyrus and the right middle temporal gyrus in MSA-C. These findings remained robust in the jackknife sensitivity analysis, and no significant heterogeneity was detected.Conclusion: A different pattern of brain atrophy between MSA-P and MSA-C detected in the current study was in line with clinical manifestations and provided the evidence of the pathophysiology of the two subtypes of MSA.

Intranasal delivery of insulin for the restoration of memory signaling in Alzheimer disease

Alzheimer's disease(AD), a form of dementia, is progressive, degenerative brain disease characterized by marked atrophy of cerebral cortex and loss of cortical and sub-cortical neurons. Weakening of insulin receptor signaling is involved in ageing-related brain degeneration such as AD. Objective of this study is to develop delivery-system to overcome BBB by employing novel, non-invasive approach via nasal route. The olfactory neural pathway provides both intraneuronal and extraneuronal pathway into brain.

Mucopolysaccharidosis III in Mainland China: natural history, clinical and molecular characteristics of 34 patients.

Objectives Sanfilippo syndrome (Mucopolysaccharidosis III, MPS III) is a rare autosomal recessive hereditary disease, which is caused by lysosomal enzyme deficiency. This study was operated to investigate clinical and molecular characteristics of patients with MPS III, which will improve the diagnosis and treatment of MPS III. Method Thirty four patients with MPS III were assessed using clinical evaluation, questionnaire, and scoring system. Results Among the 34 patients, 14 had MPS IIIA, 19 had MPS III B, and one had MPS III C. Speech delay (100%) and intellectual disability (100%) were the most prevalent clinical manifestations in this cohort, followed by hyperactivity (94.12%), hirsutism (91.18%), enlarged head circumference (73.52%), repeated diarrhea (67.64%), sparse teeth (67.64%), and Mongolian spots (64.71%). There were two clinical manifestations that were significantly different between IIIA and IIIB: Hepatosplenomegaly and serrated teeth. The most common initial symptoms at diagnosis were speech delay (52.94%), hyperactivity (35.29%), and mental retardation (29.41%). Genetic analysis of 25 patients was conducted, which identified 12 novel mutations. Conclusion When language retardation, mental retardation, and rough facial features occurred, MPS III should be considered. At same time, more examination should be operated, such as examination of changes in cranial magnetic resonance imaging of cerebral cortex atrophy. Hepatosplenomegaly and serrated teeth could be used clinically to preliminarily distinguish IIIA from IIIB.

Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy.

ObjectiveThe study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy.MethodsThrough diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.ResultsBiallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.ConclusionsThese data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.

Characteristic Analysis and Literature Review of Hereditary Spinocerebellar Ataxia With Lumbar Spondylolisthesis and Valvular Prolapse

Spinocerebellar ataxia (SCA) is an autosomal dominant disease with high genetic heterogeneity, which cannot be cured until now. According to clinical manifestations or genetic pathology classification, SCA types 1 to 47 have been characterized so far, and the pathogenic genes of 28 SCA types have been identified. The clinical manifestations of the disease are diverse and easy to be misdiagnosed. This study aims to describe the family characteristics, specific clinical manifestations and genotyping of SCA patients. Magnetic resonance imaging (MRI) was used to check the atrophy of the brain and spinal cord. The lumbar spondylolisthesis was examined by computed tomography (CT). The possible influencing factors were analyzed by questioning each member of the patient’s family, especially the persons with the disease, to draw the genetic genealogy. Relevant literatures were searched to compare differences in genotypes between the patient and similar clinical manifestations. Craniocerebral MRI showed that cerebellar sulcus widened and deepened, vermis atrophy; enlargement of the cistern around the brainstem; cerebral cortex atrophy, furrow, fissure widen. Lumbar CT showed L3 spondylolisthesis slightly to the right. Genetic genealogy showed that the children of the patients still had the disease, and the children of the patients without the disease were all normal, which is consistent with the autosomal dominant genetic law. Compared with the literature, the patient had the same clinical manifestations as Machado’s disease: convex eyes, dysarthria, terminal muscles atrophy, ataxia gait, weakened tendon reflex, and arched foot. The same clinical manifestations of SCA40 included ataxia, wide-based gait, poor range discrimination and rotation movement disorder, but there were also many discrepancies. The patient’s lumbar spondylolisthesis and valvular prolapse were not present in any of the previous types. In conclusion, craniocerebral MRI and gene sequencing can help distinguish and diagnosis the subtypes of SCA; whether this patient is a new subtype with lumbar spondylolisthesis and heart valve prolapse needs further study; this genealogy supports that through eugenics dominant genetic diseases being passed on to the offspring can be avoided. J Neurol Res. 2019;9(4-5):81-88 doi: https://doi.org/10.14740/jnr544

Characteristic Analysis and Literature Review of Hereditary Spinocerebellar Ataxia With Lumbar Spondylolisthesis and Valvular Prolapse

Spinocerebellar ataxia (SCA) is an autosomal dominant disease with high genetic heterogeneity, which cannot be cured until now. According to clinical manifestations or genetic pathology classification, SCA types 1 to 47 have been characterized so far, and the pathogenic genes of 28 SCA types have been identified. The clinical manifestations of the disease are diverse and easy to be misdiagnosed. This study aims to describe the family characteristics, specific clinical manifestations and genotyping of SCA patients. Magnetic resonance imaging (MRI) was used to check the atrophy of the brain and spinal cord. The lumbar spondylolisthesis was examined by computed tomography (CT). The possible influencing factors were analyzed by questioning each member of the patient’s family, especially the persons with the disease, to draw the genetic genealogy. Relevant literatures were searched to compare differences in genotypes between the patient and similar clinical manifestations. Craniocerebral MRI showed that cerebellar sulcus widened and deepened, vermis atrophy; enlargement of the cistern around the brainstem; cerebral cortex atrophy, furrow, fissure widen. Lumbar CT showed L3 spondylolisthesis slightly to the right. Genetic genealogy showed that the children of the patients still had the disease, and the children of the patients without the disease were all normal, which is consistent with the autosomal dominant genetic law. Compared with the literature, the patient had the same clinical manifestations as Machado’s disease: convex eyes, dysarthria, terminal muscles atrophy, ataxia gait, weakened tendon reflex, and arched foot. The same clinical manifestations of SCA40 included ataxia, wide-based gait, poor range discrimination and rotation movement disorder, but there were also many discrepancies. The patient’s lumbar spondylolisthesis and valvular prolapse were not present in any of the previous types. In conclusion, craniocerebral MRI and gene sequencing can help distinguish and diagnosis the subtypes of SCA; whether this patient is a new subtype with lumbar spondylolisthesis and heart valve prolapse needs further study; this genealogy supports that through eugenics dominant genetic diseases being passed on to the offspring can be avoided. J Neurol Res. 2019;9(4-5):81-88 doi: https://doi.org/10.14740/jnr544

IMMUNOPATHOGENETIC ASPECTS OF ISCHEMIC STROKE

Immune system plays a key role in pathogenesis of ischemic stroke. Ischemic brain injury causes destruction of cells and extracellular matrix proteins, and the release of „danger“ molecules that cause rapid activation of innate immunity, and induce adaptive autoimmune reactions. The cells of innate immunity are responsible for elimination of cellular and extracellular debris and tissue repair, being, however, involved in post-ischemic inflammation causing brain injury. An adaptive immune response which develops within a few days is directed against self-antigens, being not related to nervous tissue damage in acute phase of stroke. The cells of adaptive immunity are able to regulate microglial activity and promote repair processes in the central nervous system. However, long-term persistence of lymphocytes with reactivity for brain-derived antigens may be involved into the atrophy of cerebral cortex, and development of dementia in remote post-stroke period. Immune response following ischemic brain stroke is manifesting by local and systemic reactions. Nevertheless, in contrast to prolonged local intracerebral inflammation in infarction area, and peri-infarction region, a systemic inflammatory response is quickly replaced by development of immunosuppression, as evidenced by lymphopenia, lymphoid organ atrophy and defective functions of immune cells. Immunosuppression is largely due to activation of sympathoadrenal system, aiming for limitation of inflammatory and autoimmune reactions. However, excessive immunosuppression leads to development of infectious complications, which may often cause lethal outcomes, and also may have a negative impact on efficiency of repair processes. The present review provides experimental and clinical data describing the innate and adaptive immune reactions in response to cerebral ischemia. Moreover, this review discusses possible pathogenetic importance of immune cells and their positive or negative effects, thus allowing further development of new therapeutic approaches for treatment of ischemic stroke.

New clinical signs and genotypes of known mitochondrial disorders

Objective: Mitochondrial disorders present a heterogeneous group of inherited disorders with wide clinical manifestations including neurological symptoms. As age of onset and symptoms considerably vary, NGS technologies become the main diagnostic approach for searching a genetic cause of mitochondrial pathology and could be effective to expand knowledge about phenotypic spectrum in this group of diseases. Methods: We've applied a target sequencing of 62 mitochondrial nuclear genes using NGS technology on IonTorrent PGM to define a molecular defect in our patients. Main including criteria were clinical phenotype, brain MRI abnormalities, PEO signs, high FGF21 blood level. Results: We present two interesting cases. 1. Two affected sibs (13-year-old boy, 7-year-old girl) of healthy non-consagenious parents were thought to have just cerebral palsy. They were born in time, had development delay, sleep and feeding problems since birth, epileptic seizures (since 2 y.o.), dystonic movements, bulbar syndrome. Brain MRI in both cases revealed diffuse symmetric atrophy of cerebral cortex. The boy had cataract since 11.5-y.o. They had no abnormalities in blood acylcarnitines, lysosomal enzymes activities and urine organic acids level. NCL1/2 and gangliosidosis were excluded. Mitochondrial disease was suspected. Genetic testing detected two compound heterozygous substitutions in DNA2 gene c.C1078A:p.Q360K/ c.C1795T:p.R599C. Both have high predicted scores of pathogenicity and low frequency of occurrence. Parents were confirmed to be heterozygous carriers. High score of mtDNA depletion was measured. It became the first description of this disease in children. 2. A girl of consagenious parents was born with hypertrophic cardiomyopathy, high lactate level in blood (6–8 mmol/l) and urine, severe muscle hypotonia and respiratory insufficiency. Blood acylcarnitines level was normal. Mitochondrial disease was suspected. NGS analysis revealed a new homozygous mutation c.C1037T:p.S346L in COX10 gene. Conclusion: Our results show that NGS tool is essential and effective approach as routine molecular diagnostic for inherited neurologic pediatric disorders.

Cerebral cortex involvement in Machado-Joseph disease.

Machado-Joseph disease (MJD/SCA3) is the most frequent spinocerebellar ataxia, characterized by brainstem, basal ganglia and cerebellar damage. Few magnetic resonance imaging based studies have investigated damage in the cerebral cortex. The objective was to determine whether patients with MJD/SCA3 have cerebral cortex atrophy, to identify regions more susceptible to damage and to look for the clinical and neuropsychological correlates of such lesions. Forty-nine patients with MJD/SCA3 (mean age 47.7 ± 13.0 years, 27 men) and 49 matched healthy controls were enrolled. All subjects underwent magnetic resonance imaging scans in a 3 T device, and three-dimensional T1 images were used for volumetric analyses. Measurement of cortical thickness and volume was performed using the FreeSurfer software. Groups were compared using ancova with age, gender and estimated intracranial volume as covariates, and a general linear model was used to assess correlations between atrophy and clinical variables. Mean CAG expansion, Scale for Assessment and Rating of Ataxia (SARA) score and age at onset were 72.1 ± 4.2, 14.7 ± 7.3 and 37.5 ± 12.5 years, respectively. The main findings were (i) bilateral paracentral cortex atrophy, as well as the caudal middle frontal gyrus, superior and transverse temporal gyri, and lateral occipital cortex in the left hemisphere and supramarginal gyrus in the right hemisphere; (ii) volumetric reduction of basal ganglia and hippocampi; (iii) a significant correlation between SARA and brainstem and precentral gyrus atrophy. Furthermore, some of the affected cortical regions showed significant correlations with neuropsychological data. Patients with MJD/SCA3 have widespread cortical and subcortical atrophy. These structural findings correlate with clinical manifestations of the disease, which support the concept that cognitive/motor impairment and cerebral damage are related in disease.

Mapping Cortical Degeneration in ALS with Magnetization Transfer Ratio and Voxel-Based Morphometry

Pathological and imaging data indicate that amyotrophic lateral sclerosis (ALS) is a multisystem disease involving several cerebral cortical areas. Advanced quantitative magnetic resonance imaging (MRI) techniques enable to explore in vivo the volume and microstructure of the cerebral cortex in ALS. We studied with a combined voxel-based morphometry (VBM) and magnetization transfer (MT) imaging approach the capability of MRI to identify the cortical areas affected by neurodegeneration in ALS patients. Eighteen ALS patients and 18 age-matched healthy controls were examined on a 1.5T scanner using a high-resolution 3D T1 weighted spoiled gradient recalled sequence with and without MT saturation pulse. A voxel-based analysis (VBA) was adopted in order to automatically compute the regional atrophy and MT ratio (MTr) changes of the entire cerebral cortex. By using a multimodal image analysis MTr was adjusted for local gray matter (GM) atrophy to investigate if MTr changes can be independent of atrophy of the cerebral cortex. VBA revealed several clusters of combined GM atrophy and MTr decrease in motor-related areas and extra-motor frontotemporal cortex. The multimodal image analysis identified areas of isolated MTr decrease in premotor and extra-motor frontotemporal areas. VBM and MTr are capable to detect the distribution of neurodegenerative alterations in the cortical GM of ALS patients, supporting the hypothesis of a multi-systemic involvement in ALS. MT imaging changes exist beyond volume loss in frontotemporal cortices.

Direct recording of the output of the motor cortex produced by transcranial magnetic stimulation in a patient with cerebral cortex atrophy

To examine the descending motor activity evoked by transcranial magnetic stimulation (TMS) in a chronic alcoholic patient with a slight atrophy of the peri-central cortex and compare with that observed in neurologically intact subjects. EMGs from the first dorsal interosseous (FDI) muscle, and descending activity from an electrode implanted in the high cervical epidural space for relief of pain were recorded after TMS of the hand area of motor cortex. A figure-of-8 coil was used to induce either a posterior-anterior (PA) or a latero-medial (LM) flow across the central sulcus. In intact subjects, LM stimulation evoked the earliest volley, which we termed a D wave. This was followed by later, presumed I waves at intervals of about 1.5 ms. At a stimulus intensity of 120% resting threshold (RMT), up to 5 I waves were seen. PA stimulation rarely evoked D waves at intensities up to 120% RMT, but 3 or 4 I waves were visible in all subjects. The patient had an increased resting threshold, and the descending volleys were dominated by a D wave. I waves were unclear, with two possible small peaks at 5.5 and 7.2 ms. The lack of I waves in the patient was probably due to an impairment of interneuronal circuitry in the context of the brain damage related to chronic alcohol abuse, and is consistent with a trans-synaptic origin of the I waves in humans. The intact D wave is consistent with the assumption that the D wave represents direct stimulation of the axons of intact corticospinal neurones in the subcortical white matter. The patient's increased RMT reflects the fact that usually multiple descending volleys are needed to discharge resting spinal motoneurones.

Cortical and subcortical neuropeptides in Alzheimer's disease

Given the clinical features of AD, the severe atrophy of cerebral cortex that accompanies the disease, and the predominant cortical location of plaques and tangles, it is not surprising to find the most consistent changes in neuropeptides in this disease occurring in the cerebral cortex. The neuropeptide changes that have been reproducibly demonstrated in AD are reduced hippocampal and neocortical SS and CRF concentrations and a reduced CSF level of SS. In cerebral cortex, SS and CRF are found in GABAergic local circuit neurons in layers II, III, and VI. The function of these neurons is not well established, although these cells may act to integrate the flow of incoming and outgoing information in cerebral cortex. If this is true, then dysfunction of this integration could produce widespread failure of cerebrocortical function, resulting in the various neurobehavioral deficits seen in AD. The interpretation of neuropeptide changes in subcortical brain regions, either those that project to cortex, or those that are the efferent targets of cortical projections, is also uncertain. The observed neuropeptide abnormalities in these brain regions in AD are less consistent than are those seen in cerebral cortex. Perhaps the most intriguing result in these regions is the increases in galanin-immunoreactive terminals seen in the nucleus basalis of AD brains. Galanin has been shown to inhibit acetylcholine release and to impair memory function in rats (46,113).(ABSTRACT TRUNCATED AT 250 WORDS)

Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington's disease.

We performed morphometric analysis of five standardized coronal brain slices at anterior frontal (AF), caudate-putamen-accumbens (CAP), globus pallidus (GP), lateral geniculate nucleus (LGN), and parieto-occipital fissure (OCP) levels in 30 patients with Huntington's disease (HD) and 13 controls. Associated with the 30% mean reduction in brain weight in HD patients (p less than 0.001) were significantly smaller overall cross-sectional areas of brain at all five levels studied, with striking losses in cerebral cortex (21-29%), white matter (29-34%), caudate (57%), putamen (64%), and thalamus (28%) (all p less than 0.005). In addition, the ventricular system was dilated up to 2.5 times normal at CAP, GP, and LGN levels, 9.5 times normal at the OCP level, and 13 times normal at the AF level. Higher grades of severity of HD had greater reductions in the cross-sectional area of the caudate, putamen, thalamus, and cerebral cortex (p less than 0.005-0.001), and larger ventricles (p = 0.08) compared to lower (less severe) grades of HD. The findings confirm and quantitate the severe atrophy of the neostriatum, in addition to demonstrating a severe loss of cerebral cortex and subcortical white matter in HD. The global atrophy of cerebral cortex and white matter observed in all degrees of HD may account for the cognitive and neuropsychiatric impairments which often precede the onset of chorea.