RESUMO
BACKGROUND: Secondary prevention clinical trials for Alzheimer's disease (AD) target amyloid accumulation in asymptomatic, amyloid-positive individuals, but it is unclear to what extent other pathophysiological processes, such as small vessel cerebrovascular disease, account for participant performance on the primary cognitive outcomes in those trials. White matter hyperintensities are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) that reflect small vessel cerebrovascular disease. They are associated with cognitive functioning in older adults and with clinical presentation and course of AD, particularly when distributed in posterior brain regions. The purpose of this study was to examine to what degree regional WMH volume is associated with performance on the primary cognitive outcome measure in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, a secondary prevention trial. METHODS: Data from 1791 participants (59.5% women, mean age (SD) 71.6 (4.74)) in the A4 study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) companion study at the screening visit were used to quantify WMH volumes on T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Cognition was assessed with the preclinical Alzheimer cognitive composite (PACC). We tested the association of total and regional WMH volumes with PACC performance, adjusting for age, education, and amyloid positivity status, with general linear models. We also considered interactions between WMH and amyloid positivity status. RESULTS: Increased frontal and parietal lobe WMH volume was associated with poorer performance on the PACC. While amyloid positivity was also associated with lower cognitive test scores, WMH volumes did not interact with amyloid positivity status. CONCLUSION: These results highlight the potential of small vessel cerebrovascular disease to drive AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered when evaluating outcome in trials, both as potential effect modifiers and as a possible target for intervention or prevention.
Assuntos
Doença de Alzheimer , Transtornos Cerebrovasculares , Disfunção Cognitiva , Substância Branca , Idoso , Feminino , Humanos , Masculino , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/patologia , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/patologia , Cognição , Disfunção Cognitiva/patologia , Imageamento por Ressonância Magnética , Estudos Prospectivos , Substância Branca/patologia , Ensaios Clínicos como AssuntoRESUMO
Importance: By age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer's disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hypothesized to be mediated by inflammatory factors. Objective: To examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS. Design: Cross sectional analysis of neuroimaging, plasma, and clinical data. Setting: Participants were enrolled in Alzheimer's Biomarker Consortium - Down Syndrome (ABC-DS), a multisite study of AD in adults with DS. Participants: One hundred eighty-five participants (mean [SD] age=45.2 [9.3] years) with available MRI and plasma biomarker data were included. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI scans and plasma biomarker concentrations of amyloid beta (Aß42/Aß40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays. Main Outcomes and Measures: We examined the bivariate relationships of WMH, Aß42/Aß40, p-tau217, and GFAP with age-residualized NfL across AD diagnostic groups. A series of mediation and path analyses examined causal pathways linking WMH and AD pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. Results: There was a direct and indirect bidirectional effect through GFAP of WMH on p-tau217 concentration, which was associated with NfL concentration in the entire sample. Among cognitively stable participants, WMH was directly and indirectly, through GFAP, associated with p-tau217 concentration, and in those with MCI, there was a direct effect of WMH on p-tau217 and NfL concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. Conclusions and Relevance: The findings suggest that among individuals with DS, CVD promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of AD. This work joins an emerging literature that implicates CVD and its interface with neuroinflammation as a core pathological feature of AD in adults with DS.
RESUMO
INTRODUCTION: There is an unmet need for mechanism-based biomarkers and effective disease modifying treatments in amyotrophic lateral sclerosis (ALS). Previous findings have provided evidence that histone deacetylases (HDAC) are altered in ALS, providing a rationale for testing HDAC inhibitors as a therapeutic option. METHODS: We measured class I and II HDAC protein and transcript levels together with acetylation levels of downstream substrates by using Western blotting in postmortem tissue of ALS and controls. [11 C]Martinostat, a novel HDAC positron emission tomography ligand, was also used to assess in vivo brain HDAC alterations in patients with ALS and healthy controls (HC). RESULTS: There was no significant difference in HDAC levels between patients with ALS and controls as measured by Western blotting and reverse-transcription quantitative polymerase chain reaction. Similarly, no differences were detected in [11 C]Martinostat-positron emission tomography uptake in ALS participants compared with HCs. DISCUSSION: These findings provide evidence that alterations in HDAC isoforms are not a dominant pathological feature at the bulk tissue level in ALS.
Assuntos
Esclerose Lateral Amiotrófica/genética , Histona Desacetilases/genética , Córtex Motor/metabolismo , Medula Espinal/metabolismo , Adamantano/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Estudos Transversais , Feminino , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Molecular , Córtex Motor/diagnóstico por imagem , Córtex Motor/patologia , Imagem Multimodal , Tomografia por Emissão de Pósitrons , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologiaRESUMO
INTRODUCTION: RNS60 is a novel immune-modulatory agent that has shown neuroprotective effects in amytrophic lateral sclerosis (ALS) preclinical models. RNS60 is administered by weekly intravenous infusion and daily nebulization. The objective of this pilot open-label trial was to test the feasibility, safety, and tolerability of long-term RNS60 administration in ALS patients. METHODS: The planned treatment duration was 23 weeks and the primary outcomes were safety and tolerability. Secondary outcomes included PBR28 positron emission tomography (PET) imaging and plasma biomarkers of inflammation. RESULTS: Sixteen participants with ALS received RNS60 and 13 (81%) completed 23 weeks of RNS60 treatment. There were no serious adverse events and no participants withdrew from the trial due to drug-related adverse events. There were no significant changes in the biomarkers. DISCUSSION: Long-term RNS60 administration was safe and well-tolerated. A large, multicenter, phase II trial of RNS60 is currently enrolling participants to test the effects of RNS60 on ALS biomarkers and disease progression. Muscle Nerve 59:303-308, 2019.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Administração por Inalação , Adulto , Idoso , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/fisiopatologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Biomarcadores/análise , Encéfalo/diagnóstico por imagem , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Força Muscular , Neuroimagem , Projetos Piloto , Tomografia por Emissão de Pósitrons , Cloreto de Sódio/efeitos adversos , Cloreto de Sódio/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
Objective: To determine the relationship between brain tissue metabolites measured by in vivo magnetic resonance spectroscopy (1H-MRS), and glial activation assessed with [11C]-PBR28 uptake in people with amyotrophic lateral sclerosis (ALS). Methods: Forty ALS participants were evaluated clinically using the revised ALS functional rating scale (ALSFRS-R) and upper motor neuron burden (UMNB). All participants underwent simultaneous brain [11C]-PBR28 PET and MR imaging including diffusion tensor imaging to acquire fractional anisotropy (FA). [11C]-PBR28 uptake was measured as standardized uptake values normalized by whole brain mean (SUVR). 1H-MRS metabolite ratios (myo-inositol/creatine, mI/Cr; N-acetylaspartate/creatine, NAA/Cr) were measured within the precentral gyri and brain stem (regions known to be involved in ALS pathophysiology), and precuneus (which served as a control region). Whole brain voxel-wise correlation analyses were employed to identify brain regions exhibiting an association between metabolites within the VOIs and [11C]-PBR28 uptake. Results: In the precentral gyri, [11C]-PBR28 uptake correlated positively with mI/Cr and negatively with NAA/Cr. The same correlations were not statistically significant in the brain stem, or in the control precuneus region. Whole brain voxel-wise correlation analyses between the estimated brain metabolites within the VOIs and SUVR were highly correlated in the precentral gyri. Decreased FA values in the precentral gyri were correlated with reduced NAA/Cr and elevated mI/Cr. Higher UMNB was correlated with increased [11C]-PBR28 uptake and mI/Cr, and decreased NAA/Cr. ALSFRS-R total score correlated positively with NAA/Cr and negatively with mI/Cr. Conclusion: Integrated PET-MR and 1H-MRS imaging demonstrates associations between markers for neuronal integrity and neuroinflammation and may provide valuable insights into disease mechanisms in ALS.
Assuntos
Acetamidas , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Radioisótopos de Carbono , Imagem de Tensor de Difusão/métodos , Tomografia por Emissão de Pósitrons/métodos , Espectroscopia de Prótons por Ressonância Magnética/métodos , Piridinas , Adulto , Esclerose Lateral Amiotrófica/metabolismo , Feminino , Humanos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodosRESUMO
OBJECTIVE: To characterize [11 C]-PBR28 brain uptake using positron emission tomography (PET) in people with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). We have previously shown increased [11 C]-PBR28 uptake in the precentral gyrus in a small group of ALS patients. Herein, we confirm our initial finding, study the longitudinal changes, and characterize the gray versus white matter distribution of [11 C]-PBR28 uptake in a larger cohort of patients with ALS and PLS. METHODS: Eighty-five participants including 53 with ALS, 11 with PLS, and 21 healthy controls underwent integrated [11 C]-PBR28 PET-magnetic resonance brain imaging. Patients were clinically assessed using the Upper Motor Neuron Burden (UMNB) and the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). [11 C]-PBR28 uptake was quantified as standardized uptake value ratio (SUVR) and compared between groups. Cortical thickness and fractional anisotropy were compared between groups and correlated with SUVR and the clinical data. [11 C]-PBR28 uptake and ALSFRS-R were compared longitudinally over 6 months in 10 ALS individuals. RESULTS: Whole brain voxelwise, surface-based, and region of interest analyses revealed increased [11 C]-PBR28 uptake in the precentral and paracentral gyri in ALS, and in the subcortical white matter for the same regions in PLS, compared to controls. The increase in [11 C]-PBR28 uptake colocalized and correlated with cortical thinning, reduced fractional anisotropy, and increased mean diffusivity, and correlated with higher UMNB score. No significant changes were detected in [11 C]-PBR28 uptake over 6 months despite clinical progression. INTERPRETATION: Glial activation measured by in vivo [11 C]-PBR28 PET is increased in pathologically relevant regions in people with ALS and correlates with clinical measures. Ann Neurol 2018;83:1186-1197.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Esclerose Lateral Amiotrófica/genética , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico , Estudos de Coortes , Correlação de Dados , Estudos Transversais , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Pirimidinas/farmacocinética , Receptores de GABA/genética , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Glia activation is thought to contribute to neuronal damage in several neurodegenerative diseases based on preclinical and human post-mortem studies, but its role in primary lateral sclerosis (PLS) is unknown. OBJECTIVES: To localize and measure glia activation in people with PLS compared to healthy controls (HC). METHODS: Ten participants with PLS and ten age-matched HCs underwent simultaneous magnetic resonance (MR) and proton emission tomography (PET). The radiotracer [11C]-PBR28 was used to obtain PET-based measures of 18 kDa translocator protein (TSPO) expression, a marker of activated glial cells. MR techniques included a structural sequence to measure cortical thickness and diffusion tensor imaging (DTI) to assess white matter integrity. RESULTS: PET data showed increased [11C]-PBR28 uptake in anatomically-relevant motor regions which co-localized with areas of regional gray matter atrophy and decreased subcortical fractional anisotropy. CONCLUSIONS: This study supports a link between glia activation and neuronal degeneration in PLS, and suggests that these disease mechanisms can be measured in vivo in PLS. Future studies are needed to determine the longitudinal changes of these imaging measures and to clarify if MR-PET with [11C]-PBR28 can be used as a biomarker for drug development in the context of clinical trials for PLS.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Doença dos Neurônios Motores/diagnóstico por imagem , Doença dos Neurônios Motores/patologia , Neuroglia/metabolismo , Adulto , Idoso , Radioisótopos de Carbono , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Receptores de GABA/metabolismo , Substância Branca/patologiaRESUMO
OBJECTIVE: In this cross-sectional study, we aimed to evaluate brain structural abnormalities in relation to glial activation in the same cohort of participants. METHODS: Ten individuals with amyotrophic lateral sclerosis (ALS) and 10 matched healthy controls underwent brain imaging using integrated MR/PET and the radioligand [11C]-PBR28. Diagnosis history and clinical assessments including Upper Motor Neuron Burden Scale (UMNB) were obtained from patients with ALS. Diffusion tensor imaging (DTI) analyses including tract-based spatial statistics and tractography were applied. DTI metrics including fractional anisotropy (FA) and diffusivities (mean, axial, and radial) were measured in regions of interest. Cortical thickness was assessed using surface-based analysis. The locations of structural changes, measured by DTI and the areas of cortical thinning, were compared to regional glial activation measured by relative [11C]-PBR28 uptake. RESULTS: In this cohort of individuals with ALS, reduced FA and cortical thinning colocalized with regions demonstrating higher radioligand binding. [11C]-PBR28 binding in the left motor cortex was correlated with FA (r = -0.68, p < 0.05) and cortical thickness (r = -0.75, p < 0.05). UMNB was correlated with glial activation (r = +0.75, p < 0.05), FA (r = -0.77, p < 0.05), and cortical thickness (r = -0.75, p < 0.05) in the motor cortex. CONCLUSIONS: Increased uptake of the glial marker [11C]-PBR28 colocalizes with changes in FA and cortical thinning. This suggests a link between disease mechanisms (gliosis and inflammation) and structural changes (cortical thinning and white and gray matter changes). In this multimodal neuroimaging work, we provide an in vivo model to investigate the pathogenesis of ALS.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Substância Cinzenta/patologia , Córtex Motor/patologia , Neurônios Motores/patologia , Neuroglia/patologia , Adulto , Idoso , Esclerose Lateral Amiotrófica/diagnóstico , Estudos Transversais , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Córtex Motor/anormalidadesRESUMO
BACKGROUND Intestinal lymphangiectasia (IL) is a rare disease characterized by a dilatation of the intestinal lymphatics and loss of lymph fluid into the gastrointestinal tract leading to hypoproteinemia, edema, lymphocytopenia, hypogammaglobinemia, and immunological abnormalities. Iron, calcium, and other serum components (e.g., lipids, fat soluble vitamins) may also be depleted. A literature search revealed more than 200 reported cases of IL. Herein, we report our observations of a patient diagnosed with IL; we also present our conclusion for our review of the published literature. CASE REPORT A 24-year-old male was admitted to Aleppo University Hospital with the complaints of abdominal pain, headache, arthralgia, fever, and rigors. His past medical history was remarkable for frequent episodes of diarrhea, recurrent infections, and swelling in the lower limbs. In addition, he had been hospitalized several times in non-academic hospitals due to edema in his legs, cellulitis, and recurrent infections. In the emergency department, a physical examination revealed a patient in distress. He was weak, dehydrated, pale, and had a high-grade fever. His lower extremities were edematous, swollen, and extremely tender to touch. The overlying skin was erythematous and warm. Moreover, the patient was tachycardic, tacypneic, and moderately hypotensive. The patient was resuscitated with IV fluids, and Tylenol was administered to bring the temperature down. Blood tests showed anemia and high levels of inflammatory markers. The patient's white blood cell count was elevated with an obvious left shift. However, subsequent investigations showed that the patient had IL. Suitable diet modification plans were applied as a long-term management plan. CONCLUSIONS IL is a rare disease of challenging nature due to its systematic effects and lack of comprehensive studies that can evaluate the effectiveness of specific treatments in a large cohort of patients. MCT (medium-chain triglyceride) oils and diet modification strategies are effective in reducing the loss of body proteins and in maintaining near-normal blood levels of immunoglobulins. However, octreotide and MCT oils had no proven role in shrinking edema in our patient.
Assuntos
Diarreia/etiologia , Gerenciamento Clínico , Intestinos/diagnóstico por imagem , Linfangiectasia Intestinal/diagnóstico , Biópsia , Diagnóstico Diferencial , Diarreia/diagnóstico , Diarreia/terapia , Endoscopia do Sistema Digestório , Humanos , Linfangiectasia Intestinal/complicações , Linfangiectasia Intestinal/terapia , Masculino , Radiografia Abdominal , Tomografia Computadorizada por Raios X , Ultrassonografia , Adulto JovemRESUMO
BACKGROUND: Pancreatic endocrine tumors (PETs) are rare and can occur as part of neurofibromatosis type 1 (NF1). Gastrinomas are functional PETs that are rarely associated with NF1. Only two cases of their occurrence have been reported in the literature. CASE REPORT: A 28-year-old woman was admitted for further evaluation of epigastric soreness, heartburn, nausea, vomiting, diarrhea, and a significant weight loss. Physical examination was remarkable for cutaneous findings (axillary freckling and multiple café-au-lait spots) as well as neurofibromas (dermal, plexiform). A diagnosis of NF1 was confirmed. Esophagogastroduodenoscopy (EGD) revealed multiple ulcers in the duodenum and the upper jejunum. A fasting gastrin level exceeded ten times the normal limit. An abdominal multi-slice 128 computed tomography (CT) scan revealed an oval mass of 26 mm in diameter adjacent to the second section of the duodenum. The patient was examined carefully to rule out multiple endocrine neoplasia type 1 (MEN1). Surgical resection was performed and a gastrinoma, causing Zollinger-Ellison syndrome (ZES), was diagnosed by histological examinations of the extirpated mass. The serum gastrin level decreased to normal limits shortly after surgery. Continuous follow-up revealed that the symptoms and the EGD findings completely resolved without recurrences. CONCLUSIONS: Although NF1 has common skeletal, visual, neurological, and cardiovascular complications, it also has a rare association with duodenal or pancreatic gastrinomas. Vigilance for this possible association is important to promote timely and careful management to help eliminate serious and potentially life-threatening complications.
Assuntos
Neurofibromatose 1/complicações , Síndrome de Zollinger-Ellison/complicações , Adulto , Feminino , Humanos , Neurofibromatose 1/diagnóstico , Síndrome de Zollinger-Ellison/diagnósticoRESUMO
OBJECTIVE: To investigate the relation between fractional anisotropy (FA), a suggested biomarker for tissue integrity, and motor recovery in patients with stroke after postacute rehabilitation. DESIGN: Retrospective study. SETTING: Acute rehabilitation hospital. PARTICIPANTS: Subjects (N=43) diagnosed with ischemic stroke (n=28) and hemorrhagic stroke (n=15). The average age for subjects was 68±14 years. INTERVENTIONS: Magnetic resonance imaging and diffusion tensor imaging were conducted on all patients. MAIN OUTCOME MEASURES: The admission and discharge motor subscores of the FIM were obtained from medical records, and relative gain was calculated using the Montebello Rehabilitation Factor Score (MRFS). K-means cluster analysis (K=3) using both the MRFS and the gain of the FIM motor subscore (ΔFIM) was performed. Analysis of variance was used to determine the difference in FA among the clusters. Spearman analysis was conducted to examine the relation between FA, ΔFIM, and MRFS in each cluster. RESULTS: FA was significantly higher in the clusters of good and moderate recovery in the corticospinal tract (CST), peduncle, and posterior limb of the internal capsule bilaterally (all P<.05) compared with the poor recovery group. Significant positive correlations were observed in multiple regions along the CST between FA, ΔFIM, and MRFS in the clusters of good and moderate recovery, but not in the poor recovery group. CONCLUSIONS: Our results showed an association between FA values within the corticospinal tract and motor recovery in patients with stroke undergoing postacute rehabilitation. This finding may help to identify novel targets for new interventions to promote stroke recovery.
Assuntos
Imagem de Tensor de Difusão/métodos , Movimento/fisiologia , Tratos Piramidais/fisiopatologia , Recuperação de Função Fisiológica/fisiologia , Reabilitação do Acidente Vascular Cerebral/métodos , Idoso , Idoso de 80 Anos ou mais , Anisotropia , Biomarcadores , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Tratos Piramidais/diagnóstico por imagem , Centros de Reabilitação , Estudos RetrospectivosRESUMO
We used established databases in standard ways to systematically characterize gene ontologies, pathways and functional linkages in the large set of genes now associated with autism spectrum disorders (ASDs). These conditions are particularly challenging--they lack clear pathognomonic biological markers, they involve great heterogeneity across multiple levels (genes, systemic biological and brain characteristics, and nuances of behavioral manifestations)-and yet everyone with this diagnosis meets the same defining behavioral criteria. Using the human gene list from Simons Foundation Autism Research Initiative (SFARI) we performed gene set enrichment analysis with the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database, and then derived a pathway network from pathway-pathway functional interactions again in reference to KEGG. Through identifying the GO (Gene Ontology) groups in which SFARI genes were enriched, mapping the coherence between pathways and GO groups, and ranking the relative strengths of representation of pathway network components, we 1) identified 10 disease-associated and 30 function-associated pathways 2) revealed calcium signaling pathway and neuroactive ligand-receptor interaction as the most enriched, statistically significant pathways from the enrichment analysis, 3) showed calcium signaling pathways and MAPK signaling pathway to be interactive hubs with other pathways and also to be involved with pervasively present biological processes, 4) found convergent indications that the process "calcium-PRC (protein kinase C)-Ras-Raf-MAPK/ERK" is likely a major contributor to ASD pathophysiology, and 5) noted that perturbations associated with KEGG's category of environmental information processing were common. These findings support the idea that ASD-associated genes may contribute not only to core features of ASD themselves but also to vulnerability to other chronic and systemic problems potentially including cancer, metabolic conditions and heart diseases. ASDs may thus arise, or emerge, from underlying vulnerabilities related to pleiotropic genes associated with pervasively important molecular mechanisms, vulnerability to environmental input and multiple systemic co-morbidities.