Alzheimer's drugs, APPlication for Down syndrome?

Accumulation of the amyloid ß (Aß) peptide, derived from Aß precursor protein (APP), is a trait of Down syndrome (DS), as is early development of dementia that resembles Alzheimer's disease (AD). Treatments for this AD in DS simply do not. New drug therapies for AD, e.g., Lecanemab, are monoclonal antibodies designed to clear amyloid plaques composed of Aß. The increasingly real ability to target and dispose of Aß favors the use of these drugs in individuals with AD in DS, and, perhaps as earlier intervention for cognitive impairment. We present pertinent similarities between DS and AD in adult DS subjects, discuss challenges to target APP metabolites, and suggest that recently developed antibody treatments against Aß may be worth investigating to treat AD in DS.

APPlications of amyloid-ß precursor protein metabolites in macrocephaly and autism spectrum disorder.

Metabolites of the Amyloid-ß precursor protein (APP) proteolysis may underlie brain overgrowth in Autism Spectrum Disorder (ASD). We have found elevated APP metabolites (total APP, secreted (s) APPα, and α-secretase adamalysins in the plasma and brain tissue of children with ASD). In this review, we highlight several lines of evidence supporting APP metabolites' potential contribution to macrocephaly in ASD. First, APP appears early in corticogenesis, placing APP in a prime position to accelerate growth in neurons and glia. APP metabolites are upregulated in neuroinflammation, another potential contributor to excessive brain growth in ASD. APP metabolites appear to directly affect translational signaling pathways, which have been linked to single gene forms of syndromic ASD (Fragile X Syndrome, PTEN, Tuberous Sclerosis Complex). Finally, APP metabolites, and microRNA, which regulates APP expression, may contribute to ASD brain overgrowth, particularly increased white matter, through ERK receptor activation on the PI3K/Akt/mTOR/Rho GTPase pathway, favoring myelination.

Neurodevelopmental disorders and microcephaly: how apoptosis, the cell cycle, tau and amyloid-ß precursor protein APPly.

Recent studies promote new interest in the intersectionality between autism spectrum disorder (ASD) and Alzheimer's Disease. We have reported high levels of Amyloid-ß Precursor Protein (APP) and secreted APP-alpha (sAPPa) and low levels of amyloid-beta (Aß) peptides 1-40 and 1-42 (Aß40, Aß42) in plasma and brain tissue from children with ASD. A higher incidence of microcephaly (head circumference less than the 3rd percentile) associates with ASD compared to head size in individuals with typical development. The role of Aß peptides as contributors to acquired microcephaly in ASD is proposed. Aß may lead to microcephaly via disruption of neurogenesis, elongation of the G1/S cell cycle, and arrested cell cycle promoting apoptosis. As the APP gene exists on Chromosome 21, excess Aß peptides occur in Trisomy 21-T21 (Down's Syndrome). Microcephaly and some forms of ASD associate with T21, and therefore potential mechanisms underlying these associations will be examined in this review. Aß peptides' role in other neurodevelopmental disorders that feature ASD and acquired microcephaly are reviewed, including dup 15q11.2-q13, Angelman and Rett syndrome.

Early cognitive and behavioral problems in children with nodular heterotopia.

Adults with periventricular nodular heterotopia (PNH) have epilepsy and dyslexia, but most have normal intelligence. It is not known whether PNH-related reading difficulty can be detected earlier in childhood or whether associated behavioral problems are present. We studied 10 children with PNH, 3 of whom did not have seizures, and 10 matched controls with neuropsychological testing and parental rating instruments at two time points separated by about 1 year. Children with PNH performed significantly worse than controls on a task related to reading fluency. In addition, those with PNH showed significantly worse adaptive skills, and a measure of conduct problems significantly worsened over time. Mood and behavioral problems were reported more commonly, though not significantly so, in children with PNH. These findings demonstrate that reading dysfluency can be evident in children with nodular heterotopia, even in the absence of epilepsy, but also highlight difficulties with behavior in this population.

Longitudinal MRI brain findings in the R1349Q pathogenic variant of CACNA1A.

Pathogenic CACNA1A gene variants are associated with a spectrum of disorders including migraine with or without hemiplegia, ataxia, epilepsy, and developmental disability. We present a case of a pathogenic variant (c.4046G>A, p.R1349Q) in the CACNA1A gene associated with a clinical phenotype of global developmental delay, left hemiparesis, epilepsy, and stroke-like episodes. Longitudinal neuroimaging demonstrates hemispheric encephalomalacia with mismatched perfusion and angiographic imaging, in addition to progressive cerebellar atrophy.

FMRP Regulates the Nuclear Export of Adam9 and Psen1 mRNAs: Secondary Analysis of an N6-Methyladenosine Dataset.

Fragile X mental retardation protein (FMRP) binds to and regulates the translation of amyloid-ß protein precursor (App) mRNA, but the detailed mechanism remains to be determined. Differential methylation of App mRNA could underlie FMRP binding, message localization and translation efficiency. We sought to determine the role of FMRP and N6-methyladeonsine (m6A) on nuclear export of App mRNA. We utilized the m6A dataset by Hsu and colleagues to identify m6A sites in App mRNA and to determine if the abundance of message in the cytoplasm relative to the nucleus is altered in Fmr1 knockout mouse brain cortex. Given that processing of APP to Aß and soluble APP alpha (sAPPα) contributes to disease phenotypes, we also investigated whether Fmr1KO associates with nuclear export of the mRNAs for APP protein processing enzymes, including ß-site amyloid cleaving enzyme (Bace1), A disintegrin and metalloproteinases (Adams), and presenilins (Psen). Fmr1KO did not alter the nuclear/cytoplasmic abundance of App mRNA. Of 36 validated FMRP targets, 35 messages contained m6A peaks but only Agap2 mRNA was selectively enriched in Fmr1KO nucleus. The abundance of the APP processing enzymes Adam9 and Psen1 mRNA, which code for a minor alpha-secretase and gamma-secretase, respectively, were selectively enriched in wild type cytoplasm.

Gene associated with seizures, autism, and hepatomegaly in an Amish girl.

A genetic defect causing autism and epilepsy involving the contactin associated protein-like 2 gene (CNTNAP2) has been discovered in a selected cohort of Amish children. These children were found to have focal seizures and autistic regression. Surgical biopsy of the anterior temporal lobe of two such children revealed cortical dysplasia and a single nucleotide polymorphism mutation of this gene. The present case is that of a related but geographically distant proband with a similar phenotype but a single-base-pair deletion in the CNTNAP2 gene. This patient exhibited the additional features of periventricular leukomalacia and hepatomegaly.

Novel Contribution of Secreted Amyloid-ß Precursor Protein to White Matter Brain Enlargement in Autism Spectrum Disorder.

The most replicated neuroanatomical finding in autism is the tendency toward brain overgrowth, especially in younger children. Research shows that both gray and white matter are enlarged. Proposed mechanisms underlying brain enlargement include abnormal inflammatory and neurotrophic signals that lead to excessive, aberrant dendritic connectivity via disrupted pruning and cell adhesion, and enlargement of white matter due to excessive gliogenesis and increased myelination. Amyloid-ß protein precursor (ßAPP) and its metabolites, more commonly associated with Alzheimer's disease (AD), are also dysregulated in autism plasma and brain tissue samples. This review highlights findings that demonstrate how one ßAPP metabolite, secreted APPα, and the ADAM family α-secretases, may lead to increased brain matter, with emphasis on increased white matter as seen in autism. sAPPα and the ADAM family α-secretases contribute to the anabolic, non-amyloidogenic pathway, which is in contrast to the amyloid (catabolic) pathway known to contribute to Alzheimer disease. The non-amyloidogenic pathway could produce brain enlargement via genetic mechanisms affecting mRNA translation and polygenic factors that converge on molecular pathways (mitogen-activated protein kinase/MAPK and mechanistic target of rapamycin/mTOR), promoting neuroinflammation. A novel mechanism linking the non-amyloidogenic pathway to white matter enlargement is proposed: α-secretase and/or sAPPα, activated by ERK receptor signaling activates P13K/AKt/mTOR and then Rho GTPases favoring myelination via oligodendrocyte progenitor cell (OPC) activation of cofilin. Applying known pathways in AD to autism should allow further understanding and provide options for new drug targets.

Anti-phospholipid antibodies in cerebrospinal fluid but not serum from a boy with psychosis.

A 12-year-old African American boy with mental retardation and Asperger's disorder presented with acute psychosis. Antiphospholipid antibody testing with enzyme-linked immunosorbent assay showed increased levels of immunoglobulin G anticardiolipin antibodies in the cerebrospinal fluid, but not in the serum. Although antiphospholipid antibodies have been reported in the serum of patients with thrombotic and neurologic disorders, there are only a few reports of these antibodies in cerebrospinal fluid. This finding is consistent with a recent report of antiphospholipid antibodies found in the cerebrospinal fluid of adults with acute psychosis.

Absolute pitch in a four-year-old boy with autism.

Absolute pitch is the ability to identify the pitch of an isolated tone. We report on a 4-year-old boy with autism and absolute pitch, one of the youngest reported in the literature. Absolute pitch is thought to be attributable to a single gene, transmitted in an autosomal-dominant fashion. The association of absolute pitch with autism raises the speculation that this talent could be linked to a genetically distinct subset of children with autism. Further, the identification of absolute pitch in even young children with autism may lead to a lifelong skill.

Neuropsychologic outcomes in a case series of twins discordant for perinatal stroke.

Perinatal stroke may affect cognitive development, but few studies have addressed the details of cognitive function after perinatal stroke. The present study was designed to compare the neuropsychologic features of five sets of twins discordant for perinatal stroke. All of the affected children had unilateral middle cerebral artery infarction (two left, three right); four of the five infarcts were large-branch, affecting the entire M1 territory. Three of the five affected children had comorbid epilepsy. Measures of intelligence, memory, language, attention, executive function, visual-motor integration, and fine motor skills were administered to children at a median age of 5 years (range, 5-8 years). Relative to their unaffected co-twins, the twins with perinatal stroke exhibited lower levels of full scale (p=0.005), verbal (p=0.006), and nonverbal (p=0.005) intelligence. Children with perinatal stroke also showed significant deficits on tests of verbal memory (p=0.041), receptive language (p=0.011), verbal fluency (p=0.019), and visual attention (p=0.011), compared with their unaffected co-twins. Twin gestation may be a risk factor for poor cognitive outcome after perinatal stroke. Large infarct size and comorbid epilepsy may have contributed to some of the poor cognitive outcomes in this cohort.

Antiphospholipid antibodies in blood and cerebrospinal fluids of patients with psychosis.

Antiphospholipid antibodies (aPL) have been reported in the cerebrospinal fluids (CSF) of neurology patients but no CSF studies with psychiatric patients exist. We tested serum from 100 hospitalized psychotic patients having hallucinations and/or delusions for aPL. Patients with positive serum aPL findings were asked to submit CSF for aPL testing. Five CSF samples had aPL specificities not found in the patient's serum suggesting the possibility of intrathecal synthesis. Specificity and isotype discordance between CSF and blood aPL in these psychiatric patients implicates a central nervous system independent autoimmune process that may have an underlying association with the pathophysiology of their diseases.

Lingual epilepsia partialis continua in a girl.

Epilepsia partialis continua (EPC) is characterized by focal seizures that cannot be stopped. The most common cause of EPC in children is Rasmussen's encephalitis. In this video case report, we describe an 11-year old female with continuous lingual EPC for two years. She has shown no signs of Rasmussen's Encephalitis or other neurodegenerative process and structural MRI is normal. [Published with video sequences].

False-positive metaiodobenzylguanidine scan for neuroblastoma in a child with opsoclonus-myoclonus syndrome treated with adrenocorticotropic hormone (acth).

We describe the case of a 2-year-old girl with opsoclonus-myoclonus syndrome treated with chronic adrenocorticotropic hormone (ACTH) in which a metaiodobenzylguanidine scan showed abnormal radiotracer uptake in the left adrenal gland region, interpreted as the site of an occult neuroblastoma. As this finding was not corroborated by previous or subsequent metaiodobenzylguanidine scans or by computed tomography (CT) or magnetic resonance imaging (MRI), we attribute the finding to being a false-positive result from adrenal hyperplasia owing to chronic use of ACTH and not to neuroblastoma. Metaiodobenzylguanidine scintigraphy is an extremely important nuclear medicine examination tool used for the evaluation and staging of pediatric neuroblastoma. We highlight the need for cautious interpretation of metaiodobenzylguanidine as a screening tool for neuroblastoma in patients treated with ACTH.

High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression.

Autism is characterized by restricted, repetitive behaviors and impairment in socialization and communication. Although no neuropathologic substrate underlying autism has been found, the findings of brain overgrowth via neuroimaging studies and increased levels of brain-derived neurotrophic factor (BDNF) in neuropathologic and blood studies favor an anabolic state. We examined acetylcholinesterase, plasma neuronal proteins, secreted beta-amyloid precursor protein (APP), and amyloid-beta 40 and amyloid-beta 42 peptides in children with and without autism. Children with severe autism and aggression expressed secreted beta-amyloid precursor protein at two or more times the levels of children without autism and up to four times more than children with mild autism. There was a trend for children with autism to show higher levels of secreted beta-amyloid precursor protein and nonamyloidogenic secreted beta-amyloid precursor protein and lower levels of amyloid-beta 40 compared with controls. This favors an increased alpha-secretase pathway in autism (anabolic), opposite to what is seen in Alzheimer disease. Additionally, a complex relationship between age, acetylcholinesterase, and plasma neuronal markers was found.

Finding novel distinctions between the sAPPα-mediated anabolic biochemical pathways in Autism Spectrum Disorder and Fragile X Syndrome plasma and brain tissue.

UNLABELLED: Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are developmental disorders. No validated blood-based biomarkers exist for either, which impedes bench-to-bedside approaches. Amyloid-ß (Aß) precursor protein (APP) and metabolites are usually associated with Alzheimer's disease (AD). APP cleavage by α-secretase produces potentially neurotrophic secreted APPα (sAPPα) and the P3 peptide fragment. ß-site APP cleaving enzyme (BACE1) cleavage produces secreted APPß (sAPPß) and intact Aß. Excess Aß is potentially neurotoxic and can lead to atrophy of brain regions such as amygdala in AD. By contrast, amygdala is enlarged in ASD but not FXS. We previously reported elevated levels of sAPPα in ASD and FXS vs. CONTROLS: We now report elevated plasma Aß and total APP levels in FXS compared to both ASD and typically developing controls, and elevated levels of sAPPα in ASD and FXS vs. CONTROLS: By contrast, plasma and brain sAPPß and Aß were lower in ASD vs. controls but elevated in FXS plasma vs. CONTROLS: We also detected age-dependent increase in an α-secretase in ASD brains. We report a novel mechanistic difference in APP pathways between ASD (processing) and FXS (expression) leading to distinct APP metabolite profiles in these two disorders. These novel, distinctive biochemical differences between ASD and FXS pave the way for blood-based biomarkers for ASD and FXS.

Neuroimaging in autistic spectrum disorder (ASD).

Autistic spectrum disorder (ASD) is a lifelong developmental disorder characterized by impairment in socialization and communication. Neuroimaging research has shown abnormalities in the frontal lobes, limbic systems, and cerebella of individuals with ASD. Recently, abnormal developmental trajectories of brain growth have been reported, with increases in brain volume (in both gray and white matter) seen in younger rather than older individuals with this disorder. Despite 30 years of research, a reliable marker for ASD has not been identified. Therefore, routine neuroimaging for individuals with ASD is not recommended.

Hydrogen proton magnetic resonance spectroscopy in autism: preliminary evidence of elevated choline/creatine ratio.

Hydrogen proton magnetic resonance spectroscopy is only beginning to be studied in autistic individuals. We report an association between hydrogen proton magnetic resonance spectroscopy choline/creatine ratios and severity of autism as measured by the Children's Autistic Rating Scale (Pearson r = .657, P = .04) in 10 autistic children. Hydrogen proton magnetic resonance spectroscopy choline/creatine ratio measures the concentration of cytosolic choline including free choline used in the synthesis of acetylcholine. Elevation in this ratio has been interpreted as a result of membrane degradation such as caused by a tumor or, alternatively, as a result of choline synthesis associated with increased cellular proliferation. Recent neuropathologic evidence has implicated disruption of acetylcholine transmission in the brains of autistic adults. A case-controlled study of hydrogen proton magnetic resonance spectroscopy choline/creatine ratios is warranted.