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Importance: Anti-β-amyloid immunotherapy using lecanemab is becoming increasingly available to patients with Alzheimer disease (AD). Individuals with Down syndrome (DS) develop AD neuropathology by age 40 years, representing a significant cohort of genetically determined AD., Objective: To investigate the binding properties of lecanemab in the brains of people with DS, in anticipation of their inclusion in clinical trials or access to antiamyloid immunotherapies., Design, Setting, Participants: The study included cases of postmortem brain tissue analysis from 15 individuals with DS aged 43 to 68 years that were acquired from Alzheimer Disease research centers at the University of California, Irvine and the University of Kentucky from 2008 to 2021. Data were analyzed from August 2023 through May 2024., Exposure: The binding properties of lecanemab were assessed in brain tissue., Main Outcome: The primary outcome was the extent of lecanemab binding to amyloid plaques and brain blood vessels., Results: Tissue from 15 people (8 were female [53%]) with DS ranging in age from 43 to 68 (mean, 56.6) years were included in the study. Lecanemab-labeled amyloid plaques appeared in all 15 DS cases studied, indicating potential target engagement. However, extensive binding of lecanemab to brain blood vessels in DS was observed, raising significant safety concerns. These findings underscore the necessity for clinical trials of lecanemab in people with DS to evaluate both safety and efficacy, particularly in individuals older than 43 years., Conclusions and Relevance: These findings suggest significant binding of lecanemab to cerebral amyloid angiopathy in DS. Lecanemab should be rigorously tested in clinical trials for AD in the DS population to determine its safety and efficacy, especially in those older than 43 years.

Background: Down syndrome (DS) is associated with increased risk for Alzheimer's disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS., Objective: Does lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS?, Methods: Resting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38-61 years)., Results: Lower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity., Conclusion: Reduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion.

Down syndrome (DS) is a common intellectual disability, with an incidence of 1 in 700 and is caused by trisomy 21. People with DS develop Alzheimer's disease (AD)-like neuropathology by the age of 40. As metal ion dyshomeostasis (particularly zinc, iron and copper) is one of the characteristics of AD and is believed to be involved in the pathogenesis of disease, we reasoned that it may also be altered in DS. Thus, we used inductively coupled plasma mass spectrometry to examine metal levels in post-mortem brain tissue from DS individuals with concomitant AD pathology. Size exclusion-ICPMS was also utilised to characterise the metalloproteome in these cases. We report here for the first time that iron levels were higher in a number of regions in the DS brain, including the hippocampus (40%), frontal cortex (100%) and temporal cortex (34%), compared to controls. Zinc and copper were also elevated (both 29%) in the DS frontal cortex, but zinc was decreased (23%) in the DS temporal cortex. Other elements were also examined, a number of which also showed disease-specific changes. The metalloproteomic profile in the DS brain was also different to that in the controls. These data suggest that metals and metal:protein interactions are dysregulated in the DS brain which, given the known role of metals in neurodegeneration and AD, is likely to contribute to the pathogenesis of disease. Interrogation of the underlying cellular mechanisms and consequences of this failure in metal ion homeostasis, and the specific contributions of the individual DS and AD phenotypes to these changes, should be explored.

Down syndrome (DS) results in an overproduction of amyloid-β (Aβ) peptide associated with early onset of Alzheimer's disease (AD). DS cases have Aβ deposits detectable histologically as young as 12-30 years of age, primarily in the form of diffuse plaques, the type of early amyloid pathology also seen at pre-clinical (i.e., pathological aging) and prodromal stages of sporadic late onset AD. In DS subjects aged >40 years, levels of cortical Aβ deposition are similar to those observed in late onset AD and in addition to diffuse plaques involve cored plaques associated with dystrophic neurites (neuritic plaques), which are of neuropathological diagnostic significance in AD. The purpose of this review is to summarize and discuss findings from amyloid PET imaging studies of DS in reference to postmortem amyloid-based neuropathology. PET neuroimaging applied to subjects with DS has the potential to (a) track the natural progression of brain pathology, including the earliest stages of amyloid accumulation, and (b) determine whether amyloid PET biomarkers predict the onset of dementia. In addition, the question that is still incompletely understood and relevant to both applications is the ability of amyloid PET to detect Aβ deposits in their earliest form., (© 2019 Wiley Periodicals, Inc.)

Adults with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by 40 years of age. Synaptophysin (SYN) consistently declines with age and is further reduced with sporadic AD. Thus, we hypothesized that SYN would be reduced in DS with AD. The gene for synaptojanin-1 (SYNJ1), involved in synaptic vesicle recycling, is on chromosome 21. We measured SYN and SYNJ1 in an autopsy series of 39 cases with DS and 28 without DS, along with 7 sporadic AD cases. SYN was significantly lower in DSAD compared with DS alone and similar to sporadic AD. Reduced SYN is associated with AD neuropathology and with Aβ levels in DS, as is seen in sporadic AD. SYNJ1 was significantly higher in DS and correlated with several measures of Aβ. SYNJ1 was higher in DSAD and significantly higher than SYNJ1 in sporadic AD. Although significantly higher in DS, SYNJ1 is further increased with AD neuropathology suggesting interesting differences in a synapse-associated protein that is overexpressed in trisomy 21.

This chapter reviews the neurological phenotype of Down syndrome (DS) in early development, childhood, and aging. Neuroanatomic abnormalities in DS are manifested as aberrations in gross brain structure as well as characteristic microdysgenetic changes. As the result of these morphological abnormalities, brain circuitry is impaired. While an intellectual disability is ubiquitous in DS, there is a wide range of variation in cognitive performance and a growing understanding between aberrant brain circuitry and the cognitive phenotype. Hypotonia is most marked at birth, affecting gait and ligamentous laxity. Seizures are bimodal in presentation with infantile spasms common in infancy and generalized seizures associated with cognitive decline observed in later years. While all individuals have the characteristic neuropathology of Alzheimer's disease (AD) by age 40 years, the prevalence of dementia is not universal. The tendency to develop AD is related, in part, to several genes on chromosome 21 that are overexpressed in DS. Intraneuronal accumulation of β-amyloid appears to trigger a cascade of neurodegeneration resulting in the neuropathological and clinical manifestations of dementia. Functional brain imaging has elucidated the temporal sequence of amyloid deposition and glucose metabolic rate in the development of dementia in DS. Mitochondrial abnormalities contribute to oxidative stress which is part of AD pathogenesis in DS as well as AD in the general population. A variety of medical comorbidities threaten cognitive performance including sleep apnea, abnormalities in thyroid metabolism, and behavioral disturbances. Mouse models for DS are providing a platform for the formulation of clinical trials with intervention targeted to synaptic plasticity, brain biochemistry, and morphological brain alterations., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alpha-secretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Abeta) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Abeta degradation and clearance.

Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology progressively with age but clinical signs of dementia are delayed by at least 10 years after the first signs of disease. Some individuals with DS do not develop dementia despite extensive AD neuropathology. Given the discordance between clinical decline and AD neuropathology, compensatory events may be of particular relevance for this group. Imaging studies using PET suggest compensatory increases in metabolic rate in vulnerable brain regions in DS prior to the development of dementia. Neurobiological studies of similarly aged DS autopsy cases provide further evidence of activation of plasticity mechanisms. Genes that are overexpressed in DS (APP, DSCAM, MNB/DYRK1A, and RCAN1) produce proteins critical for neuron and synapse growth, development and maintenance. We present the hypothesis that these genes may lead to developmental cognitive deficits but paradoxically with aging, may participate in molecular cascades supporting neuronal compensation. Enhancing or supporting compensatory mechanisms in aging individuals with DS may be beneficial as suggested by intervention studies in animal models. In combination, adults with DS may be a unique group of individuals well-suited for studies involving the manipulation or upregulation of compensatory responses as an approach to promote successful brain aging in the general population.

The processes involved with beta-amyloid (Abeta) degradation and clearance in human brain are not well understood. We hypothesized that the distribution of oxidatively modified Abeta, as determined by an affinity-purified antibody in the entorhinal and frontal cortices of Alzheimer's disease (AD), Down syndrome (DS), nondemented elderly control cases, and canine brain, would provide insight into the mechanisms of Abeta accumulation. Based upon plaque counts, oxidized Abeta was present within 46-48% of diffuse and primitive plaques and 98% of cored plaques. Dense punctate deposits of oxidized Abeta were distributed throughout the neuropil in AD and DS brains but were also present within controls with mild neuropathology and isolated cognitive impairments. Confocal studies indicate that punctate oxidized Abeta deposits were within activated microglia. Oxidatively modified Abeta may reflect the efforts of microglial cells to take up and degrade Abeta. Oxidative modification of Abeta may be an early event in Abeta pathogenesis and may be important for plaque biogenesis., (Copyright 2001 Academic Press.)

To study the link between beta-amyloid (Abeta) and neuroinflammation, we examined the levels of complement as a function of age and extent of Abeta deposition in Down Syndrome (DS) brain. C1q, the first component of the complement cascade, was visualized using immunohistochemistry in the frontal, entorhinal cortex, and hippocampus of 12 DS ranging from 31 to 69 years of age. C1q was consistently associated with thioflavine-S positive Abeta plaques in DS brain and increased with more extensive age-dependent Abeta deposition. In contrast, little or no C1q labeling was associated with diffuse or thioflavine-S negative Abeta deposits. Neurons in the hippocampus and entorhinal cortex, but less frequently in frontal cortex, were C1q positive in DS cases with sufficient neuropathology to have a diagnosis of Alzheimer's disease. C1q-positive neurons were associated with activated microglia. These results provide evidence for Abeta-mediated inflammatory factors contributing to the rapid accumulation of neuropathology in DS brain., (Copyright 2001 Academic Press.)

beta-Amyloid (Abeta) is a constituent of senile plaques found with increasing age in individuals with Down syndrome (DS) and in the canine model of aging. Sections of DS and dog brain were immunostained using an affinity-purified polyclonal antibody for a posttranslationally modified Abeta with a racemized aspartate at position 7 (d7C16). The immunostaining characteristics of d7C16 Abeta in DS and dog brain indicate that it is present in all plaque subtypes, including the thioflavin-S-negative diffuse plaques that develop with age in dogs. The youngest DS case exhibited weak immunolabeling for d7C16 but the extent of d7C16-positive plaques increased with age. In addition, d7C16-positive plaques were initially found in clusters in the superficial layers of the frontal and entorhinal cortex but, with advancing age, increasing numbers appeared in deeper layers, suggesting a progression of Abeta deposition from superficial to deeper cortical layers. Ultrastructural studies in DS brain were confirmed using perfused dog brain and provided consistent results; thioflavin-S-negative diffuse plaques consist of fibrillar Abeta and racemized Abeta is associated with thicker and more highly interwoven fibrils than nonracemized Abeta. The use of antibodies to modified forms of the Abeta protein should provide insight into the progression of plaque pathology in DS and Alzheimer's disease brain., (Copyright 2000 Academic Press.)

MRI studies to date have confirmed and expanded upon findings of morphologic differences between the brains of subjects with DS and those of the general population found by CT and post-mortem examination. [table; see text] Hippocam pal and neocortical structures are smaller in DS while unexpectedly the parahippocampal gyrus was found to be larger. MRI has demonstrated that subjects with DS develop signs associated with [table; see text] brain aging at an earlier age. These findings include increased rate of dilatation of ventricles, increased peripheral atrophy, and increased deep white matter lesions. In addition, changes that are associated with AD occur earlier in the DS population. Functional studies reveal decreasing cerebral perfusion with age in adults with DS, a pattern similar to non-DS subjects with clinically progressive dementia, and provide evidence for altered blood-brain barrier permeability. Dynamic MRI studies have also shown adults with DS to have fluctuating cortical CSF volumes, similar to some elderly non-DS subjects and subjects with shunted hydrocephalus. This is a new finding in brain aging that suggests a relationship between aging in DS and edematous states of the brain.

A 13.5-year-old boy with biotinidase deficiency was studied 8 days before and 5 months after biotin treatment by positron emission tomography (PET) and computerized electroencephalographic topography (CET). With biotin treatment there was a marked improvement in the presenting symptom of loss of visual acuity and a more modest recovery in spastic quadraparesis. By PET scanning, the relative metabolic rate for glucose was more than 2 standard deviations lower in the temporal and occipital cortices than in adult or age-matched controls. With biotin treatment, these values rose to normal limits for both control groups. By CET, normalized EEG equivalent to the relative glucose metabolic rate showed asymmetric slowing in the left temporal and frontal regions before treatment, whereas none of the 32 leads exceeded normal limits of delta, theta, alpha or beta after treatment. These results suggest a strong correlation between clinical, metabolic and electrical measures of brain function as related to biotin treatment in biotinidase deficiency.

The contribution of the cerebral cortex to the generation of sensory evoked potentials was studied in an infant with hydranencephaly. On CT scan no tissue above the thalamus was noted. Long-latency potentials to auditory stimuli were absent whereas the short-latency or brain-stem auditory evoked potentials and some of the components of the middle latency auditory evoked potentials (No and Po) were present. To visual stimulation only the electroretinogram was detected. To somatosensory stimulation only the spinal cord potentials could be detected. The absence of long-latency components in each of the sensory modalities supports the concept that these potentials require intact cerebral hemispheres in man.

Two infants with the cerebro-hepato-renal syndrome (Zellweger's disease) exhibited cholestasis and progressive liver damage. Because abnormalities of mitochondrial structure and function have been reported in this condition, we examined the bile acids for evidence of defects in the mitochondrial phase of bile acid synthesis, namely, oxidation of the cholesterol side chain to form C-24 bile acids. The presence of increased amounts of the C-27 bile acid intermediates (trihydroxycoprostanic acid, varanic acid, and dihydroxycoprostanic acid) were noted and identified by gas-liquid chromatography-mass spectrosocopy confirming that a defect in the mitochondrial pathways for bile acid side chain cleavage is involved in this entity. The clinical course, liver histopathology, and hepatocyte ultrastructural abnormalities suggest that these bile acids may reflect an underlying mitochondrial dysfunction in this disease and possibly may contribute to the progressive hepatic lobular fibrosis observed in these patients.

A 13 1/2-year-old child died with vitamin B6-dependent seizures in progress. Microscopic findings in brain included an abnormally sparse quantity of central myelinated fibers in the cerebral hemispheres. Glutamic acid concentrations were elevated and GABA concentrations reduced in the frontal and occipital cortices but not in the spinal cord. All other amino acid concentrations were normal, except for increased cystathionine in the occipital cortex. Pyridoxal-5-phosphate (PLP) was reduced in the frontal cortex. Glutamic acid decarboxylase activity comparable to that of controls was detected when the PLP concentration was greater than 0.05 mM. These findings suggest that pyridoxine-dependent seizures in man are associated with reduced GABA concentrations in the brain and with diminished central white matter structures.

The principal neuropathologic abnormality observed in three autopsy cases of Menkes steely hair syndrome was widespread nerve cell loss and gliosis, especially severe in the cerebral and cerebellar cortex and in the relay nuclei of the thalamus. Granular stellate cells of neocortical layer IV and the granule cells of the cerebellum are cell classes which were particularly severely depopulated. The degree of reduction of myelinated axons is consistent with axonal degeneration secondary to nerve cell loss. There are also prominent abnormalities in the patterns of dendritic arborization of surviving cortical pyramids and cerebellar Purkinje cells as seen in Golgi impregnations. The deviant neuronal forms are probably due, in part, to failure of innervation by afferent fiber systems during the fetal as well as postnatal epochs.

A cerebral biopsy specimen from a 4-year-old girl with a moderately advanced stage of the late infantile form of neuronal ceroid-lipofuscinosis was observed in routine cell and fiber stains and in Golgi and electronmicroscopic preparations. There was no evidence of neuronal degeneration or loss. Golgi impregnations identified a fusiform enlargement of proximal axon segments of most pyramidal neurons and some polymorphic neurons but not of other cortical neuronal classes. Typical curvilinear inclusions were found in all cells and appeared to be impacted within the dilated proximal axon segments of pyramidal neurons. The numbers of type II synapses on the axon hillock and dilated proximal axon segments of pyramidal neurons were much reduced, whereas type I synapses remained abundant in the neuropil.