2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and Down-Syndrome

Down syndrome (DS) predisposes individuals to early Alzheimer's disease (AD). Using Pittsburgh Compound B ([

Topics: Adult; Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Cohort Studies; Down Syndrome; Female; Frontal Lobe; Heterozygote; Humans; Longitudinal Studies; Male; Middle Aged; Parietal Lobe; Thiazoles; Time Factors; Ventral Striatum

Down's syndrome is a chromosomal disorder that invariably results in both intellectual disability and Alzheimer's disease neuropathology. However, only a limited number of studies to date have investigated intrinsic brain network organisation in people with Down's syndrome, none of which addressed the links between functional connectivity and Alzheimer's disease. In this cross-sectional study, we employed

Topics: Adult; Alzheimer Disease; Amyloid; Aniline Compounds; Carbon Radioisotopes; Cerebral Cortex; Connectome; Cross-Sectional Studies; Down Syndrome; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Beta-amyloid (Aβ) deposition in brain accumulates as a function of age in people with Down syndrome (DS) with subsequent development into Alzheimer disease neuropathology, typically by 40 years of age. In vivo imaging using the Pittsburgh compound B (PiB) ligand has facilitated studies linking Aβ, cognition, and dementia in DS. However, there are no studies of PiB binding across the lifespan in DS. The current study describes in vitro

Topics: Adolescent; Adult; Aged; Aging; Amyloid beta-Peptides; Aniline Compounds; Autopsy; Cerebral Amyloid Angiopathy; Child; Child, Preschool; Cognition; Down Syndrome; Female; Frontal Lobe; Humans; Infant; Ligands; Male; Middle Aged; Positron-Emission Tomography; Protein Binding; Thiazoles; Young Adult

Adults with Down syndrome (DS) have a high incidence of Alzheimer's disease (AD), providing a unique opportunity to explore the early, preclinical stages of AD neuropathology. We examined change in brain amyloid-β accumulation via the positron emission tomography tracer [11C] Pittsburgh compound B (PiB) across 2 data collection cycles, spaced 3 years apart, and decline in cognitive functioning in 58 adults with DS without clinical AD. PiB retention increased in the anterior cingulate gyrus, precuneus cortex, parietal cortex, and anterior ventral striatum. Across the 2 cycles, 14 (27.5%) participants were consistently PiB+, 31 (60.8%) were consistently PiB-, and 6 (11.7%) converted from PiB- at cycle 1 to PiB+ at cycle 2. Increased global amyloid-β was related to decline in verbal episodic memory, visual episodic memory, executive functioning, and fine motor processing speed. Participants who were consistently PiB+ demonstrated worsening of episodic memory, whereas participants who were consistently PiB- evidenced stable or improved performance. Amyloid-β accumulation may be a contributor to or biomarker of declining cognitive functioning in preclinical AD in DS.

Topics: Adult; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition; Cognitive Dysfunction; Down Syndrome; Executive Function; Female; Humans; Male; Memory, Episodic; Middle Aged; Phenanthrolines; Positron-Emission Tomography; Thiazoles; Time Factors

People with Down syndrome (DS) have a neurodevelopmentally distinct brain and invariably developed amyloid neuropathology by age 50. This cross-sectional study aimed to provide a detailed account of DS brain morphology and the changes occuring with amyloid neuropathology. Forty-six adults with DS underwent structural and amyloid imaging-the latter using Pittsburgh compound B (PIB) to stratify the cohort into PIB-positive (n = 19) and PIB-negative (n = 27). Age-matched controls (n = 30) underwent structural imaging. Group differences in deep gray matter volumetry and cortical thickness were studied. PIB-negative people with DS have neurodevelopmentally atypical brain, characterized by disproportionately thicker frontal and occipitoparietal cortex and thinner motor cortex and temporal pole with larger putamina and smaller hippocampi than controls. In the presence of amyloid neuropathology, the DS brains demonstrated a strikingly similar pattern of posterior dominant cortical thinning and subcortical atrophy in the hippocampus, thalamus, and striatum, to that observed in non-DS Alzheimer's disease. Care must be taken to avoid underestimating amyloid-associated morphologic changes in DS due to disproportionate size of some subcortical structures and thickness of the cortex.

Topics: Adult; Aged; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Aniline Compounds; Brain Diseases, Metabolic; Cerebral Cortex; Cross-Sectional Studies; Down Syndrome; Female; Gray Matter; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Thiazoles

In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer-like neuropathology.. PET imaging with carbon 11-labeled Pittsburgh compound B examined the pattern of amyloid-β deposition in 68 nondemented adults with DS (30-53 years) to determine the relationship between deposition and normal aging. Standard uptake value ratio (SUVR) images were created with cerebellar gray matter as the reference region.. Multiple linear regression revealed slight but highly significant (corrected P < .05) positive correlations between SUVR and age. The striatum showed the strongest correlation, followed by precuneus, parietal cortex, anterior cingulate, frontal cortex, and temporal cortex.. There is an age-related amyloid-β deposition in the DS population, but as a pattern of elevated cortical retention becomes apparent, the correlation of SUVR with age ceases to be significant. Factors unrelated to aging may drive an increase in deposition during early Alzheimer's disease pathogenesis.

Topics: Adult; Aging; Aniline Compounds; Apolipoproteins E; Brain; Carbon Radioisotopes; Cohort Studies; Down Syndrome; Female; Humans; Linear Models; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Nearly all adults with Down syndrome show neuropathology of Alzheimer's disease, including amyloid-β deposition, by their fifth decade of life. In the current study, we examined the association between brain amyloid-β deposition, assessed via in vivo assessments of neocortical Pittsburgh compound B, and scores on an extensive neuropsychological battery of measures of cognitive functioning in 63 adults (31 male, 32 female) with Down syndrome aged 30-53 years who did not exhibit symptoms of dementia. Twenty-two of the adults with Down syndrome were identified as having elevated neocortical Pittsburgh compound B retention levels. There was a significant positive correlation (r = 0.62, P < 0.0001) between age and neocortical Pittsburgh compound B retention. This robust association makes it difficult to discriminate normative age-related decline in cognitive functioning from any potential effects of amyloid-β deposition. When controlling for chronological age in addition to mental age, there were no significant differences between the adults with Down syndrome who had elevated neocortical Pittsburgh compound B retention levels and those who did not on any of the neuropsychological measures. Similarly, when examining Pittsburgh compound B as a continuous variable, after controlling for mental age and chronological age, only the Rivermead Picture Recognition score was significantly negatively associated with neocortical Pittsburgh compound B retention. Our findings indicate that many adults with Down syndrome can tolerate amyloid-β deposition without deleterious effects on cognitive functioning. However, we may have obscured true effects of amyloid-β deposition by controlling for chronological age in our analyses. Moreover, our sample included adults with Down syndrome who were most 'resistant' to the effects of amyloid-β deposition, as adults already exhibiting clinical symptoms of dementia symptoms were excluded from the study.

Topics: Adult; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition Disorders; Down Syndrome; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neocortex; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

The positron emission tomography (PET) ligand (11) C-labeled Pittsburgh compound B (PIB) is used to image β-amyloid (Aβ) deposits in the brains of living subjects with the intent of detecting early stages of Alzheimer's disease (AD). However, deposits of human-sequence Aβ in amyloid precursor protein transgenic mice and non-human primates bind very little PIB. The high stoichiometry of PIB:Aβ binding in human AD suggests that the PIB-binding site may represent a particularly pathogenic entity and/or report local pathologic conditions. In this study, (3) H-PIB was employed to track purification of the PIB-binding site in > 90% yield from frontal cortical tissue of autopsy-diagnosed AD subjects. The purified PIB-binding site comprises a distinct, highly insoluble subfraction of the Aβ in AD brain with low buoyant density because of the sodium dodecyl sulfate-resistant association with a limited subset of brain proteins and lipids with physical properties similar to lipid rafts and to a ganglioside:Aβ complex in AD and Down syndrome brain. Both the protein and lipid components are required for PIB binding. Elucidation of human-specific biological components and pathways will be important in guiding improvement of the animal models for AD and in identifying new potential therapeutic avenues. A lipid-associated subpopulation of Aβ accounts for the high-affinity binding of Pittsburgh compound B (PIB) in Alzheimer's disease brain. Mass spectrometry of the isolated PIB-binding site from frontal cortex identified Aβ peptides and a set of plaque-associated proteins in AD but not age-matched normal brain. The PIB-binding site may represent a particularly pathogenic entity and/or report local pathologic conditions.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Binding Sites; Brain Chemistry; Down Syndrome; Female; Frontal Lobe; Humans; In Vitro Techniques; Lipid Metabolism; Male; Proteomics; Thiazoles

Down syndrome (DS) is one of the most common causes of intellectual disability. Although DS accounts for only 15% of all individuals with intellectual disabilities, adults with DS account for approximately 60% of individuals with intellectual disabilities and Alzheimer's disease. This is thought to be because of overproduction of the β-amyloid (Aβ) protein due to trisomy for the Aβ precursor protein gene on chromosome 21. Pittsburgh compound B (PiB) is a noninvasive in vivo positron emission tomography tracer used to image amyloid deposition in living humans. Studies using PiB have shown an age-dependent asymptomatic amyloid deposition in more than 20% of the cognitively normal elderly population. Presymptomatic carriers of presenilin (PS-1) and Aβ precursor protein gene mutations who are destined to develop Alzheimer's disease also show preclinical amyloid deposition. This report describes a pilot study involving the use of PiB in seven adults with DS (age: 20-44 years). Compared with objective cutoffs for amyloid positivity in older non-DS cognitively normal control subjects, only two of the seven DS subjects (age: 38 and 44 years) showed increased PiB retention. The remaining five subjects aged between 20 and 35 years showed no detectable increase in PiB retention. Interestingly, the two subjects who showed elevated PiB retention showed a striatal-predominant pattern similar to that previously reported for PS-1 mutation carriers. These results demonstrate the feasibility of conducting PiB positron emission tomography scanning in this special population, and suggest a link between Aβ overproduction and early striatal deposition of fibrillar Aβ.

Topics: Adult; Amyloidogenic Proteins; Aniline Compounds; Brain; Down Syndrome; Female; Humans; Male; Neuroimaging; Pilot Projects; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles; Young Adult

To investigate the safety, acceptability, and feasibility of positron emission tomography (PET) using carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) to measure cerebral β-amyloid in adults with Down syndrome (DS) and to explore if the technique differentiates between participants with and without Alzheimer disease (AD).. Proof-of-principle case-controlled study of a nonrandomly selected cohort of participants with DS (with or without AD) compared within group and with healthy controls without DS. All had dynamic [(11)C]PiB PET and magnetic resonance imaging. Carbon 11-labeled PiB binding in the regions of interest associated with AD was quantitatively analyzed.. Wolfson Brain Imaging Centre, Cambridge, England.. Nine with DS (aged 25-64 years), of whom 5 had a diagnosis of AD, and 14 healthy controls without DS (aged 33-69 years).. Positive [(11)C]PiB binding in regions of interest.. The scanning process was feasible and acceptable with no adverse events or safety concerns. Maps and regional values of nondisplaceable binding potential were produced using the reference tissue-input Logan plot, with the cerebellum used as the reference tissue. When compared with the healthy control group without DS, only participants with DS older than 45 years had significant [(11)C]PiB binding in regions of interest usually associated with AD, whether or not they had clinical evidence of dementia.. Dynamic [(11)C]PiB PET can be used successfully to measure cerebral β-amyloid deposition in DS. A clinical diagnosis of AD and age appear to be predictors of [(11)C]PiB binding in regions of interest, but given the small numbers, we cannot generalize the results.

Topics: Adult; Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Benzothiazoles; Brain; Brain Mapping; Down Syndrome; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Thiazoles; Young Adult