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Individuals with Down syndrome (DS) have a genetic predisposition for amyloid-β (Aβ) overproduction and earlier onset of Aβ deposits compared to patients with sporadic late-onset Alzheimer's disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relationship with heterogeneous Aβ forms aggregated within amyloid deposits is not well understood. We performed quantitative in vitro 3H-PiB binding assays and enzyme-linked immunosorbent assays of fibrillar (insoluble) unmodified Aβ40 and Aβ42 forms and N -terminus truncated and pyroglutamate-modified AβNpE3-40 and AβNpE3-42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43–63 years and 17 late-onset AD cases aged 62–99 years. Both diagnostic groups had frequent neocortical neuritic plaques, while the DS group had more severe vascular amyloid pathology (cerebral amyloid angiopathy, CAA). Compared to the AD group, the DS group had higher levels of Aβ40 and AβNpE3-40, while the two groups did not differ by Aβ42 and AβNpE3-42 levels. This resulted in lower ratios of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 in the DS group compared to the AD group. Correlations of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 ratios with CAA severity were strong in DS cases and weak in AD cases. Pyroglutamate-modified Aβ levels were lower than unmodified Aβ levels in both diagnostic groups, but within group proportions of both pyroglutamate-modified Aβ forms relative to both unmodified Aβ forms were lower in the DS group but not in the AD group. The two diagnostic groups did not differ by 3H-PiB binding levels. These results demonstrate that compared to late-onset AD cases, adult DS individuals with similar severity of neocortical neuritic plaques and greater CAA pathology have a preponderance of both pyroglutamate-modified AβNpE3-40 and unmodified Aβ40 forms. Despite the distinct molecular profile of Aβ forms and greater vascular amyloidosis in DS cases, cortical 3H-PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. This underscores the need for the development of CAA-selective PET radiopharmaceuticals to detect and track the progression of cerebral vascular amyloid deposits in relation to Aβ plaques in individuals with DS. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the sensitivity of visual read (VR) to detect early amyloid pathology and the overall utility of regional VR. Methods: [18F]Flutemetamol PET images of 497 subjects (ALFA+ N = 352; ADC N = 145) were included. Scans were visually assessed according to product guidelines, recording the number of positive regions (0–5) and a final negative/positive classification. Scans were quantified using the standard and regional Centiloid (CL) method. The agreement between VR-based classification and published CL-based cut-offs for early (CL = 12) and established (CL = 30) pathology was determined. An optimal CL cut-off maximizing Youden's index was derived. Global and regional CL quantification was compared to VR. Finally, 28 post-mortem cases from the [18F]flutemetamol phase III trial were included to assess the percentage agreement between VR and neuropathological classification of neuritic plaque density. Results: VR showed excellent agreement against CL = 12 (κ =.89, 95.2%) and CL = 30 (κ =.88, 95.4%) cut-offs. ROC analysis resulted in an optimal CL = 17 cut-off against VR (sensitivity = 97.9%, specificity = 97.8%). Each additional positive VR region corresponded to a clear increase in global CL. Regional VR was also associated with regional CL quantification. Compared to mCERADSOT-based classification (i.e., any region mCERADSOT > 1.5), VR was in agreement in 89.3% of cases, with 13 true negatives, 12 true positives, and 3 false positives (FP). Regional sparse-to-moderate neuritic and substantial diffuse Aβ plaque was observed in all FP cases. Regional VR was also associated with regional plaque density. Conclusion: VR is an appropriate method for assessing early amyloid pathology and that grading the extent of visual amyloid positivity could present clinical value. [ABSTRACT FROM AUTHOR]

Background: The binding substrates of [18F]flutemetamol and [11C]PiB PET consist of fibrillar amyloid‐β (Aβ) aggregates in morphologically and structurally distinct diffuse plaques (DP) and cored plaques (CP) which are present at different proportions across brain regions in Alzheimer's disease (AD). To account for this heterogeneity, an unbiased quantitative measure integrating plaque size and density of amyloid‐β (Aβ) fibrils in plaques could help avoid false positive results, improve imaging‐to‐autopsy correlations, and further advance our understanding of pathological substrates for binding of amyloid PET tracers. Method: Sixteen subjects underwent [18F]flutemetamol PET imaging in the pivotal Phase III end‐of‐life study (Study GE067‐007 and GE067‐026) and later came to autopsy (mean imaging‐to‐autopsy interval was 111 ± 87.6 days). [18F]flutemetamol SUVRpons values in four neocortical regions were correlated with region‐matched postmortem measures of cyano‐flutemetamol labeling of all plaques, as well as CP and DP separately, using percent area coverage, mean grayscale intensity of fluorescence, or a combination of the two measures referred to as integrated density. Result: In the analysis of all cyano‐flutemetamol‐labeled plaques, [18F]flutemetamol SUVRpons values were more closely associated with integrated density measures than percent area coverage and mean grayscale values. Similarly, when CP and DP were analyzed separately, the integrated density values showed the closest association with neocortical region‐matched [18F]flutemetamol SUVRpons values. When area coverage of CP and DP were each expressed as a fraction of total plaque area coverage with or without integrating fluorescence intensity values, [18F]flutemetamol SUVRpons values within each region of interest were associated with the DP, but not the CP, area coverage measure. Conclusion: The association of antemortem [18F]flutemetamol PET and region‐matched postmortem integrated density measurements of cyano‐flutemetamol labeled plaques further supports the hypothesis that amyloid PET signal is influenced both by plaque size and Aβ fibril density within DP and CP. Further elucidating the relative contributions of each plaque type to the retention of amyloid PET radioligands could influence how a positive amyloid PET signal is interpreted in relation to postmortem pathology data. [ABSTRACT FROM AUTHOR]

Background: People with Down syndrome (DS) have a higher risk of developing Alzheimer disease (AD), due to an extra copy of the amyloid precursor protein (APP) gene on chromosome 21. Overexpression of APP is associated with increased production of amyloid beta (Aβ) in DS, and contributes to early onset of AD. Some studies suggest women with DS are at a higher risk for AD, while others find the opposite. Sex differences may be mediated by estrogen, which is critically involved in neuronal survival and modulation. We hypothesized that lower levels of ERα protein would correlate with increasing AD pathology in DS. Method: We examined 34 brains (frontal and occipital cortices) of people with DS and DS with AD. Serial sections were immunostained for phosphorylated tau (pTau ‐AT8) and Aβ (6E10) along with ERα and quantified using QuPath. Spearman rank correlations using log transformed % load data were calculated, Kruskal‐Wallis was used to compare men (n = 19) and women(n = 15). Result: No significant differences in protein levels of ERα, Aβ, or tau were observed when comparing men and women with DS. However, we found higher levels of ERα protein were associated with higher levels of Aβ in the gray matter of the occipital cortex (r = 0.7078; p = 0.0005) in all cases. This positive correlation was driven primarily by women. Females with DS showed a significant positive association with Aβ and ERα (r = 0.93; p = 0.00012) whereas men showed a weaker trend (r = 0.62; p = 0.057). In contrast, no significant associations between ERα, Aβ or pTau were observed in the frontal cortex. PTau measures in the occipital cortex in women with DS were positively associated with ERα (r = 0.61; p = 0.055), whereas men with DS showed a slight negative, though not significant association (r = ‐0.29; p = 0.41). There was no such trend in the frontal cortex. Conclusion: These results suggest ERα, in contrast to our original hypothesis, may be increasing in response to AD pathology to preserve neuronal health in the occipital cortex. Lack of similar positive associations in the frontal cortex may be related to AD progression, with the occipital cortex being affected later in disease, giving us the opportunity to observe increased ERα. [ABSTRACT FROM AUTHOR]

Background: Trauma-related neurodegeneration can be difficult to differentiate from multifactorial neurodegenerative syndromes, both clinically and radiographically. We have initiated a protocol for in vivo imaging of patients with suspected TBI-related neurodegeneration utilizing volumetric MRI and PET studies, including [18F]FDG indexing cerebral glucose metabolism, [11C]PiB for Aβ deposition, and [18F]AV-1451 for tau deposition. Objective: To present results from a neuroimaging protocol for in vivo evaluation of TBI-related neurodegeneration in patients with early-onset cognitive decline and a history of TBI. Methods: Patients were enrolled in parallel TBI studies and underwent a comprehensive neuropsychological test battery as well as an imaging protocol of volumetric MRI and PET studies. Findings from two patients were compared with two age-matched control subjects without a history of TBI. Results: Both chronic TBI patients demonstrated cognitive deficits consistent with early-onset dementia on neuropsychological testing, and one patient self-reported a diagnosis of probable early-onset AD. Imaging studies demonstrated significant [18F]AV-1451 uptake in the bilateral occipital lobes, substantial [11C]PiB uptake throughout the cortex in both TBI patients, and abnormally decreased [18F]FDG uptake in the posterior temporoparietal areas of the brain. One TBI patient also had subcortical volume loss. Control subjects demonstrated no appreciable [18F]AV-1451 or [11C]PiB uptake, had normal cortical volumes, and had normal cognition profiles on neuropsychological testing. Conclusions: In the two patients presented, the [11C]PiB and [18F]FDG PET scans demonstrate uptake patterns characteristic of AD. [11C]PiB PET scans showed widespread neocortical uptake with less abnormal uptake in the occipital lobes, whereas there was significant [18F]AV-1451 uptake in both occipital lobes. [ABSTRACT FROM AUTHOR]

Although, by age 40, individuals with Down syndrome (DS) develop amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimer's disease (AD), not all people with DS develop dementia. Whether Aβ plaques and NFTs are associated with individuals with DS with (DSD +) and without dementia (DSD −) is under-investigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and conformational (Alz50, MC1) epitopes, as well as Aβ and its precursor protein (APP) to frontal cortex (FC) and striatal tissue from DSD + to DSD − cases. Expression profiling of single pS422 labeled FC layer V and VI neurons was also determined using laser capture microdissection and custom-designed microarray analysis. Analysis revealed that cortical and striatal Aβ plaque burdens were similar in DSD + and DSD − cases. In both groups, most FC plaques were neuritic, while striatal plaques were diffuse. By contrast, FC AT8-positive NFTs and neuropil thread densities were significantly greater in DSD + compared to DSD −, while striatal NFT densities were similar between groups. FC pS422-positive and TauC3 NFT densities were significantly greater than Alz50-labeled NFTs in DSD + , but not DSD − cases. Putaminal, but not caudate pS422-positive NFT density, was significantly greater than TauC3-positive NFTs. In the FC, AT8 + pS422 + Alz50, TauC3 + pS422 + Alz50, pS422 + Alz50, and TauC3 + pS422 positive NFTs were more frequent in DSD + compared to DSD- cases. Single gene-array profiling of FC pS422 positive neurons revealed downregulation of 63 of a total of 864 transcripts related to Aβ/tau biology, glutamatergic, cholinergic, and monoaminergic metabolism, intracellular signaling, cell homeostasis, and cell death in DSD + compared DSD − cases. These observations suggest that abnormal tau aggregation plays a critical role in the development of dementia in DS. [ABSTRACT FROM AUTHOR]

Abstract Traumatic brain injury (TBI) is a risk factor for development of chronic neurodegenerative disorders later in life. This review summarizes the current knowledge and concepts regarding the connection between long-term consequences of TBI and aging-associated neurodegenerative disorders including Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and Parkinsonism, with implications for novel therapy targets. Several aggregation-prone proteins such as the amyloid-beta (Aβ) peptides, tau proteins, and α-synuclein protein are involved in secondary pathogenic cascades initiated by a TBI and are also major building blocks of the hallmark pathological lesions in chronic human neurodegenerative diseases with dementia. Impaired metabolism and degradation pathways of aggregation-prone proteins are discussed as potentially critical links between the long-term aftermath of TBI and chronic neurodegeneration. Utility and limitations of previous and current preclinical TBI models designed to study the link between TBI and chronic neurodegeneration, and promising intervention pharmacotherapies and non-pharmacologic strategies to break this link, are also summarized. Complexity of long-term neuropathological consequences of TBI is discussed, with a goal of guiding future preclinical studies and accelerating implementation of promising therapeutics into clinical trials. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury". Highlights • TBI is a risk factor for development of chronic neurodegenerative disorders later in life. • Prolonged secondary injury cascades after TBI can result in chronic neurodegeneration. • Chronic TBI and aging-related dementias involve similar changes in aggregation prone molecules. • Novel preclinical animal models of TBI are needed to better mimic the human condition. • Polypathology of TBI supports the need for development of multifunctional therapies. [ABSTRACT FROM AUTHOR]