Neuritic Plaque Score Research Articles

A proteome-derived temporal model of neurodegeneration in older brains.

We previously developed a temporal model for unobserved molecular changes occurring during late-onset Alzheimer's Disease (AD) for RNA-Seq data. Here we apply this method to proteomics data from an AD case-control cohort and show that the model's estimate of disease progression is associated with clinical and neuropathological endpoints, and identify changes in the proteome across stages of AD. Manifold learning defines an order across samples based on their similarity of expression. This ordering estimates pseudotime, an inference of molecular disease progression, quantitatively measured as the distance of each sample from the start of the inferred trajectory. We applied this approach to TMT-proteomics data from human postmortem brain samples from the ROS/MAP study within the Accelerating Medicine Partnership-AD consortia (AMP-AD) (N=400). We examined associations between pseudotime and neuropathological and clinical endpoints. We performed differential expression analysis on tree branches to identify progression-specific pathways, and used gene set enrichment analysis to identify significant GO terms from a set that have been curated into 15 distinct AD-relevant biological domains. Pseudotime estimates were significantly associated with LOAD status (females, p=3.67x10-7; males, p=1.03x10-3), such that "early" (low pseudotime) samples are enriched for controls, and "late" (high pseudotime) samples are enriched for cases. Pseudotime was associated with cognitive diagnosis (females, p=2.46x10-5; males, p=1.14x10-3), Braak stage (females, p=1.48x10-5; males, p=1.52x10-3), and CERAD neuritic plaque score (females, p=1.17x10-11; males, p=1.32x10-4). Proteins involved in immune response were upregulated, while mitochondrial metabolism was downregulated, consistently across pseudotime. We observed differences between branches in biological domains encompassing vascular function, structural stabilization, lipid metabolism, apoptosis regulation, and epigenetics. Synaptic dysfunction was downregulated during mid-to-late pseudotime in women, but not in men. This approach to identifying biological changes associated with AD progression has now been applied to two data modalities, and despite substantial differences in data used to order trajectories, pseudotime was associated with multiple measures of AD progression in both studies. We also uncovered proteome-specific changes, providing opportunities to glean new insights about genetic drivers of AD across disease severity.

Age-related progression of Alzheimer disease neuropathologic change (ADNC) in cognitively normal individuals: Toward a definition of resilience and resistance.

An intriguing group of individuals, termed "resilient", demonstrate neuropathologic changes consistent with Alzheimer disease (AD), yet display no cognitive impairment. Neuropathologic studies have reported less neuronal loss overall, less gliosis, and fewer comorbidities in these individuals. We sought to investigate the unique clinical characteristics of this subgroup as well as individuals who are "resistant" to AD neuropathologic change. Utilizing data from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and Neuropathology Data Set, we demonstrate the age-related progression of AD neuropathologic changes in all individuals (cognitively impaired and normal, n=6,144) as well as in only cognitively normal individuals (CDR = 0, n=662). With plots generated from these data, we have established standard lines that may be used to measure the extent to which an individual's AD pathology varies from the estimated normal range of pathology. We have also defined levels of AD neuropathologic change above which an individual could be considered "resilient" against the neuropathologic changes and levels below which an individual could be considered "resistant" to the neuropathologic changes. With this definition, we have identified 43 resilient and 23 resistant individuals and have analyzed the UDS for any significant clinical variations in these subgroups of individuals. Our plots demonstrate that although Braak stage and Thal phase increase with age in cognitively normal individuals, CERAD neuritic plaque score and ADNC remain at low levels, suggesting a critical role for neuritic plaques in the development of cognitive decline. Analyses of NACC UDS and NP datasets comparing resilient to other CDR = 0 individuals revealed significant differences in medication use, as well as comorbid pathologies. When comparing resistant individuals to other cognitively normal individuals, we found variations in blood pressure, as well as neuropsychiatric differences and subjective differences in the clinical impression of an individual's cognition without CDR scores indicating MCI. In conclusion, we are able to identify resilient and resistant individuals based off of a linear model of Braak stage progression with age. These individuals display differences that could provide insight into the protective mechanisms by which they evade the neuropathologic changes and/or associated cognitive decline observed in AD.

Long-term exposure to ambient air pollution is associated with neuropathologic change of Alzheimer's Disease at Autopsy

BACKGROUND AND AIM: There is a growing body of evidence linking exposure to air pollution with dementia and Alzheimer’s disease (AD). However, the detailed molecular mechanisms explaining how air pollution exposures may affect the human brain are still largely unknown. Investigating the impact of air pollution on markers of AD neuropathology might provide mechanistic insights. We evaluated associations of long-term exposure to air pollution prior to death with three different measures of AD neuropathology: Braak stage; Consortium to Establish a Registry for AD (CERAD) neuritic plaque score; and combined AD neuropathologic change (ABC score). METHODS: We obtained data on the neuropathology markers from autopsy samples collected after 2008 from the Emory University Goizueta Alzheimer’s Disease Research Center Neuropathology Core Brain Bank (N=145 donors from Metro Atlanta, Georgia, USA). Long-term exposures to PM2.5, CO, and NOx were estimated at the deceased’s last address for a fixed 7-year period (2002-2008) via the Research LINE source model (resolution: 250m). We performed ordinal logistic regression for each marker adjusting for age at death, race, gender, educational attainment, and APOE genotype. RESULTS:The average age at death was 76 years (SD=9.5). The medians of exposure to PM2.5, CO, and NOx were 0.32µg/m3, 157.9ppb, 12.9ppb, respectively. After adjustment, one unit increase in 7-year average PM2.5 was associated with higher Braak stage [OR = 5.40 (1.30, 28.25)]. Associations with CERAD [0.83 (0.12, 5.61)] and ABC [2.41 (0.42, 13.95)] scores were not significant and no significant associations were found for CO and NOx (Braak stage: 1.00 (0.99, 1.01) and 1.04 (0.99, 1.10), respectively). CONCLUSIONS:PM2.5 was associated with neuropathologic changes assessed by Braak stage, which characterizes the abundance of neurofibrillary tangles. As Braak staging is the neuropathology marker showing the strongest association with cognitive performance and decline, these findings could have implication for both AD and AD-related dementias. KEYWORDS: Air pollution, Neurodegenerative outcomes.

Cognitive performance among participants with Alzheimer’s disease and cerebral amyloid angiopathy

AbstractBackgroundBeta‐amyloid found in Alzheimer’s disease (AD) plaques can also be present in the brain’s blood vessels as cerebral amyloid angiopathy (CAA). Co‐occurrence of AD and CAA is common. We examined the relationship between AD and CAA, and cognitive performance.MethodData were obtained from the National Alzheimer’s Coordinating Center. The sample was restricted to those with an autopsy ≤2 years of their last clinic visit and non‐missing data on Braak neurofibrillary tangle stage, neuritic plaque score, and CAA at autopsy. We excluded participants who had autopsy evidence of rare neuropathological diseases. Linear regression models with generalized estimating equations were run comparing CDR® Dementia Staging Instrument sum of boxes (CDR‐SB) and cognitive domain z‐scores across four groups (AD+/CAA+, AD+/CAA‐, AD‐/CAA+, AD‐/CAA‐). AD+ included those with Braak III‐VI and moderate/frequent neuritic plaques. Overall neocortical amyloid angiopathy was assessed for presence of CAA. Models accounted for clustering by center and adjusted for covariates. We also examined the mean differences in CDR‐SB by CAA severity (absent, mild, moderate, severe), stratifying by AD+/‐ and APOE ε4+/‐.ResultWe identified 1723 AD+/CAA+, 547 AD+/CAA‐, 443 AD‐/CAA+, and 741 AD‐/CAA‐ participants. All groups were more likely to be APOE ε4 carriers compared to AD‐/CAA‐. CAA+ participants, regardless if they had AD, were more likely to have arteriolosclerosis. After adjusting for covariates, AD+/CAA+ and AD+/CAA‐ participants had worse CDR‐SB scores compared to AD‐/CAA‐. There was no significant difference in CDR‐SB scores among AD‐ participants with or without CAA. Similar results were seen when examining differences in cognitive domain z‐scores, where AD+ participants performed worse regardless of the presences of CAA when compared to AD‐/CAA‐ participants. We did not observe significant differences in CDR‐SB scores by CAA severity after adjusting for covariates.ConclusionThese results demonstrate that the presence of AD neuropathologic features appears to be driving the cognitive performance irrespective of the presence or severity of CAA. Our observation that arteriolosclerosis was more likely to be present among those with CAA even in the absence of AD is of note and something to investigate further. Future work should also examine if these differences hold true when examining longitudinal cognitive performance.

Cognitive impairment and risk factors of LATE in the oldest old: The 90+ Study

AbstractBackgroundLimbic predominant age related TDP‐43 encephalopathy (LATE) is a newly proposed term to denote the contribution of TDP‐43 pathology to dementia at older age. The aim of this work was to study the role of LATE in cognitive impairment and its risk factors in the oldest old.Method240 participants of The 90+ Study with comprehensive clinical, neuropsychology, and neuropathology data were included. Dementia status, clinical syndrome, and impaired cognitive domains were determined at multi‐disciplinary post‐mortem case conferences blind to autopsy data. Alzheimer’s disease neuropathology (ADNP) was defined as CERAD neuritic plaque score≥2 and Braak neurofibrillary tangle stage≥5. We defined LATE as those with at least amygdala and hippocampal TDP‐43 pathology (stage>2). We explored the association of LATE and ADNP with cognition measures as outcome by logistic regression analyses adjusting for age, sex, and education. We separately explored the association between medical histories (as potential risk factors) and LATE and ADNP as outcomes adjusting for the above covariates.Result52% of the participants (N=125) died with dementia and of those, 33% were LATE positive (Table 1). There was no association between LATE and sex, age at death, or education. Compared with ADNP, LATE was as important a predictor of dementia and clinical diagnosis of Alzheimer’s at death (Table 2). Both pathologies were associated with impaired memory, language, visuospatial ability, and orientation. Only ADNP, but not TDP‐43, was associated with impaired executive function. Lower likelihood of LATE was associated with histories of hypertension (but not hypertension medications), cataract, alcohol use (median 1 drink/day), and macular degeneration (trended toward significant association). History of COPD was significantly associated and history of autoimmune conditions (thyroid or rheumatological diseases) trended towards an association with a higher likelihood of LATE (Figure). None of the above relationships were seen for ADNP.ConclusionLATE is an important degenerative pathology in the oldest old comparable to ADNP in its relation to dementia and clinical diagnosis of Alzheimer’s. The intriguing associations of LATE with other health conditions warrant further investigation of the potential effect of autoimmunity, reduced brain perfusion, and chronic hypoxia in its development.

Distinct patterns of gray matter atrophy in hippocampal sclerosis of aging and Alzheimer’s disease neuropathology

AbstractBackgroundHippocampal sclerosis of aging (HS) and Alzheimer’s Disease Neuropathology (ADNP) both contribute to dementia in the elderly but are difficult to distinguish in vivo. Currently, there are no established biomarkers for HS, and few studies have investigated the distinction between HS‐ and ADNP‐related patterns of brain atrophy. We hypothesized that HS‐related atrophy would be restricted to the hippocampus and surrounding structures, while ADNP‐related atrophy would be most pronounced in the lateral temporal and parietal lobes.MethodWe used data from the National Alzheimer’s Coordinating Center (NACC) (09/2005‐03/2017) and identified 134 participants with suitable 3D T1w MRI and autopsy data. HS pathology was available as present/absent and we defined ADNP as present by a combination of high Braak stage (V/VI) and CERAD neuritic plaque score (3). We used the Computational Anatomy Toolbox (CAT12) to segment the MRI scans into tissue types and generate gray matter density maps. We examined the following regions of interest (ROIs): hippocampus, parahippocampus, amygdala, temporal and parietal regions, and global tissues measures. Additionally, we performed a voxel‐based morphometry (VBM) analysis. We studied the relationship between volumes/densities and neuropathologies using multiple linear regression models while adjusting for sex, age, education, dementia status, years from MRI to death, and intracranial volume.Result Table 1 depicts participant characteristics. We found that HS, but not ADNP, was associated with the volumes of the hippocampus (HS P<0.001, ADNP P=0.4), parahippocampus (anterior only, HS P=0.007, ADNP P=0.8), and amygdala (HS P=0.009, ADNP=0.2, Table 2). ADNP was significantly associated with lateral temporal lobe volumes, most strongly the inferior/middle temporal gyri. We found a trend of association between ADNP and gray matter atrophy (P=0.051). HS was significantly associated with white matter atrophy (P=0.001). We display the VBM results in Figure 1, which largely confirm the ROI results. Additionally, we found HS was associated with bilateral thalamic and insular regions and ADNP with the left amygdala and hippocampal tail atrophy.ConclusionWhile HS is strongly associated with atrophy of the hippocampus and surrounding structures, ADNP is associated with atrophy of lateral temporal lobe regions. These diverging atrophy patterns are potential biomarkers for differentiating these two clinically indistinguishable conditions during life.

Amyloid Beta Immunoreactivity in the Retinal Ganglion Cell Layer of the Alzheimer's Eye.

Alzheimer’s disease (AD) is the most prevalent form of dementia, accounting for 60–70% of all dementias. AD is often under-diagnosed and recognized only at a later, more advanced stage, and this delay in diagnosis has been suggested as a contributing factor in the numerous unsuccessful AD treatment trials. Although there is no known cure for AD, early diagnosis is important for disease management and care. A hallmark of AD is the deposition of amyloid-β (Aβ)-containing senile neuritic plaques and neurofibrillary tangles composed of hyperphosporylated tau in the brain. However, current in vivo methods to quantify Aβ in the brain are invasive, requiring radioactive tracers and positron emission tomography. Toward development of alternative methods to assess AD progression, we focus on the retinal manifestation of AD pathology. The retina is an extension of the central nervous system uniquely accessible to light-based, non-invasive ophthalmic imaging. However, earlier studies in human retina indicate that the literature is divided on the presence of Aβ in the AD retina. To help resolve this disparity, this study assessed retinal tissues from neuropathologically confirmed AD cases to determine the regional distribution of Aβ in retinal wholemounts and to inform on future retinal image studies targeting Aβ. Concurrent post-mortem brain tissues were also collected. Neuropathological cortical assessments including neuritic plaque (NP) scores and cerebral amyloid angiopathy (CAA) were correlated with retinal Aβ using immunohistochemistry, confocal microscopy, and quantitative image analysis. Aβ load was compared between AD and control (non-AD) eyes. Our results indicate that levels of intracellular and extracellular Aβ retinal deposits were significantly higher in AD than controls. Mid-peripheral Aβ levels were greater than central retina in both AD and control eyes. In AD retina, higher intracellular Aβ was associated with lower NP score, while higher extracellular Aβ was associated with higher CAA score. Our data support the feasibility of using the retinal tissue to assess ocular Aβ as a surrogate measure of Aβ in the brain of individuals with AD. Specifically, mid-peripheral retina possesses more Aβ deposition than central retina, and thus may be the optimal location for future in vivo ocular imaging.

Mid-life and late-life vascular risk factor burden and neuropathology in old age.

ObjectiveTo determine whether vascular risk factor burden in mid‐ or late‐life associates with postmortem vascular and neurodegenerative pathologies in a community‐based sample.MethodsWe studied participants from the Framingham Heart Study who participated in our voluntary brain bank program. Overall vascular risk factor burden was calculated using the Framingham Stroke Risk Profile (FSRP). Mid‐life FSRP was measured at 50 to 60 years of age. Following death, brains were autopsied and semi‐quantitatively assessed by board‐certified neuropathologists for cerebrovascular outcomes (cortical infarcts, subcortical infarcts, atherosclerosis, arteriosclerosis) and Alzheimer’s disease pathology (Braak stage, cerebral amyloid angiopathy, and neuritic plaque score). We estimated adjusted odds ratios between vascular risk burden (at mid‐life and before death) and neuropathological outcomes using logistic and proportional‐odds logistic models.ResultsThe median time interval between FSRP and death was 33.4 years for mid‐life FSRP and 4.4 years for final FSRP measurement before death. Higher mid‐life vascular risk burden was associated with increased odds of all cerebrovascular pathology, even with adjustment for vascular risk burden before death. Late‐life vascular risk burden was associated with increased odds of cortical infarcts (OR [95% CI]: 1.04 [1.00, 1.08]) and arteriosclerosis stage (OR [95% CI]: 1.03 [1.00, 1.05]). Mid‐life vascular risk burden was not associated with Alzheimer’s disease pathology, though late‐life vascular risk burden was associated with increased odds of higher Braak stage (OR [95% CI]: 1.03 [1.01, 1.05]).InterpretationMid‐life vascular risk burden was predictive of cerebrovascular but not Alzheimer’s disease neuropathology, even after adjustment for vascular risk factors before death.

Neuroimaging correlates with neuropathologic schemes in neurodegenerative disease

IntroductionNeuroimaging biomarkers are important for early diagnosis of Alzheimer's disease, and comparing multimodality neuroimaging to autopsy data is essential. MethodsWe compared the pathologic findings from a prospective autopsy cohort (n = 100) to Pittsburgh compound B PET (PiB-PET), 18F-fluorodeoxyglucose PET (FDG-PET), and MRI. Correlations between neuroimaging biomarkers and neuropathologic schemes were assessed. ResultsPiB-PET showed strong correlations with Thal amyloid phase and Consortium to Establish a Registry for Alzheimer's Disease score and categorized 44% of Thal phase 1 participants as positive. FDG-PET and MRI correlated modestly with Braak tangle stage in Alzheimer's type pathology. A subset of participants with “none” or “sparse” neuritic plaque scores had elevated PiB-PET signal due to diffuse amyloid plaque. Participants with findings characterized as “suspected non-Alzheimer's pathophysiology” represented 15% of the group. DiscussionPiB-PET is associated with Alzheimer's disease, neuritic plaques, and diffuse plaques. FDG-PET and MRI have modest correlation with neuropathologic schemes. Participants with findings characterized as suspected non-Alzheimer's pathophysiology most commonly had primary age-related tauopathy.

Correlations Between Single Nucleotide Polymorphisms, Cognitive Dysfunction, and Postmortem Brain Pathology in Alzheimer's Disease Among Han Chinese.

In this study, the distribution of five Alzheimer's disease (AD)-related single nucleotide polymorphisms (SNPs) in the Han population was examined in combination with the evaluation of clinical cognition and brain pathological analysis. The associations among SNPs, clinical daily cognitive states, and postmortem neuropathological changes were analyzed in 110 human brains from the Chinese Academy of Medical Sciences/Peking Union Medical College (CAMS/PUMC) Human Brain Bank. APOE ε4 (OR = 4.482, P = 0.004), the RS2305421 GG genotype (adjusted OR = 4.397, P = 0.015), and the RS10498633 GT genotype (adjusted OR = 2.375, P = 0.028) were associated with a higher score on the ABC (Aβ plaque score, Braak NFT stage, and CERAD neuritic plaque score) dementia scale. These results advance our understanding of the pathogenesis of AD, the relationship between pathological diagnosis and clinical diagnosis, and the SNPs in the Han population for future research.

Multisite study of the relationships between antemortem [11C]PIB-PET Centiloid values and postmortem measures of Alzheimer's disease neuropathology

IntroductionWe sought to establish the relationships between standard postmortem measures of AD neuropathology and antemortem [11C]PIB–positron emission tomography ([11C]PIB-PET) analyzed with the Centiloid (CL) method, a standardized scale for Aβ-PET quantification. MethodsFour centers contributed 179 participants encompassing a broad range of clinical diagnoses, PET data, and autopsy findings. ResultsCL values increased with each CERAD neuritic plaque score increment (median −3 CL for no plaques and 92 CL for frequent plaques) and nonlinearly with Thal Aβ phases (increases were detected starting at phase 2) with overlap between scores/phases. PET-pathology associations were comparable across sites and unchanged when restricting the analyses to the 56 patients who died within 2 years of PET. A threshold of 12.2 CL detected CERAD moderate-to-frequent neuritic plaques (area under the curve = 0.910, sensitivity = 89.2%, specificity = 86.4%), whereas 24.4 CL identified intermediate-to-high AD neuropathological changes (area under the curve = 0.894, sensitivity = 84.1%, specificity = 87.9%). DiscussionOur study demonstrated the robustness of a multisite Centiloid [11C]PIB-PET study and established a range of pathology-based CL thresholds.

Exposure to Strong Anticholinergic Medications and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort.

Anticholinergic medication exposure has been associated with increased risk for dementia. No study has examined the association between anticholinergic medication use and neuropathologic lesions in a community-based sample. To examine the relationship between anticholinergic exposure and dementia-related neuropathologic changes. Within a community-based autopsy cohort (N = 420), we ascertained use of anticholinergic medications over a 10-year period from automated pharmacy data and calculated total standardized daily doses (TSDD). We used modified Poisson regression to calculate adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the association between anticholinergic exposure and dementia-associated neuropathology. Inverse probability weighting was used to account for selection into the autopsy cohort. Heavy anticholinergic exposure (≥1,096 TSDD) was not associated with greater neuropathologic changes of Alzheimer's disease; the adjusted RRs for heavy use of anticholinergics (≥1,096 TSDD) compared to no use were 1.22 (95% CI 0.81-1.88) for neuritic plaque scores and 0.89 (0.47-1.66) for extent of neurofibrillary degeneration. Moderate (91-1,095 TSDD) and heavy use of anticholinergics was associated with a significantly lower cerebral microinfarct burden compared with no use with adjusted RRs of 0.44 (0.21-0.89) and 0.24 (0.09-0.62), respectively. Anticholinergic exposure was not associated with macroscopic infarcts or atherosclerosis. Use of anticholinergic medications is not associated with Alzheimer's disease-related neuropathologic changes but is associated with lower cerebral microinfarct burden. Further research into biological mechanisms underlying the anticholinergic-dementia link is warranteds.

Traumatic brain injury history is associated with an earlier age of dementia onset in autopsy-confirmed Alzheimer's disease.

To evaluate whether a history of traumatic brain injury (TBI) with reported loss of consciousness (LOC) is a risk factor for earlier onset of Alzheimer's disease (AD) in an autopsy-confirmed sample. Data from 2,133 participants with autopsy-confirmed AD (i.e., at least Braak neurofibrillary tangle stages III to VI and CERAD neuritic plaque score moderate to frequent) were obtained from the National Alzheimer's Coordinating Center (NACC). Participants were categorized by presence/absence of self-reported remote (i.e., >1 year prior to their first Alzheimer's Disease Center visit) history of TBI with LOC (TBI+ vs. TBI-). Analyses of Covariance (ANCOVA) controlling for sex, education, and race compared groups on clinician-estimated age of symptom onset and age of diagnosis. Average age of onset was 2.34 years earlier (p = .01) for the TBI+ group (n = 194) versus the TBI- group (n = 1900). Dementia was diagnosed on average 2.83 years earlier (p = .002) in the TBI+ group (n = 197) versus the TBI- group (n = 1936). Using more stringent neuropathological criteria (i.e., Braak stages V-VI and CERAD frequent), both age of AD onset and diagnosis were 3.6 years earlier in the TBI+ group (both p's < .001). History of TBI with reported LOC appears to be a risk factor for earlier AD onset. This is the first study to use autopsy-confirmed cases, supporting previous investigations that used clinical criteria for the diagnosis of AD. Further investigation as to possible underlying mechanisms of association is needed. (PsycINFO Database Record

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson’s disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.

A novel detection method of cleaved plasma high-molecular-weight kininogen reveals its correlation with Alzheimer's pathology and cognitive impairment

IntroductionAccumulation of β-amyloid is a pathological hallmark of Alzheimer's disease (AD). β-Amyloid activates the plasma contact system leading to kallikrein-mediated cleavage of intact high-molecular-weight kininogen (HKi) to cleaved high-molecular-weight kininogen (HKc). Increased HKi cleavage is observed in plasma of AD patients and mouse models by Western blot. For potential diagnostic purposes, a more quantitative method that can measure HKc levels in plasma with high sensitivity and specificity is needed. MethodsHKi/c, HKi, and HKc monoclonal antibodies were screened from hybridomas using direct ELISA with a fluorescent substrate. ResultsWe generated monoclonal antibodies recognizing HKi or HKc specifically and developed sandwich ELISAs that can quantitatively detect HKi and HKc levels in human. These new assays show that decreased HKi and increased HKc levels in AD plasma correlate with dementia and neuritic plaque scores. DiscussionHigh levels of plasma HKc could be used as an innovative biomarker for AD.

Dendritic spines provide cognitive resilience against Alzheimer's disease.

Neuroimaging and other biomarker assays suggest that the pathological processes of Alzheimer's disease (AD) begin years prior to clinical dementia onset. However, some 30 to 50% of older individuals who harbor AD pathology do not become symptomatic in their lifetime. It is hypothesized that such individuals exhibit cognitive resilience that protects against AD dementia. We hypothesized that in cases with AD pathology, structural changes in dendritic spines would distinguish individuals who had or did not have clinical dementia. We compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 dorsolateral prefrontal cortex using the Golgi-Cox technique in 12 age-matched pathology-free controls, 8 controls with AD pathology (CAD), and 21 AD cases. We used highly optimized methods to trace impregnated dendrites from bright-field microscopy images that enabled accurate 3-dimensional digital reconstruction of dendritic structure for morphologic analyses. Spine density was similar among control and CAD cases but was reduced significantly in AD. Thin and mushroom spines were reduced significantly in AD compared to CAD brains, whereas stubby spine density was decreased significantly in CAD and AD compared to controls. Increased spine extent distinguished CAD cases from controls and AD. Linear regression analysis of all cases indicated that spine density was not associated with neuritic plaque score but did display negative correlation with Braak staging. These observations provide cellular evidence to support the hypothesis that dendritic spine plasticity is a mechanism of cognitive resilience that protects older individuals with AD pathology from developing dementia. Ann Neurol 2017;82:602-614.

Increased Transforming Growth Factor β2 in the Neocortex of Alzheimer's Disease and Dementia with Lewy Bodies isCorrelated with Disease Severity andSoluble Aβ42 Load.

Of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden. To measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively. Postmortem samples from temporal cortex (BA21) were measured for TGFβ2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aβ42. TGFβ2 was significantly increased in AD and DLB, but not in PDD. TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42, or monomeric α-synuclein immunoreactivity. TGFβ2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aβ42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aβ. Our study also indicates the potential utility of targeting TGFβ2 in pharmacotherapeutic approaches to AD and DLB.

Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis

Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging-Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β -4·0, 95% CI -5·5 to -2·6; p<0·0001; R2 0·22, p<0·0001) and with survival (-2·0, -3·2 to -0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology. US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).

Distribution and Load of Amyloid-β Pathology in Parkinson Disease and Dementia with Lewy Bodies.

Parkinson disease (PD), Parkinson disease with dementia (PDD), and Dementia with Lewy bodies (DLB) differ clinically with regard to the presence and timing of dementia. In this postmortem study, we evaluated whether the burden and distribution pattern of amyloid-β (Aβ) pathology differs among these disease entities. We assessed Aβ phases and neuritic plaque scores in 133 patients fulfilling clinical diagnostic criteria for PD, PDD, and DLB, and determined the presence and load of Aβ pathology in 5 cortical and 4 subcortical regions in a subset of patients (n = 89) using a multispectral imaging system. Aβ phases and neuritic plaque scores were higher in DLB versus PDD (both p < 0.001) and in PDD vs PD patients (p = 0.020 and 0.022, respectively). Aβ pathology was more often observed in the entorhinal cortex, amygdala and putamen in DLB versus PDD patients; Aβ load was higher in both cortical and subcortical regions. PDD patients had more frequent Aβ pathology in temporal cortex and higher Aβ load in cortical regions and striatum versus PD patients. Our findings suggest that the load and extent of Aβ pathology may contribute to cognitive dysfunction in PDD and the early-stage severe dementia in DLB.

Subcellular Changes in Bridging Integrator 1 Protein Expression in the Cerebral Cortex During the Progression of Alzheimer Disease Pathology.

Genome-wide association studies have established BIN1 (Bridging Integrator 1) as the most significant late-onset Alzheimer disease (AD) susceptibility locus after APOE We analyzed BIN1 protein expression using automated immunohistochemistry on the hippocampal CA1 region in 19 patients with either no, mild, or moderate-to-marked AD pathology, who had been assessed by Clinical Dementia Rating and CERAD scores. We also examined the amygdala, prefrontal, temporal, and occipital regions in a subset of these patients. In non-demented controls without AD pathology, BIN1 protein was expressed in white matter, glia, particularly oligodendrocytes, and in the neuropil in which the BIN1 signal decorated axons. With increasing severity of AD, BIN1 in the CA1 region showed: 1) sustained expression in glial cells, 2) decreased areas of neuropil expression, and 3) increased cytoplasmic neuronal expression that did not correlate with neurofibrillary tangle load. In patients with AD, both the prefrontal cortex and CA1 showed a decrease in BIN1-immunoreactive (BIN1-ir) neuropil areas and increases in numbers of BIN1-ir neurons. The numbers of CA1 BIN1-ir pyramidal neurons correlated with hippocampal CERAD neuritic plaque scores; BIN1 neuropil signal was absent in neuritic plaques. Our data provide novel insight into the relationship between BIN1 protein expression and the progression of AD-associated pathology and its diagnostic hallmarks.