Alzheimer's Disease Neuropathologic Change Research Articles

Clustering of tau-immunoreactive pathology in chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder which may result from repetitive brain injury. A variety of tau-immunoreactive pathologies are present, including neurofibrillary tangles (NFT), neuropil threads (NT), dot-like grains (DLG), astrocytic tangles (AT), and occasional neuritic plaques (NP). In tauopathies, cellular inclusions in the cortex are clustered within specific laminae, the clusters being regularly distributed parallel to the pia mater. To determine whether a similar spatial pattern is present in CTE, clustering of the tau-immunoreactive pathology was studied in the cortex, hippocampus, and dentate gyrus in 11 cases of CTE and 7 cases of Alzheimer's disease neuropathologic change (ADNC) without CTE. In CTE: (1) all aspects of tau-immunoreactive pathology were clustered and the clusters were frequently regularly distributed parallel to the tissue boundary, (2) clustering was similar in two CTE cases with minimal co-pathology compared with cases with associated ADNC or TDP-43 proteinopathy, (3) in a proportion of cortical gyri, estimated cluster size was similar to that of cell columns of the cortico-cortical pathways, and (4) clusters of the tau-immunoreactive pathology were infrequently spatially correlated with blood vessels. The NFT and NP in ADNC without CTE were less frequently randomly or uniformly distributed and more frequently in defined clusters than in CTE. Hence, the spatial pattern of the tau-immunoreactive pathology observed in CTE is typical of the tauopathies but with some distinct differences compared to ADNC alone. The spread of pathogenic tau along anatomical pathways could be a factor in the pathogenesis of the disease.

Primary age-related tauopathy and the amyloid cascade hypothesis: the exception that proves the rule?

Extensive data supports the amyloid cascade hypothesis, which states that Alzheimer's disease (AD) stems from neurotoxic forms of the amyloid-beta (Aβ) peptide. But the poor correlation between Aβ plaques and neurodegeneration/cognitive impairment, the spaciotemporal disparity between Aβ and tau pathology, and the disappointing results following several large clinical trials using Aβ-targeting agents are inconsistent with this explanation. The most perplexing inconsistency is the existence of AD-type dementia patients that develop abundant neurofibrillary tangles that are indistinguishable from those in early to moderate-stage AD in the absence of compelling evidence of amyloid toxicity. This neuropathological phenotype, which is distinct from other diseases with tangles, represents a conceptual disconnect, because it does not fall within any previously established category of tauopathy and ostensibly invalidates the amyloid cascade hypothesis. Instead, recent efforts have led to consensus criteria for a new alternative diagnostic category, which presupposes that these tangle-only dementia patients represent extreme examples of a distinct primary age-related tauopathy (PART) that is universally observed, albeit to varying degrees, in the aging brain. The cause of PART is unknown, but sufficient evidence exists to hypothesize that it stems from an Aβ-independent mechanism, such as mechanical injury. Should the PART hypothesis withstand further experimental testing, it would represent a shift in the way a subset of subjects with AD neuropathological change are classified and has the potential to focus and reaffirm the amyloid cascade hypothesis.

Thal Amyloid Stages Do Not Significantly Impact the Correlation Between Neuropathological Change and Cognition in the Alzheimer Disease Continuum.

The 2012 neuropathological criteria for the diagnosis of Alzheimer disease (AD) summarize the extent of AD neuropathological change with an ABC score, which is a composite of the Thal stage of amyloid deposition (A), the Braak stage of neurofibrillary tangles (NFTs) (B), and the CERAD neuritic plaque score (C). NFTs and neuritic plaques are well-established contributors to cognitive impairment, but whether the Thal amyloid stage independently predicts antemortem cognition remains unknown. We used the National Alzheimer's Coordinating Center autopsy data set to build adjacent-categories logit regression models with CDR-SOB and Mini-Mental State Examination (MMSE) scores as cognitive outcome variables. Increasing CERAD scores were independently associated with higher CDR-SOB scores, whereas increasing Braak NFT stages predicted both higher CDR-SOB and lower MMSE scores. Increasing Thal amyloid stages were not significantly independently associated with either outcome measure. Increasing ABC scores predicted higher CDR-SOB and lower MMSE scores. These results raise the possibility that Thal amyloid stages do not substantially contribute to predicting antemortem cognition compared to CERAD neuritic plaque scores and Braak NFT stages, and suggest that the diffuse amyloid deposits participating in the assignment of Thal amyloid stages are neutral with respect to clinically detectable cognitive and functional changes.

Cytoskeletal Pathologies of Age-Related Diseases between Elderly Sri Lankan (Colombo) and Indian (Bangalore) Brain Samples.

Within South Asia, Sri Lanka represents fastest aging with 13% of the population was aged over 60's in 2011, whereas in India it was 8%. Majority of the Sri Lankan population based genetic studies have confirmed their origin on Indian mainland. As there were inadequate data on aging cytoskeletal pathologies of these two nations with their close genetic affiliations, we performed a comparison on their elderly. Autopsy brain samples of 50 individuals from Colombo, Sri Lanka (mean age 72.1 yrs ± 7.8, mean ± S.D.) and 42 individuals from Bangalore, India (mean age 65.9 yrs ± 9.3) were screened for neurodegenerative pathologies using immunohistochemical techniques. A total of 79 cases with incomplete clinical history (Colombo- 47 and Bangalore- 32) were subjected to statistical analysis and 13 cases, clinically diagnosed with dementia and/or Parkinsonism disorders were excluded. As per National Institute on Aging- Alzheimer's Association guidelines, between Colombo and Bangalore samples, Alzheimer's disease neuropathologic change for intermediate/ high level was 4.25% vs. 3.12% and low level was 19.15% vs. 15.62% respectively. Pathologies associated with Parkinsonism including brainstem predominant Lewy bodies- 6.4% and probable progressive supra nuclear palsy- 2.13% were found solely in Colombo samples. Alzheimer related pathologies were not different among elders, however, in Colombo males, neurofibrillary tangle grade was significantly higher in the region of hippocampus (odds ratio = 1.46, 95% confidence interval = 0.07-0.7) and at risk in midbrain substantia nigra (p = 0.075). Other age-related pathologies including spongiform changes (p < 0.05) and hippocampus cell loss in dentate gyrus region (p < 0.05) were also identified prominently in Colombo samples. Taken together, aging cytoskeletal pathologies are comparatively higher in elderly Sri Lankans and this might be due to their genetic, dietary and/ or environmental variations.

Amyloid-Beta Positron Emission Tomography Imaging of Alzheimer's Pathology in Parkinson's Disease Dementia.

Neuronal loss and α-synuclein (α-syn) pathology are diagnostic of PD in the appropriate clinical context. However, some PD patients have co-morbid Alzheimer's disease (AD) pathology on autopsy, including amyloid-β (Aβ) plaques and neurofibrillary tangles. Florbetapir(18F) is a PET ligand that detects Aβ pathology. We hypothesized that florbetapir(18F) imaging could detect Aβ pathology in Parkinson disease dementia (PDD) patients prior to death. To determine the utility of florbetapir(18F) PET imaging in detecting Aβ pathology in patients with autopsy-confirmed PDD. Five participants with PDD had florbetapir(18F) PET imaging prior to death as a part of a longitudinal research study of cognitive decline in PD. PET scans were evaluated by expert raters blinded to clinical and neuropathological information. At autopsy, all five participants underwent semi-quantitative assessments of regional Aβ and tau immunohistochemistry. All participants met neuropathological criteria for PD. Two had both positive florbetapir(18F) scans and Aβ-positive plaques in multiple brain regions. Regional florbetapir(18F) binding correlated with regional semi-quantitative Aβ pathology in these cases. Three cases had negative florbetapir(18F) scans. Two of these had significant tau pathology without Aβ pathology, consistent with progressive supranuclear palsy (PSP) in one case and argyrophilic grain disease (AGD) in the other. The last case had a low level of AD neuropathological change. Florbetapir(18F) Aβ imaging can detect the presence of Aβ neuropathology in patients with PDD. This imaging technique may aid the clinical evaluation of PDD patients to determine if cognitive decline is occurring in the setting of Aβ accumulation.

Cerebrospinal Fluid Biomarkers Predict Clinical Evolution in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

Background: Determination of Alzheimer's disease (AD) by cerebrospinal fluid (CSF) biomarkers - 42-amino-acid amyloid-β (Aβ₄₂), total tau and phosphorylated tau (p-tau) - has demonstrated high validity for detecting AD neuropathological changes. However, their prognostic utility to predict the onset of dementia in predementia subjects is still questioned. We aimed to study the prospective clinical evolution of a group of subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) and to determine the prognostic capacity of AD CSF biomarkers. Methods: 149 subjects with MCI or SCD, not meeting dementia criteria, underwent a prospective clinical, neuropsychological and CSF biomarker study. Patients were initially classified as SCD or MCI following internationally accepted criteria. CSF sampling was obtained and analysed following consensus protocols. Neuropsychological and clinical evaluations were conducted at the follow-up. Statistical analysis considering the final clinical diagnosis, regression analysis to define risk factors and survival curves for progression were made. Results: 72.4% of subjects (83% MCI and 27% SCD) with a pathological CSF ratio (Aβ₄₂/p-tau) met criteria for dementia during the 5-year follow-up versus 18.7% of subjects from the group with a normal ratio. The pathological CSF ratio was a powerful marker of risk for AD dementia (OR 27.1; 95% CI 10.3-71.2). Kaplan-Meier survival curves showed that only 15% of subjects with a pathological CSF ratio remained free of AD dementia at 5 years of follow-up. All subjects who reverted to normal cognition presented a normal CSF profile at baseline. Conclusion: An abnormal AD CSF biomarker profile in predementia subjects is a powerful predictor of cognitive and/or functional decline in the medium term.

Tau Protein, Ischemic Injury and Vascular Dementia

Clinical, neuroimaging and neuropathological studies have confirmed overlap between Alzheimer's disease (AD) and vascular dementia (VaD). Classical neuropathological changes of AD (plaques and tangles) can be present in VaD. We review neuroimaging, biochemical and animal studies to consider the role of tau protein in ischemic injury and VaD pathogenesis. The evidence comes largely from transgenic animal studies that confirm that tau transgenes influence cerebral vasculature. Clinicobiochemical studies in the cerebrospinal fluid (CSF) have, similarly, confirmed alterations in both total and phosphorylated tau protein in VaD. These data suggest that tau protein not only serves as a potential diagnostic tool for differential diagnosis of VaD from other types of dementia, but may also be a therapeutic target in ischemic stroke.

Characterizing Apolipoprotein E ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques.

β-Amyloid peptide (Aβ) plaques are a cardinal neuropathologic feature of Alzheimer disease (AD), yet more than one-third of apolipoprotein E ε4 (APOE4) noncarriers with the clinical diagnosis of mild to moderate Alzheimer dementia may not meet positron emission tomographic criteria for significant cerebral amyloidosis. To clarify the percentage of APOE4 carriers and noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia near the end of life and minimal Aβ plaques noted at autopsy and the extent to which these cases are associated with appreciable neurofibrillary degeneration or a primary neuropathologic diagnosis other than AD. Data on participants included in this study were obtained from the National Alzheimer Coordinating Center's Uniform Data Set, which comprises longitudinal clinical assessments performed at the AD centers funded by the National Institute on Aging. Neuropathology data are available for the subset of participants who died. A total of 100 APOE4 noncarriers and 100 APOE4 carriers had the primary clinical diagnosis of mild to moderate Alzheimer dementia at their last visit, known APOE4 genotype, died within the ensuing 24 months, and underwent neuropathologic evaluation on autopsy. The study was conducted from September 1, 2005, to September 1, 2012; analysis was performed from October 9, 2012, to March 20, 2015. Standardized histopathologic assessments of AD neuropathologic changes were the primary measures of interest in this study, specifically Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque density score, diffuse plaque density score, and Braak stage for neurofibrillary degeneration. The distributions of scores for these measures were the primary outcomes. Of the 37 APOE4 noncarriers with minimal neuritic plaques, 16 individuals (43.2%) had Braak stages III to VI ratings, and 15 of the others (75.0%) met neuropathologic criteria for other dementia-related diseases. Of the 13 APOE4 carriers with minimal neuritic plaques, 6 individuals (46.2%) had Braak stages III to VI ratings and met neuropathologic criteria for other dementia-related diseases. Similarly, of the 7 APOE4 carriers with minimal neuritic plaques and Braak stages 0 to II, 4 participants (57.1%) were thought to have pathologic changes and alterations resulting from non-AD neuropathologic features. In this study, more than one-third of APOE4 noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia had minimal Aβ plaque accumulation in the cerebral cortex and, thus, may show limited or no benefit from otherwise effective anti-Aβ treatment. Almost half of the participants with a primary clinical diagnosis of mild to moderate Alzheimer dementia and minimal Aβ plaque accumulation had an extensive topographic distribution of neurofibrillary degeneration. Additional studies are needed to better understand and provide treatment for patients with this unexpectedly common cliniconeuropathologic condition.

Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease

IntroductionNeuropathologic assessment is the current “gold standard” for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used. MethodsFifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change. ResultsCurrent practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77–0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable. DiscussionAD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements.

Cerebral amyloid angiopathy and its co-occurrence with Alzheimer's disease and other cerebrovascular neuropathologic changes

We examined the relationship between cerebral amyloid angiopathy (CAA), Alzheimer's disease neuropathologic changes, other vascular brain pathologies, and cognition in a large multicenter autopsy sample. Data were obtained from the National Alzheimer's Coordinating Center on autopsied subjects (N = 3976) who died between 2002 and 2012. Descriptive statistics and multivariable regression models estimated the associations between CAA and other pathologies, and between CAA severity and cognitive test scores proximal to death. CAA tended to co-occur with Alzheimer's disease neuropathologic changes but a minority of cases were discrepant. CAA was absent in 22% (n = 520) of subjects with frequent neuritic plaques but present in 20.9% (n = 91) of subjects with no neuritic plaques. In subjects with no/sparse neuritic plaques, nonhemorrhagic brain infarcts were more common in those with CAA pathology than without (p = 0.007). In subjects without the APOE ε4 allele, CAA severity was associated with lower cognition proximal to death, factoring in other pathologies. The presence of CAA in patients without Alzheimer's disease may indicate a distinct cerebrovascular condition.

Genetic differences between symptomatic and asymptomatic persons with Alzheimer's disease neuropathologic change

Genetic differences between symptomatic and asymptomatic persons with Alzheimer's disease neuropathologic change

APOEε2 is associated with milder clinical and pathological Alzheimer disease.

The Alzheimer disease (AD) APOEε4 risk allele associates with an earlier age at onset and increased amyloid-β deposition, whereas the protective APOEε2 allele delays the onset and appears to prevent amyloid-β deposition. Yet the clinical and pathological effects of APOEε2 remain uncertain because of its relative rarity. We investigated the effects of APOEε2 and ε4 alleles on AD pathology and cognition in a large US data set of well-characterized AD patients. We studied individuals from the National Alzheimer's Coordinating Center autopsy cohort across the entire clinicopathological continuum of AD. Multivariate models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOEε3/ε3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination). Compared to APOEε3/ε3, APOEε2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOEε4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance (ε2 > ε3 > ε4). Mediation analysis suggests that this is largely explained through effects on pathology. Even when adjusted for age at onset, symptom duration, and other demographic variables, APOEε2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOEε3 and ε4 alleles, suggesting a relative neuroprotective effect of APOEε2 in AD.

In vivo SPECT imaging of amyloid-β deposition with radioiodinated imidazo[1,2-a]pyridine derivative DRM106 in a mouse model of Alzheimer's disease.

Noninvasive determination of amyloid-β peptide (Aβ) deposition has important significance for early diagnosis and medical intervention for Alzheimer's disease (AD). In the present study, we investigated the availability of radiolabeled DRM106 ((123/125)I-DRM106 [6-iodo-2-[4-(1H-3-pyrazolyl)phenyl]imidazo[1,2-a]pyridine]), a compound with sufficient affinity for the synthesis of human Aβ fibrils and satisfactory metabolic stability, as a SPECT ligand in living brains. The sensitivity of (125)I-DRM106 for detecting Aβ deposition was compared with that of (125)I-IMPY (2-(4'-dimethylaminophenyl)-6-iodo-imidazo[1,2-a]pyridine), a well-known amyloid SPECT ligand, by ex vivo autoradiographic analyses in 18-mo-old amyloid precursor protein transgenic mice. To verify the sensitivity and quantitation of radiolabeled DRM106 for in vivo imaging, we compared the detectability of Aβ plaques with (123)I-DRM106 and a well-known amyloid PET agent, (11)C-labeled Pittsburgh compound B ((11)C-PiB), in 29-mo-old transgenic mice and age-matched nontransgenic littermates. Additionally, we compared the binding characteristics of (125)I-DRM106 with those of (11)C-PiB and (11)C-PBB3, which selectively bind to Aβ plaques and preferentially to tau aggregates, respectively, in postmortem AD brain sections. Ex vivo autoradiographic analysis showed that measurement with (125)I-DRM106 has a higher sensitivity for detecting Aβ accumulation than with (125)I-IMPY in transgenic mice. SPECT imaging with (123)I-DRM106 also successfully detected Aβ deposition in living aged transgenic mice and showed strong correlation (R = 0.95, P < 0.01) in quantitative analysis for Aβ plaque detection by PET imaging with (11)C-PiB, implying that sensitivity and quantitation of SPECT imaging with (123)I-DRM106 are almost as good as (11)C-PiB PET for the detectability of Aβ deposition. Further, the addition of nonradiolabeled DRM106 fully blocked the binding of (125)I-DRM106 and (11)C-PiB, but not (11)C-PBB3, to AD brain sections, and (125)I-DRM106 showed a lower binding ratio of the diffuse plaque-rich lateral temporal cortex to the dense-cored/neuritic plaque-rich hippocampal CA1 area, compared with (11)C-PiB. All of these data demonstrated the high potential of (123)I-DRM106 for amyloid imaging in preclinical and clinical application, and it might more preferentially detect dense-cored/neuritic amyloid deposition, which is expected to be closely associated with neuropathologic changes of AD.

Neuropsychological changes in asymptomatic persons with Alzheimer disease neuropathology.

To determine whether asymptomatic persons with Alzheimer disease (AD) neuropathologic change differ in the trajectory of their cognitive performance compared to asymptomatic persons without AD neuropathologic change. Longitudinal performance on standard neuropsychological tests was examined in participants who died within 2 years of their last cognitive assessment and who were never diagnosed with mild cognitive impairment or dementia (Clinical Dementia Rating global score of 0 at all assessments). Using cognitive and neuropathologic data collected between 2005 and 2013 from the 34 National Institute on Aging-sponsored Alzheimer's Disease Centers, cognitive trajectories were compared for persons with and without evidence of AD neuropathologic change. We evaluated rates of decline in 4 domains (episodic memory, language, attention/working memory, executive function). The significance of the differences (β) in rates of decline was tested using linear regression, adjusting for age, education, sex, and other neuropathologic lesions. Participants who had low to high levels of AD neuropathologic change (n = 131) showed a greater rate of decline on the attention/working memory domain score (β = -0.11; 95% confidence interval = -0.19, -0.02; p = 0.02) when compared to 80 participants who died without evidence of AD neuropathologic change. Clinically normal individuals who come to autopsy with AD neuropathologic change exhibit subtle evidence of declining cognitive trajectories for attention/working memory.

Neuropathologic Changes Associated With Atrial Fibrillation in a Population-Based Autopsy Cohort

Atrial fibrillation (AF) is associated with higher risk of dementia and Alzheimer's disease. To better understand the mechanism, we examined neuropathologic changes seen with AF. We analyzed data from an autopsy series arising from a population-based, prospective cohort study set within Group Health, an integrated health care delivery system. Participants were people aged 65 and older, community-dwelling, and nondemented at study enrollment, who died during follow-up and underwent autopsy. AF was defined from medical records. Permanent AF was defined as having two or more electrocardiograms showing AF between 6 and 36 months apart with no evidence of sinus rhythm in between. The primary study outcomes were gross infarcts, neuritic plaques, and neurofibrillary tangles, ascertained using consensus guidelines. Adjusted relative risks and 95% CIs were calculated using modified Poisson regression, weighted to account for selection into the autopsy cohort. Three hundred and twenty-eight participants underwent autopsy; 134 (41%) had AF. People with AF were more likely to have gross infarcts than those without AF (45% vs 31%; relative risk 1.82, 95% CI 1.23-2.71); in 30%, these infarcts were not clinically recognized before death. Alzheimer's disease neuropathologic changes were not associated with ever having AF but were more common in people with permanent AF. Adjusted relative risks for frequent neuritic plaques and neurofibrillary tangles were 1.47 (0.96-2.28) and 1.40 (0.79-2.49), respectively, for people with permanent AF versus no AF. AF is associated with gross infarcts. Permanent AF may contribute to Alzheimer's disease neuropathologic changes, but more study is needed.

Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology

We sought to identify demographic and clinical features that were associated with expression of symptoms in the presence of Alzheimer disease (AD) neuropathologic changes. We studied 82 asymptomatic (Clinical Dementia Rating global score = 0) and 824 symptomatic subjects (Clinical Dementia Rating score >0) with low to high AD neuropathologic changes at autopsy who were assessed at 1 of 34 National Institute on Aging-funded Alzheimer's Disease Centers. All subjects underwent a clinical examination within 1 year of death. Logistic regression was used to evaluate factors associated with the odds of being asymptomatic vs symptomatic. Asymptomatic subjects tended to have low neurofibrillary tangle scores but a wide range of neuritic plaque frequencies. There were, however, a few asymptomatic subjects with very high tangle and neuritic plaque burden, as well as symptomatic subjects with few changes. In the multivariable model, asymptomatic subjects were older (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 1.01-1.07), had lower clinical Hachinski Ischemic Score (OR = 0.82; 95% CI = 0.69-0.97), were less likely to have an APOE ε4 allele (OR = 0.36; 95% CI = 0.16-0.83), and had lower neurofibrillary tangle score (OR = 0.28; 95% CI = 0.17-0.45) compared with symptomatic subjects. Dissociating clinical symptoms from pathologic findings better allows for investigation of preclinical AD. Our results suggest that although the severity of the pathology, particularly neurofibrillary tangles, has a large role in determining the extent of symptoms, other factors, including age, APOE status, and comorbidities such as cerebrovascular disease also explain differences in clinical presentation.

Digital pathology and image analysis for robust high-throughput quantitative assessment of Alzheimer disease neuropathologic changes.

Quantitative neuropathologic methods provide information that is important for both research and clinical applications. The technologic advancement of digital pathology and image analysis offers new solutions to enable valid quantification of pathologic severity that is reproducible between raters regardless of experience. Using an Aperio ScanScope XT and its accompanying image analysis software, we designed algorithms for quantitation of amyloid and tau pathologies on 65 β-amyloid (6F/3D antibody) and 48 phospho-tau (PHF-1)-immunostained sections of human temporal neocortex. Quantitative digital pathologic data were compared with manual pathology counts. There were excellent correlations between manually counted and digitally analyzed neuropathologic parameters (R² = 0.56-0.72). Data were highly reproducible among 3 participants with varying degrees of expertise in neuropathology (intraclass correlation coefficient values, >0.910). Digital quantification also provided additional parameters, including average plaque area, which shows statistically significant differences when samples are stratified according to apolipoprotein E allele status (average plaque area, 380.9 μm² in apolipoprotein E [Latin Small Letter Open E]4 carriers vs 274.4 μm² for noncarriers; p < 0.001). Thus, digital pathology offers a rigorous and reproducible method for quantifying Alzheimer disease neuropathologic changes and may provide additional insights into morphologic characteristics that were previously more challenging to assess because of technical limitations.

Finding a pathological diagnosis for Alzheimer's disease: Are inflammatory molecules the answer?

Conventional diagnostic tools for Alzheimer's disease (AD) are currently based on a number of clinical criteria, and a definitive diagnosis still relies on pathological evaluation at autopsy. Moreover, neurodegenerative changes are believed to begin years before clinical presentation. There is therefore an essential need for a reliable AD biomarker to aid in the identification of preclinical disease, early diagnosis, prediction of disease progression and treatment response. There is mounting evidence that chronic inflammatory processes play a fundamental role in the progression of neuropathological changes in AD. Clinical and experimental evidence supports the involvement of inflammatory changes in the early stages of AD, even before the appearance of amyloid deposits. Therefore biomarkers that reflect the inflammatory process in AD hold promise. Tests based on these should preferably be reliable, noninvasive and costeffective, which has led to an increasing focus on the use of blood-based biomarkers. This review considers the current progress in AD inflammatory biomarker research followed by a detailed analysis of two leading putative inflammatory biomarkers: α-2-macroglobulin and clusterin.

GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology

Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both. We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD). Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8-31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2-17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2-6.6; p = 0.92). There was a highly significant trend test across groups (χ(2)(1) = 19.3; p = 1.1 × 10(-5)), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB. GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.

Measurement of brain metabolites by 1H-MR spectroscopy in patients with Alzheimer disease: a Meta analysis

Objective To have a systemic review of the association between relative ratio in proton magnetic resonance spectroscopy (1H-MRS) and Alzheimer's disease (AD). Methods A search in Medline and China National Knowledge Infrastructure (CNKI) was performed,and relevant English and Chinese-language articles about assessing AD with 1 H-MRS were identifed.The data of relative metabolic ratios (NAA/Cr,Cho/Cr,mI/Cr ) from different brain regions (hippocampus,posterior cingulate gyrus,temporal lobe,parietal lobe,frontal lobe,occipital lobe) were extracted from the articles.The quality of the articles was evaluated according to the standard recommended by Newcastle-Ottawa criteria. The Meta-analysis was done with the Review Manager 4.2 to calculate pooled weighted mean difference (WMD) with 95％ confidence interval (95％ CI ),and linear correlation analysis between NAA/Cr ratio and mI/Cr ratio was done by SPSS 17.0.Results Thirty six articles (27 English articles,9 Chinese articles) were included. After heterogeneity test was done,fixed effects model or random effects model was selected. The meta-analysis showed that the NAA/Cr ratio in patients with AD was higher than that in controls ( WMD:-0.14,95％CI:-0.17 to -0.11 ).The mI/Cr ratio in patients with AD was lower than that in controls ( WMD:0.10,95％ CI:0.07 to 0.13 ).There were greatest changes in NAA/Cr ratio and mI/Cr ratio on the hippocampus ( WMD of NAA/Cr: - 0.27,95％ CI:- 0.36 to - 0.19 ; WMD of mI/Cr:0.21,95％ CI:0.10 to 0.33). There were also no differences between patients with AD and controls with respect to the Cho/Cr ratio (WMD:0.01,95％ CI:0.00 to 0.01,P ＞0.05). The NAA/Cr and mI/Cr changes are markedly correlated with each other in different brain regions ( r =0.947,P =0.004). Conclusion The hippocampus region is the first to present neuropathological changes in AD and the changes of NAA/Cr and MI/Cr might reflect the neurodegenerative process of AD. Key words: Alzheimer disease ; Magnetic resonance spectroscopy ; Meta analysis