Alzheimer's Disease and Non-Demented High Pathology Control Nonagenarians: Comparing and Contrasting the Biochemistry of Cognitively Successful Aging

Amyloid plaques stained by the Campbell-Switzer technique.

The histological fields are representative of the amyloid plaque burden shown in 40 µm coronal sections of the frontal lobe.

The amyloid cascade hypothesis provides an economical mechanistic explanation for Alzheimer's disease (AD) dementia and correlated neuropathology. However, some nonagenarian individuals (high pathology controls, HPC) remain cognitively intact while enduring high amyloid plaque loads for decades. If amyloid accumulation is the prime instigator of neurotoxicity and dementia, specific protective mechanisms must enable these HPC to evade cognitive decline. We evaluated the neuropathological and biochemical differences existing between non-demented (ND)-HPC and an age-matched cohort with AD dementia. The ND-HPC selected for our study were clinically assessed as ND and possessed high amyloid plaque burdens. ELISA and Western blot analyses were used to quantify a group of proteins related to APP/Aβ/tau metabolism and other neurotrophic and inflammation-related molecules that have been found to be altered in neurodegenerative disorders and are pivotal to brain homeostasis and mental health. The molecules assumed to be critical in AD dementia, such as soluble or insoluble Aβ40, Aβ42 and tau were quantified by ELISA. Interestingly, only Aβ42 demonstrated a significant increase in ND-HPC when compared to the AD group. The vascular amyloid load which was not used in the selection of cases, was on the average almost 2-fold greater in AD than the ND-HPC, suggesting that a higher degree of microvascular dysfunction and perfusion compromise was present in the demented cohort. Neurofibrillary tangles were less frequent in the frontal cortices of ND-HPC. Biochemical findings included elevated vascular endothelial growth factor, apolipoprotein E and the neuroprotective factor S100B in ND-HPC, while anti-angiogenic pigment epithelium derived factor levels were lower. The lack of clear Aβ-related pathological/biochemical demarcation between AD and ND-HPC suggests that in addition to amyloid plaques other factors, such as neurofibrillary tangle density and vascular integrity, must play important roles in cognitive failure (Full text).

Neuropathologic Correlates of Hippocampal Atrophy in the Elderly: A Clinical, Pathologic, Postmortem MRI Study

The volume of the hippocampus measured with structural magnetic resonance imaging (MRI) is increasingly used as a biomarker for Alzheimer's disease (AD). However, the neuropathologic basis of structural MRI changes in the hippocampus in the elderly has not been directly assessed. Postmortem MRI of the aging human brain, combined with histopathology, could be an important tool to address this issue. Therefore, this study combined postmortem MRI and histopathology in 100 elderly subjects from the Rush Memory and Aging Project and the Religious Orders Study. 

A typical three-dimensional region of interest created by manually outlining the hippocampal formation in consecutive T₂-weighted sagittal images of a human cerebral hemisphere.

Shape analysis of (A) hippocampi affected by Alzheimer's disease (AD) and not hippocampal sclerosis (HS) compared to controls, (B) hippocampi most severely affected by AD compared to controls, and (C) hippocampi affected by HS with or without AD compared to controls.The top row of images contains the superior view of the hippocampus, while the bottom row contains the inferior view. Within each comparison, the left side shows a map of the difference in distance between points on the surface mesh of the first group versus the corresponding points on the surface mesh of the second group, projected along a unit vector that is normal to the surface. Thus, red shading shows areas of inward deformation of the first group relative to the second group, and green shading shows areas of outward deformation. The right side of each comparison shows significance maps with color indicating P-value. The significance maps show regions where points on the surface mesh of the first group are significantly displaced from the corresponding points on the surface mesh of the second group in any direction.

First, to validate the information contained in postmortem MRI data, we tested the hypothesis that postmortem hippocampal volume is smaller in subjects with clinically diagnosed Alzheimer's disease compared to subjects with mild or no cognitive impairment, as observed in antemortem imaging studies. Subsequently, the relations of postmortem hippocampal volume to AD pathology, Lewy bodies, amyloid angiopathy, gross infarcts, microscopic infarcts, and hippocampal sclerosis were examined. It was demonstrated that hippocampal volume was smaller in persons with a clinical diagnosis of AD compared to those with no cognitive impairment (P = 2.6×10⁻⁷) or mild cognitive impairment (P = 9.6×10⁻⁷). Additionally, hippocampal volume was related to multiple cognitive abilities assessed proximate to death, with its strongest association with episodic memory. Among all pathologies investigated, the most significant factors related to lower hippocampal volume were shown to be AD pathology (P = 0.0018) and hippocampal sclerosis (P = 4.2×10⁻⁷). Shape analysis allowed for visualization of the hippocampal regions most associated with volume loss for each of these two pathologies. Overall, this investigation confirmed the relation of hippocampal volume measured postmortem to clinical diagnosis of AD and measures of cognition, and concluded that both AD pathology and hippocampal sclerosis affect hippocampal volume in old age, though the impacts of each pathology on the shape of the hippocampus may differ.

Reference: Dawe RJ, Bennett DA, Schneider JA, Arfanakis K, 2011 Neuropathologic Correlates of Hippocampal Atrophy in the Elderly: A Clinical, Pathologic, Postmortem MRI Study. PLoS ONE 6(10): e26286. doi:10.1371/journal.pone.0026286 Free full text

Cerebrospinal Fluid Levels of sAPPα and sAPPβ in Lewy Body and Alzheimer's Disease: Clinical and Neurochemical Correlates

AbstractWe measured cerebrospinal fluid (CSF) levels of the soluble isoforms of amyloid precursor protein (APP; sAPPα sAPPβ) and other CSF biomarkers in 107 patients with Alzheimer's disease (AD), dementia with Lewy body dementia (DLB), Parkinson's disease dementia (PDD), and normal controls (NC) using commercial kits. DLB and PDD were combined in a Lewy body dementia group (LBD). No differences were observed in sAPPα and sAPPβ levels between the groups. Significant correlations were observed between sAPPα and sAPPβ and between sAPPβ and Mini-Mental State Examination scores in the total group analysis as well as when LBD and AD groups were analyzed separately. sAPPα and sAPPβ levels correlated with Aβ38, Aβ40, Aβ42, and Tau in the LBD group. In AD, sAPPα correlated with p-Tau and sAPPβ with Aβ40. The differential association between sAPPα and sAPPβ with Aβ and Tau species between LBD and AD groups suggests a possible relationship with the underlying pathologies in LBD and AD.

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Leading role of 18F-FDG-PET imaging in early diagnosis of Alzheimer’s disease: an overview

Early detection of Alzheimer’s disease (AD) is important to reveal preclinical pathological alterations, to monitor disease progression, and to evaluate response to therapy. The study of cerebral glucose metabolism through ¹⁸F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) plays a leading role in early detection of AD because the decrease of cerebral glucose metabolism largely precedes the onset of AD symptoms. This technique demonstrated high sensitivity in early diagnosis of AD, allowing a qualitative and quantitative estimate of cerebral glucose metabolism. Furthermore FDG-PET imaging may help to discriminate the subjects of a high-risk population (like patients with mild cognitive impairment) who more probably will develop AD: an early stage of AD generally shows hypometabolism of medial temporal lobes and parietotemporal posterior cortices; other cerebral cortices are later involved. The combination of FDG-PET with other biomarkers, such as genotype, cerebrospinal fluid markers, and amyloid plaque imaging, may increase the preclinical diagnostic accuracy and offer promising approaches to assess individual prognosis in AD patients.

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Multiple Indices of Diffusion Identifies White Matter Damage in Mild Cognitive Impairment and Alzheimer’s Disease

The study of multiple indices of diffusion, including axial (DA), radial (DR) and mean diffusion (MD), as well as fractional anisotropy (FA), enables WM damage in Alzheimer’s disease (AD) to be assessed in detail. Here, tract-based spatial statistics (TBSS) were performed on scans of 40 healthy elders, 19 non-amnestic MCI (MCIna) subjects, 14 amnestic MCI (MCIa) subjects and 9 AD patients. Significantly higher DA was found in MCIna subjects compared to healthy elders in the right posterior cingulum/precuneus. Significantly higher DA was also found in MCIa subjects compared to healthy elders in the left prefrontal cortex, particularly in the forceps minor and uncinate fasciculus. In the MCIa versus MCIna comparison, significantly higher DA was found in large areas of the left prefrontal cortex. For AD patients, the overlap of FA and DR changes and the overlap of FA and MD changes were seen in temporal, parietal and frontal lobes, as well as the corpus callosum and fornix. Analysis of differences between the AD versus MCIna, and AD versus MCIa contrasts, highlighted regions that are increasingly compromised in more severe disease stages. Microstructural damage independent of gross tissue loss was widespread in later disease stages. Our findings suggest a scheme where WM damage begins in the core memory network of the temporal lobe, cingulum and prefrontal regions, and spreads beyond these regions in later stages. DA and MD indices were most sensitive at detecting early changes in MCIa.

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Combined imaging markers dissociate Alzheimer’s disease and frontotemporal lobar degeneration – an ALE meta-analysis

To compare and dissociate the neural correlates of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD), we combine and synthesize here recent comprehensive meta-analyses. Systematic and quantitative meta-analyses were conducted according to the QUOROM statement by calculating anatomical likelihood estimates (ALE). AD (n = 578) and the three subtypes of FTLD, frontotemporal dementia, semantic dementia (SD), and progressive non-fluent aphasia (n = 229), were compared in conjunction analyses, separately for atrophy and reductions in glucose metabolism. Atrophy coincided in the amygdala and hippocampal head in AD and the FTLD subtype SD. The other brain regions did not show any overlap between AD and FTLD subtypes for both atrophy and changes in glucose metabolism. For AD alone (n = 826), another conjunction analysis revealed a regional dissociation between atrophy and hypoperfusion/hypometabolism, whereby hypoperfusion and hypometabolism coincided in the angular/supramarginal gyrus and inferior precuneus/posterior cingulate gyrus. Our data together with other imaging studies suggest a specific dissociation of AD and FTLD if, beside atrophy, additional imaging markers in AD such as abnormally low parietal glucose utilization and perfusion are taken into account. Results support the incorporation of standardized imaging inclusion criteria into future diagnostic systems, which is crucial for early individual diagnosis and treatment in the future (Full text).

Multi-modal MRI analysis with disease-specific spatial filtering: initial testing to predict mild cognitive impairment patients who convert

Background: Alterations of the gray and white matter have been identified in Alzheimer’s disease (AD) by structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). However, whether the combination of these modalities could increase the diagnostic performance is unknown. Methods: Participants included 19 AD patients, 22 amnestic mild cognitive impairment (aMCI) patients, and 22 cognitively normal elderly (NC). The aMCI group was further divided into an “aMCI-converter” group (converted to AD dementia within 3 years), and an “aMCI-stable” group who did not convert in this time period. A T1-weighted image, a T2 map, and a DTI of each participant were normalized, and voxel-based comparisons between AD and NC groups were performed. Regions-of-interest, which defined the areas with significant differences between AD and NC, were created for each modality and named “disease-specific spatial filters” (DSF). Linear discriminant analysis was used to optimize the combination of multiple MRI measurements extracted by DSF to effectively differentiate AD from NC. The resultant DSF and the discriminant function were applied to the aMCI group to investigate the power to differentiate the aMCI-converters from the aMCI-stable patients. Results: The multi-modal approach with AD-specific filters led to a predictive model with an area under the receiver operating characteristic curve (AUC) of 0.93, in differentiating aMCI-converters from aMCI-stable patients. This AUC was better than that of a single-contrast-based approach, such as T1-based morphometry or diffusion anisotropy analysis. Conclusion: The multi-modal approach has the potential to increase the value of MRI in predicting conversion from aMCI to AD (Full text).