Typical Alzheimer's Disease Patients Research Articles

Understand the uncoupling of tauopathy and dementia through comparative analysis of subgroups of atypical Alzheimer's disease patients.

Typical Alzheimer's disease (AD) patient brains show characteristic neurofibrillary tangles (NFTs), which protein tau aggregates to form bundles of microtubule-associated neurofibrillary tangle (NFT). A major focus of AD research has been the understanding of the roles of pathological tau in neurons and NFTs (tauopathy) in the disease initiation and progression, which severity can be measured with Braak staging. A subpopulation of patients also exist, whose brain showed typical AD-like high NFTs, but with no or low cognitive deterioration (Asymptomatic AD or AsymAD) or present severe cognitive impairment but low NFTs (low-NFT AD). We performed differential expression analyses on both RNA and protein expression data from the atypical groups of MSBB and ROSMAP using typical AD patients as reference, then combined with pathway analysis to search for enriched pathway and upstream regulators which may play the neuron-protective or neuron-vulnerable role in the two atypical AD subgroups. We identified oppositely regulated pathways as compared with typical AD group for the two atypical groups in MSBB cohort, such as oxidative phosphorylation pathway. Several enriched pathways related to immune response in the brain in the low-NFT AD group are absent from AsymAD group. In ROSMAP cohort, we identified higher expression of actin-binding proteins and ROS eliminating genes in AsymAD group, as well as higher expression of immune-related proteins/mRNAs and PP1 regulatory genes/proteins in the low-NFT AD group. Through the comparative analyses on transcriptomic and proteomic data, we identified several pathways/genes that may potentially render neuron-protection or neuron-vulnerability to AD for subgroups of atypical AD patients, including oppositely regulated oxidative phosphorylation and mitochondrial functions, elevated actin binding signals in AsymAD, and elevated inflammatory and PP1 regulatory signals in low-NFT AD group. Further bioinformatic analysis will be performed to identify candidate genes/proteins and prioritize them for future in vivo animal model experiments. This work will not only improve precision medicine in AD, but also provide insights to prevent or slow down cognitive impairment during the long disease progression.

A systematic review of atypical Alzheimer's disease including behavioural and psychological symptoms.

Alzheimer's disease (AD) is the commonest cause of dementia, characterized by the clinical presentation of progressive anterograde episodic memory impairment. However, atypical presentation of patients is increasingly recognized. These atypical AD include logopenic aphasia, behavioural variant AD, posterior cortical atrophy, and corticobasal syndrome. These atypical AD are more common in patients with young onset AD before the age of 65 years old. Since medical needs (including the behavioural and psychological symptoms of dementia) of atypical AD patients could be different from typical AD patients, it is important for clinicians to be aware of these atypical forms of AD. In addition, disease modifying treatment may be available in the future. This review aims at providing an update on various important subtypes of atypical AD including behavioural and psychological symptoms.

Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer's disease (AD). We report the molecular structure of a specific fibril polymorph, formed by 40-residue Aβ peptides (Aβ40), that is derived from cortical tissue of an AD patient by seeded fibril growth. The structure is determined from cryogenic electron microscopy (cryoEM) images, supplemented by mass-per-length (MPL) measurements and solid-state NMR (ssNMR) data. Previous ssNMR studies with multiple AD patients had identified this polymorph as the most prevalent brain-derived Aβ40 fibril polymorph from typical AD patients. The structure, which has 2.8-Å resolution according to standard criteria, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformations and its organization of cross-β subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three Aβ40 molecules per 4.8-Å β-sheet spacing, a four-layered architecture, and fully extended conformations for molecules in the central two cross-β layers. The cryoEM density, ssNMR data, and MPL data are consistent with β-hairpin conformations for molecules in the outer cross-β layers. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.

Parieto-occipital sulcus widening differentiates posterior cortical atrophy from typical Alzheimer disease

ObjectivesPosterior Cortical Atrophy (PCA) is an atypical presentation of Alzheimer disease (AD) characterized by atrophy of posterior brain regions. This pattern of atrophy is usually evaluated with Koedam visual rating scale, a score developed to enable visual assessment of parietal atrophy on magnetic resonance imaging (MRI). However, Koedam scale is complex to assess and its utility in the differential diagnosis between PCA and typical AD has not been demonstrated yet. The aim of this study is therefore to spot a simple and reliable MRI element able to differentiate between PCA and typical AD using visual rating scales. Methods15 patients who presented with progressive complex visual disorders and predominant occipitoparietal hypometabolism on PET-FDG were selected from our centre and compared with 30 typical AD patients and 15 healthy subjects. We used previously validated visual rating scales including Koedam scale, which we divided into three major components: posterior cingulate, precuneus and parieto-occipital. Subsequently we validated the results using the automated software Brainvisa Morphologist and Voxel Based Morphometry (VBM). ResultsPatients with PCA, compared to typical AD, showed higher widening of the parieto-occipital sulcus, assessed both with visual rating scales and Brainvisa. In the corresponding areas, the VBM analysis showed an inverse correlation between the results obtained from the visual evaluation scales with the volume of the grey matter and a direct correlation between the same results with the cerebrospinal fluid volume. ConclusionsA visually based rating scale for parieto-occipital sulcus can distinguish Posterior Cortical Atrophy from typical Alzheimer disease.

Working memory in posterior cortical atrophy.

We used an ad hoc created neuropsychological battery to evaluate in details both verbal and visuospatial working memory (WM) in patients with posterior cortical atrophy (PCA, n = 5). PCA is a rare, early-onset neurodegenerative dementia, often due to Alzheimer's disease (AD) pathology. Clinically, PCA patients present with visual, visuospatial, and visuomotor deficits, and no memory complaints. PCA patients' patterns of performance were compared with those of 11 typical, amnestic AD patients matched for disease severity, as well as with 17 age-matched healthy controls. Both groups of patients had impaired WM performance compared to controls. However, PCA patients were more impaired than typical AD patients for both verbal and visuospatial WM. Moreover, PCA patients showed a more consistent impairment of visuospatial WM, as compared with verbal WM. Systematic WM evaluation should be part of the standard assessment in PCA. WM deficits affect patients' quality of life and can be detrimental to rehabilitation programs.

Amyloid PET Positivity in Different Primary Progressive Aphasia Phenotypes.

Primary progressive aphasia (PPA) is a neurological syndrome in which language functions become progressively impaired with relative sparing of memory and other instrumental functions. The pathologic causes of PPA are heterogeneous, but studies suggest that logopenic PPA (LPA) is underpinned by Alzheimer disease (AD) pathology in a high proportion of cases. The purposes of this descriptive and retrospective study were to characterize F-florbetapir PET imaging in a group of patients with a clinical syndrome of PPA, to determine the value of clinical characterization based on language phenotype in predicting the underlying pathology of PPA with F-florbetapir, and to quantify amyloid load in PPA subjects classified as "positive" F-florbetapir scans. Then, we compare the quantification and distribution of F-florbetapir uptake with those of typical, predominantly amnestic AD patients. We conducted a PET study with F-florbetapir in a cohort of 12 right-handed patients diagnosed with PPA: 3 patients with semantic-variant PPA, 5 with nonfluent PPA, 1 with LPA, and 3 unclassifiable patients. We evaluated amyloid deposition between APP groups and 11 patients with typical amnestic AD. Among the 12 patients with PPA syndrome, 8 (66.7%) were considered as amyloid positive. One of the 3 patients with semantic-variant PPA was F-florbetapir positive. In contrast, 4 of the 5 nonfluent-variant PPA, 2 of the 3 unclassifiable cases and the single patient with LPA were F-florbetapir positive. A significantly higher F-florbetapir uptake was observed in PPA F-florbetapir-positive patients compared with typical AD patients. This difference was observed in all regions of interest, except in posterior cingulate and temporal cortex. These results suggest that F-florbetapir PET may be useful in a routine clinical procedure to improve the reliability of identifying AD pathology in patients with PPA syndrome, with different clinical subtypes of the PPA syndrome.

Association between precuneus volume and autobiographical memory impairment in posterior cortical atrophy: Beyond the visual syndrome.

Posterior cortical atrophy is a neurodegenerative syndrome characterised by progressive disruption of visual and perceptual processing, associated with atrophy in the parieto-occipital cortex. Current diagnostic criteria describe relative sparing of episodic memory function, but recent findings suggest that anterograde memory is often impaired. Whether these deficits extend to remote memory has not been addressed. A large body of evidence suggests that the recollection of an autobiographical event from the remote past coincides with the successful retrieval of visual images. We hypothesised that the profound visual processing deficits in posterior cortical atrophy would result in impaired autobiographical memory retrieval. Fourteen posterior cortical atrophy patients, eighteen typical Alzheimer's disease patients and twenty-eight healthy controls completed the Autobiographical Interview. Autobiographical memory in posterior cortical atrophy was characterised by a striking loss of internal, episodic detail relative to controls and to same extent as typical Alzheimer's disease patients, in conjunction with an increase in external details tangential to the memory described. The memory narratives of posterior cortical atrophy patients showed a specific reduction in spatiotemporal and perceptual detail. Voxel-based morphometry analysis revealed atrophy of the parieto-occipital cortices in posterior cortical atrophy but relatively spared hippocampi bilaterally, compared with characteristic atrophy of the medial temporal lobes in typical Alzheimer's disease. Analysis of brain regions showing posterior cortical atrophy-specific atrophy revealed a correlation between perceptual details in autobiographical memory and grey matter density in the right precuneus. This study demonstrates remote memory impairment in posterior cortical atrophy despite relatively preserved medial temporal lobe structures. The results demonstrate, for the first time, profound autobiographical memory impairment in PCA and suggest that this is driven by the well-recognised deficits in higher-order visual processing. The findings are discussed in the context of posterior parietal contributions to imagery and memory, and the clinical implications of autobiographical memory impairment for diagnostic and management protocols in posterior cortical atrophy.

A Pilot Study on Clinical and Neuroimaging Characteristics of Chinese Posterior Cortical Atrophy: Comparison with Typical Alzheimer's Disease.

Posterior cortical atrophy (PCA) is a clinicoradiologic neurodegenerative syndrome characterized by predominant impairment of higher visual functions. Neuroimaging and neuropathological studies show that PCA is probably an atypical presentation of Alzheimer’s disease. However, in China PCA has rarely been studied and remains largely unknown. Our study therefore aimed to analyze the clinical manifestations and patterns of cerebral atrophy, amyloid beta deposition and regional glucose metabolism in Chinese PCA patients, comparing them directly with those of typical Alzheimer’s disease (TAD). Seven PCA patients, 6 TAD patients and 5 controls underwent neuropsychological assessment, MRI scan, 11C-PIB PET scan and 18F-FDG PET scan. Cerebral atrophy including ventricular enlargement, posterior atrophy and medial temporal lobe atrophy were evaluated with MRI. The uptake of 11C-PIB was quantified at the voxel level using the standardized uptake value ratio. Comparisons of regional cerebral glucose metabolism were calculated with statistical parametric mapping. PCA patients showed significant impairment on visuospatial function in neuropsychological assessment. And PCA patients showed more severe posterior atrophy and less severe left medial temporal lobe atrophy compared with TAD patients. The data from 11C-PIB PET scanning showed that amyloid beta deposition in PCA was comparable to TAD. Moreover, in PCA the results from 18F-FDG PET scanning revealed significant hypometabolism in the temporoparietooccipital region and identified specific hypometabolism in the right occipital lobe, compared with TAD. Our study thus provides a preliminary view of PCA in Chinese patients. A further study with a larger number of subjects would be recommended to confirm these findings.

Reduced modulation of scanpaths in response to task demands in posterior cortical atrophy

A difficulty in perceiving visual scenes is one of the most striking impairments experienced by patients with the clinico-radiological syndrome posterior cortical atrophy (PCA). However whilst a number of studies have investigated perception of relatively simple experimental stimuli in these individuals, little is known about multiple object and complex scene perception and the role of eye movements in posterior cortical atrophy. We embrace the distinction between high-level (top-down) and low-level (bottom-up) influences upon scanning eye movements when looking at scenes. This distinction was inspired by Yarbus (1967), who demonstrated how the location of our fixations is affected by task instructions and not only the stimulus’ low level properties. We therefore examined how scanning patterns are influenced by task instructions and low-level visual properties in 7 patients with posterior cortical atrophy, 8 patients with typical Alzheimer’s disease, and 19 healthy age-matched controls.Each participant viewed 10 scenes under four task conditions (encoding, recognition, search and description) whilst eye movements were recorded. The results reveal significant differences between groups in the impact of test instructions upon scanpaths. Across tasks without a search component, posterior cortical atrophy patients were significantly less consistent than typical Alzheimer's disease patients and controls in where they were looking. By contrast, when comparing search and non-search tasks, it was controls who exhibited lowest between-task similarity ratings, suggesting they were better able than posterior cortical atrophy or typical Alzheimer’s disease patients to respond appropriately to high-level needs by looking at task-relevant regions of a scene. Posterior cortical atrophy patients had a significant tendency to fixate upon more low-level salient parts of the scenes than controls irrespective of the viewing task. The study provides a detailed characterisation of scene perception abilities in posterior cortical atrophy and offers insights into the mechanisms by which high-level cognitive schemes interact with low-level perception.

The Centiloid Project: Standardizing quantitative amyloid plaque estimation by PET

Although amyloid imaging with PiB-PET ([C-11]Pittsburgh Compound-B positron emission tomography), and now with F-18-labeled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (≤45 years) and typical Alzheimer's disease patients. The units of this scale have been named “Centiloids.” Basically, we describe a “standard” method of analyzing PiB PET data and then a method for scaling any “nonstandard” method of PiB PET analysis (or any other tracer) to the Centiloid scale.

REDUCED MODULATION OF SCANPATHS IN RESPONSE TO TASK DEMANDS IN POSTERIOR CORTICAL ATROPHY

A difficulty in perceiving visual scenes is one of the most striking impairments experienced by patients with the clinico-radiological syndrome posterior cortical atrophy (PCA). However whilst a number of studies have investigated perception of relatively simple experimental stimuli in these individuals, little is known about multiple object and complex scene perception and the role of eye movements in posterior cortical atrophy. We embrace the distinction between high-level (top-down) and low-level (bottom-up) influences upon scanning eye movements when looking at scenes. This distinction was inspired by Yarbus (1967), who demonstrated how the location of our fixations is affected by task instructions and not only the stimulus' low level properties. We therefore examined how scanning patterns are influenced by task instructions and low-level visual properties in 7 patients with posterior cortical atrophy, 8 patients with typical Alzheimer's disease, and 19 healthy age-matched controls. Each participant viewed 10 scenes under four task conditions (encoding, recognition, search and description) whilst eye movements were recorded. The results reveal significant differences between groups in the impact of test instructions upon scanpaths. Across tasks without a search component, posterior cortical atrophy patients were significantly less consistent than typical Alzheimer's disease patients and controls in where they were looking. By contrast, when comparing search and non-search tasks, it was controls who exhibited lowest between-task similarity ratings, suggesting they were better able than posterior cortical atrophy or typical Alzheimer's disease patients to respond appropriately to high-level needs by looking at task-relevant regions of a scene. Posterior cortical atrophy patients had a significant tendency to fixate upon more low-level salient parts of the scenes than controls irrespective of the viewing task. The study provides a detailed characterisation of scene perception abilities in posterior cortical atrophy and offers insights into the mechanisms by which high-level cognitive schemes interact with low-level perception.

FACILITATING READING IN POSTERIOR CORTICAL ATROPHY

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterised by progressive visual impairment and parietal and occipital brain atrophy. Most frequently a consequence of underlying Alzheimer's disease (AD) pathology, PCA involves prominent visuoperceptual and visuospatial impairment with relatively spared episodic memory and insight. Reading problems, particularly when reading passages of text, are a common and debilitating early symptom of PCA, occurring as a result of deficits including visual disorientation, visual crowding, and a reduced effective field of vision. This project intends to 1) conduct the first quantitative investigation of passage reading deficits in PCA; 2) maximise reading ability in PCA by manipulating the presentation of text in order to circumvent dementia-related visual deficits. 15 PCA, 6 typical AD and 6 healthy control participants read aloud news articles presented normally or under two reading interventions (single- and double-word). Reading interventions were developed based on the notion that reducing the spatial, perceptual and oculomotor demands of passage reading would support poor reading in PCA. The efficacy of reading interventions was evaluated through reading performance (accuracy, latency and independent ratings of global comprehension), measures of eye tracking (fixations and saccades) and self-rated measures of reading ability (ease and comprehension). PCA patients' mean reading accuracy for normal passage text was 57.2% in contrast to near-ceiling accuracy in typical AD patients (97.5%) and healthy controls (99.4%); spatial aspects of text were the primary determinants of passage reading ability in PCA (see Figure 1). PCA patients made more saccades, more fixations and longer fixations than typical AD patients (p<.05) and healthy controls (p<.005; see Table 1). The interventions led to considerable and consistent gains in PCA patients' reading accuracy (both p<.001). Under the single-word intervention, mean reading accuracy increased from 57.2% to 95.6%. PCA patients' fixations were of increased duration and saccades were of decreased amplitude (both p<.05). Both interventions also resulted in improvements on self-rated measures of reading (ease: both p<.005; comprehension: both p<.005; pleasantness; both p<.05). Findings highlight the contribution of various visual and oculomotor deficits in limiting reading above the single-word level in PCA and provide a basis for developing software-based reading aids. A) Heatmap of PCA accuracy data from a sample passage (mean group accuracy rates: PCA=75%, tAD=98%, controls=100%). Lighter colours indicates the location of words most commonly missed or mis-read, and indicates spatial blases towards worse reading in later paragraph and lines and in the centre of dense, crowded passages of text. B) Order of first forty words read by i) a PCA patient with MMSE score = 13/30; and, ii) a PCA patient with MMSE score = 22/30. Transcripts of the participants' corresponding spoken output are beneath each example (Italicised text). Numbers refer to where words were repeated. Each hyphen (-) in the transcript beneath each example indicates a pause of 3 seconds.

Neural Correlates of Spatial Navigation Changes in Mild Cognitive Impairment and Alzheimer’s Disease

Although the memory impairment is a hallmark of Alzheimer’s disease (AD), AD has also been characterized by spatial disorientation, which is present from its early stages. Spatial disorientation in AD manifests itself in getting lost in familiar and unfamiliar places and have been characterized more specifically using spatial navigation tests in both real space and virtual environments as an impairment in multiple spatial abilities, including allocentric and egocentric navigation strategies, visuo-spatial perception, or selection of relevant information for successful navigation. Patients suffering mild cognitive impairment (MCI), who are at a high risk of development of dementia, show impairment in a subset of these abilities, mainly connected with allocentric and egocentric processing. While spatial disorientation in typical AD patients probably reflects neurodegenerative changes in medial and posterior temporal, parietal, and frontal lobes, and retrosplenial cortex, the impairment of spatial navigation in MCI seem to be connected mainly with the medial temporal and also parietal brain changes. In this review, we will summarize the signs of brain disease in most MCI and AD patients showing in various tasks of spatial memory and navigation.

Temporoparietal Cortex Atrophy Suggests Alzheimer's

Jeff Evans is a senior editor with Elsevier Global Medical News. BALTIMORE — Atrophy in the temporoparietal cortex might be a common identifier of Alzheimer's disease patients that differentiates individuals who have atypical clinical presentations of the disease from those who have other types of dementia, according to a small magnetic resonance scanning study. Patients who have an atypical presentation of Alzheimer's disease (AD) but nonetheless have the amyloid-beta plaques and neurofibrillary tangles of tau protein that pathologically identify the disease have much less hippocampal atrophy than do patients who present with the typical clinical characteristics used to diagnose AD—loss of episodic memory, executive dysfunction, visuospatial and perceptual deficits, and language dysfunction—Keith A. Josephs, MD, reported at the annual meeting of the American Neurological Association. Differentiating AD from other dementias is important if treatments differ, said Dr. Josephs of the department of neurology at the Mayo Clinic, Rochester, Minn. He and his associates compared 14 atypical AD patients with 14 patients with pathologically diagnosed frontotemporal lobar degeneration (FTLD) who had the same dementia syndromes. They also compared the atypical AD patients with 14 patients who had both the typical clinical symptoms and pathological signs of AD and with 20 healthy patients as controls. In each group, patients had a mean age of about 64 years at disease onset with a mean of 3.4 years from disease onset to the time of the MRI scan. Half of the patients in each group were women. The typical AD patients showed expected areas of atrophy in the temporoparietal cortex and hippocampi. However, atypical AD patients had temporoparietal atrophy but no hippocampal atrophy. FTLD patients had anterior-temporal, some posterior-frontal, and hippocampal atrophy. “Temporoparietal atrophy may be a signature of Alzheimer's disease independent of syndromic presentation…. Hippocampal atrophy does not appear to be at least an early prominent feature of atypical Alzheimer's disease. Later on, 5-6 years down the road, as the process progresses and there's degeneration, well, you might find hippocampal atrophy then,” Dr. Josephs said.

アルツハイマー病は血管病としての治療すべきである（Ｐｒｏ）

Elevated plasma homocysteine levels are associated with an increased risk of developing atherosclerotic vascular disorders such as stroke, but have also been implicated for neurodegenerative diseases including Alzheimer's disease (AD). Other studies have reported that hyperhomocysteinemia is associated with developing silent brain infarctions and white matter lesions in community-dwelling elderly people. It is not uncommon for such ischemic cerebrovascular lesions to be found in otherwise typical AD patients on magnetic resonance imaging. Such co-existing cerebrovascular diseases in AD must be important in developing aspiration pneumonia and falls. Previous studies demonstrated that basal ganglia infarcts, either silent or symptomatic, impaired swallowing function and these lesions were associated with an increased risk of developing aspiration pneumonia in AD patients, particularly in later stages. Further, periventricular white matter lesions are associated with an increased risk of falls irrespective of clinical stages of AD.