Posterior Cortical Atrophy Patients Research Articles

Secondary language impairment in posterior cortical atrophy: insights from sentence repetition.

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive impairment in visuospatial and perceptual function linked to atrophy of the occipito-parietal cortex. Besides the salient visual impairment, several studies have documented subtle changes in language may also be present. Sentence repetition is a highly constrained linguistic task involving multiple linguistic and cognitive processes and have been shown to be impaired in other AD spectrum disorders, with little consensus on its relevance in PCA. This aim of this study was to further delineate the linguistic and cognitive features of impaired language in PCA using a sentence repetition task. Seven PCA patients and 16 healthy controls verbally repeated 16 sentences from the Boston Diagnostic Aphasia Examination. Responses were transcribed orthographically and coded for accuracy (percentage accuracy; percentage Correct Information Units; Levenshtein Distance) and for temporal characteristics (preparation duration (ms); utterance duration (ms); silent pause duration (ms); speech duration (ms); dysfluency duration (ms)). The potential modulating effects of attentional control and working memory capacity were explored. PCA patients showed lower overall accuracy with retained semantic content of the sentences, and lower phonological accuracy. Temporal measures revealed longer preparation and utterance duration for PCA patients compared to controls, alongside longer speech duration but comparable dysfluency duration. PCA patients also showed comparable silent pause duration to controls. Attentional control, measured using the Hayling sentence completion task, predicted accuracy of sentence repetition. The findings suggest that sentence repetition is impaired in PCA and is characterized by phonological, response planning and execution difficulties, underpinned in part by attentional control mechanisms. The emerging profile of language impairment in PCA suggests vulnerability of similar cognitive systems to other Alzheimer's syndromes, with subtle differences in clinical presentation.

Altered structural and functional connectivity in Posterior Cortical Atrophy and Dementia with Lewy bodies

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show distinct atrophy and overlapping hypometabolism profiles, but it is unknown how disruptions in structural and functional connectivity compare between these disorders and whether breakdowns in connectivity relate to either atrophy or hypometabolism.Thirty amyloid-positive PCA patients, 24 amyloid-negative DLB patients and 30 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN, and underwent a 3T head MRI, including structural MRI, resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) sequences, as well as [18F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR.On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB.These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

Abnormality of the pulvinar in posterior cortical atrophy: A multimodal MRI study

AbstractBackgroundAlthough the pulvinar is known for its extensive connections with both ventral and dorsal visual streams, details of pulvinar functional connectivity in the setting of posterior cortical atrophy (PCA) remain unclearTo study pulvinar functional connectivity and relevant associations with higher visual dysfunction in PCA.MethodA total of 29 patients with PCA and 30 normal controls were recruited. Each participant underwent comprehensive neuropsychological assessment and both structural and resting‐state functional MRI scanning. Voxel‐based morphometry (VBM) and seed‐based functional connectivity analyses were conducted to assess pulvinar gray matter volume as well as connectivity between the pulvinar and whole brain regions. A partial correlation analysis was performed to analyze neuropsychological test and pulvinar imaging data.ResultCognitive and visual functions including visuospatial processing, visual perception, episodic memory, and naming were impaired among PCA patients. Marked pulvinar atrophy was noted in PCA patients. Furthermore, functional connectivity between the pulvinar and precuneus was significantly decreased in PCA patients as compared to normal controls (FWE corrected; P<0.001). Left pulvinar gray matter volume was found to associate with object agnosia (r = 0.42, P<0.05) and right–left disorientation (r = 0.29, P<0.05) among PCA patients. The bilateral pulvinar region was found to associate with Boston Naming Test (left, r = 0.51, P = 0.015; right, r = 0.46, P = 0.03) and Activities of Daily Living (left, r = ‐0.46, P = 0.019; right, r = ‐0.53, P = 0.006) scores. Correlation analyses did not reveal significant findings concerning functional connectivity.ConclusionOur findings confirm pulvinar degeneration and its contributions in the setting of PCA.

Neurofunctional Correlates of Activities of Daily Living in Patients with Posterior Cortical Atrophy

AbstractBackgroundResearch on posterior cortical atrophy (PCA) has concentrated on cognitive decline, especially visual processing deficits. However, few studies have focused on the activities of daily living (ADL), and no study has investigated the neurometabolic basis of ADL impairments. We aimed to identify regions of hypometabolism associated with ADL in PCA patients.MethodTwenty‐nine PCA patients, 35 typical Alzheimer’s disease (tAD) patients, and 26 healthy volunteers were recruited. Each subject completed a scale for total ADL [TADL, including basic ADL (BADL) and instrumental ADL (IADL) subscales] and 18F fluorodeoxyglucose positron emission tomography. Voxel‐wise multivariable regression analysis was conducted at the level of the whole‐brain, PCA‐related hypometabolism patterns, and PCA‐specific hypometabolism patterns.ResultThe general cognitive status of PCA patients was similar to tAD patients; however, they performed worse in TADL, BADL, and IADL. In all analysis levels, TADL was associated with the bilateral parietal lobe, including the right superior parietal lobe, right inferior parietal cortex, right angular gyrus, and left superior parietal lobe. BADL was associated with the bilateral parietal lobe located in the right superior parietal lobe, right inferior parietal cortex, and left superior parietal lobe. IADL was associated with the bilateral superior parietal lobe. Bilateral superior parietal lobe hypometabolism was associated with TADL, BADL, and IADL.ConclusionHypo‐metabolism in the bilateral superior parietal lobes contributes to the decline of ADL in PCA, which is a promising target for future non‐invasive neuromodulation interventions.

Ultra‐high‐resolution quantitative MRI at the grey/white interface in Alzheimer’s disease and posterior cortical atrophy

AbstractBackgroundCortical grey matter (CGM) and superficial white matter (SWM) undergo pathological changes, but standard MRI spatial resolutions make interpreting disease‐related effects at their interface challenging. We present findings from a study investigating the grey/white interface in typical amnestic Alzheimer’s disease (tAD), posterior cortical atrophy (PCA) and healthy controls using ultra‐high‐resolution quantitative MRI measures sensitive to microstructural properties.MethodEleven participants (Table 1) were scanned at 7T using multi‐echo FLASH (0.5mm isotropic resolution with prospective motion correction) and diffusion MRI (dMRI) (1.25mm isotropic resolution). The hMRI toolbox produced multi‐parametric mapping (MPM) measures: R1, R2* and Proton Density (PD) (Vaculciakova et al., 2021https://doi.org/10.1002/mrm.29253). dMRI processing included denoising and correcting for Gibbs ringing, eddy currents, susceptibility artifacts and motion. Metrics from dMRI were fractional anisotropy (FA), and mean diffusivity (MD), as well as tissue fraction (TF), neurite density index (NDI) and orientation dispersion index (ODI) from Neurite Orientation Dispersion and Density Imaging (NODDI). A deep learning segmentation approach estimated the grey/white boundary (Billot et al., 2021, arXiv:2107.09559). MPM and dMRI measures were sampled from the CGM into the SWM at 0.5mm increments in regions of interest (Harvard‐Oxford cortical atlas). Tissue‐weighted (tw) averages were calculated for NDI and ODI. Metrics were visualized across the grey/white interface using boxplots.ResultFigures 1‐2 show MPM and dMRI measures in the precuneus (dashed lines indicate group medians). Qualitatively, most tAD and PCA participants had lower R1 and R2* than controls, most prominently 0.5mm into the SWM (Figure 1). PD appeared higher in tAD and PCA patients across the grey/white interface. Qualitatively, most tAD and PCA participants had lower TF and higher MD in the CGM, where twNDI and FA appeared lower than controls across grey/white interface (Figure 2). Most tAD and PCA had qualitatively lower twODI in CGM and a flatter slope across the grey/white interface compared to controls.ConclusionMacromolecular (R1, R2* and twNDI) and iron content (R2*) MR measures at 7T appear reduced in tAD and PCA across the grey/white interface, whereas neurite organisational complexity (twODI) may become more homogeneous. Ongoing study will assess if these findings are consistent with further participants.

Social cognition and behavioral changes in patients with posterior cortical atrophy.

Posterior cortical atrophy (PCA) is a rare neurodegenerative condition characterized by progressive visual and visuospatial dysfunction. The consensus criteria state that patients should present "relatively spared behavior and personality" in early stages. However, limited research has focused on these symptoms in PCA. This study compared 157 patients with PCA in early stages of the disease with 352 healthy controls (HC), 202 typical AD (tAD), and 177 logopenic variant primary progressive aphasia (lvPPA) patients from the National Alzheimer's Coordinating Center (NACC) dataset. They were compared using clinician ratings of behavioral symptoms, informant- and clinician-filled questionnaires and patient-facing tests of behavior and social cognition. Results showed that PCA individuals exhibited many behavioral symptoms, the more frequently reported being anxiety, depression, apathy, and irritability. During cognitive testing, clinicians observed disorganized and reactive behaviors, but no insensitive behaviors. Informant reports indicated that PCA patients exhibited higher levels of inhibition and anxiety in response to stimuli associated with non-reward, novelty, and punishment. Social norms knowledge and empathy were overall preserved, although slight decreases in perspective-taking and socioemotional sensitivity were observed on informant-rated questionnaires. Except for more elevated neuropsychiatric symptoms in tAD, the three AD variants had similar profiles. Our findings provide insights into the social cognition and behavioral profiles of PCA, highlighting patterns of preservations and mild impairments, even in the early stages of the disease. These results contribute to a more complete understanding of non-visual symptoms in PCA and have implications for diagnostic and intervention strategies.

Neurofunctional Correlates of Activities of Daily Living in Patients with Posterior Cortical Atrophy.

Research on posterior cortical atrophy (PCA) has focused on cognitive decline, especially visual processing deficits. However, few studies have examined the impact of PCA on activities of daily living (ADL) and the neurofunctional and neuroanatomic bases of ADL. To identify brain regions associated with ADL in PCA patients. A total of 29 PCA patients, 35 typical Alzheimer's disease (tAD) patients, and 26 healthy volunteers were recruited. Each subject completed an ADL questionnaire that included basic and instrumental subscales (BADL and IADL, respectively), and underwent hybrid magnetic resonance imaging and 18F fluorodeoxyglucose positron emission tomography. Voxel-wise regression multivariable analysis was conducted to identify specific brain regions associated with ADL. General cognitive status was similar between PCA and tAD patients; however, the former had lower total ADL scores and BADL and IADL scores. All three scores were associated with hypometabolism in bilateral parietal lobes (especially bilateral superior parietal gyri) at the whole-brain level, PCA-related hypometabolism level, and PCA-specific hypometabolism level. A cluster that included the right superior parietal gyrus showed an ADL×group interaction effect that was correlated with the total ADL score in the PCA group (r = -0.6908, p = 9.3599e-5) but not in the tAD group (r = 0.1006, p = 0.5904). There was no significant association between gray matter density and ADL scores. Hypometabolism in bilateral superior parietal lobes contributes to a decline in ADL in patients with PCA and can potentially be targeted by noninvasive neuromodulatory interventions.

APOE ɛ4 Influences Within and Between Network Functional Connectivity in Atypical Alzheimer Disease (P11-6.006)

<h3>Objective:</h3> To assess functional connectivity in posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) and evaluate how within and between-network functional connectivity differs based on the apolipoprotein E (<i>APOE)</i> ɛ4 status. <h3>Background:</h3> <i>APOE</i> ɛ4 influences atrophy and tau deposition in patients with atypical Alzheimer’s disease (AD), with <i>APOE</i> ɛ4 carriers having greater predisposition to medial temporal involvement. This raises questions on whether the <i>APOE</i> genotype would influence memory network connectivity, a network mainly comprised of medial temporal structures. <h3>Design/Methods:</h3> One-hundred forty amyloid-positive PCA (n=58) and LPA (n=82) patients were recruited by the Neurodegenerative Research Group and underwent structural and resting state functional MRI. Spatially preprocessed data were analyzed to explore the default mode network (DMN), salience, language, visual and memory networks, using a region of interest approach in Conn toolbox. Bayesian hierarchical linear models (BHLM) adjusted for age and sex, assessed the influence of APOE ɛ4 on within and between-network connectivity. <h3>Results:</h3> We found reduced within-network connectivity in the memory and language networks in LPA, with an increase in salience network connectivity in PCA, in <i>APOE</i> ɛ4 carriers compared to non-carriers. <i>APOE</i> ɛ4 did not influence memory within-network connectivity in PCA. Between-network analysis showed evidence of reduced connectivity from the DMN in both groups, with reduced DMN-to-salience and DMN-to-language network connectivity in PCA <i>APOE</i> ɛ4 carriers, and reduced DMN-to-visual network connectivity in LPA <i>APOE</i> ɛ4 carriers. In addition, we found reduced connectivity from the visual-to-language and visual-to-salience networks in <i>APOE</i> ɛ4 carriers compared to non-carriers in both PCA and LPA. Both network-level and voxel-level findings concurred with the BHLM findings, specifically showing reductions in the within-network connectivity for the memory network in LPA <i>APOE</i> ɛ4 carriers. <h3>Conclusions:</h3> The <i>APOE</i> genotype influences brain connectivity, both within and between-networks, in atypical AD variants. However, there was evidence that the modulatory effects of <i>APOE</i> differ across phenotype. <b>Disclosure:</b> Dr. Singh has nothing to disclose. Mr. Martin has nothing to disclose. Dr. Graff-Radford has received personal compensation for serving as an employee of Mayo Clinic. Dr. Graff-Radford has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NINDS/NIH. Dr. Graff-Radford has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. The institution of Dr. Graff-Radford has received research support from NIH. The institution of Dr. Machulda has received research support from NIH. Minerva Carrasquillo has nothing to disclose. The institution of Dr. Taner has received research support from NIH. Dr. Josephs has nothing to disclose. Dr. Whitwell has nothing to disclose.

Decline in Visual and Posterior Cortical Functions in Logopenic Progressive Aphasia (P5-6.001)

<h3>Objective:</h3> To determine how frequently features of posterior cortical atrophy (PCA) occur in patients with logopenic progressive aphasia (LPA) and determine the neuroimaging correlates of these features. <h3>Background:</h3> LPA and PCA are two atypical clinical variants of Alzheimer’s disease. Overlap can be observed clinically between phenotypes, although it is unclear how frequently patients meeting criteria for LPA develop clinical PCA features, and whether these features are associated with neuroanatomical overlap with PCA. <h3>Design/Methods:</h3> Thirty-six LPA patients recruited by the Neurodegenerative Research Group underwent extensive neuropsychological testing, MRI and [¹⁸F] flortaucipir PET. All patients were evaluated for PCA features including simultanagnosia, Gerstmann syndromes, ideomotor apraxia, and visuospatial and visuoperceptual function, with cut-points used to define abnormality. Patients were classified as Pure-LPA (having no PCA feature), LPA+ (impairment on one test) or LPA-PCA (impairment on 2+ tests). Neuroimaging profiles in each of the three LPA groups were compared to 14 matched healthy controls and 14 matched typical PCA patients using multiple regression analysis in SPM12. <h3>Results:</h3> Eleven patients (31%) were classified as pure-LPA, 16 (44%) as LPA+ and 9 (25%) as LPA-PCA. There were no differences in disease duration, naming, or sentence repetition across groups. The LPA+ group showed worse simultanagnosia (29%), ideomotor apraxia and Gerstmann syndrome (34%) compared to Pure-LPA group. The LPA-PCA group showed further worsening in simultanagnosia (89%), and visuospatial and visuoperceptual impairment compared to LPA+ group. All three LPA groups showed greater left temporoparietal volume loss and flortaucipir uptake compared to controls and PCA, with greater flortaucipir uptake occurring in the occipital and frontal lobes in LPA+ and LPA-PCA compared to Pure-LPA. <h3>Conclusions:</h3> Our results demonstrate that LPA patients can develop features of PCA related to spread of tau into occipito-frontal regions, highlighting syndromic and anatomical overlap between atypical variants of AD. <b>Disclosure:</b> Dr. Singh has nothing to disclose. Dr. Graff-Radford has received personal compensation for serving as an employee of Mayo Clinic. Dr. Graff-Radford has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NINDS/NIH. Dr. Graff-Radford has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. The institution of Dr. Graff-Radford has received research support from NIH. Arenn Faye Carlos, MD has nothing to disclose. The institution of Dr. Machulda has received research support from NIH. Christopher Schwarz has received personal compensation for serving as an employee of Mayo Clinic. The institution of Christopher Schwarz has received research support from NIH. Matthew Senjem has received stock or an ownership interest from Align Technology, Inc.. Matthew Senjem has received stock or an ownership interest from Inovio Biomedical Corp.. Matthew Senjem has received stock or an ownership interest from Johnson &amp; Johnson. Matthew Senjem has received stock or an ownership interest from Mesa Laboratories, Inc.. Matthew Senjem has received stock or an ownership interest from Nvidia Inc.. Matthew Senjem has received stock or an ownership interest from LHC Group, Inc.. Matthew Senjem has received stock or an ownership interest from Natus Medical Incorporated. Matthew Senjem has received stock or an ownership interest from Varex Imaging Corporation. Matthew Senjem has received personal compensation in the range of $100,000-$499,999 for serving as a IT Technical Specialist II with Mayo Clinic. The institution of Dr. Jack has received research support from NIH. The institution of Dr. Jack has received research support from Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. Dr. Lowe has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AVID Radiopharmaceutical. Dr. Lowe has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai Inc. The institution of Dr. Lowe has received research support from AVID Radiopharmaceuticals. Dr. Josephs has nothing to disclose. Dr. Whitwell has nothing to disclose.

Altered functional connectivity networks in logopenic progressive aphasia and posterior cortical atrophy

AbstractBackgroundResting state functional connectivity (rsfMRI) studies have shown functional network disruptions in logopenic progressive aphasia (LPA) (reduced connectivity within the left temporal language network) and posterior cortical atrophy (PCA) (reduced connectivity within ventral visual network). However, little is known about how these networks compare and how connectivity differs within and between networks in these atypical Alzheimer’s Disease (AD) phenotypes.MethodFifty‐nine amyloid‐positive PCA patients and eighty‐five amyloid‐positive LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent structural and resting state functional MRI. Spatially preprocessed data was analyzed using the CONN functional connectivity toolbox to explore the default mode network (DMN), salience, sensorimotor, left language, visual and memory networks, which were generated by averaging multiple regions‐of‐interest (ROI) within each network. The data was analyzed at both the voxel‐level and network‐level (ROI‐ROI).ResultVoxel‐level differences in functional connectivity between PCA and LPA were observed in all networks (p&lt;0.05; cluster size, FWE=0.05). PCA showed reduced connectivity in the occipital lobe in visual and memory networks, parietal lobe in language and DMN, and sensorimotor strip in sensorimotor network, particularly on the right, compared to LPA. Conversely, LPA showed reduced connectivity in the frontal cortex in salience, memory, visual and sensorimotor networks, inferior parietal lobe in visual network, and anterior temporal pole and sensorimotor cortex in the language network, compared to PCA. Between network differences (p&lt;0.05; cluster size, FDR=0.05) were observed between groups, with PCA showing reduced connectivity between the visual and sensorimotor networks, while LPA showed reduced connectivity between the language and sensorimotor networks. The DMN was anti‐correlated to the language network in PCA, while it was positively correlated to the language network in LPA. In both phenotypes, the DMN was anticorrelated with the salience network. The visual network in PCA showed connections to all networks, while in LPA, it was only connected to the salience, language and DMN.ConclusionThe atypical AD phenotypes were associated with multiple disruptions in connectivity, both within and between brain networks. Phenotype specific differences in connectivity patterns were noted in visual network for PCA and language network for LPA.

Altered functional connectivity networks in logopenic progressive aphasia and posterior cortical atrophy

AbstractBackgroundResting state functional connectivity (rsfMRI) studies have shown functional network disruptions in logopenic progressive aphasia (LPA) (reduced connectivity within the left temporal language network) and posterior cortical atrophy (PCA) (reduced connectivity within ventral visual network). However, little is known about how these networks compare and how connectivity differs within and between networks in these atypical Alzheimer’s Disease (AD) phenotypes.MethodFifty‐nine amyloid‐positive PCA patients and eighty‐five amyloid‐positive LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent structural and resting state functional MRI. Spatially preprocessed data was analyzed using the CONN functional connectivity toolbox to explore the default mode network (DMN), salience, sensorimotor, left language, visual and memory networks, which were generated by averaging multiple regions‐of‐interest (ROI) within each network. The data was analyzed at both the voxel‐level and network‐level (ROI‐ROI).ResultVoxel‐level differences in functional connectivity between PCA and LPA were observed in all networks (p&lt;0.05; cluster size, FWE=0.05). PCA showed reduced connectivity in the occipital lobe in visual and memory networks, parietal lobe in language and DMN, and sensorimotor strip in sensorimotor network, particularly on the right, compared to LPA. Conversely, LPA showed reduced connectivity in the frontal cortex in salience, memory, visual and sensorimotor networks, inferior parietal lobe in visual network, and anterior temporal pole and sensorimotor cortex in the language network, compared to PCA. Between network differences (p&lt;0.05; cluster size, FDR=0.05) were observed between groups, with PCA showing reduced connectivity between the visual and sensorimotor networks, while LPA showed reduced connectivity between the language and sensorimotor networks. The DMN was anti‐correlated to the language network in PCA, while it was positively correlated to the language network in LPA. In both phenotypes, the DMN was anticorrelated with the salience network. The visual network in PCA showed connections to all networks, while in LPA, it was only connected to the salience, language and DMN.ConclusionThe atypical AD phenotypes were associated with multiple disruptions in connectivity, both within and between brain networks. Phenotype specific differences in connectivity patterns were noted in visual network for PCA and language network for LPA.

Unique brain iron profiles associated with logopenic progressive aphasia and posterior cortical atrophy

AbstractBackgroundQuantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating the local tissue magnetic susceptibility of every voxel. Dysregulation of neuronal iron has been correlated with typical Alzheimer’s disease (tAD), but little is known about iron distribution in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA).MethodEleven PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five‐echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions‐of‐interest across the brain using the Mayo Clinic Adult Lifespan Template. Hierarchical models were fit per‐region and per‐hemisphere to compare PCA and LPA to each other, to 20 healthy controls, and to 20 patients with tAD recruited by the Alzheimer’s Disease Research Center.ResultStrong evidence (posterior probability&gt;0.99) was observed for greater susceptibility in the left middle occipital gyrus and amygdala in both LPA and PCA, and in the right precuneus and inferior temporal gyrus in PCA compared to controls. Moderate evidence for greater susceptibility (posterior probability&gt;0.90) was also observed in the left insula, inferior occipital gyrus, entorhinal cortex, and right inferior parietal gyrus and amygdala in both LPA and PCA, along with right angular gyrus and middle occipital gyrus in PCA and right insula and caudate in LPA, when compared to controls. Comparing between phenotypes, LPA showed moderate evidence for greater susceptibility in the caudate, hippocampus, substantia nigra, left supramarginal gyrus and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right precuneus compared to LPA. Both LPA and PCA showed moderate‐strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions.ConclusionUnique iron profiles were identified in LPA and PCA within cortical and subcortical structures. These changes are in line with disease‐related neurodegenerative changes in the clinical phenotypes, suggesting that QSM could be an informative marker to study iron deposition in these patients.

Tau accumulation and degeneration differ across functional networks in atypical Alzheimer's disease phenotypes

AbstractBackgroundRecent models of Alzheimer's disease (AD) posit that pathogenic tau propagates through interconnected structural networks, suggesting amnestic and non‐amnestic AD (aAD &amp; naAD) phenotypes could reflect differential involvement of functional networks. We tested this hypothesis by contrasting longitudinal grey matter (GM) atrophy and tau accumulation across AD clinical phenotypes in 7 canonical functional networks.MethodsWe analyzed longitudinal 3‐Tesla T1‐weighted MRI from 122 patients [aAD=49; logopenic primary progressive aphasia (lvPPA)=31; posterior cortical atrophy (PCA)=23; behavioral/dysexecutive AD (bvAD)=6; corticobasal syndrome (CBS)=6; mixed naAD=4] with autopsy or CSF evidence of AD pathology and 91 cognitively normal controls (Table 1). Thirty‐one patients (aAD=9; lvPPA=7; PCA=9; bvAD=2; CBS=3; naAD=1) had longitudinal flortaucipir PET (FTP‐PET) data. We computed baseline values and annualized change for GM volume and FTP‐PET standardized uptake value ratios (SUVRs) in the 100‐label, 7‐network parcellation of Schaefer et al. (2018). Linear mixed effects models (α=0.05, corrected) adjusting for MMSE assessed group differences in atrophy and tau accumulation.ResultsAll groups exhibited significant baseline and longitudinal atrophy vs. controls in multiple networks (Figs. 1‐2). Differences in longitudinal atrophy rate (Fig. 2) were observed in the dorsal attention network [PCA&gt;lvPPA, t(371)=3.1, p&lt;0.04], salience network [PCA&gt;aAD, t(371)=3.1, p&lt;0.04], and limbic network [CBS&gt;aAD, t(371)=3.3, p&lt;0.02; CBS&gt;bvAD, t(371)=3.7, p&lt;0.006]. PCA patients exhibited FTP‐PET SUVR increases in all networks (all p&lt;0.02), while aAD patients displayed increases in all networks except visual and limbic (all others p&lt;0.0001). LvPPA patients exhibited net SUVR increases only in the somatomotor network [t(97)=3.5, p&lt;0.001]. At baseline, lvPPA patients had left &gt; right atrophy in all networks [all t&gt;3.7, p&lt;0.0002]; right &gt; left atrophy was observed in the visual network for PCA and CBS; the salience network for PCA and bvAD; and in the dorsal attention, frontoparietal control, and default mode networks for bvAD [all t&gt;3.0, p&lt;0.03]. In longitudinal analyses, no hemispheric differences were found in rates of GM volume loss or FTP‐PET change.ConclusionAD clinical variants exhibited GM atrophy and tau accumulation in partially overlapping networks. Investigating early‐stage disease will be crucial for assessing whether disease spread through canonical functional networks can explain anatomic differences in aAD and naAD phenotypes.

Regional white matter hyperintensities in posterior cortical atrophy and logopenic progressive aphasia

AbstractBackgroundWhite matter hyperintensities (WMH) are markers of cerebral small vessel disease and have been associated with higher risk of typical amnestic Alzheimer’s disease (AD), however, little is known about the role of WMHs in atypical variants of AD. This study aimed to determine the frequency and distribution of WMH in two atypical variants of AD: logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA), and determine whether WMH are associated with demographic and clinical outcomes in these cohorts.MethodSeventy‐five LPA and 39 PCA patients were recruited by the Neurodegenerative Research Group and underwent two‐ dimensional fluid‐attenuated inversion recovery (FLAIR) MRI and Pittsburgh Compound B (PiB) PET. All patients were PiB‐positive. All FLAIR images were segmented using an in‐house software, then were manually edited by a trained imaging analyst. WMH volume was scaled by total intracranial volume to correct for differences in head size. Adjusted WMH burdens were compared between LPA and PCA, and associations were assessed between WMH burden and age, global PiB standard uptake value ratios (SUVRs), and clinical metrics, including tests of general cognitive impairment, executive function, naming, repetition, visuospatial and visuoperceptual function, and parkinsonism. Associations between WMHs and clinical scores were adjusted for age and brain volume to correct for atrophy.ResultTotal WMH burden was similar in PCA and LPA, however, regional differences were identified with PCA having greater subcortical WMH burden in right occipital, parietal, and temporal lobes compared to LPA, and LPA having greater WMH burden in left deep grey and white matter and greater subcortical burden in left parietal lobe compared to PCA. Total WMH burden was greater with older age in both groups but was not related to global PiB SUVR either globally or locally. Greater total WMH was associated with visuoperceptual performance in both cohorts after correcting for atrophy. When assessed regionally, visuoperceptual performance was associated with right subcortical occipital WMH across the cohort.ConclusionRegional distribution of WMHs differ across clinical variants of atypical AD and WMHs may impact clinical outcomes, although further work is needed to determine whether they reflect cerebrovascular disease or regionally specific neurodegenerative changes.

Unique brain iron profiles associated with logopenic progressive aphasia and posterior cortical atrophy

AbstractBackgroundQuantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating the local tissue magnetic susceptibility of every voxel. Dysregulation of neuronal iron has been correlated with typical Alzheimer’s disease (tAD), but little is known about iron distribution in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA).MethodEleven PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five‐echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions‐of‐interest across the brain using the Mayo Clinic Adult Lifespan Template. Hierarchical models were fit per‐region and per‐hemisphere to compare PCA and LPA to each other, to 20 healthy controls, and to 20 patients with tAD recruited by the Alzheimer’s Disease Research Center.ResultStrong evidence (posterior probability&gt;0.99) was observed for greater susceptibility in the left middle occipital gyrus and amygdala in both LPA and PCA, and in the right precuneus and inferior temporal gyrus in PCA compared to controls. Moderate evidence for greater susceptibility (posterior probability&gt;0.90) was also observed in the left insula, inferior occipital gyrus, entorhinal cortex, and right inferior parietal gyrus and amygdala in both LPA and PCA, along with right angular gyrus and middle occipital gyrus in PCA and right insula and caudate in LPA, when compared to controls. Comparing between phenotypes, LPA showed moderate evidence for greater susceptibility in the caudate, hippocampus, substantia nigra, left supramarginal gyrus and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right precuneus compared to LPA. Both LPA and PCA showed moderate‐strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions.ConclusionUnique iron profiles were identified in LPA and PCA within cortical and subcortical structures. These changes are in line with disease‐related neurodegenerative changes in the clinical phenotypes, suggesting that QSM could be an informative marker to study iron deposition in these patients.

Atypical Alzheimer's disease phenotypes with normal or borderline PET biomarker profiles.

Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are clinical syndromes that commonly have underlying Alzheimer's disease (AD), although non-AD pathologies have also been reported. PET imaging allows for identification of beta-amyloid (Aβ) and tau in AD, so we aimed to assess these in a large cohort to identify patients that do not have evidence for biomarker-defined AD. Eight-one patients, 47 PCA and 34 LPA, underwent extensive neurological and neuropsychological testing, [11C] Pittsburgh compound B, [18F] flortaucipir and [18F] fluorodeoxyglucose PETs. Global Aβ and tau-PET standardized uptake value ratios (SUVRs) were plotted for all patients and outliers, and patients with abnormally low SUVRs compared to the biomarker-classic cohort were identified. Six (7.4%) biomarker-outlier cases were identified, and three patterns were observed: (i) negative/borderline Aβ-PET and striking widespread tau-PET uptake (two LPA); (ii) negative/borderline Aβ-PET and low tau-PET uptake (three PCA) and (iii) elevated Aβ-PET uptake but mild focal tau-PET uptake (one LPA). Among the unusual patients in group ii, two patients showed no abnormal tau uptake suggesting non-AD pathology, with one developing features of cortico-basal syndrome and the other dementia with Lewy bodies. The remaining patient showed very mild focal tau uptake. This study demonstrates that a small minority (~ 8%) of PCA and LPA patients do not show the typical striking patterns of Aβ and tau PET uptake, with only 2% showing absence of both proteins. These findings will help inform the use of molecular PET in clinical treatment trials that include patients with atypical phenotypes of AD.

Investigating Heterogeneity and Neuroanatomic Correlates of Longitudinal Clinical Decline in Atypical Alzheimer Disease.

The aims of this work were to compare rates of longitudinal change in neurologic and neuropsychological test performance between the logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA) variants of atypical Alzheimer disease (AD) and to use unbiased principal component analysis to assess heterogeneity in patterns of change and relationships to demographics and concurrent brain atrophy. Patients with PCA or LPA who were positive for amyloid and tau AD biomarkers and had undergone serial neurologic and neuropsychological assessments and structural MRI were identified. Rates of change in 13 clinical measures were compared between groups in a case-control design, and principal component analysis was used to assess patterns of clinical change unbiased by clinical phenotype. Components were correlated with rates of regional brain atrophy with tensor-based morphometry. Twenty-eight patients with PCA and 27 patients with LPA were identified. Those with LPA showed worse baseline performance and faster rates of decline in naming, repetition, and working memory, as well as faster rates of decline in verbal episodic memory, compared to those with PCA. Conversely, patients with PCA showed worse baseline performance in tests of visuospatial and perceptual function and on the Clinical Dementia Rating Scale and faster rates of decline in visuoperceptual function compared to those with LPA. Principal component analysis showed that patterns of clinical decline were highly heterogeneous across the cohort, with 10 principal components required to explain >90% of the variance. The first principal component reflected overall severity, with higher scores in LPA than PCA reflecting faster decline in LPA, and was related to left temporoparietal atrophy. The second and third principal components were not related to clinical phenotype but showed some relationship to regional atrophy. No relationships were identified between the principal components and age, sex, disease duration, amyloid PET findings, or apolipoprotein genotype. Longitudinal patterns of clinical decline differ between LPA and PCA but are heterogeneous and related to different patterns of topographic spread. PCA is associated with a more slowly progressive course than LPA.

Posterior cortical atrophy: Primary occipital variant.

Posterior cortical atrophy (PCA) is one of the atypical Alzheimer's disease variants, characterized by predominant visuospatial and visuoperceptual deficits, with established dorsal and ventral subtypes. A third primary occipital (caudal) variant has been suggested. We aimed to determine its demographics, clinical manifestations, and biomarker findings. Fifty-two PCA patients were investigated. Patients underwent neuropsychological assessment, magnetic resonance imaging, and fluorodeoxyglucose (FDG)-, amyloid-, and tau-positron emission tomography (tau-PET) scans. Normalized regional FDG-PET values were represented as z-scores relative to a control population. Patients were divided into "primary occipital" and "other PCA" subgroups according to FDG-PET-defined criteria, with primary occipital defined as patients in which the z-scores for occipital subregions were at least one standard deviation lower (SD) (i.e., more abnormal) than the z-scores in all other brain regions. Global amyloid-PET, temporo-parietal FDG-PET, and temporal tau-PET regions-of-interest (ROIs) were calculated. Nine patients were classified as primary occipital; they were older (p=0.034) and had more years of education (p=0.007) than other PCA patients. The primary occipital group performed worse on the Ishihara test for color perception (p<0.001), while other PCA patients performed worse on the Western Aphasia Battery (WAB) praxis scale (p=0.005). Overall neuropsychiatric symptom burden was lower in the primary occipital group (p<0.001). The FDG-PET meta-ROI was higher in the primary occipital subtype (p=0.006), but no differences were observed in amyloid- and tau-PET. Our findings suggest that primary occipital PCA is characterized by an older age at onset, more color perception dysfunction, less severe ideomotor apraxia, and less hypometabolism in temporo-parietal meta-ROI compared to established phenotypes.

Medial Temporal Atrophy in Posterior Cortical Atrophy and Its Relationship to the Cingulate Island Sign.

It has been hypothesized that medial temporal sparing may be related to preserved posterior cingulate metabolism and the cingulate island sign (CIS) on [18F]fluorodeoxyglucose (FDG) PET in posterior cortical atrophy (PCA). To assess the severity of medial temporal atrophy in PCA and determine whether the presence of a CIS is related to medial temporal sparing. Fifty-five PCA patients underwent MRI and FDG-PET. The degree and symmetry of medial temporal atrophy on MRI was visually assessed using a five-point scale for both hemispheres. Visual assessments of FDG-PET coded the presence/absence of a CIS and whether the CIS was symmetric or asymmetric. Hippocampal volumes and a quantitative CIS were also measured. Medial temporal atrophy was most commonly mild or moderate, was symmetric in 55% of patients, and when asymmetric was most commonly worse on the right (76%). Older age and worse memory performance were associated with greater medial temporal atrophy. The CIS was observed in 44% of the PCA patients and was asymmetric in 50% of these. The patients with a CIS showed greater medial temporal asymmetry, but did not show lower medial temporal atrophy scores, compared to those without a CIS. Hippocampal volumes were not associated with quantitative CIS. Mild medial temporal atrophy is a common finding in PCA and is associated with memory impairment. However, medial temporal sparing was not related to the presence of a CIS in PCA.

Distinct brain iron profiles associated with logopenic progressive aphasia and posterior cortical atrophy

Quantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating local tissue magnetic susceptibility properties at every voxel. Iron deposition patterns are well studied in typical Alzheimer’s disease (tAD), but little is known about these patterns in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). Seventeen PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five-echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions-of-interest across the brain using the Mayo Clinic Adult Lifespan Template. Bayesian hierarchical models were fit per-region and per-hemisphere to compare PCA, LPA, 63 healthy controls, and 20 tAD patients. Strong evidence (posterior probability > 0.99) was observed for greater susceptibility in the middle occipital gyrus and amygdala in both LPA and PCA, and in the right inferior parietal, inferior temporal, and angular gyri in PCA and the caudate and substantia nigra in LPA compared to controls. Moderate evidence for greater susceptibility (posterior probability > 0.90) was also observed in the inferior occipital gyrus, precuneus, putamen and entorhinal cortex in both LPA and PCA, along with superior frontal gyrus in PCA and inferior temporal gyri, insula and basal ganglia in LPA, when compared to controls. Between phenotypic comparisons, LPA had greater susceptibility in the caudate, hippocampus, and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right superior frontal and middle temporal gyri compared to LPA. Both LPA and PCA showed moderate and strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions, while tAD showed greater susceptibility in the hippocampus and basal ganglia. This study proposes the possibility of unique iron profiles existing between LPA and PCA within cortical and subcortical structures. These changes match well with the disease-related changes of the clinical phenotypes, suggesting that QSM could be an informative candidate marker to study iron deposition in these patients.