Citations

AbstractBackgroundPosterior Cortical Atrophy (PCA) is one of the atypical Alzheimer’s Disease (AD) variants, characterized by predominant visuospatial and visuoperceptual deficits, with dorsal and ventral subtypes recognized clinically and radiographically. A third primary occipital (caudal) variant has been suggested. The objective of this study was to determine its demographics, clinical manifestations, and biomarker findings.MethodFifty‐two PCA patients with positive amyloid PET scans were investigated. Patients underwent neuropsychological assessment, 3T MRI imaging and FDG‐, amyloid‐ and tau‐PET scans. Regional FDG‐PET values were normalized to the pons and 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 (i.e., more abnormal) than the z scores in all other brain regions. Global amyloid‐PET, temporoparietal FDG‐PET and temporal tau‐PET regions‐of‐interest (ROI) were calculated. Student’s T test and Fisher’s exact analyses were used to investigate differences in demographics, clinical findings, and imaging biomarkers across the two groups.ResultNine patients were classified as primary occipital; primary occipital patients were older (64.8±6.9 versus 59.3±6.8, p=0.034) and had more years of education (17.7±1.7 versus 15.1±2.6, p=0.007) compared to the other PCA patients. Clinical evaluation revealed worse performance for the primary occipital group on the Ishihara test for color perception (p<0.001), while the other PCA patients performed worse on the Western Aphasia Battery (WAB) praxis scale (p=0.005). Overall neuropsychiatric symptom burden as defined by the NPI‐Q was lower in the primary occipital group (p<0.001). The FDG‐PET meta‐ROI (weighted median uptake in angular gyrus, posterior cingulate, and inferior temporal ROIs, normalized to the pons and vermis) was higher in the primary occipital subtype (p=0.006), but no differences were observed in amyloid and tau‐PET.ConclusionClinical and biomarker findings suggest primary occipital PCA is characterized by an older age at onset, more color perception dysfunction, less severe ideomotor apraxia and less hypometabolism in temporal‐parietal meta‐ROI compared to more established phenotypes.

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<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<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.

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>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>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.

AbstractBackgroundMulti‐compartment modelling of white matter (WM) microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) can provide information on WM health through the neurite (axons and dendrites) density index and free water measures. We hypothesized that cerebrovascular disease (CVD), Alzheimer’s disease (AD), and an FDG pattern suggestive of TDP‐43 proteinopathy would be associated with distinct NODDI readouts of WM damage which would be informative for identifying the substrate for cognitive impairment.MethodWe identified two independent cohorts with multi‐shell diffusion MRI, amyloid and tau PET, and cognitive assessments. One, were participants from the Mayo Clinic Study of Aging, a population‐based cohort of 347 elderly randomly sampled from the Olmsted county, Minnesota. The second were 61 amyloid positive AD participants from the Mayo AD Research Center.ResultWe observed an increase in free water and decrease in neurite density in the genu of the corpus callosum associated with vascular risk factors, which we refer to as vascular WM component (Figure 1). Tau PET signal reflective of 3R/4R tau deposition was associated with worsening neurite density index in the temporal WM where we measured parahippocampal cingulum and inferior temporal WM bundles. Worsening temporal neurite density was associated with (antemortem confirmed) FDG TDP‐43 signature. Post‐mortem neuropathologic data on a small subset (n=9) of this sample lend support to our findings. In the population‐based cohort where vascular disease was more prevalent, the vascular WM component explained variability in global cognition (partial R2 of free water and neurite density = 8.3%) and MMSE performance (8.2%) which was comparable to amyloid PET (7.4% for global cognition and 6.6% for memory) (Table 1). In the AD dementia clinic‐based cohort, tau deposition was the greatest contributor to cognitive performance (9.6%), but there was also a non‐trivial contribution of the temporal WM component (8.5%) to cognitive performance. The differences observed between the two cohorts were reflective of their distinct clinical composition.ConclusionWhite matter microstructural damage assessed using advanced diffusion models may add significant value for distinguishing the underlying substrate (whether CVD versus neurodegenerative disease caused by tau deposition or TDP‐43 pathology) for cognitive impairment in older individuals.

AbstractBackgroundWe previously demonstrated that Alzheimer’s disease (AD) patients ≥70 y/o tend to have smaller medial temporal volumes in the presence of relatively less medial temporal 18F‐flortaucipir‐PET uptake compared to young AD patients. TAR DNA‐binding protein 43 (TDP‐43) is frequently found in the brains of AD patients and is associated with old age and medial temporal atrophy. In this study, we aimed to determine whether TDP‐43 could be contributing to the mismatch between medial temporal volumes and flortaucipir‐PET uptake in older AD patients.MethodWe identified 77 participants (median age at death 79 years [range: 51‐99]) who had been enrolled into the Mayo Clinic Alzheimer’s Disease Research Center or Neurodegenerative Research Group (NRG), had undergone flortaucipir‐PET and volumetric MRI scans close to death, and autopsy confirmed AD neuropathological changes, as well as TDP‐43 assessments. Grey matter volumes and flortaucipir standard uptake value ratios (SUVRs) were calculated for hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices. We used bivariate‐response linear regression modelling, adjusting for Braak neurofibrillary tangle stage, to estimate the effect of TDP‐43 and age on gray matter volume and flortaucipir uptake, and tested whether TDP‐43 effect sizes varied according to age.ResultAfter accounting for Braak stage, older individuals tended to have significantly lower flortaucipir uptake across regions and lower hippocampal and entorhinal cortex (ERC) volumes. TDP‐43 was associated with reduced hippocampus and ERC volumes but was unrelated to flortaucipir SUVRs (Figure 1). Notably, the TDP‐43 effect size for the hippocampus and ERC was largely consistent across age, i.e., at any age, TDP‐43‐positive participants had significantly smaller hippocampal (∼12% decrease) and ERC (13% decrease) volumes than TDP‐43‐negative participants. However, at older ages, the mean volumes in the whole cohort and, more evidently, in those with dementia moved closer towards the mean of those with TDP‐43 (Figure 1), likely attributable to the increasing frequency of TDP‐43 with age.ConclusionTDP‐43 is a major contributor to the mismatch between flortaucipir uptake and medial temporal lobe volumes in older AD patients where lower medial temporal regional volumes are observed in the presence of less flortaucipir uptake.

AbstractBackgroundTDP‐43 is a nuclear RNA‐binding protein involved in various neurodegenerative diseases, including Alzheimer’s Disease (AD), and normal aging. It strongly affects cognition and memory loss in AD. Concomitant TDP‐43 pathology increases the likelihood of being cognitively impaired at death.MethodMayo Clinic has amassed a large database with 1072 study participants with known TDP‐43 pathology status, who were prospectively recruited and followed in the Mayo Clinic Alzheimer’s Disease Research Center, Mayo Clinic Study of Aging, and Neurodegenerative Research Group. All underwent neurologic, genetic, and neuropathologic evaluations. Amygdala sections immunostained with antibodies against TDP‐43 were screened for TDP‐43‐immunoreactive inclusions and successively staged using the Josephs staging scheme. The frequency of TDP‐43 pathology by age at death was estimated using logistic regression with age modelled using a restricted cubic spline. Models were fit for all cases including the subset of 581 cases with dementia.ResultOur cohort was predominantly White (99%) with median age at death of 87 years (IQR: 80‐92) and relatively even sex distribution (52% female). About 55% had Braak stage V‐VI and 61% had Thal amyloid phase ≥3. Fifty‐two percent met criteria for intermediate‐high probability AD. TDP‐43‐immunoreactivity (TDP‐43+) was detected in 44% with median TDP‐43 stage of 3 (IQR: 1‐5), and in 54% with a median stage of 3 (IQR: 2‐5) in those with dementia. TDP‐43+ frequency increased approximately linearly with age at death. At 70 years at death, an estimated 30% (95% CI: 25–35) of the cohort was TDP‐43+ versus 33% (CI: 27–40) of those with dementia. By 90 years at death, 49% (CI: 45–52) of the overall cohort and 68% (CI:62‐73) of those with dementia were TDP‐43+.ConclusionThe results from our large cohort confirm that TDP‐43 pathology frequency increases in elderly White study participants with age of death, independent of cognitive status. Furthermore, TDP‐43 pathology frequency increases to a greater degree with age in those with dementia. Given the clear links between TDP‐43 and impaired cognition, the contribution of TDP‐43 to an individual’s cognitive impairment is likely to increase with age; a dynamic with significant public health consequences given our aging population.

AbstractPrior studies have shown communication‐related participation restrictions in patients with degenerative disease do not always match clinician judgment of symptom severity. Relatedly, there is a growing body of literature documenting discrepancies between patients with dementia and care partner perception of participation restrictions. However, it is not known how care partner perceptions of communication participation restrictions match or diverge from the patient's experience, which was the topic of this study.Toward that end, 28 patients with apraxia of speech and/or dysarthria associated with primary progressive apraxia of speech, nonfluent/agrammatic primary progressive aphasia, or progressive supranuclear palsy, all types of frontotemporal dementia, were seen for speech‐language examinations. The patients and their care partners were asked to independently complete the Communication Participation Item Bank (CPIB), short form, which is a 10‐question survey about communication in different contexts; higher scores reflect less interference from their condition on communication. Care partners were instructed to complete the form with their perception of the patient's restrictions. The total CPIB score (maximum 30) and difference scores were calculated and visualized.The data (Figure) suggest mismatches exist in care partner and patient ratings of communication participation restrictions. Of 28 patients, only 1 pair had identical scores, each rating severe interference in all communication contexts. 57% of patients rated communication as less impacted (higher scores) compared to their family member, leaving 39% of family members rating communication as less impacted than their loved one's perception. This study lays the foundation for future research to include patient and care partner ratings when examining the benefit of impairment‐based therapy, utilization of compensatory speech strategies, effectiveness of such strategies, and impact of other augmentative or alternative means of communication. The CPIB may be useful to document reduced psychosocial impact of disease and diminished burden and burnout on care partners with different intervention options. Future studies will explore possible differences between FTD phenotypes and, more specifically, whether 1) the motor speech disorder (MSD) disorder is primary or secondary to other motor impairment, 2) the nature or severity of the MSD, or 3) concomitant cognitive‐communication impairment predict the existence of and/or direction of a discrepancy.

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.

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<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<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.

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>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>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.