Differential Vulnerability of Hippocampal Subfields to Amyloid and Tau Deposition in the Lewy Body Diseases.

BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) copathologies of ß-amyloid and tau are common in the Lewy body diseases (LBD), dementia with Lewy bodies (DLB) and Parkinson disease (PD), and target distinct hippocampal subfields compared with Lewy pathology, including subiculum and CA1. We investigated the hypothesis that AD copathologies impact the pattern of hippocampal subregion volume loss and cognitive function in LBD. METHODS: This was a cross-sectional and longitudinal, single-center, observational cohort study. Participants underwent neuropsychological testing and 3T-MRI with hippocampal segmentation using FreeSurferV7. PiB-PET and flortaucipir-PET imaging of comorbid ß-amyloid (A) and tau (T) were acquired. The association of functional cognition, ß-amyloid, and tau loads with hippocampal subregion volume was assessed. The contribution of subregion volumes to the relationship of AD-related deposits on functional cognition was examined with mediation analysis. The effects of AD-related deposits on the rate of subregion atrophy were evaluated with mixed-effects models. RESULTS: Of 103 participants (mean age: 70.3 years; 37.3% female), 52 had LBD with impaired cognition (LBD-I), 26 had normal cognition (LBD-N), and 25 were A- healthy controls (HCs). Volumes of hippocampal subregions prone to AD copathologies, including subiculum (F = 6.9, p = 0.002), presubiculum (F = 7.3, p = 0.001), and parasubiculum (F = 5.9, p = 0.004), were reduced in LBD-I compared with LBD-N and HC. Volume was preserved in CA2/3, Lewy pathology susceptible subregions. In LBD-I, reduced CA1, subiculum, and presubiculum volumes were associated with greater functional cognitive impairment (all p < 0.05). Compared with HC, subiculum volume was reduced in A+T+ but not A-T- participants (F = 2.62, p = 0.043). Reduced subiculum volume mediated the effect of amyloid on functional cognition (0.12, 95% CI: 0.005 to 0.26, p = 0.040). In 26 longitudinally-evaluated participants, baseline tau deposition was associated with faster CA1 (p = 0.021) and subiculum (p = 0.002) atrophy. DISCUSSION: In LBD, volume loss in hippocampal output subregions-particularly the subiculum-is associated with functional cognition and AD-related deposits. Tau deposition appears to accelerate subiculum and CA1 atrophy, whereas Aß does not. Subiculum volume may have value as a biomarker of AD copathology-mediated neurodegeneration and disease progression.

The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort.

INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

Atrophy in behavioural variant frontotemporal dementia spans multiple large-scale prefrontal and temporal networks.

The identification of a neurodegenerative disorder's distributed pattern of atrophy-or atrophy 'signature'-can lend insights into the cortical networks that degenerate in individuals with specific constellations of symptoms. In addition, this signature can be used as a biomarker to support early diagnoses and to potentially reveal pathological changes associated with said disorder. Here, we characterized the cortical atrophy signature of behavioural variant frontotemporal dementia (bvFTD). We used a data-driven approach to estimate cortical thickness using surface-based analyses in two independent, sporadic bvFTD samples (n = 30 and n = 71, total n = 101), using age- and gender-matched cognitively and behaviourally normal individuals. We found highly similar patterns of cortical atrophy across the two independent samples, supporting the reliability of our bvFTD signature. Next, we investigated whether our bvFTD signature targets specific large-scale cortical networks, as is the case for other neurodegenerative disorders. We specifically asked whether the bvFTD signature topographically overlaps with the salience network, as previous reports have suggested. We hypothesized that because phenotypic presentations of bvFTD are diverse, this would not be the case, and that the signature would cross canonical network boundaries. Consistent with our hypothesis, the bvFTD signature spanned rostral portions of multiple networks, including the default mode, limbic, frontoparietal control and salience networks. We then tested whether the signature comprised multiple anatomical subtypes, which themselves overlapped with specific networks. To explore this, we performed a hierarchical clustering analysis. This yielded three clusters, only one of which extensively overlapped with a canonical network (the limbic network). Taken together, these findings argue against the hypothesis that the salience network is preferentially affected in bvFTD, but rather suggest that-at least in patients who meet diagnostic criteria for the full-blown syndrome-neurodegeneration in bvFTD encompasses a distributed set of prefrontal, insular and anterior temporal nodes of multiple large-scale brain networks, in keeping with the phenotypic diversity of this disorder.

Gray to white matter signal ratio as a novel biomarker of neurodegeneration in Alzheimer's disease.

Alzheimer's disease (AD) is characterized neuropathologically by ß-amyloid (Aß) plaques, hyperphosphorylated tau neurofibrillary tangles, and neurodegeneration, which lead to a phenotypically heterogeneous cognitive-behavioral dementia syndrome. Our understanding of how these neuropathological and neurodegeneration biomarkers relate to each other is still evolving. A relatively new approach to measuring structural brain change, gray matter to white matter signal intensity ratio (GWR), quantifies the signal contrast between these tissue compartments, and has emerged as a promising marker of AD-related neurodegeneration. We sought to validate GWR as a novel MRI biomarker of neurodegeneration in 29 biomarker positive individuals across the atypical syndromic spectrum of AD. Bivariate correlation analyses revealed that GWR was associated with cortical thickness, tau PET, and amyloid PET, with GWR showing a larger magnitude of abnormality than cortical thickness. We also found that combining GWR, cortical thickness, and amyloid PET better explained observed tau PET signal than using these modalities alone, suggesting that the three imaging biomarkers contribute independently and synergistically to explaining the variance in the distribution of tau pathology. We conclude that GWR is a uniquely sensitive in vivo marker of neurodegenerative change that reflects pathological mechanisms which may occur prior to cortical atrophy. By using all of these imaging biomarkers of AD together, we may be better able to capture, and possibly predict, AD neuropathologic changes in vivo. We hope that such an approach will ultimately contribute to better endpoints to evaluate the efficacy of therapeutic interventions as we move toward an era of disease-modifying treatments for this devastating disease.

Association of Regional Cortical Network Atrophy With Progression to Dementia in Patients With Primary Progressive Aphasia.

BACKGROUND AND OBJECTIVES: Patients with primary progressive aphasia (PPA) have gradually progressive language deficits during the initial phase of the illness. As the underlying neurodegenerative disease progresses, patients with PPA start losing independent functioning due to the development of nonlanguage cognitive or behavioral symptoms. The timeline of this progression from the mild cognitive impairment stage to the dementia stage of PPA is variable across patients. In this study, in a sample of patients with PPA, we measured the magnitude of cortical atrophy within functional networks believed to subserve diverse cognitive and affective functions. The objective of the study was to evaluate the utility of this measure as a predictor of time to subsequent progression to dementia in PPA. METHODS: Patients with PPA with largely independent daily function were recruited through the Massachusetts General Hospital Frontotemporal Disorders Unit. All patients underwent an MRI scan at baseline. Cortical atrophy was then estimated relative to a group of amyloid-negative cognitively normal control participants. For each patient, we measured the time between the baseline visit and the subsequent visit at which dementia progression was documented or last observation. Simple and multivariable Cox regression models were used to examine the relationship between cortical atrophy and the likelihood of progression to dementia. RESULTS: Forty-nine patients with PPA (mean age = 66.39 ± 8.36 years, 59.2% females) and 25 controls (mean age = 67.43 ± 4.84 years, 48% females) were included in the data analysis. Greater baseline atrophy in not only the left language network (hazard ratio = 1.47, 95% CI = 1.17-1.84) but also in the frontoparietal control (1.75, 1.25-2.44), salience (1.63, 1.25-2.13), default mode (1.55, 1.19-2.01), and ventral frontotemporal (1.41, 1.16-1.71) networks was associated with a higher risk of progression to dementia. A multivariable model identified contributions of the left frontoparietal control (1.94, 1.09-3.48) and ventral frontotemporal (1.61, 1.09-2.39) networks in predicting dementia progression, with no additional variance explained by the language network (0.75, 0.43-1.31). DISCUSSION: These results suggest that baseline atrophy in cortical networks subserving nonlanguage cognitive and affective functions is an important predictor of progression to dementia in PPA. This measure should be included in precision medicine models of prognosis in PPA.

Using Generative Artificial Intelligence to Classify Primary Progressive Aphasia from Connected Speech.

Neurodegenerative dementia syndromes, such as Primary Progressive Aphasias (PPA), have traditionally been diagnosed based in part on verbal and nonverbal cognitive profiles. Debate continues about whether PPA is best subdivided into three variants and also regarding the most distinctive linguistic features for classifying PPA variants. In this study, we harnessed the capabilities of artificial intelligence (AI) and natural language processing (NLP) to first perform unsupervised classification of concise, connected speech samples from 78 PPA patients. Large Language Models discerned three distinct PPA clusters, with 88.5% agreement with independent clinical diagnoses. Patterns of cortical atrophy of three data-driven clusters corresponded to the localization in the clinical diagnostic criteria. We then used NLP to identify linguistic features that best dissociate the three PPA variants. Seventeen features emerged as most valuable for this purpose, including the observation that separating verbs into high and low-frequency types significantly improves classification accuracy. Using these linguistic features derived from the analysis of brief connected speech samples, we developed a classifier that achieved 97.9% accuracy in predicting PPA subtypes and healthy controls. Our findings provide pivotal insights for refining early-stage dementia diagnosis, deepening our understanding of the characteristics of these neurodegenerative phenotypes and the neurobiology of language processing, and enhancing diagnostic evaluation accuracy.

Clinical, radiologic, and pathologic features of the globular glial tauopathy subtype of frontotemporal lobar degeneration in right temporal variant frontotemporal dementia with salient features of Geschwind syndrome.

Globular Glial Tauopathy (GGT) is a rare form of Frontotemporal Lobar Degeneration (FTLD) consisting of 4-repeat tau globular inclusions in astrocytes and oligodendrocytes. We present the pathological findings of GGT in a previously published case of a 73-year-old woman with behavioral symptoms concerning for right temporal variant frontotemporal dementia with initial and salient features of Geschwind syndrome. Clinically, she lacked motor abnormalities otherwise common in previously published GGT cases. Brain MRI showed focal right anterior temporal atrophy (indistinguishable from five FTLD-TDP cases) and subtle ipsilateral white matter signal abnormalities. Brain autopsy showed GGT type III and Alzheimer's neuropathologic changes. .

Structural integrity of the anterior mid-cingulate cortex contributes to resilience to delirium in SuperAging.

Despite its devastating clinical and societal impact, approaches to treat delirium in older adults remain elusive, making it important to identify factors that may confer resilience to this syndrome. Here, we investigated a cohort of 93 cognitively normal older patients undergoing elective surgery recruited as part of the Successful Aging after Elective Surgery study. Each participant was classified either as a SuperAger (n = 19) or typically aging older adult (n = 74) based on neuropsychological criteria, where the former was defined as those older adults whose memory function rivals that of young adults. We compared these subgroups to examine the role of preoperative memory function in the incidence and severity of postoperative delirium. We additionally investigated the association between indices of postoperative delirium symptoms and cortical thickness in functional networks implicated in SuperAging based on structural magnetic resonance imaging data that were collected preoperatively. We found that SuperAging confers the real-world benefit of resilience to delirium, as shown by lower (i.e. zero) incidence of postoperative delirium and decreased severity scores compared with typical older adults. Furthermore, greater baseline cortical thickness of the anterior mid-cingulate cortex-a key node of the brain's salience network that is also consistently implicated in SuperAging-predicted lower postoperative delirium severity scores in all patients. Taken together, these findings suggest that baseline memory function in older adults may be a useful predictor of postoperative delirium risk and severity and that superior memory function may contribute to resilience to delirium. In particular, the integrity of the anterior mid-cingulate cortex may be a potential biomarker of resilience to delirium, pointing to this region as a potential target for preventive or therapeutic interventions designed to mitigate the risk or consequences of developing this prevalent clinical syndrome.

A category-selective semantic memory deficit for animate objects in semantic variant primary progressive aphasia.

Data are mixed on whether patients with semantic variant primary progressive aphasia exhibit a category-selective semantic deficit for animate objects. Moreover, there is little consensus regarding the neural substrates of this category-selective semantic deficit, though prior literature has suggested that the perirhinal cortex and the lateral posterior fusiform gyrus may support semantic memory functions important for processing animate objects. In this study, we investigated whether patients with semantic variant primary progressive aphasia exhibited a category-selective semantic deficit for animate objects in a word-picture matching task, controlling for psycholinguistic features of the stimuli, including frequency, familiarity, typicality and age of acquisition. We investigated the neural bases of this category selectivity by examining its relationship with cortical atrophy in two primary regions of interest: bilateral perirhinal cortex and lateral posterior fusiform gyri. We analysed data from 20 patients with semantic variant primary progressive aphasia (mean age = 64 years, S.D. = 6.94). For each participant, we calculated an animacy index score to denote the magnitude of the category-selective semantic deficit for animate objects. Multivariate regression analysis revealed a main effect of animacy (ß = 0.52, t = 4.03, P < 0.001) even after including all psycholinguistic variables in the model, such that animate objects were less likely to be identified correctly relative to inanimate objects. Inspection of each individual patient's data indicated the presence of a disproportionate impairment in animate objects in most patients. A linear regression analysis revealed a relationship between the right perirhinal cortex thickness and animacy index scores (ß = -0.57, t = -2.74, P = 0.015) such that patients who were more disproportionally impaired for animate relative to inanimate objects exhibited thinner right perirhinal cortex. A vertex-wise general linear model analysis restricted to the temporal lobes revealed additional associations between positive animacy index scores (i.e. a disproportionately poorer performance on animate objects) and cortical atrophy in the right perirhinal and entorhinal cortex, superior, middle, and inferior temporal gyri, and the anterior fusiform gyrus, as well as the left anterior fusiform gyrus. Taken together, our results indicate that a category-selective semantic deficit for animate objects is a characteristic feature of semantic variant primary progressive aphasia that is detectable in most individuals. Our imaging findings provide further support for the role of the right perirhinal cortex and other temporal lobe regions in the semantic processing of animate objects.

Cortical thickness across the lifespan in a Colombian cohort with autosomal-dominant Alzheimer's disease: A cross-sectional study.

INTRODUCTION: Cortical thinning is a marker of neurodegeneration in Alzheimer's disease (AD). We investigated the age-related trajectory of cortical thickness across the lifespan (9-59 years) in a Colombian kindred with autosomal dominant AD (ADAD). METHODS: Two hundred eleven participants (105 presenilin-1 [PSEN1] E280A mutation carriers, 16 with cognitive impairment; 106 non-carriers) underwent magnetic resonance imaging. A piecewise linear regression identified change-points in the age-related trajectory of cortical thickness in carriers and non-carriers. RESULTS: Unimpaired carriers exhibited elevated cortical thickness compared to non-carriers, and thickness more negatively correlated with age and cognition in carriers relative to non-carriers. We found increased cortical thickness in child carriers, after which thickness steadied compared to non-carriers prior to a rapid reduction in the decade leading up to the expected age at cognitive impairment in carriers. DISCUSSION: Findings suggest that cortical thickness may fluctuate across the ADAD lifespan, from early-life increased thickness to atrophy proximal to clinical onset.

18F-AV-1451 positron emission tomography in neuropathological substrates of corticobasal syndrome.

Multiple neuropathological processes can manifest in life as a corticobasal syndrome. We sought to relate retention of the tau-PET tracer 18F-AV-1451 and structural magnetic resonance measures of regional atrophy to clinical features in clinically diagnosed and neuropathologically confirmed cases of corticobasal syndrome and to determine whether these vary with the underlying neuropathological changes. In this observational, cross-sectional study, 11 subjects (eight female and three male, median age 72 years) with corticobasal syndrome underwent structural MRI, tau-PET with 18F-AV-1451, amyloid-PET with 11C-Pittsburgh compound B, detailed clinical examinations and neuropsychological testing. Of the 11, three had evidence of high amyloid burden consistent with Alzheimer's disease while eight did not. Neuropathological evaluations were acquired in six cases. Mixed effects general linear models were used to compare 18F-AV-1451 retention and atrophy in amyloid-negative corticobasal syndrome cases to 32 age-matched healthy control subjects and to relate cortical and subcortical 18F-AV-1451 retention and atrophy to clinical features. Subjects without amyloid, including three with pathologically confirmed corticobasal degeneration, showed greater regional 18F-AV-1451 retention and associated regional atrophy in areas commonly associated with corticobasal degeneration pathology than healthy control subjects [retention was higher compared to healthy controls (P = 0.0011), driven especially by the precentral gyrus (P = 0.011) and pallidum (P < 0.0001), and greater atrophy was seen in subjects compared to control subjects (P = 0.0004)]. Both 18F-AV-1451 retention and atrophy were greater in the clinically more affected hemisphere [on average, retention was 0.173 standardized uptake value ratio units higher on the more affected side (95% confidence interval, CI 0.11-0.24, P < 0.0001), and volume was 0.719 lower on the more affected side (95% CI 0.35-1.08, P = 0.0001)]. 18F-AV-1451 retention was greater in subcortical than in cortical regions, P < 0.0001. In contrast to these findings, subjects with amyloid-positive corticobasal syndrome, including two neuropathologically confirmed cases of Alzheimer's disease, demonstrated greater and more widespread 18F-AV-1451 retention and regional atrophy than observed in the amyloid-negative cases. There was thalamic 18F-AV-1451 retention but minimal cortical and basal ganglia uptake in a single corticobasal syndrome subject without neuropathological evidence of tau pathology, likely representing non-specific signal. Asymmetric cortical and basal ganglia 18F-AV-1451 retention consonant with the clinical manifestations characterize corticobasal syndrome due to corticobasal degeneration, whereas the cortical retention in cases associated with Alzheimer's disease is greater and more diffuse.

Regional prefrontal cortical atrophy predicts specific cognitive-behavioral symptoms in ALS-FTD.

Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD) may present typical behavioral variant FTD symptoms. This study aims to determine whether profile and severity of cognitive-behavioral symptoms in ALS/ALS-FTD are predicted by regional cortical atrophy. The hypothesis is that executive dysfunction can be predicted by dorsolateral prefrontal cortical (dlPFC) atrophy, apathy by dorsomedial PFC (dmPFC) and anterior cingulate cortical (ACC) atrophy, disinhibition by orbitofrontal cortical (OFC) atrophy. 3.0 Tesla MRI scans were acquired from 22 people with ALS or ALS-FTD. Quantitative cortical thickness analysis was performed with FreeSurfer. A priori-defined regions of interest (ROI) were used to measure cortical thickness in each participant and calculate magnitude of atrophy in comparison to 115 healthy controls. Spearman correlations were used to evaluate associations between frontal ROI cortical thickness and cognitive-behavioral symptoms, measured by Neuropsychiatric Inventory Questionnaire (NPI-Q) and Clinical Dementia Rating (CDR) scale. ALS-FTD participants exhibited variable degrees of apathy (NPI-Q/apathy: 1.6 ± 1.2), disinhibition (NPI-Q/disinhibition: 1.2 ± 1.2), executive dysfunction (CDR/judgment-problem solving: 1.7 ± 0.8). Within the ALS-FTD group, executive dysfunction correlated with dlPFC atrophy (ρ:-0.65;p < 0.05); similar trends were seen for apathy with ACC (ρ:-0.53;p < 0.10) and dmPFC (ρ:-0.47;p < 0.10) atrophy, for disinhibition with OFC atrophy (ρ:-0.51;p < 0.10). Compared to people with ALS, those with ALS-FTD showed more diffuse atrophy involving precentral gyrus, prefrontal, temporal regions. Profile and severity of cognitive-behavioral symptoms in ALS-FTD are predicted by regional prefrontal atrophy. These findings are consistent with established brain-behavior models and support the role of quantitative MRI in diagnosis, management, counseling, monitoring and prognostication for a neurodegenerative disorder with diverse phenotypes.

Topography of cortical thinning in the Lewy body diseases.

OBJECTIVE: Regional cortical thinning in dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) may underlie some aspect of their clinical impairments; cortical atrophy likely reflects extensive Lewy body pathology with alpha-synuclein deposits, as well as associated Alzheimer's disease co-pathologies, when present. Here we investigated the topographic distribution of cortical thinning in these Lewy body diseases compared to cognitively normal PD and healthy non-PD control subjects, explored the association of regional thinning with clinical features and evaluated the impact of amyloid deposition. METHODS: Twenty-one participants with dementia with Lewy bodies (DLB), 16 with Parkinson disease (PD) - associated cognitive impairment (PD-MCI and PDD), and 24 cognitively normal participants with PD underwent MRI, PiB PET, and clinical evaluation. Cortical thickness across the brain and in regions of interest (ROIs) was compared across diagnostic groups and across subgroups stratified by amyloid status, and was related to clinical and cognitive measures. RESULTS: DLB and PD-impaired groups shared a similar distribution of cortical thinning that included regions characteristic of AD, as well as the fusiform, precentral, and paracentral gyri. Elevated PiB retention in DLB and PD-impaired but not in PD-normal participants was associated with more extensive and severe cortical thinning, in an overlapping topography that selectively affected the medial temporal lobe in DLB participants. In DLB, greater thinning in AD signature and fusiform regions was associated with greater cognitive impairment. CONCLUSIONS: The pattern of cortical thinning is similar in DLB and PD-associated cognitive impairment, overlapping with and extending beyond AD signature regions to involve fusiform, precentral, and paracentral regions. Cortical thinning in AD signature and fusiform regions in these diseases reflects cognitive impairment and is markedly accentuated by amyloid co-pathology. Further work will be required to determine whether the distinct topography of cortical thinning in DLB and PD-associated cognitive impairment might have value as a diagnostic and/ or outcome biomarker in clinical trials.

Word retrieval across the biomarker-confirmed Alzheimer's disease syndromic spectrum.

Alzheimer's disease (AD) is now conceptualized as a biological entity defined by amyloid and tau deposition and neurodegeneration, with heterogeneous clinical presentations. With the aid of in vivo biomarkers, clinicians are better poised to examine clinical syndromic variability arising from a common pathology. Word retrieval deficits, measured using verbal fluency and confrontation naming tests, are hallmark features of the early clinical stages of the amnestic presentations of AD, specifically in category fluency and naming with relatively spared letter fluency. As yet, there is no consensus regarding performance on these tests in atypical clinical phenotypes of AD, including posterior cortical atrophy (PCA) and logopenic primary progressive aphasia (lvPPA), in individuals who are amyloid-positive (Aß+) but present with different clinical profiles and patterns of neurodegeneration compared to amnestic AD. The goal of the current study is to determine how Aß+ individuals across the syndromic spectrum of AD perform on three different word retrieval tasks. A secondary goal is to determine the neuroanatomical substrates underlying word retrieval performance in these Aß+ individuals. Thirty-two Aß+ participants with the amnestic presentation, 16 with Aß+ PCA, 22 with Aß+ lvPPA, and 99 amyloid-negative (Aß-) control participants were evaluated with verbal fluency and visual confrontation naming tests as well as high-resolution MRI. The Aß+ patient groups were rated at very mild or mild levels of severity (CDR 0.5 or 1) and had comparable levels of global cognitive impairment (average MMSE = 23.7 ± 3.9). Behaviorally, we found that the word retrieval profile of PCA patients is comparable to that of amnestic patients, characterized by intact letter fluency but impaired category fluency and visual confrontation naming, while lvPPA patients demonstrated impairment across all tests of word retrieval. Across all AD variants, we observed that letter fluency was associated with cortical thickness in prefrontal, central precuneus, lateral parietal and temporal cortex, while category fluency and naming were associated with cortical thickness in left middle frontal gyrus, posterior middle temporal gyrus, and lateral parietal cortex. Visual confrontation naming was uniquely associated with atrophy in inferior temporal and visual association cortex. We conclude that a better understanding of the word retrieval profiles and underlying neurodegeneration across the AD syndromic spectrum will help improve interpretation of neuropsychological profiles with regard to the localization of neurodegeneration, particularly in the atypical AD variants.

Visual cognition in non-amnestic Alzheimer's disease: Relations to tau, amyloid, and cortical atrophy.

Heterogeneity within the Alzheimer's disease (AD) syndromic spectrum is typically classified in a domain-specific manner (e.g., language vs. visual cognitive function). The central aim of this study was to investigate whether impairment in visual cognitive tasks thought to be subserved by posterior cortical dysfunction in non-amnestic AD presentations is associated with tau, amyloid, or neurodegeneration in those regions using 18F-AV-1451 and 11C-PiB positron emission tomography (PET) and magnetic resonance imaging (MRI). Sixteen amyloid-positive patients who met criteria for either Posterior Cortical Atrophy (PCA; n = 10) or logopenic variant Primary Progressive Aphasia (lvPPA; n = 6) were studied. All participants underwent a structured clinical assessment, neuropsychological battery, structural MRI, amyloid PET, and tau PET. The neuropsychological battery included two visual cognitive tests: VOSP Number Location and Benton Facial Recognition. Surface-based whole-cortical general linear models were used to first explore the similarities and differences between these biomarkers in the two patient groups, and then to assess their regional associations with visual cognitive test performance. The results show that these two variants of AD have both dissociable and overlapping areas of tau and atrophy, but amyloid is distributed with a stereotyped localization in both variants. Performance on both visual cognitive tests were associated with tau and atrophy in the right lateral and medial occipital association cortex, superior parietal cortex, and posterior ventral occipitotemporal cortex. No cortical associations were observed with amyloid PET. We further demonstrate that cortical atrophy has a partially mediating effect on the association between tau pathology and visual cognitive task performance. Our findings show that non-amnestic variants of AD have partially dissociable spatial patterns of tau and atrophy that localize as expected based on symptoms, but similar patterns of amyloid. Further, we demonstrate that impairments of visual cognitive dysfunction are strongly associated with tau in visual cortical regions and mediated in part by atrophy.

Fractionating the Rey Auditory Verbal Learning Test: Distinct roles of large-scale cortical networks in prodromal Alzheimer's disease.

Successful episodic memory calls upon a number of different cognitive processes that are supported by the coordination of several large-scale cortical networks. Previous work from our group has demonstrated dissociable anatomic substrates at different stages of memory in patients with dementia due to Alzheimer's disease (AD). The aim of the current study was to extend the understanding of brain-behavior associations underlying a commonly administered neuropsychological assessment of verbal episodic memory (Rey Auditory Verbal Learning Test; RAVLT) by determining the cortical network contributions to the performance at early vs. late stages of list learning, delayed recall, and retention, in 235 very mild biomarker positive (A+/T+/N+) individuals diagnosed with amnestic mild cognitive impairment (aMCI; MMSE = 27.7). We measured cortical atrophy in four large-scale cortical networks impacted by AD: default mode (DMN), dorsal attention (DAN), frontoparietal (FPN), and language (LN) networks. We also evaluated the role of hippocampal atrophy at each stage of memory performance. Partial correlation analyses controlling for age, sex, and education and corrected for multiple comparisons revealed that early learning was most strongly associated with cortical thickness in the DAN, while late learning was most strongly associated with hippocampal volume, but also related to cortical thickness in the DAN, FPN, DMN, and LN. Delayed recall was associated most strongly with hippocampal volume, but was also related to cortical thickness in the FPN and DMN, while retention was associated only with hippocampal volume. These findings are consistent with prior models of the neural substrates of different stages of verbal list learning and retrieval, provide new insights into the cortical networks undergoing neurodegeneration even at very mild stages of prodromal AD, and inform our thinking about the networks and regions being interrogated by this kind of neuropsychological assessment of episodic memory.

Quantification of motor speech impairment and its anatomic basis in primary progressive aphasia.

OBJECTIVE: To evaluate whether a quantitative speech measure is effective in identifying and monitoring motor speech impairment (MSI) in patients with primary progressive aphasia (PPA) and to investigate the neuroanatomical basis of MSI in PPA. METHODS: Sixty-four patients with PPA were evaluated at baseline, with a subset (n = 39) evaluated longitudinally. Articulation rate (AR), a quantitative measure derived from spontaneous speech, was measured at each time point. MRI was collected at baseline. Differences in baseline AR were assessed across PPA subtypes, separated by severity level. Linear mixed-effects models were conducted to assess groups differences across PPA subtypes in rate of decline in AR over a 1-year period. Cortical thickness measured from baseline MRIs was used to test hypotheses about the relationship between cortical atrophy and MSI. RESULTS: Baseline AR was reduced for patients with nonfluent variant PPA (nfvPPA) compared to other PPA subtypes and controls, even in mild stages of disease. Longitudinal results showed a greater rate of decline in AR for the nfvPPA group over 1 year compared to the logopenic and semantic variant subgroups. Reduced baseline AR was associated with cortical atrophy in left-hemisphere premotor and supplementary motor cortices. CONCLUSIONS: The AR measure is an effective quantitative index of MSI that detects MSI in mild disease stages and tracks decline in MSI longitudinally. The AR measure also demonstrates anatomic localization to motor speech-specific cortical regions. Our findings suggest that this quantitative measure of MSI might have utility in diagnostic evaluation and monitoring of MSI in PPA.

Executive dysfunction contributes to verbal encoding and retrieval deficits in posterior cortical atrophy.

Posterior Cortical Atrophy (PCA) is a neurodegenerative syndrome that typically presents with predominant visual and spatial impairments. The early diagnostic criteria specify a relative sparing of functioning in other cognitive domains, including executive functions, language, and episodic memory, yet little is known of the cognitive profile of PCA as the disease progresses. Studies of healthy adults and other posterior cortical lesion patients implicate posterior parietal and temporal regions in executive functions of working memory and verbal fluency, both of which may impact episodic memory. Relatively little has been reported about these cognitive functions in PCA, and to our knowledge there has not yet been a study of the impact of such deficits on memory function in PCA. We sought to examine PCA patients' performance on tests of executive function and the associations to verbal episodic memory encoding, storage, and delayed recall. Nineteen individuals with PCA underwent neuropsychological and neuroimaging evaluations as part of a comprehensive clinical assessment. We developed a novel consensus rating method-the Neuropsychological Assessment Rating (NAR) scale-to grade the severity of test performance impairments in selected cognitive domains and subdomains. Hypothesis-driven analyses demonstrated relative deficits in working memory and lexical-semantic retrieval. Preliminary analyses suggested associations between both deficits and atrophy in the left-hemisphere inferior parietal lobule. These executive deficits were also associated with impairments in verbal encoding and delayed recall, but not with recognition discriminability. We conclude that deficits in verbal executive functions impact verbal episodic memory in PCA. Our findings also support theories emphasizing the role of the posterior parietal cortex in supporting executive and lexical-semantic contributions to verbal episodic memory.

The personalized Alzheimer's disease cortical thickness index predicts likely pathology and clinical progression in mild cognitive impairment.

INTRODUCTION: An Alzheimer's disease (AD) biomarker adjusted for age-related brain changes should improve specificity for AD-related pathological burden. METHODS: We calculated a brain-age-adjusted "personalized AD cortical thickness index" (pADi) in mild cognitive impairment patients from the Alzheimer's Disease Neuroimaging Initiative. We performed receiver operating characteristic analysis for discrimination between patients with and without cerebrospinal fluid evidence of AD and logistic regression in an independent sample to determine if a dichotomized pADi predicted conversion to AD dementia. RESULTS: Receiver operating characteristic area under the curve was 0.69 and 0.72 in the two samples. Three empirical methods identified the same cut-point for pADi in the discovery sample. In the validation sample, 83% of pADi+ mild cognitive impairment patients were cerebrospinal fluid AD biomarker positive. pADi+ mild cognitive impairment patients (n = 63, 38%) were more likely to progress to AD dementia after 1 (odds ratio = 2.9) and 3 (odds ratio = 2.6) years. DISCUSSION: The pADi is a personalized, magnetic resonance imaging-derived AD biomarker that predicts progression to dementia.

Effects of cognitive reserve depend on executive and semantic demands of the task.

BACKGROUND: Cognitive reserve (CR) is one factor that helps to maintain cognitive function in patients with Alzheimer's disease (AD). Whether the effects of CR depend on the semantic/executive components of the task remains unknown. METHODS: 470 patients (138 with AD, 332 with mild cognitive impairment (MCI)) were selected from the Alzheimer's Disease Neuroimaging Initiative database. Linear regression models were used to determine the effects of CR (years of education) on cognitive performance after controlling for demographic factors and regional cortical atrophy. First, we assessed memory tasks with low (Auditory Verbal Learning Test (AVLT) discriminability), moderate (AVLT delayed recall) and high (Logical Memory Test (LMT) delayed recall) executive/semantic components. Next, we assessed tasks with lower (digit span forward, Trails A) or higher (digit span backwards, Trails B) executive demands, and lower (figure copying) or higher (naming, semantic fluency) semantic demands. RESULTS: High CR was significantly associated with performance on the LMT delayed recall, approached significance in the AVLT delayed recall and was not significantly associated with performance on AVLT discriminability. High CR was significantly associated with performance on the Trails B and digit span backwards, mildly associated with Trails A performance and was not associated with performance on digit span forwards. High CR was associated with performance on semantic but not visuospatial tasks. High CR was associated with semantic tasks in patients with both MCI and AD, but was only associated with executive functions in patients with MCI. CONCLUSION: CR may relate to executive functioning and semantic knowledge, leading to preserved cognitive performance in patients with AD pathology.