Clinical Manifestations.

Background: The multisite SuperAging Research Initiative (SRI) was established in 2021 to identify resilience and resistance factors promoting cognitive healthspan through a harmonized multidisciplinary protocol with prospective data collection. The designation of SuperAger is reserved for individuals age 80+ with episodic memory performance that is at least average for those 2-3 decades younger. Research studies of this relatively uncommon phenotype allow for investigations of fundamental importance to the neurobiology of brain aging, resilience, resistance, and avoidance of cognitive decline related to "average aging" and more severe impairments associated with Alzheimer's and related dementias (ADRD).

Successful cognitive aging is associated with thicker anterior cingulate cortex and lower tau deposition compared to typical aging.

Introduction: There is no consensus on either the definition of successful cognitive aging (SA) or the underlying neural mechanisms.

Methods: We examined the agreement between new and existing definitions using: (1) a novel measure, the cognitive age gap (SA-CAG, cognitive-predicted age minus chronological age), (2) composite scores for episodic memory (SA-EM), (3) non-memory cognition (SA-NM), and (4) the California Verbal Learning Test (SA-CVLT).

Results: Fair to moderate strength of agreement was found between the four definitions.

Geometric deep learning reveals a structuro-temporal understanding of healthy and pathologic brain aging.

Background: Brain age has historically been investigated primarily at the whole brain level. The ability to deconstruct the brain into its composite parts and explore brain age at the sub-structure level offers unique advantages. These include the exploration of dynamic and interconnected relationships between different brain structures in healthy and pathologic aging.

Focal amyloid and asymmetric tau in an imaging-to-autopsy case of clinical primary progressive aphasia with Alzheimer disease neuropathology.

Quantification of in vivo amyloid and tau PET imaging relationships with postmortem measurements are critical for validating the sensitivity and specificity imaging biomarkers across clinical phenotypes with Alzheimer disease neuropathologic change (ADNC). This study examined the quantitative relationship between regional binding of in vivo F-florbetapir amyloid PET and F-flortaucipir tau PET with postmortem stereological counts of amyloid plaques and neurofibrillary tangles (NFT) in a case of primary progressive aphasia (PPA) with ADNC, where neurodegeneration asymmetrically targets the left hemisphere. Beginning 2 years prior to death, a 63-year-old right-handed man presenting with agrammatic variant PPA underwent a florbetapir and flortaucpir PET scan, and neuropsychological assessments and magnetic resonance imaging sessions every 6 months.

Relationships among tau burden, atrophy, age, and naming in the aphasic variant of Alzheimer's disease.

Introduction: Examination of pathologic, anatomic, and cognitive relationships has been limited in primary progressive aphasia (PPA) with underlying Alzheimer's disease (AD) neuropathology.

Methods: Spatial relationships between tau positron emission tomography (PET), cortical thickness, age, and naming on the Boston Naming Test (BNT) in PPA with biomarker evidence of AD (PPA-AD) were examined.

Results: Higher tau PET burden was associated with atrophy and younger age.

Functional decline in the aphasic variant of Alzheimer's disease.

Introduction: Primary progressive aphasia (PPA) is a clinical dementia syndrome associated with frontotemporal lobar degeneration (FTLD) or Alzheimer's disease (AD). Impairment in activities of daily living is essential for dementia diagnosis, yet less is known about the neuropathologic impact on functional decline in PPA, especially over time.

Methods: Activities of Daily Living Questionnaire (ADLQ) ratings were compared by suspected underlying pathology between 17 PPA and 11 PPA participants at 6-month intervals for 2 years using a linear mixed-effects model.

Interpretation of Brain Morphology in Association to Alzheimer's Disease Dementia Classification Using Graph Convolutional Networks on Triangulated Meshes.

We propose a mesh-based technique to aid in the classification of Alzheimer's disease dementia (ADD) using mesh representations of the cortex and subcortical structures. Deep learning methods for classification tasks that utilize structural neuroimaging often require extensive learning parameters to optimize. Frequently, these approaches for automated medical diagnosis also lack visual interpretability for areas in the brain involved in making a diagnosis.

Accumulation of neurofibrillary tangles and activated microglia is associated with lower neuron densities in the aphasic variant of Alzheimer's disease.

The neurofibrillary tangles (NFT) and amyloid-ß plaques (AP) that comprise Alzheimer's disease (AD) neuropathology are associated with neurodegeneration and microglial activation. Activated microglia exist on a dynamic spectrum of morphologic subtypes that include resting, surveillant microglia capable of converting to activated, hypertrophic microglia closely linked to neuroinflammatory processes and AD neuropathology in amnestic AD. However, quantitative analyses of microglial subtypes and neurons are lacking in non-amnestic clinical AD variants, including primary progressive aphasia (PPA-AD).

Differential neurocognitive network perturbation in amnestic and aphasic Alzheimer disease.

Objective: To determine if Alzheimer disease (AD) is associated with aphasic rather than amnestic dementias in certain circumstances related in part to perturbations in different networks.

Methods: Three groups were investigated: 14 participants suspected of having the neuropathology of AD based on clinically diagnosed amnestic dementia of the Alzheimer type (DAT), 26 individuals with primary progressive aphasia (PPA) with either a positive F-florbetapir amyloid PET scan or confirmed AD at autopsy, and 26 neurologically intact controls. The groups were compared using rs-fMRI.

Neuroimaging modality fusion in Alzheimer's classification using convolutional neural networks.

Automated methods for Alzheimer's disease (AD) classification have the potential for great clinical benefits and may provide insight for combating the disease. Machine learning, and more specifically deep neural networks, have been shown to have great efficacy in this domain. These algorithms often use neurological imaging data such as MRI and FDG PET, but a comprehensive and balanced comparison of the MRI and amyloid PET modalities has not been performed.

Clinical and cortical decline in the aphasic variant of Alzheimer's disease.

Introduction: Primary progressive aphasia (PPA) displays variable progression trajectories that require further elucidation.

Methods: Longitudinal quantitation of atrophy and language over 12 months was completed for PPA patients with and without positive amyloid PET (PPA and PPA), an imaging biomarker of underlying Alzheimer's disease.

Results: Over 12 months, both PPA groups showed significantly greater cortical atrophy rates in the left versus right hemisphere, with a more widespread pattern in PPA.

Proof of concept demonstration of optimal composite MRI endpoints for clinical trials.

Background: Atrophy measures derived from structural MRI are promising outcome measures for early phase clinical trials, especially for rare diseases such as primary progressive aphasia (PPA), where the small available subject pool limits our ability to perform meaningfully powered trials with traditional cognitive and functional outcome measures.

Methods: We investigated a composite atrophy index in 26 PPA participants with longitudinal MRIs separated by two years. Rogalski .

Aphasic variant of Alzheimer disease: Clinical, anatomic, and genetic features.

Objective: To identify features of primary progressive aphasia (PPA) associated with Alzheimer disease (AD) neuropathology. A related objective was to determine whether logopenic PPA is a clinical marker for AD.

Methods: A total of 139 prospectively enrolled participants with a root diagnosis of PPA constituted the reference set.

Frontotemporal networks and behavioral symptoms in primary progressive aphasia.

Objective: To determine if behavioral symptoms in patients with primary progressive aphasia (PPA) were associated with degeneration of a ventral frontotemporal network.

Methods: We used diffusion tensor imaging tractography to quantify abnormalities of the uncinate fasciculus that connects the anterior temporal lobe and the ventrolateral frontal cortex. Two additional ventral tracts were studied: the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus.

Is in vivo amyloid distribution asymmetric in primary progressive aphasia?

We aimed to determine whether (18) F-florbetapir amyloid positron emission tomography imaging shows a clinically concordant, left-hemisphere-dominant pattern of deposition in primary progressive aphasia (PPA). Elevated cortical amyloid (Aβ(+) ) was found in 19 of 32 PPA patients. Hemispheric laterality of amyloid burden was compared between Aβ(+) PPA and an Aβ(+) amnestic dementia groups (n = 22).

Morphometric and histologic substrates of cingulate integrity in elders with exceptional memory capacity.

This human study is based on an established cohort of "SuperAgers," 80+-year-old individuals with episodic memory function at a level equal to, or better than, individuals 20-30 years younger. A preliminary investigation using structural brain imaging revealed a region of anterior cingulate cortex that was thicker in SuperAgers compared with healthy 50- to 65-year-olds. Here, we investigated the in vivo structural features of cingulate cortex in a larger sample of SuperAgers and conducted a histologic analysis of this region in postmortem specimens.

Asymmetry of cortical decline in subtypes of primary progressive aphasia.

Objective: The aim of this study was to provide quantitative measures of changes in cortical atrophy over a 2-year period associated with 3 subtypes of primary progressive aphasia (PPA) using whole-brain vertex-wise and region-of-interest (ROI) neuroimaging methods. The purpose was to quantitate disease progression, establish an empirical basis for clinical expectations, and provide outcome measures for therapeutic trials.

Methods: Changes in cortical thickness and volume loss as well as neuropsychological performance were assessed at baseline and 2-year follow-up in 26 patients who fulfilled criteria for logopenic (8 patients), agrammatic (10 patients), and semantic (8 patients) PPA subtypes.

Naming vs knowing faces in primary progressive aphasia: a tale of 2 hemispheres.

Objectives: This study examines the anatomical correlates of naming vs recognizing faces using a novel measure that utilizes culturally relevant and age-appropriate items, the Northwestern University Famous Faces (NUFFACE) Test, in primary progressive aphasia (PPA), a syndrome characterized by progressive language deficits and associated with cortical atrophy in areas important for word and object representations.

Methods: NUFFACE Test performance of 27 controls (mean age 62.3 years) was compared with that of 30 patients with PPA (mean age 62 years).

A novel frontal pathway underlies verbal fluency in primary progressive aphasia.

The frontal aslant tract is a direct pathway connecting Broca's region with the anterior cingulate and pre-supplementary motor area. This tract is left lateralized in right-handed subjects, suggesting a possible role in language. However, there are no previous studies that have reported an involvement of this tract in language disorders.