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. In this study we used diffusion tractography to define the anatomy of the frontal aslant tract in relation to verbal fluency and grammar impairment in primary progressive aphasia. Thirty-five patients with primary progressive aphasia and 29 control subjects were recruited. Tractography was used to obtain indirect indices of microstructural organization of the frontal aslant tract. In addition, tractography analysis of the uncinate fasciculus, a tract associated with semantic processing deficits, was performed. Damage to the frontal aslant tract correlated with performance in verbal fluency as assessed by the Cinderella story test. Conversely, damage to the uncinate fasciculus correlated with deficits in semantic processing as assessed by the Peabody Picture Vocabulary Test. Neither tract correlated with grammatical or repetition deficits. Significant group differences were found in the frontal aslant tract of patients with the non-fluent/agrammatic variant and in the uncinate fasciculus of patients with the semantic variant. These findings indicate that degeneration of the frontal aslant tract underlies verbal fluency deficits in primary progressive aphasia and further confirm the role of the uncinate fasciculus in semantic processing. The lack of correlation between damage to the frontal aslant tract and grammar deficits suggests that verbal fluency and grammar processing rely on distinct anatomical networks.

This human study is based on an established cohort of "SuperAgers," 80ϩ-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. A region-of-interest MRI structural analysis found cingulate cortex to be thinner in cognitively average 80ϩ year olds (n ϭ 21) than in the healthy middle-aged group (n ϭ 18). A region of the anterior cingulate cortex in the right hemisphere displayed greater thickness in SuperAgers (n ϭ 31) compared with cognitively average 80ϩ year olds and also to the much younger healthy 50 -60 year olds (p Ͻ 0.01). Postmortem investigations were conducted in the cingulate cortex in five SuperAgers, five cognitively average elderly individuals, and five individuals with amnestic mild cognitive impairment. Compared with other subject groups, SuperAgers showed a lower frequency of Alzheimer-type neurofibrillary tangles (p Ͻ 0.05). There were no differences in total neuronal size or count between subject groups. Interestingly, relative to total neuronal packing density, there was a higher density of von Economo neurons (p Ͻ 0.05), particularly in anterior cingulate regions of SuperAgers. These findings suggest that reduced vulnerability to the age-related emergence of Alzheimer pathology and higher von Economo neuron density in anterior cingulate cortex may represent biological correlates of high memory capacity in advanced old age.

Preferential neurodegeneration of the left hemisphere language network is a common denominator for all 3 PPA subtypes, even as the disease progresses. Using a focal cortical language network ROI as an outcome measure of disease progression appears to be more sensitive than whole-brain or ventricular volume measures of change and may be helpful for designing future clinical trials in PPA.

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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). Associations between NUFFACE Test performance and cortical thickness measures were quantified within the PPA group.Results: Patients with PPA displayed significant impairment on the NUFFACE Test, demonstrating that it is a useful measure of famous-face identification for individuals with relatively young-onset dementias. Despite widespread distribution of atrophy in the PPA group, face naming impairments were correlated with atrophy of the left anterior temporal lobe while face recognition impairments were correlated with bitemporal atrophy.Conclusions: In addition to their clinical relevance for highlighting the distinction between face naming and recognition impairments in individuals with young-onset dementia, these findings add new insights into the dissociable clinico-anatomical substrates of lexical retrieval and object knowledge. Difficulty recalling names of people is a common symptom of advancing age. More severe deficits, especially when accompanied by face recognition impairments, arise as part of neurodegenerative diseases that damage language and object recognition networks. Although several tests assess knowledge of famous faces, none were designed recently and therefore contain stimuli unfamiliar to younger individuals (i.e., aged 40-65 years) who are seeking neurologic assessment and treatment. Furthermore, these tests rarely differentiate face naming from recognition, a distinction of major neurologic significance regarding the locus of the underlying impairment. The current study was based on the Northwestern University Famous Faces (NUFFACE) Test, which addresses the aforementioned concerns by using stimuli relevant for individuals younger than 65 years, and explores the anatomical substrates of face naming and recognition.Participants included individuals with a diagnosis of primary progressive aphasia (PPA) and healthy controls of a similar age. PPA is a predominantly young-onset clinical dementia characterized by selective language disruption and relative preservation of other cognitive abilities during the initial disease stages.1 Atrophy in PPA is initially asymmetrically concentrated within the language-dominant (usually left) hemisphere but eventually extends to adjacent and contralateral areas with individual variations from patient to patient. Although the most severe face identification impairments in PPA are encountered in its semantic subtype, this study included all subtypes, thereby providing a subject group with a spectrum of...

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. Those with autopsy or biomarker evidence of AD, and who had been evaluated at mild disease stages (Aphasia Quotient $85), were included (n 5 19). All had quantitative language testing and APOE genotyping. Fifteen had MRI morphometry.Results: Impaired word-finding was the universal presenting complaint in the aphasic AD group.PPA clinical subtype was logopenic (n 5 13) and agrammatic (n 5 6). Fluency, repetition, naming, and grammaticality ranged from preserved to severely impaired. All had relative preservation of word comprehension. Eight of the 15 aphasic participants with AD showed no appreciable cortical atrophy at the individual level on MRI. As a group, atrophy was asymmetrically concentrated in the left perisylvian cortex. APOE e4 frequency was not elevated.Conclusions: There is a close, but not obligatory, association between logopenic PPA and AD. No language measure, with the possible exception of word comprehension, can confirm or exclude AD in PPA. Biomarkers are therefore essential for diagnosis. Asymmetry of cortical atrophy and normal APOE e4 prevalence constitute deviations from typical AD. These and additional neuropathologic features suggest that AD has biological subtypes, one of which causes PPA. Better appreciation of this fact should promote the inclusion of individuals with PPA and positive AD biomarkers into relevant clinical trials. Neurology ® 2016;87:1337-1343 GLOSSARY AD 5 Alzheimer disease; AQ 5 aphasia quotient; FDR 5 false discovery rate; FTLD 5 frontotemporal lobar degeneration; NAT 5 Northwestern Anagram Test; NAVS-SPPT 5 Sentence Production Priming Test of the Northwestern Assessment of Verbs and Sentences; NFT 5 neurofibrillary tangles; PPA 5 primary progressive aphasia; PPA-G 5 primary progressive aphasia agrammatic subtype; PPA-L 5 primary progressive aphasia logopenic subtype; PPA-S 5 primary progressive aphasia semantic subtype; SOB 5 sum of boxes; WAB-R 5 Western Aphasia Battery-Revised; WPM 5 words per minute.Primary progressive aphasia (PPA) is diagnosed when language impairment arises in relative isolation and progresses to become the primary obstacle to daily functioning. Frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD) are its most common neuropathologic correlates. The primary pathology is frequently FTLD-tau in agrammatic subtypes (PPA-G), FTLD-TDP in semantic subtypes (PPA-S), and AD in logopenic subtypes (PPA-L). 1The goal of this report is to characterize the features of PPA associated with AD. Previous investigations were based on samples of convenience with aphasias of variable severity and language testing of limited coverage, especially in the domain of grammar. The current report is based on 19 individuals w...

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). PPA‐AD is a language disorder characterized by cortical atrophy and NFT densities concentrated to the language‐dominant hemisphere. Here, a stereologic investigation of five PPA‐AD participants determined the densities and distributions of neurons and microglial subtypes to examine how cellular changes relate to AD neuropathology and may contribute to cortical atrophy. Adjacent series of sections were immunostained for neurons (NeuN) and microglia (HLA‐DR) from bilateral language and non‐language regions where in vivo cortical atrophy and Thioflavin‐S‐positive APs and NFTs were previously quantified. NeuN‐positive neurons and morphologic subtypes of HLA‐DR‐positive microglia (i.e., resting [ramified] microglia and activated [hypertrophic] microglia) were quantified using unbiased stereology. Relationships between neurons, microglia, AD neuropathology, and cortical atrophy were determined using linear mixed models. NFT densities were positively associated with hypertrophic microglia densities (P < 0.01) and inversely related to neuron densities (P = 0.01). Hypertrophic microglia densities were inversely related to densities of neurons (P < 0.01) and ramified microglia (P < 0.01). Ramified microglia densities were positively associated with neuron densities (P = 0.02) and inversely related to cortical atrophy (P = 0.03). Our findings provide converging evidence of divergent roles for microglial subtypes in patterns of neurodegeneration, which includes hypertrophic microglia likely driving a neuroinflammatory response more sensitive to NFTs than APs in PPA‐AD. Moreover, the accumulation of both NFTs and activated hypertrophic microglia in association with low neuron densities suggest they may collectively contribute to focal neurodegeneration characteristic of PPA‐AD.

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. In order to accurately determine the relative strength of each imaging variant, this work performs a comparison study in the context of Alzheimer’s dementia classification using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset with identical neural network architectures. Furthermore, this work analyzes the benefits of using both modalities in a fusion setting and discusses how these data types may be leveraged in future AD studies using deep learning.