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Background and Objectives: The 3 clinical presentations of primary progressive aphasia (PPA) reflect heterogenous neuropathology, which is difficult to be recognized in vivo. Resting-state (RS) EEG is promising for the investigation of brain electrical substrates in neurodegenerative conditions. In this study, we aim to explore EEG cortical sources in the characterization of the 3 variants of PPA., Methods: This is a cross-sectional, single-center, memory center-based cohort study. Patients with PPA and healthy controls were consecutively recruited at the Neurology Unit, IRCCS San Raffaele Scientific Institute (Milan, Italy). Each participant underwent an RS 19-channel EEG. Using standardized low-resolution brain electromagnetic tomography, EEG current source densities were estimated at voxel level and compared among study groups. Using an RS functional MRI-driven model of source reconstruction, linear lagged connectivity (LLC) values within language and extra-language brain networks were obtained and analyzed among groups., Results: Eighteen patients with logopenic PPA variant (lvPPA; mean age = 72.7 ± 6.6; % female = 52.4), 21 patients with nonfluent/agrammatic PPA variant (nfvPPA; mean age = 71.7 ± 8.1; % female = 66.6), and 9 patients with semantic PPA variant (svPPA; mean age = 65.0 ± 6.9; % female = 44.4) were enrolled in the study, together with 21 matched healthy controls (mean age = 69.2 ± 6.5; % female = 57.1). Patients with lvPPA showed a higher delta density than healthy controls ( p < 0.01) and patients with nfvPPA ( p < 0.05) and svPPA ( p < 0.05). Patients with lvPPA also displayed a greater theta density over the left posterior hemisphere ( p < 0.01) and lower alpha2 values ( p < 0.05) over the left frontotemporal regions than controls. Patients with nfvPPA showed a diffuse greater theta density than controls ( p < 0.05). LLC was altered in all patients relative to controls ( p < 0.05); the alteration was greater at slow frequency bands and within language networks than extra-language networks. Patients with lvPPA also showed greater LLC values at theta band than patients with nfvPPA ( p < 0.05)., Discussion: EEG findings in patients with PPA suggest that lvPPA-related pathology is associated with a characteristic disruption of the cortical electrical activity, which might help in the differential diagnosis from svPPA and nfvPPA. EEG connectivity was disrupted in all PPA variants, with distinct findings in disease-specific PPA groups., Classification of Evidence: This study provides Class IV evidence that EEG analysis can distinguish PPA due to probable Alzheimer disease from PPA due to probable FTD from normal aging.

Background and Objectives: MRI connectomics is an ideal tool to test a network-based model of pathologic propagation from a disease epicenter in neurodegenerative disorders. In this study, we used a novel graph theory-based MRI paradigm to explore functional connectivity reorganization, discerning between direct and indirect connections from disease epicenters, and its relationship with neurodegeneration across clinical presentations of the frontotemporal dementia (FTD) spectrum, including behavioral variant of FTD (bvFTD), nonfluent variant of primary progressive aphasia (nfvPPA), and semantic variant of primary progressive aphasia (svPPA)., Methods: In this observational cross-sectional study, disease epicenters were defined as the peaks of atrophy of a cohort of patients with high confidence of frontotemporal lobar degeneration pathology (Mayo Clinic). These were used as seed regions for stepwise functional connectivity (SFC) analyses in an independent (Milan) set of patients with FTD to assess connectivity in regions directly and indirectly connected to the epicenters. Correlations between SFC architecture in healthy conditions and atrophy patterns in patients with FTD were also tested., Results: As defined by comparing the 42 Mayo Clinic patients with 15 controls, disease epicenters were the left anterior insula for bvFTD, left supplementary motor area for nfvPPA, and left inferior temporal gyrus (ITG) for svPPA. Compared with 94 age-matched controls, patients with bvFTD (n = 64) and nfvPPA (n = 34) of the Milan cohort showed widespread decreased SFC in bilateral cortical regions with direct/indirect connections with epicenters and increased SFC either in directly connected regions, physically close to the respective seed region, or in more distant cortical/cerebellar areas with indirect connections. Across all link steps, svPPA (n = 36) showed SFC decrease mostly within the temporal lobes, with co-occurrent SFC increase in cerebellar regions at indirect link steps. The average stepwise topological distance from the left ITG in a reference group of 50 young healthy controls correlated with regional gray matter volume in svPPA, consistent with network-based degeneration., Discussion: Our findings demonstrate that each FTD syndrome is associated with a characteristic interplay of decreased and increased functional connectivity with the disease epicenter, affecting both direct and indirect connections. SFC revealed novel insights regarding the topology of functional disconnection across FTD syndromes, holding the promise to be used to model disease progression in future longitudinal studies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: A significant overlap between amyotrophic lateral sclerosis (ALS) and behavioral variant of frontotemporal dementia (bvFTD) has been observed at clinical, genetic, and pathologic levels. Within this continuum of presentations, the presence of mild cognitive or behavioral symptoms in patients with ALS has been consistently reported, although it is unclear whether this is to be considered a distinct phenotype or rather a natural evolution of ALS. Here, we used mathematical modeling of MRI connectomic data to decipher common and divergent neural correlates across the ALS-frontotemporal dementia (FTD) spectrum., Methods: We included 83 patients with ALS, 35 patients with bvFTD, and 61 healthy controls, who underwent clinical, cognitive, and MRI assessments. Patients with ALS were classified according to the revised Strong criteria into 54 ALS with only motor deficits (ALS-cn), 21 ALS with cognitive or behavioral involvement (ALS-ci/bi), and 8 ALS with bvFTD (ALS-FTD). First, we assessed the functional and structural connectivity patterns across the ALS-FTD spectrum. Second, we investigated whether and where MRI connectivity alterations of patients with ALS with any degree of cognitive impairment (i.e., ALS-ci/bi and ALS-FTD) resembled more the pattern of damage of one (ALS-cn) or the other end (bvFTD) of the spectrum, moving from group-level to single-subject analysis., Results: As compared with controls, extensive structural and functional disruption of the frontotemporal and parietal networks characterized bvFTD (bvFTD-like pattern), while a more focal structural damage within the sensorimotor-basal ganglia areas characterized ALS-cn (ALS-cn-like pattern). ALS-ci/bi patients demonstrated an ALS-cn-like pattern of structural damage, diverging from ALS-cn with similar motor impairment for the presence of enhanced functional connectivity within sensorimotor areas and decreased functional connectivity within the bvFTD-like pattern. On the other hand, patients with ALS-FTD resembled both structurally and functionally the bvFTD-like pattern of damage with, in addition, the structural ALS-cn-like damage in the motor areas., Discussion: Our findings suggest a maladaptive role of functional rearrangements in ALS-ci/bi concomitantly with similar structural alterations compared to ALS-cn, supporting the hypothesis that ALS-ci/bi might be considered as a phenotypic variant of ALS, rather than a consequence of disease worsening., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: To assess cortical, subcortical, and cerebellar gray matter (GM) atrophy using MRI in patients with disorders of the frontotemporal lobar degeneration (FTLD) spectrum with known genetic mutations., Methods: Sixty-six patients carrying FTLD-related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty-one patients with sporadic FTLD (sFTLD) matched for age, sex, and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls. A whole-brain voxel-based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were obtained., Results: Compared with controls, GM atrophy on VBM was greater and more diffuse in genetic FTD, followed by sporadic FTD and genetic MND cases, whereas patients with sporadic MND (sMND) showed focal motor cortical atrophy. Patients carrying C9orf72 and GRN mutations showed the most widespread cortical volume loss, in contrast with GM sparing in SOD1 and TARDBP . Globally, patients with gFTLD showed greater atrophy of parietal cortices and thalami compared with sFTLD. In volumetric analysis, patients with gFTLD showed volume loss compared with sFTLD in the caudate nuclei and thalami, in particular comparing C9-MND with sMND cases. In the cerebellum, patients with gFTLD showed greater atrophy of the right lobule VIIb than sFTLD. Thalamic volumes of patients with gFTLD with a C9orf72 mutation showed an inverse correlation with Frontal Behavioral Inventory scores., Discussion: Measures of deep GM and cerebellar structural involvement may be useful markers of gFTLD, particularly C9orf72 -related disorders, regardless of the clinical presentation within the FTLD spectrum., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To investigate the types of errors produced in a picture naming task by patients with neurodegenerative dementia due to different etiologies and their neural correlates., Methods: The same standardized picture naming test was administered to a consecutive sample of patients (n = 148) who had been studied with [ 18 F] FDG-PET. The errors were analyzed in 3 categories (visual, semantic, and phonologic). The PET data were analyzed using an optimized single-subject procedure, and the statistical parametric mapping multiple regression design was used to explore the correlation between each type of error and brain hypometabolism in the whole group. Metabolic connectivity analyses were run at the group level on 7 left hemisphere cortical areas corresponding to an a priori defined naming network., Results: Semantic errors were predominant in most patients, independent of clinical diagnosis. In the whole group analysis, visual errors correlated with hypometabolism in the right inferior occipital lobe and in the left middle occipital lobe. Semantic errors correlated with hypometabolism in the left fusiform gyrus, the inferior and middle temporal gyri, and the temporal pole. Phonologic errors were associated with hypometabolism in the left superior and middle temporal gyri. Both positive (occipital-posterior fusiform) and negative (anterior fusiform gyrus and the superior anterior temporal lobe) connectivity changes were associated with semantic errors., Conclusions: Naming errors reflect the dysfunction of separate stages of the naming process and are specific markers for different patterns of brain involvement. These correlations are not limited to primary progressive aphasia but extend to other neurodegenerative dementias., (© 2020 American Academy of Neurology.)

Objective: To understand whether the clinical phenotype of nonfluent/agrammatic primary progressive aphasia (nfvPPA) could present differences depending on the patient's native language., Methods: In this cross-sectional study, we analyzed connected speech samples in monolingual English (nfvPPA-E) and Italian speakers (nfvPPA-I) who were diagnosed with nfvPPA and matched for age, sex, and Mini-Mental State Examination scores. Patients also received a comprehensive neuropsychological battery. All patients and 2 groups of age-matched healthy controls underwent an MRI scan with 3D T1-weighted sequences. Connected speech measures and the other cognitive features were compared between patient groups. MRI variables, in terms of gray matter volume, were compared between each patient group and the corresponding controls., Results: Compared to nfvPPA-E, nfvPPA-I had fewer years of education and shorter reported disease duration. The 2 groups showed similar regional atrophy compatible with clinical diagnosis. Patients did not differ in nonlanguage domains, comprising executive scores. Connected speech sample analysis showed that nfvPPA-E had significantly more distortions than nfvPPA-I, while nfvPPA-I showed reduced scores in some measures of syntactic complexity. On language measures, Italian speakers performed more poorly on syntactic comprehension., Conclusions: nfvPPA-E showed greater motor speech impairment than nfvPPA-I despite higher level of education and comparable disease severity and atrophy changes. The data also suggest greater grammatical impairment in nfvPPA-I. This study illustrates the need to take into account the possible effect of the individual's spoken language on the phenotype and clinical presentation of primary progressive aphasia variants., (© 2020 American Academy of Neurology.)

Objective: To investigate functional brain network architecture in early-onset Alzheimer disease (EOAD) and behavioral variant frontotemporal dementia (bvFTD)., Methods: Thirty-eight patients with bvFTD, 37 patients with EOAD, and 32 age-matched healthy controls underwent 3D T1-weighted and resting-state fMRI. Graph analysis and connectomics assessed global and local functional topologic network properties, regional functional connectivity, and intrahemispheric and interhemispheric between-lobe connectivity., Results: Despite similarly extensive cognitive impairment relative to controls, patients with EOAD showed severe global functional network alterations (lower mean nodal strength, local efficiency, clustering coefficient, and longer path length), while patients with bvFTD showed relatively preserved global functional brain architecture. Patients with bvFTD demonstrated reduced nodal strength in the frontoinsular lobe and a relatively focal altered functional connectivity of frontoinsular and temporal regions. Functional connectivity breakdown in the posterior brain nodes, particularly in the parietal lobe, differentiated patients with EOAD from those with bvFTD. While EOAD was associated with widespread loss of both intrahemispheric and interhemispheric functional correlations, bvFTD showed a preferential disruption of the intrahemispheric connectivity., Conclusions: Disease-specific patterns of functional network topology and connectivity alterations were observed in patients with EOAD and bvFTD. Graph analysis and connectomics may aid clinical diagnosis and help elucidate pathophysiologic differences between neurodegenerative dementias., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To identify early cognitive and neuroimaging features of sporadic nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) caused by frontotemporal lobar degeneration (FTLD) subtypes., Methods: We prospectively collected clinical, neuroimaging, and neuropathologic data in 11 patients with sporadic nfvPPA with FTLD-tau (nfvPPA-tau, n = 9) or FTLD-transactive response DNA binding protein pathology of 43 kD type A (nfvPPA-TDP, n = 2). We analyzed patterns of cognitive and gray matter (GM) and white matter (WM) atrophy at presentation in the whole group and in each pathologic subtype separately. We also considered longitudinal clinical data., Results: At first evaluation, regardless of pathologic FTLD subtype, apraxia of speech (AOS) was the most common cognitive feature and atrophy involved the left posterior frontal lobe. Each pathologic subtype showed few distinctive features. At presentation, patients with nfvPPA-tau presented with mild to moderate AOS, mixed dysarthria with prominent hypokinetic features, clear agrammatism, and atrophy in the GM of the left posterior frontal regions and in left frontal WM. While speech and language deficits were prominent early, within 3 years of symptom onset, all patients with nfvPPA-tau developed significant extrapyramidal motor signs. At presentation, patients with nfvPPA-TDP had severe AOS, dysarthria with spastic features, mild agrammatism, and atrophy in left posterior frontal GM only. Selective mutism occurred early, when general neurologic examination only showed mild decrease in finger dexterity in the right hand., Conclusions: Clinical features in sporadic nfvPPA caused by FTLD subtypes relate to neurodegeneration of GM and WM in frontal motor speech and language networks. We propose that early WM atrophy in nfvPPA is suggestive of FTLD-tau pathology while early selective GM loss might be indicative of FTLD-TDP.

Objective: To investigate whether brain functional network connectivity is disrupted in patients with the behavioral variant of frontotemporal dementia (bvFTD)., Methods: Graph theoretical analysis was applied to resting state functional MRI data from 18 patients with probable bvFTD and 50 healthy individuals. Functional connectivity between 90 cortical and subcortical brain regions was estimated using bivariate correlation analysis and thresholded to construct a set of undirected graphs. Correlations between network properties and cognitive variables were tested., Results: Global topologic organization of the functional brain network in bvFTD was significantly disrupted as indicated by reduced mean network degree, clustering coefficient, and global efficiency and increased characteristic path length and assortativity relative to normal subjects. Compared to controls, bvFTD data showed retention of major "hub" regions in the medial parietal, temporal, and occipital lobes, but cortical hubs were not noted in the frontal lobes. Medial and dorsal frontal regions, left caudate nucleus, left insular cortices, and some regions of the temporal, parietal, and occipital lobes showed decreased nodal centrality. BvFTD patients showed the greatest decrease in inter-regional connectivity between the frontal and occipital regions, and the insular cortices and occipital, temporal, subcortical, and frontal regions. In bvFTD, altered global network properties correlated with executive dysfunction., Conclusions: Global and local functional networks are altered in bvFTD, suggesting a loss of efficiency in information exchange between both distant and close brain areas. Altered brain regions are located in structures that are closely associated with neuropathologic changes in bvFTD. Aberrant topology of the functional brain networks in bvFTD appears to underlie cognitive deficits in these patients.

Objective: To assess whether different patterns of regional gray matter loss in patients with mild cognitive impairment (MCI) are associated with different risks of conversion to Alzheimer disease (AD), using MRI and voxel-based morphometry (VBM)., Methods: The authors recruited 22 patients with MCI, 22 patients with probable AD, and 20 healthy subjects (HS). T1 volumes from each subject were postprocessed according to an optimized VBM protocol. All patients were clinically followed up (mean [SD] time = 28.7 [5.7] months), and patients with MCI were reclassified into two groups (converters and nonconverters to AD)., Results: When comparing patients with AD to HS, widespread areas of reduced gray matter density were found predominantly in temporal, frontal, and parietal lobes and in the insula. Comparing MCI converters and nonconverters with HS, the converters showed more widespread areas of reduced gray matter density than nonconverters, with a pattern of abnormalities similar to that seen in patients with AD. Conversely, when comparing the same groups with patients with AD, MCI nonconverters showed a pattern of gray matter density similar to that of HS. Areas of decreased gray matter density were also found in MCI converters compared with nonconverters., Conclusions: Different patterns of gray matter density distribution in patients with mild cognitive impairment may be associated to different rates of conversion to Alzheimer disease.

The authors measured mean diffusivity (D) and magnetization transfer ratio (MTR) of the brain from 18 patients with AD and 16 healthy control subjects. The peak heights of cortical gray matter (cGM) D (p < 0.001) and MTR (p < 0.001) histograms were lower and average cGM D (p < 0.01) higher in patients with AD than in control subjects. A composite MR score based on brain volume and cGM MTR peak height was correlated with patient cognitive impairment (r = 0.65, p = 0.003). This preliminary study presents a novel approach to quantify AD-related tissue damage in-vivo.