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Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

ObjectivesTo investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD).MethodsWe studied 72 LBD patients (Parkinson disease (PD)=2, PD-MCI=25, PD with dementia=10, dementia with Lewy bodies=35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Aβ1-42 >0.3) (LBD+AD, N=19), and those without AD co-pathology (LBD-AD, N=53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD-AD=14, LBD+AD=7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Aβ, and alpha-synuclein using digital histopathology in five representative neocortical regions.ResultsThe LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P&nbsp

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns. Electronic supplementary material The online version of this article (10.1007/s00401-020-02158-2) contains supplementary material, which is available to authorized users.

Frontotemporal lobar degeneration proteinopathies with tau inclusions (FTLD-Tau) or TDP-43 inclusions (FTLD-TDP) are associated with clinically similar phenotypes. However, these disparate proteinopathies likely differ in cellular severity and regional distribution of inclusions in white matter (WM) and adjacent grey matter (GM), which have been understudied. We performed a neuropathological study of subcortical WM and adjacent GM in a large autopsy cohort (n = 92; FTLD-Tau = 37, FTLD-TDP = 55) using a validated digital image approach. The antemortem clinical phenotype was behavioral-variant frontotemporal dementia (bvFTD) in 23 patients with FTLD-Tau and 42 with FTLD-TDP, and primary progressive aphasia (PPA) in 14 patients with FTLD-Tau and 13 with FTLD-TDP. We used linear mixed-effects models to: (1) compare WM pathology burden between proteinopathies; (2) investigate the relationship between WM pathology burden and WM degeneration using luxol fast blue (LFB) myelin staining; (3) study regional patterns of pathology burden in clinico-pathological groups. WM pathology burden was greater in FTLD-Tau compared to FTLD-TDP across regions (beta = 4.21, SE = 0.34, p p = 0.002) and FTLD-TDP (beta = 0.40, SE = 0.08, p p

ImportanceBiomarkers are lacking that can discriminate frontotemporal lobar degeneration (FTLD) associated with tau (FTLD-tau) or TDP-43 (FTLD-TDP).ObjectiveTo test whether plasma biomarkers glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), or their ratio (GFAP/NfL) differ between FTLD-tau and FTLD-TDP.Design, Setting, and ParticipantsThis retrospective cross-sectional study included data from 2009 to 2020 from the University of Pennsylvania Integrated Neurodegenerative Disease Database, with a median (IQR) follow-up duration of 2 (0.3-4.2) years. The training sample was composed of patients with autopsy-confirmed and familial FTLD; nonimpaired controls were included as a reference group. The independent validation sample included patients with FTD with a clinical diagnosis of progressive supranuclear palsy syndrome (PSPS) associated with tau (PSPS-tau) or amytrophic lateral sclerosis (ALS) associated with TDP-43 (ALS-TDP). In patients with FTLD with autopsy-confirmed or variant-confirmed pathology, receiver operating characteristic (ROC) curves tested the GFAP/NfL ratio and established a pathology-confirmed cut point. The cut point was validated in an independent sample of patients with clinical frontotemporal dementia (FTD). Data were analyzed from February to July 2022.ExposuresClinical, postmortem histopathological assessments, and plasma collection.Main Outcomes and MeasuresROC and area under the ROC curve (AUC) with 90% CIs evaluated discrimination of pure FTLD-tau from pure FTLD-TDP using plasma GFAP/NfL ratio; the Youden index established optimal cut points. Sensitivity and specificity of cut points were assessed in an independent validation sample.ResultsOf 349 participants with available plasma data, 234 met inclusion criteria (31 controls, 141 in the training sample, and 62 in the validation sample). In the training sample, patients with FTLD-tau were older than patients with FTLD-TDP (FTLD-tau: n = 46; mean [SD] age, 65.8 [8.29] years; FTLD-TDP: n = 95; mean [SD] age, 62.3 [7.82] years; t84.6 = 2.45; mean difference, 3.57; 95% CI, 0.67-6.48; P = .02) but with similar sex distribution (FTLD-tau: 27 of 46 [59%] were male; FTLD-TDP: 51 of 95 [54%] were male; χ21 = 0.14; P = .70). In the validation sample, patients with PSPS-tau were older than those with ALS-TDP (PSPS-tau: n = 31; mean [SD] age, 69.3 [7.35] years; ALS-TDP: n = 31; mean [SD] age, 54.6 [10.17] years; t54.6 = 6.53; mean difference, 14.71; 95% CI, 10.19-19.23; P 21 = 9.3; P = .002). ROC revealed excellent discrimination of FTLD-tau from FTLD-TDP by plasma GFAP/NfL ratio (AUC = 0.89; 90% CI, 0.82-0.95; sensitivity = 0.73; 90% CI, 0.65-0.89; specificity = 0.89; 90% CI, 0.78-0.98), which was higher than either GFAP level alone (AUC = 0.65; 90% CI, 0.54-0.76) or NfL levels alone (AUC = 0.75; 90% CI, 0.64-0.85). In the validation sample, there was sensitivity of 0.84 (90% CI, 0.66-0.94) and specificity of 0.81 (90% CI, 0.62-0.91) when applying the autopsy-derived plasma GFAP/NfL threshold.Conclusions and RelevanceThe plasma ratio of GFAP/NfL may discriminate FTLD-tau from FTLD-TDP.

Recent models of Alzheimer's disease progression propose that disease may be transmitted between brain areas either via local diffusion or long-distance transport via white matter fibre pathways. However, it is unclear whether such models are applicable in non-amnestic Alzheimer's disease, which is associated with domain-specific cognitive deficits and relatively spared episodic memory. To date, the anatomical progression of disease in non-amnestic patients remains understudied. We used longitudinal imaging to differentiate earlier atrophy and later disease spread in three non-amnestic variants, including logopenic-variant primary progressive aphasia (n = 25), posterior cortical atrophy (n = 20), and frontal-variant Alzheimer's disease (n = 12), as well as 17 amnestic Alzheimer's disease patients. Patients were compared to 37 matched controls. All patients had autopsy (n = 7) or CSF (n = 67) evidence of Alzheimer's disease pathology. We first assessed atrophy in suspected sites of disease origin, adjusting for age, sex, and severity of cognitive impairment; we then performed exploratory whole-brain analysis to investigate longitudinal disease spread both within and outside these regions. Additionally, we asked whether each phenotype exhibited more rapid change in its associated disease foci than other phenotypes. Finally, we investigated whether atrophy was related to structural brain connectivity. Each non-amnestic phenotype displayed unique patterns of initial atrophy and subsequent neocortical change that correlated with cognitive decline. Longitudinal atrophy included areas both proximal to and distant from sites of initial atrophy, suggesting heterogeneous mechanisms of disease spread. Moreover, regional rates of neocortical change differed by phenotype. Logopenic-variant patients exhibited greater initial atrophy and more rapid longitudinal change in left lateral temporal areas than other groups. Frontal-variant patients had pronounced atrophy in left insula and middle frontal gyrus, combined with more rapid atrophy of left insula than other non-amnestic patients. In the medial temporal lobes, non-amnestic patients had less atrophy at their initial scan than amnestic patients, but longitudinal rate of change did not differ between patient groups. Medial temporal sparing in non-amnestic Alzheimer's disease may thus be due in part to later onset of medial temporal degeneration than in amnestic patients rather than different rates of atrophy over time. Finally, the magnitude of longitudinal atrophy was predicted by structural connectivity, measured in terms of node degree; this result provides indirect support for the role of long-distance fibre pathways in the spread of neurodegenerative disease. 10.1093/brain/awz091_video1 awz091media1 6041544065001.

Objective To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) or tau (FTLD-Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using digital histopathology and to identify clinicopathological correlates of these distinct proteinopathies. Methods In an autopsy cohort of PPA (FTLD-TDP = 13, FTLD-Tau = 14), we analyzed laterality and regional distribution of postmortem pathology, quantified using a validated digital histopathological approach, in available brain tissue from up to 8 cortical regions bilaterally. We related digital pathology to antemortem structural neuroimaging and specific clinical language features. Results Postmortem cortical pathology was left-lateralized in both FTLD-TDP (beta = -0.15, standard error [SE] = 0.05, p = 0.007) and FTLD-Tau (beta = -0.09, SE = 0.04, p = 0.015), but the degree of lateralization decreased with greater overall dementia severity before death (beta = -8.18, SE = 3.22, p = 0.015). Among 5 core pathology regions sampled, we found greatest pathology in left orbitofrontal cortex (OFC) in FTLD-TDP, which was greater than in FTLD-Tau (F = 47.07, df = 1,17, p

Objective: To identify novel CSF biomarkers in GRN-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). Methods: Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high-resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers. Results: Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptortype tyrosine-protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin-A (CHGA), and V-set and transmembrane domain-containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers. Interpretation: We identified and validated five novel CSF biomarkers in GRN-associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers.

Altres ajuts: Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland grant numbers 7330550813, 733050103); Dioraphte Foundation (grant number 1402 1300); the European Joint Programme - Neurodegenerative Disease Research (JPND, PreFrontALS); NIH (grant number AG017586); Wyncote Foundation; Arking Family Fund; Invetissements d'avenir (grant number ANR-11-INBS-0011); Schörling Foundation - Swedish FTD Initiative; Swedish Research Council (2015-02926, 2018-02754, 2019-02248); Swedish Alzheimer's Foundation; Brain Foundation; Demensfonden, Stiftelsen för Gamla Tjänarinnor; Stohnes foundation; Region Stockholm (ALF project). Excessive microglial activation might be a central pathological process in GRN-related frontotemporal dementia (FTD-GRN). We measured soluble triggering receptor expressed on myeloid cells 2 (sTREM2), which is shed from disease-associated microglia following cleavage of TREM2, in cerebrospinal fluid of 34 presymptomatic and 35 symptomatic GRN mutation carriers, 6 presymptomatic and 32 symptomatic C9orf72 mutation carriers and 67 healthy noncarriers by ELISA. Although no group differences in sTREM2 levels were observed (GRN: symptomatic (median 5.2 ng/mL, interquartile range [3.9-9.2]) vs. presymptomatic (4.3 ng/mL [2.6-6.1]) vs. noncarriers (4.2 ng/mL [2.6-5.5]): p = 0.059; C9orf72: symptomatic (4.3 [2.9-7.0]) vs. presymptomatic (3.2 [2.2-4.2]) vs. noncarriers: p = 0.294), high levels were seen in a subset of GRN, but not C9orf72, mutation carriers, which might reflect differential TREM2-related microglial activation. Interestingly, 2 presymptomatic carriers with low sTREM2 levels developed symptoms after 1 year, whereas 2 with high levels became symptomatic after >5 years. While sTREM2 is not a promising diagnostic biomarker for FTD-GRN or FTD-C9orf72, further research might elucidate its potential to monitor microglial activity and predict disease progression.

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

The T allele in rs1768208 located in or near the myelin oligodendrocyte basic protein gene (MOBP) is a risk factor for frontotemporal degeneration pathology. We evaluated the hypothesis that the presence of a T allele in rs1768208 will be associated with rate of cognitive decline in behavioral variant frontotemporal degeneration (bvFTD) related to compromised frontal networks. We studied 81 individuals clinically diagnosed with bvFTD who were genotyped for rs1768208 and coded using a dominant model reflecting the presence (i.e., MOBP +) or absence (MOBP −) of the T risk allele. Linear mixed-effects models assessed the association of genotype on neuropsychological performance over time. Regression analyses examined differences in network structure by MOBP genotype. We found a genotype by time interaction for declining cognitive performance, whereby MOBP + individuals demonstrated faster rates of decline in executive function. The presence of a MOBP risk allele was associated with degradation of white matter network features in the frontal lobe. These findings suggest that individual genetic variation may contribute to heterogeneity in clinical progression.

ObjectiveWe implemented automated methods to analyze speech and evaluate the hypothesis that cognitive and motor factors impair prosody in partially distinct ways in patients with amyotrophic lateral sclerosis (ALS).MethodsWe recruited 213 participants, including 67 with ALS (44 with motor ALS, 23 with ALS and frontotemporal degeneration [FTD]), 33 healthy controls, and neurodegenerative reference groups with behavioral variant FTD (n = 90) and nonfluent/agrammatic primary progressive aphasia (n = 23). Digitized, semistructured speech samples obtained from picture descriptions were automatically segmented with a Speech Activity Detector; continuous speech segments were pitch-tracked; and duration measures for speech and silent pause segments were extracted. Acoustic measures were calculated, including fundamental frequency (f0) range, mean speech and pause segment durations, total speech duration, and pause rate (pause count per minute of speech). Group comparisons related performance on acoustic measures to clinical scales of cognitive and motor impairments and explored MRI cortical thinning in ALS and ALS-FTD.ResultsThe f0 range was significantly impaired in ALS spectrum disorders and was related to bulbar motor disease, and regression analyses related this to cortical thickness in primary motor cortex and perisylvian regions. Impaired speech and pause duration measures were related to the degree of cognitive impairment in ALS spectrum disorders, and regressions related duration measures to bilateral frontal opercula and left anterior insula.ConclusionAutomated analyses of acoustic speech properties dissociate motor and cognitive components of speech deficits in ALS spectrum disorders.

Neurodegeneration of the locus coeruleus (LC) in age-related neurodegenerative diseases such as Alzheimer's disease (AD) is well documented. However, detailed studies of LC neurodegeneration in the full spectrum of frontotemporal lobar degeneration (FTLD) proteinopathies comparing tauopathies (FTLD-tau) to TDP-43 proteinopathies (FTLD-TDP) are lacking. Here, we tested the hypothesis that there is greater LC neuropathology and neurodegeneration in FTLD-tau compared to FTLD-TDP. We examined 280 patients including FTLD-tau (n = 94), FTLD-TDP (n = 135), and two reference groups: clinical/pathological AD (n = 32) and healthy controls (HC, n = 19). Adjacent sections of pons tissue containing the LC were immunostained for phosphorylated TDP-43 (1D3-p409/410), hyperphosphorylated tau (PHF-1), and tyrosine hydroxylase (TH) to examine neuromelanin-containing noradrenergic neurons. Blinded to clinical and pathologic diagnoses, we semi-quantitatively scored inclusions of tau and TDP-43 both inside LC neuronal somas and in surrounding neuropil. We also digitally measured the percent area occupied of neuromelanin inside of TH-positive LC neurons and in surrounding neuropil to calculate a ratio of extracellular-to-intracellular neuromelanin as an objective composite measure of neurodegeneration. We found that LC tau burden in FTLD-tau was greater than LC TDP-43 burden in FTLD-TDP (z = - 11.38, p 0.0001). Digital measures of LC neurodegeneration in FTLD-tau were comparable to AD (z = - 1.84, p 0.05) but greater than FTLD-TDP (z = - 3.85, p 0.0001) and HC (z = - 4.12, p 0.0001). Both tau burden and neurodegeneration were consistently elevated in the LC across pathologic and clinical subgroups of FTLD-tau compared to FTLD-TDP subgroups. Moreover, LC tau burden positively correlated with neurodegeneration in the total FTLD group (rho = 0.24, p = 0.001), while TDP-43 burden did not correlate with LC neurodegeneration in FTLD-TDP (rho = - 0.01, p = 0.90). These findings suggest that patterns of disease propagation across all tauopathies include prominent LC tau and neurodegeneration that are relatively distinct from the minimal degenerative changes to the LC in FTLD-TDP and HC. Antemortem detection of LC neurodegeneration and/or function could potentially improve antemortem differentiation of underlying FTLD tauopathies from clinically similar FTLD-TDP proteinopathies.

To evaluate whether occupational attainment influences the trajectory of longitudinal cognitive decline in behavioral variant frontotemporal degeneration (bvFTD). Single-center, retrospective, longitudinal study. Sixty-three patients meeting consensus criteria for bvFTD underwent evaluation at the University of Pennsylvania Frontotemporal Degeneration Center. All patients were studied longitudinally on letter-guided fluency, category-naming fluency and Boston Naming Test (BNT). Occupational attainment was defined categorically by assigning each individual’s occupation to a professional or non-professional category. Linear mixed-effects models evaluated the interaction of neuropsychological performance change with occupational status. Regression analyses were used to relate longitudinal decline in executive function to baseline MRI grey matter atrophy. Higher occupational status was associated with a more severe slope of cognitive decline on letter-guided fluency and category-naming fluency, but not BNT. Faster rates of longitudinal decline on letter-guided and category-naming fluency were associated with more severe baseline grey matter atrophy in right dorsolateral and inferior frontal regions. Our longitudinal findings suggest that bvFTD individuals with higher lifetime cognitive experience demonstrate more rapid decline on measures of executive function. This finding converges with cross-sectional evidence suggesting that lifetime cognitive experiences contribute to heterogeneity in clinical progression in bvFTD.

ObjectiveTo test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD).MethodsPatients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN − AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology. CSF total tau (t-tau), phosphorylated tau at threonine181, and Aβ1-42 levels were compared between LBD and control groups and correlated with global cerebral pathology scores in LBD with linear regression. Diagnostic accuracy for postmortem categorization of LBD into SYN + AD vs SYN − AD or neocortical vs brainstem/limbic SYN stage was tested with receiver operating curves.ResultsSYN + AD had higher CSF t-tau (mean difference 27.0 ± 8.6 pg/mL) and lower Aβ1-42 (mean difference −84.0 ± 22.9 g/mL) compared to SYN − AD (p < 0.01, both). Increasing global cerebral tau and plaque scores were associated with higher CSF t-tau (R2 = 0.15–0.16, p < 0.05, both) and lower Aβ1-42 (R2 = 0.43–0.49, p < 0.001, both), while increasing cerebral SYN scores were associated with lower CSF Aβ1-42 (R2 = 0.31, p < 0.001) and higher CSF t-tau/Aβ1-42 ratio (R2 = 0.27, p = 0.01). CSF t-tau/Aβ1-42 ratio had 100% specificity and 90% sensitivity for SYN + AD, and CSF Aβ1-42 had 77% specificity and 82% sensitivity for neocortical SYN stage.ConclusionsHigher antemortem CSF t-tau/Aβ1-42 and lower Aβ1-42 levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies.

Introduction Mutations in the progranulin (GRN) gene are a major source of inherited frontotemporal degeneration (FTD) spectrum disorders associated with TDP-43 proteinopathy. We use structural MRI to identify regions of baseline differences and longitudinal changes in gray matter (GM) and white matter (WM) in presymptomatic GRN mutation carriers (pGRN+) compared to young controls (yCTL). Methods Cognitively intact first-degree relatives of symptomatic GRN+ FTD patients with identified GRN mutations (pGRN+; N = 11, mean age = 41.4) and matched yCTL (N = 11, mean age = 53.6) were identified. They completed a MRI session with T1-weighted imaging to assess GM density (GMD) and diffusion-weighted imaging (DWI) to assess fractional anisotropy (FA). Participants completed a follow-up session with T1 and DWI imaging (pGRN+ mean interval 2.20 years; yCTL mean interval 3.27 years). Annualized changes of GMD and FA were also compared. Results Relative to yCTL, pGRN+ individuals displayed reduced GMD at baseline in bilateral orbitofrontal, insular, and anterior temporal cortices. pGRN+ also showed greater annualized GMD changes than yCTL at follow-up in right orbitofrontal and left occipital cortices. We also observed reduced FA at baseline in bilateral superior longitudinal fasciculus, left corticospinal tract, and frontal corpus callosum in pGRN+ relative to yCTL, and pGRN+ displayed greater annualized longitudinal FA change in right superior longitudinal fasciculus and frontal corpus callosum. Conclusions Longitudinal MRI provides evidence of progressive GM and WM changes in pGRN+ participants relative to yCTL. Structural MRI illustrates the natural history of presymptomatic GRN carriers, and may provide an endpoint during disease-modifying treatment trials for pGRN+ individuals at risk for FTD., Highlights • Presymptomatic GRN mutation carriers (pGRN+) show decreased gray matter and white matter relative to young controls (yCTL) • pGRN+ show greater longitudinal changes in gray matter and white matter relative to yCTL • Regions with decreased gray matter and white matter in pGRN+ are in regions showing disease in symptomatic GRN+

Objective:To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA).Methods:We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data.Results:A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA−). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%, p < 0.01). Lexical retrieval difficulty was common in all patients with PPA and did not discriminate between groups. Compared to non-AD, PPA with AD pathology had elevated microscopic neurodegenerative pathology in the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex (p < 0.01). Low DF scores correlated with high microscopic pathologic burden in superior/midtemporal and angular gyri (p ≤ 0.03).Conclusions:Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.

Introduction Primary age-related tauopathy (PART) is a neuropathological diagnosis characterized by tau neurofibrillary tangles (NFTs) in the absence of amyloid plaque pathology. Although most individuals over 50 years of age have evidence of NFTs, the clinical and cognitive consequences of PART are not known. Methods We evaluated 226 neuropathologically confirmed PART cases from the National Alzheimer's Coordinating Center database who participated in a total of 846 longitudinal neuropsychological assessments from the Alzheimer's Disease Center program‘s Uniform Data Set. Mixed-effects statistical models tested whether cognitive decline was associated with Braak stage NFT burden. Results Higher stages of NFT burden in PART, with no evidence or minimal evidence of amyloid pathology, were associated with more rapid decline on tasks involving episodic and semantic memory along with tests of processing speed and attention. Discussion We conclude that PART has cognitive consequences that should be considered in the context of emerging tau-targeted therapies in age-associated neurodegenerative diseases.

Objective:To apply network-based statistics to diffusion-weighted imaging tractography data and detect Alzheimer disease vs non-Alzheimer degeneration in the context of corticobasal syndrome.Methods:In a cross-sectional design, pathology was confirmed by autopsy or a pathologically validated CSF total tau-to-β-amyloid ratio (T-tau/Aβ). Using structural MRI data, we identify association areas in fronto-temporo-parietal cortex with reduced gray matter density in corticobasal syndrome (n = 40) relative to age-matched controls (n = 40). Using these fronto-temporo-parietal regions of interest, we construct structural brain networks in clinically similar subgroups of individuals with Alzheimer disease (n = 21) or non-Alzheimer pathology (n = 19) by linking these regions by the number of white matter streamlines identified in a deterministic tractography analysis of diffusion tensor imaging data. We characterize these structural networks using 5 graph-based statistics, and assess their relative utility in classifying underlying pathology with leave-one-out cross-validation using a supervised support vector machine.Results:Gray matter density poorly discriminates between Alzheimer disease and non-Alzheimer pathology subgroups with low sensitivity (57%) and specificity (52%). In contrast, a statistic of local network efficiency demonstrates very good discriminatory power, with 85% sensitivity and 84% specificity.Conclusions:Our results indicate that the underlying pathologic sources of corticobasal syndrome can be classified more accurately using graph theoretical statistics derived from patterns of white matter network organization in association cortex than by regional gray matter density alone. These results highlight the importance of a multimodal neuroimaging approach to diagnostic analyses of corticobasal syndrome.

Background The differential diagnosis of progressive supranuclear palsy (PSP) and Lewy body disorders, which include Parkinson disease and dementia with Lewy bodies, is often challenging due to the overlapping symptoms. Purpose To develop a diagnostic tool based on diffusion tensor imaging (DTI) to distinguish between PSP and Lewy body disorders at the individual-subject level. Materials and Methods In this retrospective study, skeletonized DTI metrics were extracted from two independent data sets: the discovery cohort from the Swedish BioFINDER study and the validation cohort from the Penn Frontotemporal Degeneration Center (data collected between 2010 and 2018). Based on previous neuroimaging studies and neuropathologic evidence, a combination of regions hypothesized to be sensitive to pathologic features of PSP were identified (ie, the superior cerebellar peduncle and frontal white matter) and fractional anisotropy (FA) was used to compute an FA score for each individual. Classification performances were assessed by using logistic regression and receiver operating characteristic analysis. Results In the discovery cohort, 16 patients with PSP (mean age ± standard deviation, 73 years ± 5; eight women, eight men), 34 patients with Lewy body disorders (mean age, 71 years ± 6; 14 women, 20 men), and 44 healthy control participants (mean age, 66 years ± 8; 26 women, 18 men) were evaluated. The FA score distinguished between clinical PSP and Lewy body disorders with an area under the curve of 0.97 ± 0.04, a specificity of 91% (31 of 34), and a sensitivity of 94% (15 of 16). In the validation cohort, 34 patients with PSP (69 years ± 7; 22 women, 12 men), 25 patients with Lewy body disorders (70 years ± 7; nine women, 16 men), and 32 healthy control participants (64 years ± 7; 22 women, 10 men) were evaluated. The accuracy of the FA score was confirmed (area under the curve, 0.96 ± 0.04; specificity, 96% [24 of 25]; and sensitivity, 85% [29 of 34]). Conclusion These cross-validated findings lay the foundation for a clinical test to distinguish progressive supranuclear palsy from Lewy body disorders. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Shah in this issue.

We examined longitudinal change in language expression during a semi-structured speech sample in 48 patients with primary progressive aphasia (PPA) or behavioral variant frontotemporal dementia (bvFTD) and related this to longitudinal neuroimaging of cortical thickness available in 25 of these patients. All patient groups declined significantly on measures of both speech fluency and grammar, although patients with nonfluent/agrammatic PPA (naPPA) declined to a greater extent than patients with the semantic variant, the logopenic variant, and bvFTD. These patient groups also declined on several neuropsychological measures, but there was no correlation between decline in speech expression and decline in neuropsychological performance. Longitudinal decline in grammaticality, assessed by the number of well-formed sentences produced, was associated with longitudinal progression of gray matter atrophy in left frontal operculum/insula and bilateral temporal cortex.

ObjectiveTo determine autosomal dominant genetic predictors of survival in individuals with behavioral variant frontotemporal degeneration (bvFTD).MethodsA retrospective chart review of 174 cases with a clinical phenotype of bvFTD but no associated elementary neurologic features was performed, with diagnosis either autopsy-confirmed (n = 57) or supported by CSF evidence of non-Alzheimer pathology (n = 117). Genetic analysis of the 3 most common genes with pathogenic autosomal dominant mutations associated with frontotemporal degeneration was performed in all patients, which identified cases with C9orf72 expansion (n = 28), progranulin (GRN) mutation (n = 12), and microtubule-associated protein tau (MAPT) mutation (n = 10). Cox proportional hazards regressions were used to test for associations between survival and mutation status, sex, age at symptom onset, and education.ResultsAcross all patients with bvFTD, the presence of a disease-associated pathogenic mutation was associated with shortened survival (hazard ratio [HR] 2.164, 95% confidence interval [CI] 1.391, 3.368). In separate models, a GRN mutation (HR 2.423, 95% CI 1.237, 4.744), MAPT mutation (HR 8.056, 95% CI 2.938, 22.092), and C9orf72 expansion (HR 1.832, 95% CI 1.034, 3.244) were each individually associated with shorter survival relative to sporadic bvFTD. A mutation on the MAPT gene results in an earlier age at onset than a C9orf72 expansion or mutation on the GRN gene (p = 0.016).ConclusionsOur findings suggest that autosomal dominantly inherited mutations, modulated by age at symptom onset, associate with shorter survival among patients with bvFTD. We suggest that clinical trials and clinical management should consider mutation status and age at onset when evaluating disease progression.

To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD.Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN-AD = 35). Digital measures of tau, β-amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing.SYN burden was higher in SYN + AD than SYN-AD in each neocortical region (FLBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1-13 ANN NEUROL 2019;85:259-271.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/., Background: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. Methods: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). Results: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p, This study was funded by a Memorabel grant from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development, and Alzheimer Nederland grant number 7330598105), National Institutes of Health (Grants AG010124, AG032953, AG043503, NS088341, AG017586, AG052943, AG038490), the Wyncote Foundation, Dana Foundation, Brightfocus Foundation, Penn Institute on Aging, Pla estratègic de recerca i innovació en salut 2016-2020, Catalan Department of Health (grant number SLT002/16/00408), Italian Ministry of Health (Ricerca Corrente) and the German Federal Ministry of Education and Research (FTLDc 01GI1007A). MS was supported by the Else Kröner-Fresenius-Stiftung. CW was supported by the Vaillant Stiftung

Objective To use multimodal neuroimaging to evaluate the influence of heterogeneous underlying pathology in corticobasal syndrome (CBS) on the neuroanatomical distribution of disease. Methods We performed a retrospective evaluation of 35 patients with CBS with T1-weighted MRI, diffusion tensor imaging, and neuropathologic, genetic, or CSF evidence of underlying pathology. Patients were assigned to 2 groups: those with evidence of Alzheimer pathology (CBS-AD) and those without Alzheimer pathology (CBS-non-AD). Group comparisons of CBS-AD and CBS-non-AD assessed clinical features, gray matter (GM) cortical thickness, and white matter (WM) fractional anisotropy. Results CBS-AD was found in 34% (n = 12) and CBS-non-AD in 66% (n = 23) of CBS patients. Clinical evaluations revealed that CBS-non-AD had a higher frequency of asymmetric rigidity compared to CBS-AD, but groups otherwise did not differ in dementia severity, impairments in cognition, or rates of extrapyramidal symptoms. We found frontoparietal GM and WM disease in each group compared to healthy, demographically comparable controls, as well as multimodal neuroimaging evidence of a double dissociation: CBS-non-AD had WM disease in the corpus callosum, corticospinal tract, and superior longitudinal fasciculus relative to CBS-AD, and CBS-AD had reduced temporoparietal GM relative to CBS-non-AD, including the precuneus and posterior cingulate. Conclusions Patients with CBS have a pathology-mediated dissociation of GM and WM disease. Multimodality neuroimaging may be useful for improving in vivo pathologic diagnosis of CBS.

The objective of the study was to evaluate the prognostic value of regional cerebral blood flow (CBF) measured by arterial spin labeled (ASL) perfusion MRI in patients with semantic variant primary progressive aphasia (svPPA). We acquired pseudo-continuous ASL (pCASL) MRI and whole-brain T1-weighted structural MRI in svPPA patients (N = 13) with cerebrospinal fluid biomarkers consistent with frontotemporal lobar degeneration pathology. Follow-up T1-weighted MRI was available in a subset of patients (N = 8). We performed whole-brain comparisons of partial volume-corrected CBF and cortical thickness between svPPA and controls, and compared baseline and follow-up cortical thickness in regions of significant hypoperfusion and hyperperfusion. Patients with svPPA showed partial volume-corrected hypoperfusion relative to controls in left temporal lobe and insula. svPPA patients also had typical cortical thinning in anterior temporal, insula, and inferior frontal regions at baseline. Volume-corrected hypoperfusion was seen in areas of significant cortical thinning such as the left temporal lobe and insula. Additional regions of hypoperfusion corresponded to areas without cortical thinning. We also observed regions of hyperperfusion, some associated with cortical thinning and others without cortical thinning, including right superior temporal, inferior parietal, and orbitofrontal cortices. Regions of hypoperfusion and hyperperfusion near cortical thinning at baseline had significant longitudinal thinning between baseline and follow-up scans, but perfusion changes in distant areas did not show progressive thinning. Our findings suggest ASL MRI may be sensitive to functional changes not readily apparent in structural MRI, and specific changes in perfusion may be prognostic markers of disease progression in a manner consistent with cell-to-cell spreading pathology.

BACKGROUND: Dementia in Parkinson’s disease (PD) is common and disabling. Identification of modifiable risk factors for it is essential. Vascular risk factors may be associated with cognitive decline in early PD. Biomarkers that serve as surrogates of the long-term effect of vascular risk factors on PD are needed. To that end, we aimed to quantitate white matter hyperintensities in early PD, measure associations with vascular risk factors, and examine relationships between white matter hyperintensities and longitudinal cognition. METHODS: Participants in the Parkinson Progression Markers Initiative study (141 PD patients, 63 healthy controls) with adequate baseline structural brain MRIs were included. Hypertension and diabetes history, and body mass index, were combined to create a vascular risk score. White matter hyperintensities were quantitated via automated methods. Cognition was assessed annually with a comprehensive test battery. RESULTS: In the PD group, vascular risk score was associated with white matter hyperintensities for total brain (β=0.210;p=0.021), total white matter (β=0.214;p=0.013), frontal (β=0.220;p=0.002) and temporal (β=0.212;p=0.002) regions. Annual rate of change in global cognition was greater in those with higher vascular risk score (β=−0.040;p=0.007) and greater white matter hyperintensities (β=−0.029;p=0.049). Higher temporal white matter hyperintensity burden was associated with great decline over time in verbal memory (β=−0.034;p=0.031). CONCLUSION: In early PD, modifiable vascular risk factors are associated with white matter hyperintensities on brain MRI. Temporal white matter hyperintensity burden predicts decline in verbal memory. White matter hyperintensities may serve as a surrogate marker for the effect of vascular risk factors on cognitive abilities in PD.

ObjectivesThe combination of high YKL-40 (a glial inflammatory marker) and low sAPPβ (a soluble β fragment of amyloid precursor protein) in cerebrospinal fluid (CSF) has been associated with frontotemporal lobar degeneration (FTLD) in clinical series. We investigate these biomarkers in a neuropathologically confirmed cohort of patients with FTLD.MethodsCSF samples were selected from the Penn FTD Center (University of Pennsylvania). Participants were followed to autopsy and had a neuropathological diagnosis of FTLD-Tau (n=24), transactive response DNA-binding protein with 43 kDa (FTLD-TDP) (n=25) or Alzheimer’s disease (AD, n=97). We compared levels of YKL-40 and sAPPβ between groups and with cognitively normal controls (n=77), and assessed their diagnostic utility using receiver operating characteristic curves. We also investigated the effect of AD copathology and the correlation between these CSF markers and tau burden at autopsy.ResultsBoth FTLD groups had lower levels of sAPPβ, higher levels of YKL-40 and lower sAPPβ:YKL-40 ratio in CSF compared with controls. The group of pure FTLD-Tau (without AD copathology) showed higher levels of YKL-40 than AD and than pure FTLD-TDP. YKL-40 levels correlated with pathological tau burden. The sAPPβ:YKL-40 ratio had an area under the curve (AUC) of 0.91 (95% CI 0.86 to 0.96) to distinguish subjects with FTLD from controls, but lower values to distinguish FTLD from AD (AUC 0.70; 95% CI 0.61 to 0.79) and to discriminate FTLD-Tau from FTLD-TDP (AUC 0.67; 95% CI 0.51 to 0.82).ConclusionsOur study provides pathological confirmation that the combination of low sAPPβ and high YKL-40 in CSF is associated with FTLD. These biomarkers could be useful in particular clinical settings when FTLD is suspected.

The majority (90%–95%) of amyotrophic lateral sclerosis (ALS) is sporadic, and ∼50% of patients develop symptoms of frontotemporal degeneration (FTD) associated with shorter survival. The genetic polymorphism rs12608932 in UNC13A confers increased risk of sporadic ALS and sporadic FTD and modifies survival in ALS. Here, we evaluate whether rs12608932 is also associated with frontotemporal disease in sporadic ALS. We identified reduced cortical thickness in sporadic ALS with T1-weighted magnetic resonance imaging (N = 109) relative to controls (N = 113), and observed that minor allele (C) carriers exhibited greater reduction of cortical thickness in the dorsal prefrontal, ventromedial prefrontal, anterior temporal, and middle temporal cortices and worse performance on a frontal lobe–mediated cognitive test (reverse digit span). In sporadic ALS with autopsy data (N = 102), minor allele homozygotes exhibited greater burden of phosphorylated tar DNA-binding protein-43 kda (TDP-43) pathology in the middle frontal, middle temporal, and motor cortices. Our findings demonstrate converging evidence that rs12608932 may modify frontotemporal disease in sporadic ALS and suggest that rs12608932 may function as a prognostic indicator and could be used to define patient endophenotypes in clinical trials.

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-β, α-synuclein and TDP-43.

Amnestic Alzheimer’s disease is characterized by early atrophy of the hippocampus and medial temporal lobes before spreading to neocortex. In contrast, non-amnestic Alzheimer’s patients have relative sparing of the hippocampus, but the pattern in which disease spreads is unclear. We examined spreading disease in non-amnestic Alzheimer’s disease using a novel magnetic resonance imaging-based analysis adapted from pathologic staging studies, applied here to cross-sectional imaging data. We selected 240 T1-weighted scans from 129 patients with pathology confirmed by autopsy or cerebrospinal fluid, and atrophy maps were computed relative to 238 scans from 115 elderly controls. For each phenotype, the frequency of atrophy in 116 brain regions was used to infer the anatomical origin of disease and its progression across 4 phases of atrophy. Results from the amnestic cohort were used to determine appropriate parameter settings for the phase assignment algorithm, based on correspondence to Braak pathology staging. Phase 1 regions, which represent the origin of disease, included hippocampus for the amnestic group (comprising 33 scans); left lateral temporal lobe for logopenic-variant primary progressive aphasia (88 scans); occipito-parietal cortex for posterior cortical atrophy (51 scans); temporo-parietal cortex for corticobasal syndrome (31 scans); and fronto-temporal cortex for behavioral/dysexecutive variant Alzheimer’s disease (37 scans). In non-amnestic patients atrophy spread to other neocortical areas in later phases, but the hippocampus exhibited only late-phase atrophy in posterior cortical atrophy and corticobasal syndrome. Region-specific phase values were also associated with regional measures of tau, amyloid-beta, neuronal loss, and gliosis for the subset of patients (n=17) with neuropathology findings; this comparison represented a first validation of the phase assignment algorithm. We subsequently assigned a phase to each patient scan based on the similarity of regional atrophy patterns with atrophy predicted for the corresponding phenotype at each phase. Scan-specific phases were correlated with disease duration as well as global and domain-specific cognition, supporting these phase values as global estimates of patients’ disease progression. Logistic regression models based on spatial overlap with model-predicted atrophy patterns reliably discriminated non-amnestic phenotypes from each other and from amnestic Alzheimer’s disease. The frequency-based phase assignment algorithm employed in the current study thus represents a promising approach for studying the neocortical origin and spread of disease in non-amnestic Alzheimer’s disease.

IMPORTANCE Cerebrospinal fluid (CSF) core Alzheimer disease (AD) biomarkers have shown an excellent capacity for the in vivo detection of AD. Previous studies have shown that CSF levels of phosphorylated tau (p-tau) also correlate with tau pathology in frontotemporal lobar degeneration (FTLD) after accounting for AD copathology. OBJECTIVE To develop an algorithm based on core AD CSF measures to exclude cases with AD pathology and then differentiate between FTLD-tau and FTLD transactive response DNA-binding protein of approximately 43kDa (FTLD-TDP). DESIGN, SETTING, AND PARTICIPANTS A case-control study at the University of Pennsylvania. Participants were selected from a database of 1796 patients included between 1992 and 2016 with different neurodegenerative diseases with available CSF. Three patient cohorts were included: a cohort of patients with sporadic, autopsy-confirmed FTLD and AD (n = 143); a cohort of patients with frontotemporal degeneration (FTD) with TDP-associated or tau-associated mutations (n = 60); and a living cohort of patients with syndromes highly predictive of FTLD (progressive supranuclear palsy and FTD-amyotrophic lateral sclerosis; n = 62). MAIN OUTCOMES AND MEASURES Cerebrospinal fluid values of amyloid ss(1-42) (A ss(1-42)), total tau (t-tau), and p-tau obtained using the INNO-BIA AlzBio3 (xMAP; Luminex) assay or INNOTEST enzyme-linked immunosorbent assay transformed using a previously validated algorithm. Sensitivities and specificities for differentiating AD from FTLD groups were calculated. RESULTS This autopsy cohort included FTLD-tau (n = 27; mean [SD] age at onset, 60.8 [9.7] years), FTLD-TDP (n = 13; mean [SD] age at onset, 62.4 [8.5] years), AD (n = 89, mean [SD] age at onset, 66.5 [9.7] years); and mixed FTLD-AD (n = 14, mean [SD] age at onset, 70.6 [8.5] years). The p-tau/ A ss(1-42) ratio showed an excellent diagnostic accuracy to exclude AD cases in the autopsy cohort with single neurodegenerative pathologies (area under the curve [AUC], 0.98; 95% CI, 0.96-1.00). Cerebrospinal fluid p-tau levels showed a good AUC (0.87; 95% CI, 0.73-1.00) for discriminating pure FTLD-TDP from pure FTLD-tau. The application of an algorithm using cutpoints of CSF p-tau to A ss(1-42) ratio and p-tau allowed a good discrimination of pure FTLD-TDP cases from the remaining FTLD-tau and mixed FTLD cases. The diagnostic value of this algorithm was confirmed in an independent cohort of living patients with progressive supranuclear palsy and FTD-amyotrophic lateral sclerosis (AUC, 0.9; 95% CI, 0.81-0.99). However, the algorithm was less useful in FTD cases carrying a pathogenic mutation (AUC, 0.58; 95% CI, 0.38-0.77) owing to elevated p-tau levels in TDP-associated mutation carriers. CONCLUSIONS AND RELEVANCE Alzheimer disease CSF core biomarkers can be used with high specificity for the in vivo identification of patients with pure FTLD-TDP and FTLD-tau when accounting for comorbid AD and genetic status.

Digital image analysis of histology sections provides reliable, high-throughput methods for neuropathological studies but data is scant in frontotemporal lobar degeneration (FTLD), which has an added challenge of study due to morphologically diverse pathologies. Here, we describe a novel method of semi-automated digital image analysis in FTLD subtypes including: Pick’s disease (PiD, n=11) with tau-positive intracellular inclusions and neuropil threads, and TDP-43 pathology type C (FTLD-TDPC, n=10), defined by TDP-43-positive aggregates predominantly in large dystrophic neurites. To do this, we examined three FTLD-associated cortical regions: mid-frontal gyrus (MFG), superior temporal gyrus (STG) and anterior cingulate gyrus (ACG) by immunohistochemistry. We used a color deconvolution process to isolate signal from the chromogen and applied both object detection and intensity thresholding algorithms to quantify pathological burden. We found object-detection algorithms had good agreement with gold-standard manual quantification of tau- and TDP-43-positive inclusions. Our sampling method was reliable across three separate investigators and we obtained similar results in a pilot analysis using open-source software. Regional comparisons using these algorithms finds differences in regional anatomic disease burden between PiD and FTLD-TDP not detected using traditional ordinal scale data, suggesting digital image analysis is a powerful tool for clinicopathological studies in morphologically diverse FTLD syndromes.

Objective: To examine the influence of occupational attainment and education on survival in autopsy-confirmed cases of frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD). Methods: We performed a retrospective chart review of 83 demographically matched, autopsy-confirmed FTLD (n = 34) and AD (n = 49) cases. Each patient9s primary occupation was classified and ranked. Level of education was recorded in years. Survival was defined as time from symptom onset until death. Linear regression was used to test for associations among occupational attainment, education, and patient survival. Results: Median survival was 81 months for FTLD and 95 months for AD. Years of education and occupational attainment were similar for both groups. We found that higher occupational attainment was associated with longer survival in FTLD but not AD. Conclusions: Our findings suggest that higher occupational attainment is associated with longer survival in autopsy-confirmed FTLD. The identification of protective factors associated with FTLD survival has important implications for estimates of prognosis and longitudinal studies such as treatment trials.

Background and Objective: Up to half of patients with amyotrophic lateral sclerosis (ALS) may have cognitive difficulty, but most cognitive measures are confounded by a motor component. Studies relating impaired cognition in ALS to disease in gray matter and white matter are rare. Our objective was to assess executive function in patients with ALS using a simple, untimed measure with minimal motor demands, and to relate performance to structural disease. Methods: We gave the Visual-Verbal Test to 56 patients with ALS and 29 matched healthy controls. This brief, untimed measure of cognitive flexibility first assesses participants’ ability to identify a feature shared by 3 of 4 simple geometric designs. The participants’ cognitive flexibility is challenged when they are next asked to identify a different feature shared by another combination of 3 of the same 4 geometric designs. In a subset of 17 patients who underwent magnetic resonance imaging, regression analyses related test performance to gray matter atrophy and reduced white matter fractional anisotropy. Results: The patients with ALS showed significant impairment in cognitive flexibility (P < 0.01), with 48.2% making an error on the test. Regression analyses related impaired cognitive flexibility to gray matter atrophy in inferior frontal and insular regions, and to reduced fractional anisotropy in white matter projections in the inferior fronto-occipital and uncinate fasciculi and corpus callosum. Conclusions: Our patients with ALS had impaired cognitive flexibility on an untimed measure with minimal motor demands, a finding related in part to a large-scale frontal network that is degraded in ALS.

Accumulation of paired helical filament tau contributes to neurodegeneration in Alzheimer's disease (AD). (18) F-flortaucipir is a positron emission tomography (PET) radioligand sensitive to tau in AD, but its clinical utility will depend in part on its ability to predict cognitive symptoms in diverse dementia phenotypes associated with selective, regional uptake. We examined associations between (18) F-flortaucipir and cognition in 14 mildly-impaired patients (12 with cerebrospinal fluid analytes consistent with AD pathology) who had amnestic (n = 5) and non-amnestic AD syndromes, including posterior cortical atrophy (PCA, n = 5) and logopenic-variant primary progressive aphasia (lvPPA, n = 4). Amnestic AD patients had deficits in memory; lvPPA in language; and both amnestic AD and PCA patients in visuospatial function. Associations with cognition were tested using sparse regression and compared to associations in anatomical regions-of-interest (ROIs). (18) F-flortaucipir uptake was expected to show regionally-specific correlations with each domain. In multivariate analyses, uptake was elevated in neocortical areas specifically associated with amnestic and non-amnestic syndromes. Uptake in left anterior superior temporal gyrus accounted for 67% of the variance in language performance. Uptake in right lingual gyrus predicted 85% of the variance in visuospatial performance. Memory was predicted by uptake in right fusiform gyrus and cuneus as well as a cluster comprising right anterior hippocampus and amygdala; this eigenvector explained 57% of the variance in patients' scores. These results provide converging evidence for associations between (18) F-flortaucipir uptake, tau pathology, and patients' cognitive symptoms

Quantitative examinations of speech production in amyotrophic lateral sclerosis (ALS) are rare. To identify language features minimally confounded by a motor disorder, we investigated linguistic and motor sources of impaired sentence expression in ALS, and we related deficits to gray matter (GM) and white matter (WM) MRI abnormalities. We analyzed a semi-structured speech sample in 26 ALS patients and 19 healthy seniors for motor- and language-related deficits. Regression analyses related grammaticality to GM atrophy and reduced WM fractional anisotropy (FA). Results demonstrated that ALS patients were impaired relative to controls on quantity of speech, speech rate, speech articulation errors, and grammaticality. Speech rate and articulation errors were related to the patients' motor impairment, while grammatical difficulty was independent of motor difficulty. This was confirmed in subgroups without dysarthria and without executive deficits. Regressions related grammatical expression to GM atrophy in left inferior frontal and anterior temporal regions and to reduced FA in superior longitudinal and inferior frontal-occipital fasciculi. In conclusion, patients with ALS exhibit multifactorial deficits in sentence expression. They demonstrate a deficit in grammatical expression that is independent of their motor disorder. Impaired grammatical expression is related to disease in a network of brain regions associated with syntactic processing.

A growing amount of empirical data is showing that the ability to manipulate quantities in a precise and efficient fashion is rooted in cognitive mechanisms devoted to specific aspects of numbers processing. The analog number system (ANS) has a reasonable representation of quantities up to about 4, and represents larger quantities on the basis of a numerical ratio between quantities. In order to represent the precise cardinality of a number, the ANS may be supported by external algorithms such as language, leading to a "precise number system". In the setting of limited language, other number-related systems can appear. For example the parallel individuation system (PIS) supports a "chunking mechanism" that clusters units of larger numerosities into smaller subsets. In the present study we investigated number processing in non-aphasic patients with corticobasal syndrome (CBS) and posterior cortical atrophy (PCA), two neurodegenerative conditions that are associated with progressive parietal atrophy. The present study investigated these number systems in CBS and PCA by assessing the property of the ANS associated with smaller and larger numerosities, and the chunking property of the PIS. The results revealed that CBS/PCA patients are impaired in simple calculations (e.g., addition and subtraction) and that their performance strongly correlates with the size of the numbers involved in these calculations, revealing a clear magnitude effect. This magnitude effect was correlated with gray matter atrophy in parietal regions. Moreover, a numeral-dots transcoding task showed that CBS/PCA patients were able to take advantage of clustering in the spatial distribution of the dots of the array. The relative advantage associated with chunking compared to a random spatial distribution correlated with both parietal and prefrontal regions. These results shed light on the properties of systems for representing number knowledge in non-aphasic patients with CBS and PCA.

Linking structural neuroimaging data from multiple modalities to cognitive performance is an important challenge for cognitive neuroscience. In this study we examined the relationship between verbal fluency performance and neuroanatomy in 54 patients with frontotemporal degeneration (FTD) and 15 age-matched controls, all of whom had T1- and diffusion-weighted imaging. Our goal was to incorporate measures of both gray matter (voxel-based cortical thickness) and white matter (fractional anisotropy) into a single statistical model that relates to behavioral performance. We first used eigenanatomy to define data-driven regions of interest (DD-ROIs) for both gray matter and white matter. Eigenanatomy is a multivariate dimensionality reduction approach that identifies spatially smooth, unsigned principal components that explain the maximal amount of variance across subjects. We then used a statistical model selection procedure to see which of these DD-ROIs best modeled performance on verbal fluency tasks hypothesized to rely on distinct components of a large-scale neural network that support language: category fluency requires a semantic-guided search and is hypothesized to rely primarily on temporal cortices that support lexical-semantic representations; letter-guided fluency requires a strategic mental search and is hypothesized to require executive resources to support a more demanding search process, which depends on prefrontal cortex in addition to temporal network components that support lexical representations. We observed that both types of verbal fluency performance are best described by a network that includes a combination of gray matter and white matter. For category fluency, the identified regions included bilateral temporal cortex and a white matter region including left inferior longitudinal fasciculus and frontal–occipital fasciculus. For letter fluency, a left temporal lobe region was also selected, and also regions of frontal cortex. These results are consistent with our hypothesized neuroanatomical models of language processing and its breakdown in FTD. We conclude that clustering the data with eigenanatomy before performing linear regression is a promising tool for multimodal data analysis.

Objective: To determine the prognostic utility of tauopathy-associated single nucleotide polymorphisms (SNPs) in sporadic behavioral-variant frontotemporal dementia (bvFTD). Methods: Eighty-one patients with sporadic bvFTD were genotyped for tauopathy-associated SNPs at rs8070723 (microtubule-associated protein tau [ MAPT ]) and rs1768208 (myelin-associated oligodendrocyte basic protein [ MOBP ]). We performed a retrospective case-control study comparing age at onset and disease duration between carriers of ≥1 polymorphism allele and noncarriers for these SNPs. Subanalyses were performed for autopsied subgroups with tauopathy (n = 20) and TDP-43 proteinopathy (n = 12). To identify a potential biological basis for disease duration, neuroimaging measures of white matter integrity were evaluated (n = 37). Results: Carriers of risk allele (T) in rs1768208 (i.e., MOBP RA+) had a shorter median disease duration (TC/TT = 5.5 years, CC = 9.5 years; p = 0.02). This was also found in the subset of cases with autopsy-confirmed tauopathies ( p = 0.04) but not with TDP-43 proteinopathies ( p > 0.1). By comparison, polymorphisms at rs8070723 ( MAPT ) had no effect on disease duration ( p > 0.1), although carriers of protective allele (G) in rs8070723 had a younger median age at onset (AG/GG = 54.5 years, AA = 58 years; p MOBP RA+ patients had increased radial diffusivity in the superior corona radiata and midbrain, and reduced fractional anisotropy in the superior corona radiata as well as superior and inferior longitudinal fasciculi compared with noncarriers ( p Conclusions: The rs1768208 risk polymorphism in MOBP may have prognostic value in bvFTD. MOBP RA+ patients have more severe white matter degeneration in bvFTD that may contribute to shorter disease duration. Future studies are needed to help confirm these findings.

This study establishes that sparse canonical correlation analysis (SCCAN) identifies generalizable, structural MRI-derived cortical networks that relate to five distinct categories of cognition. We obtain multivariate psychometrics from the domain-specific sub-scales of the Philadelphia Brief Assessment of Cognition (PBAC). By using a training and separate testing stage, we find that PBAC-defined cognitive domains of language, visuospatial functioning, episodic memory, executive control, and social functioning correlate with unique and distributed areas of gray matter (GM). In contrast, a parallel univariate framework fails to identify, from the training data, regions that are also significant in the left-out test dataset. The cohort includes164 patients with Alzheimer's disease, behavioral-variant frontotemporal dementia, semantic variant primary progressive aphasia, non-fluent/agrammatic primary progressive aphasia, or corticobasal syndrome. The analysis is implemented with open-source software for which we provide examples in the text. In conclusion, we show that multivariate techniques identify biologically-plausible brain regions supporting specific cognitive domains. The findings are identified in training data and confirmed in test data.

article i nfo Article history: Accepted 26 November 2012 Available online 6 December 2012 Keywords: Semantic fMRI DTI Alzheimer's Temporal Prefrontal Patients with Alzheimer's disease have category-specifi cs emantic memory difficulty for natural relative to manufactured objects. We assessed the basis for this deficit by asking healthy adults and patients to judge whether pairs of words share a feature (e.g. "banana:lemon—COLOR"). In an fMRI study, healthy adults showed gray matter (GM) activation of temporal-occipital cortex (TOC) where visual-perceptual features may be represented,andprefrontalcortex(PFC)whichmaycontributetofeatureselection.Tractographyrevealeddorsal and ventral stream white matter (WM) projections between PFC and TOC. Patients had greater difficulty with natural than manufactured objects. This was associated with greater overlap between diseased GM areas corre- lated with natural kinds in patients and fMRI activation in healthy adults for natural kinds. The dorsal WM pro- jectionbetweenPFCandTOCinpatientscorrelatedonlywith judgmentsofnatural kinds.Patientsthusremained dependent on the same neural network as controls during judgments of natural kinds, despite disease in these areas. For manufactured objects, patients' judgments showed limited correlations with PFC and TOC GM areas activated by controls, and did not correlate with the PFC-TOC dorsal WM tract. Regions outside of the PFC- TOC network thus may help support patients' judgments of manufactured objects. We conclude that a large-scale neural network for semantic memory implicates both feature knowledge representations in modality-specific association cortex and heteromodal regions important for accessing this knowledge, and that patients' relative deficit for natural kinds is due in part to their dependence on this network despite disease in these areas.

To test the hypotheses that (1) antemortem cerebrospinal fluid (CSF) tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration (FTLD) and (2) tauopathy patients have higher phosphorylated-tau levels compared to transactivation response element DNA-binding protein 43 (TDP-43) proteinopathy patients while accounting for Alzheimer's disease (AD) copathology.Patients had autopsy-confirmed FTLD with tauopathy (n = 31), TDP-43 proteinopathy (n = 49), or AD (n = 26) with antemortem CSF. CSF tau levels were compared between groups and correlated with digital histology measurement of postmortem tau pathology averaged from three cerebral regions (angular gyrus, mid-frontal cortex, and anterior cingulate gyrus). Multivariate linear regression tested the association of ante mortem CSF tau levels with postmortem tau pathology adjusting for demographics.Multivariate regression found an independent association of ante mortem CSF phosphorylated tau levels with postmortem cerebral tau pathology in FTLD (Beta = 1.3; 95% confidence interval = 0.2-2.4; p0.02). After excluding patients with coincident AD-associated tau pathology accompanying sporadic FTLD, we found lower CSF phosphorylated tau levels in the TDP-43 group (median = 7.4pg/ml; interquartile range [IQR] = 6.0, 12.3; n = 26) compared to the tauopathy group (median = 12.5pg/ml; IQR = 10.7, 15.0; n = 23; Z = 2.6; p0.01).CSF phosphorylated-tau levels are positively associated with cerebral tau burden in FTLD. In vivo detection of AD copathology in sporadic FTLD patients may help stratify clinical cohorts with pure neuropathology in which low CSF phosphorylated-tau levels may have diagnostic utility to distinguish TDP-43 proteinopathy from tauopathy. Autopsy-confirmed samples are critical for FTLD biomarker development and validation. Ann Neurol 2017;82:247-258.

Semantic category learning is dependent upon several factors, including the nature of the learning task, as well as individual differences in the quality and heterogeneity of exemplars that an individual encounters during learning. We trained healthy older adults (n=39) and individuals with a diagnosis of Alzheimer’s disease or Mild Cognitive Impairment (n=44) to recognize instances of a fictitious animal, a “crutter”. Each stimulus item contained 10 visual features (e.g., color, tail shape) which took one of two values for each feature (e.g., yellow/red, curly/straight tails). Participants were presented with a series of items (learning phase) and were either told the items belonged to a semantic category (explicit condition) or were told to think about the appearance of the items (implicit condition). Half of participants saw learning items with higher similarity to an unseen prototype (high typicality learning set), and thus lower between-item variability in their constituent features; the other half learned from items with lower typicality (low typicality learning set) and higher between-item feature variability. After the learning phase, participants were presented with test items one at a time that varied in the number of typical features from 0 (antitype) to 10 (prototype). We examined between-subjects factors of learning set (lower or higher typicality), instruction type (explicit or implicit), and group (patients vs. elderly control). Learning in controls was aided by higher learning set typicality: while controls in both learning set groups demonstrated significant learning, those exposed to a high-typicality learning set appeared to develop a prototype that helped guide their category membership judgments. Overall, patients demonstrated more difficulty with category learning than elderly controls. Patients exposed to the higher-typicality learning set were sensitive to the typical features of the category and discriminated between the most and least typical test items, although less reliably than controls. In contrast, patients exposed to the low-typicality learning set showed no evidence of learning. Analysis of structural imaging data indicated a positive association between left hippocampal grey matter density in elderly controls but a negative association in the patient group, suggesting differential reliance on hippocampally-mediated learning. Contrary to hypotheses, learning did not differ between explicit and implicit conditions for either group. Results demonstrate that category learning is improved when learning materials are highly similar to the prototype.

Background Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described. To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TAR DNA-binding protein 43 (TDP-43) proteinopathy. Methods A retrospective case-control study was carried out using available cross-sectional and longitudinal clinical and neuropsychological data, MRI voxel-based morphometry (VBM) and neuropathological assessment from 64 C9P cases (ALS=31, FTLD=33) and 79 C9N cases (ALS=36, FTLD=43). Results C9P cases had an earlier age of onset (p=0.047) and, in the subset of patients who were deceased, an earlier age of death (p=0.014) than C9N. C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.6±0.3 years) compared to C9N ALS (3.8±0.4 years; log-rank λ2=4.183, p=0.041), and C9P FTLD showed a significantly greater annualised rate of decline in letter fluency (4.5±1.3 words/year) than C9N FTLD (1.4±0.8 words/year, p=0.023). VBM revealed greater atrophy in the right frontoinsular, thalamus, cerebellum and bilateral parietal regions for C9P FTLD relative to C9N FTLD, and regression analysis related verbal fluency scores to atrophy in frontal and parietal regions. Neuropathological analysis found greater neuronal loss in the mid-frontal cortex in C9P FTLD, and mid-frontal cortex TDP-43 inclusion severity correlated with poor letter fluency performance. Conclusions C9P cases may have a shorter survival in ALS and more rapid rate of cognitive decline related to frontal and parietal disease in FTLD. C9orf72 genotyping may provide useful prognostic and diagnostic clinical information for patients with ALS and FTLD.

Few studies have examined connected speech in demented and non-demented patients with Parkinson's disease (PD). We assessed the speech production of 35 patients with Lewy body spectrum disorder (LBSD), including non-demented PD patients, patients with PD dementia (PDD), and patients with dementia with Lewy bodies (DLB), in a semi-structured narrative speech sample in order to characterize impairments of speech fluency and to determine the factors contributing to reduced speech fluency in these patients. Both demented and non-demented PD patients exhibited reduced speech fluency, characterized by reduced overall speech rate and long pauses between sentences. Reduced speech rate in LBSD correlated with measures of between-utterance pauses, executive functioning, and grammatical comprehension. Regression analyses related non-fluent speech, grammatical difficulty, and executive difficulty to atrophy in frontal brain regions. These findings indicate that multiple factors contribute to slowed speech in LBSD, and this is mediated in part by disease in frontal brain regions.

While grammatical aspects of language are preserved, executive deficits are prominent in Lewy body spectrum disorder (LBSD), including Parkinson’s disease (PD), Parkinson’s dementia (PDD) and dementia with Lewy bodies (DLB). We examined executive control during sentence processing in LBSD by assessing temporary structural ambiguities. Using an on-line word detection procedure, patients heard sentences with a syntactic structure that has high-compatibility or low-compatibility with the main verb’s statistically preferred syntactic structure, and half of the sentences were lengthened strategically between the onset of the ambiguity and its resolution. We found selectively slowed processing of lengthened ambiguous sentences in the PDD/DLB subgroup. This correlated with impairments on measures of executive control. Regression analyses related the working memory deficit during ambiguous sentence processing to significant cortical thinning in frontal and parietal regions. These findings emphasize the role of prefrontal disease in the executive limitations that interfere with processing ambiguous sentences in LBSD.

Objective: Amyotrophic Lateral Sclerosis (ALS) is associated with impaired executive control. The aim of the current research was to test the hypothesis that concept formation deficits associated with an extramotor neurocognitive network involving executive and semantic resources can be found in some ALS patients. Method: Forty-one patients with clinically definite ALS were assessed with Delis Kaplan Executive Function System Sorting Test (D-KEFS), a measure of concept formation requiring patients to manipulate verbal and visual semantic information and neuropsychological tests measuring naming, semantic memory, and executive control. Using D-KEFS scale scores, a k-mean cluster analysis specifying a 3-group solution was able to classify ALS patients into groups presenting with mildly impaired, average, and above average sorting test performance. High-resolution T1 structural MRI was used to examine cortical thickness in a subset of 16 ALS patients. Results: Stepwise regression analyses related free and recognition sorting test performance to measures of action naming, single word semantic knowledge, and mental search/working memory. MRI studies found widespread cortical thinning involving bilateral frontal, temporal, and parietal regions. Regression analyses related recognition sorting performance to reduced MRI cortical thickness involving the left prefrontal and left parietal cortex. Conclusions: An extramotor cognitive network is associated with impaired concept formation in ALS.

Quantifiers are very common in everyday speech, but we know little about their cognitive basis or neural representation. The present study examined comprehension of three classes of quantifiers that depend on different cognitive components in patients with focal neurodegenerative diseases. Patients evaluated the truth-value of a sentence containing a quantifier relative to a picture illustrating a small number of familiar objects, and performance was related to MRI grey matter atrophy using voxel-based morphometry. We found that patients with corticobasal syndrome (CBS) and posterior cortical atrophy (PCA) are significantly impaired in their comprehension of cardinal quantifiers (e.g. "At least three birds are on the branch"), due in part to their deficit in quantity knowledge. MRI analyses related this deficit to temporal-parietal atrophy found in CBS/PCA. We also found that patients with behavioral variant frontotemporal dementia (bvFTD) are significantly impaired in their comprehension of logical quantifiers (e.g. "Some of the birds are on the branch"), associated with a simple form of perceptual logic, and this correlated with their deficit on executive measures. This deficit was related to disease in rostral prefrontal cortex in bvFTD. These patients were also impaired in their comprehension of majority quantifiers (e.g. "At least half of the birds are on the branch"), and this too was correlated with their deficit on executive measures. This was related to disease in the basal ganglia interrupting a frontal-striatal loop critical for executive functioning. These findings suggest that a large-scale frontal-parietal neural network plays a crucial role in quantifier comprehension, and that comprehension of specific classes of quantifiers may be selectively impaired in patients with focal neurodegenerative conditions in these areas.

The ventral medial prefrontal cortex (vmPFC) has been implicated in social and affectively influenced decision-making. Disease in this region may have clinical consequences for social judgments in patients with frontotemporal lobar degeneration (FTLD). To test this hypothesis, regional cortical activation was monitored with fMRI while healthy adults judged the acceptability of brief social scenarios such as cutting into a movie ticket line or going through a red light at 2 AM. The scenarios described: (i) a socially neutral condition, (ii) a variant of each scenario containing a negatively-valenced feature, and (iii) a variant containing a positively-valenced feature. Results revealed that healthy adults activated vmPFC during judgments of negatively-valenced scenarios relative to positive scenarios and neutral scenarios. In a comparative behavioral study, the same social decision-making paradigm was administered to patients with a social disorder due to FTLD. Patients differed significantly from healthy controls, specifically showing less sensitivity to negatively-valenced features. Comparative anatomical analysis revealed considerable overlap of vmPFC activation in healthy adults and vmPFC cortical atrophy in FTLD patients. These converging results support the role of vmPFC in social decision-making where potentially negative consequences must be considered.