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1.  Corticobasal syndrome 
Neurology: Clinical Practice  2014;4(4):304-312.
Corticobasal syndrome (CBS) is characterized by asymmetric involuntary movements including rigidity, tremor, dystonia, and myoclonus, and often associated with apraxia, cortical sensory deficits, and alien limb phenomena. Additionally, there are various nonmotor (cognitive and language) deficits. CBS is associated with several distinct histopathologies, including corticobasal degeneration, other forms of tau-related frontotemporal lobar degeneration such as progressive supranuclear palsy, and Alzheimer disease. Accurate antemortem diagnosis of underlying pathology in CBS is challenging, though certain clinical and imaging findings may be helpful. Five recent advances in the understanding of CBS are reviewed, including clinical and pathologic features, imaging and CSF biomarkers, the role of specific genes, and the concept of a spectrum of tauopathies.
PMCID: PMC4160446  PMID: 25279254
2.  Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy 
Nature Communications  2015;6:7247.
Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10−7) and MAPT H1c (17q21; rs242557; P=7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.
PMCID: PMC4469997  PMID: 26077951
3.  Frontotemporal dementia and its subtypes: a genome-wide association study 
Ferrari, Raffaele | Hernandez, Dena G | Nalls, Michael A | Rohrer, Jonathan D | Ramasamy, Adaikalavan | Kwok, John B J | Dobson-Stone, Carol | Brooks, William S | Schofield, Peter R | Halliday, Glenda M | Hodges, John R | Piguet, Olivier | Bartley, Lauren | Thompson, Elizabeth | Haan, Eric | Hernández, Isabel | Ruiz, Agustín | Boada, Mercè | Borroni, Barbara | Padovani, Alessandro | Cruchaga, Carlos | Cairns, Nigel J | Benussi, Luisa | Binetti, Giuliano | Ghidoni, Roberta | Forloni, Gianluigi | Galimberti, Daniela | Fenoglio, Chiara | Serpente, Maria | Scarpini, Elio | Clarimón, Jordi | Lleó, Alberto | Blesa, Rafael | Waldö, Maria Landqvist | Nilsson, Karin | Nilsson, Christer | Mackenzie, Ian R A | Hsiung, Ging-Yuek R | Mann, David M A | Grafman, Jordan | Morris, Christopher M | Attems, Johannes | Griffiths, Timothy D | McKeith, Ian G | Thomas, Alan J | Pietrini, P | Huey, Edward D | Wassermann, Eric M | Baborie, Atik | Jaros, Evelyn | Tierney, Michael C | Pastor, Pau | Razquin, Cristina | Ortega-Cubero, Sara | Alonso, Elena | Perneczky, Robert | Diehl-Schmid, Janine | Alexopoulos, Panagiotis | Kurz, Alexander | Rainero, Innocenzo | Rubino, Elisa | Pinessi, Lorenzo | Rogaeva, Ekaterina | George-Hyslop, Peter St | Rossi, Giacomina | Tagliavini, Fabrizio | Giaccone, Giorgio | Rowe, James B | Schlachetzki, J C M | Uphill, James | Collinge, John | Mead, S | Danek, Adrian | Van Deerlin, Vivianna M | Grossman, Murray | Trojanowsk, John Q | van der Zee, Julie | Deschamps, William | Van Langenhove, Tim | Cruts, Marc | Van Broeckhoven, Christine | Cappa, Stefano F | Le Ber, Isabelle | Hannequin, Didier | Golfier, Véronique | Vercelletto, Martine | Brice, Alexis | Nacmias, Benedetta | Sorbi, Sandro | Bagnoli, Silvia | Piaceri, Irene | Nielsen, Jørgen E | Hjermind, Lena E | Riemenschneider, Matthias | Mayhaus, Manuel | Ibach, Bernd | Gasparoni, Gilles | Pichler, Sabrina | Gu, Wei | Rossor, Martin N | Fox, Nick C | Warren, Jason D | Spillantini, Maria Grazia | Morris, Huw R | Rizzu, Patrizia | Heutink, Peter | Snowden, Julie S | Rollinson, Sara | Richardson, Anna | Gerhard, Alexander | Bruni, Amalia C | Maletta, Raffaele | Frangipane, Francesca | Cupidi, Chiara | Bernardi, Livia | Anfossi, Maria | Gallo, Maura | Conidi, Maria Elena | Smirne, Nicoletta | Rademakers, Rosa | Baker, Matt | Dickson, Dennis W | Graff-Radford, Neill R | Petersen, Ronald C | Knopman, David | Josephs, Keith A | Boeve, Bradley F | Parisi, Joseph E | Seeley, William W | Miller, Bruce L | Karydas, Anna M | Rosen, Howard | van Swieten, John C | Dopper, Elise G P | Seelaar, Harro | Pijnenburg, Yolande AL | Scheltens, Philip | Logroscino, Giancarlo | Capozzo, Rosa | Novelli, Valeria | Puca, Annibale A | Franceschi, M | Postiglione, Alfredo | Milan, Graziella | Sorrentino, Paolo | Kristiansen, Mark | Chiang, Huei-Hsin | Graff, Caroline | Pasquier, Florence | Rollin, Adeline | Deramecourt, Vincent | Lebert, Florence | Kapogiannis, Dimitrios | Ferrucci, Luigi | Pickering-Brown, Stuart | Singleton, Andrew B | Hardy, John | Momeni, Parastoo
Lancet neurology  2014;13(7):686-699.
Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. All participants had European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) and suggestive single-nucleotide polymorphisms.
We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8) that encompassed the HLA locus at 6p21.3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC, for the behavioural FTD subtype. Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation incis.
Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and possibly to shed light on the pathomechanisms contributing to FTD.
The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/ MRC Centre on Parkinson’s disease, Alzheimer’s Research UK, and Texas Tech University Health Sciences Center.
PMCID: PMC4112126  PMID: 24943344
4.  Davunetide for Progressive Supranuclear Palsy: a multicenter, randomized, double-blind, placebo controlled trial 
Lancet neurology  2014;13(7):676-685.
Davunetide (AL-108, NAP) is an eightamino acid peptide that promotes microtubule stability and decreases tau phosphorylation in pre-clinical studies. Since PSP is tightly linked to tau pathology, davunetide could be an effective treatment for PSP.The goals of this study were to evaluate the efficacy and safety of davunetide in PSP.
A phase 2/3 double-blind, parallel group, clinical trial of davunetide 30 mg or placebo (randomized 1:1) administered intranasally twice daily for 52 weeks was conducted at 48centers. Participants met modifiedNNIPPS criteria for possible or probable PSP. Co-primary endpointswere the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England ADL(SEADL) scale at up to 52 weeks. Data from all individuals who received at least one dose of medication and had a post-baseline efficacy assessment were compared using a rank-based method.Secondary outcomes included the Clinical Global Impression of Change (CGIC) and the change in regional brain volumeon MRI. identifier: NCT01110720.
360 participants were screened, 313 were randomized and 243 (77.6%) completed the study. There were no group differences in PSPRS (mean difference: 0.49 [95% CI: −1.5, 2.5], p = 0.72) or SEADL (1% [−2, 4%], p = 0.76) change from baseline (CFB) and mean 52 week CFB PSPRS scores were similar between the davunetide (11.3 [9.8,12.8]) and placebo groups (10.9 [9.1, 13.0]). There wereno differences in any of the secondary or exploratory endpoints. There were 11deaths in the davunetide group and tenin the placebo group. There were more nasal adverse events in the davunetide group.
Davunetide is well tolerated but is not an effective treatment for PSP. Clinical trials of disease modifying therapy are feasible in PSP and should be pursued with other promising tau-directed therapies.
Allon Therapeutics
PMCID: PMC4129545  PMID: 24873720
5.  If so many are “few,” how few are “many”? 
The scope of reference of a word's meaning can be highly variable. We present a novel paradigm to investigate the flexible interpretation of word meaning. We focus on quantifiers such as “many” or “few,” a class of words that depends on number knowledge but can be interpreted in a flexible manner. Healthy young adults performed a truth value judgment task on pictorial arrays of varying amounts of blue and yellow circles, deciding whether the sentence “Many/few of the circles are yellow” was an adequate description of the stimulus. The study consisted of two experiments, one focusing on “many,” one on “few.” Each experiment had three blocks. In a first “baseline” block, each individual's criterion for “many” and “few” was assessed. In a second “adaptation” block, subjects received feedback about their decisions that was different from their initial judgments in an effort to evaluate the flexibility of a subject's interpretation. A third “test” block assessed whether adaptation of quantifier meaning induced in block 2 then was generalized to alter a subject's baseline meaning for “many” and “few.” In Experiment 1, a proportion of yellow circles as small as 40% was reinforced as “many”; in Experiment 2, a proportion of yellow circles as large as 60% was reinforced as “few.” Subjects learned the new criterion for “many” in Experiment 1, which also affected their criterion for “few” although it had never been mentioned. Likewise, in Experiment 2, subjects changed their criterion for “few,” with a comparable effect on the criterion for “many” which was not mentioned. Thus, the meaning of relational quantifiers like “many” and “few” is flexible and can be adapted. Most importantly, adapting the criterion for one quantifier (e.g., “many”) also appeared to affect the reciprocal quantifier (in this case, “few”). Implications of this result for psychological interventions and for investigations of the neurobiology of the language-number interface are discussed.
PMCID: PMC4400858  PMID: 25941502
semantics; quantifiers; decision-making; numerosity; flexibility; learning
6.  Deficits in sentence expression in amyotrophic lateral sclerosis 
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.
PMCID: PMC4372458  PMID: 25482157
Dementia; aphasia; cognitive neuropsychology; language; speech
7.  Biomarkers in the primary progressive aphasias 
Aphasiology  2014;28(8-9):922-940.
Primary progressive aphasia (PPA) is a progressive disorder of language that is increasingly recognised as an important presentation of a specific spectrum of neurodegenerative conditions.
In an era of etiologically specific treatments for neurodegenerative conditions, it is crucial to establish the histopathologic basis for PPA. In this review, I discuss biomarkers for identifying the pathology underlying PPA.
Main Contribution
Clinical syndromes suggest a probabilistic association between a specific PPA variant and an underlying pathology, but there are also many exceptions. A considerable body of work with biomarkers is now emerging as an important addition to clinical diagnosis. I review genetic, neuroimaging and biofluid studies that can help determine the pathologic basis for PPA.
Together with careful clinical examination, there is great promise that supplemental biomarker assessments will lead to accurate diagnosis of the pathology associated with PPA during life and serve as the basis for clinical trials in this spectrum of disease.
PMCID: PMC4287262  PMID: 25580048
Frontotemporal degeneration; Primary progressive aphasia; Biomarker
8.  Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier 
Acta neuropathologica  2014;129(1):39-52.
C9orf72 promoter hypermethylation inhibits the accumulation of pathologies which have been postulated to be neurotoxic. We tested here whether C9orf72 hypermethylation is associated with prolonged disease in C9orf72 mutation carriers. C9orf72 methylation was quantified from brain or blood using methylation-sensitive restriction enzyme digest-qPCR in a cross-sectional cohort of 118 C9orf72 repeat expansion carriers and 19 non-carrier family members. Multivariate regression models were used to determine whether C9orf72 hypermethylation was associated with age at onset, disease duration, age at death, or hexanucleotide repeat expansion size. Permutation analysis was performed to determine whether C9orf72 methylation is heritable. We observed a high correlation between C9orf72 methylation across tissues including cerebellum, frontal cortex, spinal cord and peripheral blood. While C9orf72 methylation was not significantly different between ALS and FTD and did not predict age at onset, brain and blood C9orf72 hypermethylation was associated with later age at death in FTD (brain: β = 0.18, p = 0.006; blood: β = 0.15, p < 0.001), and blood C9orf72 hypermethylation was associated with longer disease duration in FTD (β = 0.03, p = 0.007). Furthermore, C9orf72 hypermethylation was associated with smaller hexanucleotide repeat length (β = −16.69, p = 0.033). Finally, analysis of pedigrees with multiple mutation carriers demonstrated a significant association between C9orf72 methylation and family relatedness (p < 0.0001). C9orf72 hypermethylation is associated with prolonged disease in C9orf72 repeat expansion carriers with FTD. The attenuated clinical phenotype associated with C9orf72 hypermethylation suggests that slower clinical progression in FTD is associated with reduced expression of mutant C9orf72. These results support the hypothesis that expression of the hexanucleotide repeat expansion is associated with a toxic gain of function.
PMCID: PMC4282973  PMID: 25388784
Neurodegeneration; Frontotemporal lobar degeneration; Frontotemporal dementia; Amyotrophic lateral sclerosis; Epigenetics
9.  Estimating frontal and parietal involvement in cognitive estimation: a study of focal neurodegenerative diseases 
We often estimate an unknown value based on available relevant information, a process known as cognitive estimation. In this study, we assess the cognitive and neuroanatomic basis for quantitative estimation by examining deficits in patients with focal neurodegenerative disease in frontal and parietal cortex. Executive function and number knowledge are key components in cognitive estimation. Prefrontal cortex has been implicated in multilevel reasoning and planning processes, and parietal cortex has been associated with number knowledge required for such estimations. We administered the Biber cognitive estimation test (BCET) to assess cognitive estimation in 22 patients with prefrontal disease due to behavioral variant frontotemporal dementia (bvFTD), to 17 patients with parietal disease due to corticobasal syndrome (CBS) or posterior cortical atrophy (PCA) and 11 patients with mild cognitive impairment (MCI). Both bvFTD and CBS/PCA patients had significantly more difficulty with cognitive estimation than controls. MCI were not impaired on BCET relative to controls. Regression analyses related BCET performance to gray matter atrophy in right lateral prefrontal and orbital frontal cortices in bvFTD, and to atrophy in right inferior parietal cortex, right insula, and fusiform cortices in CBS/PCA. These results are consistent with the hypothesis that a frontal-parietal network plays a crucial role in cognitive estimation.
PMCID: PMC4454843  PMID: 26089786
cognitive estimation; behavioral variant frontotemporal degeneration; corticobasal syndrome; posterior cortical atrophy; prefrontal cortices; parietal cortices
10.  Differentiating Subtypes of Apathy to Improve Person-Centered Care in Frontotemporal Degeneration 
Apathy, a reduction in goal-directed behavior (GDB), affects 90% of individuals with behavioral variant frontotemporal degeneration, which is a common cause of early onset neurodegenerative disease. The cognitive and neural impairments associated with apathy make it difficult to initiate, plan, and self-motivate activities toward a specific goal, such as dressing or bathing. These impairments are associated with significant decline in functional ability, caregiver burden, and increased cost of care due to early institutionalization. The current article reviews the evidence suggesting that apathy arises from the interruption of one or any combination of three GDB processes: initiation, planning, and motivation. From this perspective, three subtypes of apathy related to dysfunction at the level of GDB and the corresponding neuroanatomy are explored. Further research is required to confirm and measure these subtypes of apathy for use in clinical and research settings. A more precise classification of apathy by subtype will allow implementation of the most appropriate person-centered, individualized therapy.
PMCID: PMC4281275  PMID: 25199154
11.  Reduced CSF p-Tau181 to Tau ratio is a biomarker for FTLD-TDP 
Neurology  2013;81(22):1945-1952.
To validate the ability of candidate CSF biomarkers to distinguish between the 2 main forms of frontotemporal lobar degeneration (FTLD), FTLD with TAR DNA-binding protein 43 (TDP-43) inclusions (FTLD-TDP) and FTLD with Tau inclusions (FTLD-Tau).
Antemortem CSF samples were collected from 30 patients with FTLD in a single-center validation cohort, and CSF levels of 5 putative FTLD-TDP biomarkers as well as levels of total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau181) were measured using independent assays. Biomarkers most associated with FTLD-TDP were then tested in a separate 2-center validation cohort composed of subjects with FTLD-TDP, FTLD-Tau, Alzheimer disease (AD), and cognitively normal subjects. The sensitivity and specificity of FTLD-TDP biomarkers were determined.
In the first validation cohort, FTLD-TDP cases had decreased levels of p-Tau181 and interleukin-23, and increased Fas. Reduced ratio of p-Tau181 to t-Tau (p/t-Tau) was the strongest predictor of FTLD-TDP pathology. Analysis in the second validation cohort showed CSF p/t-Tau ratio <0.37 to distinguish FTLD-TDP from FTLD-Tau, AD, and healthy seniors with 82% sensitivity and 82% specificity.
A reduced CSF p/t-Tau ratio represents a reproducible, validated biomarker for FTLD-TDP with performance approaching well-established CSF AD biomarkers. Introducing this biomarker into research and the clinical arena can significantly increase the power of clinical trials targeting abnormal accumulations of TDP-43 or Tau, and select the appropriate patients for target-specific therapies.
Classification of evidence:
This study provides Class II evidence that the CSF p/t-Tau ratio distinguishes FTLD-TDP from FTLD-Tau.
PMCID: PMC3843382  PMID: 24174584
Brain and language  2012;127(2):10.1016/j.bandl.2012.10.005.
Non-fluent/agrammatic primary progressive aphasia (naPPA) is a progressive neurodegenerative condition most prominently associated with slowed, effortful speech. A clinical imaging marker of naPPA is disease centered in the left inferior frontal lobe. We used multimodal imaging to assess large-scale neural networks underlying effortful expression in 15 patients with sporadic naPPA due to frontotemporal lobar degeneration (FTLD) spectrum pathology. Effortful speech in these patients is related in part to impaired grammatical processing, and to phonologic speech errors. Gray matter (GM) imaging shows frontal and anterior-superior temporal atrophy, most prominently in the left hemisphere. Diffusion tensor imaging reveals reduced fractional anisotropy in several white matter (WM) tracts mediating projections between left frontal and other GM regions. Regression analyses suggest disruption of three large-scale GM-WM neural networks in naPPA that support fluent, grammatical expression. These findings emphasize the role of large-scale neural networks in language, and demonstrate associated language deficits in naPPA.
PMCID: PMC3610841  PMID: 23218686
primary progressive aphasia; non-fluent; agrammatic; MRI; diffusion tensor imaging; frontotemporal lobar degeneration
13.  Differential Longitudinal Decline on the Mini-Mental State Examination in Frontotemporal Lobar Degeneration and Alzheimer's Disease 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31827bdc6f.
To examine how phenotype affects longitudinal decline on the Mini-Mental State Examination (MMSE) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD)
The MMSE is the most commonly administered assessment for dementia severity; however, the effects of phenotype on longitudinal MMSE performance in FTLD and AD have not been extensively studied.
Data from 185 patients diagnosed with AD (n=106) and three FTLD (n=79) phenotypes (behavioral variant frontotemporal dementia [bvFTD], nonfluent agrammatic variant of primary progressive aphasia [nfaPPA], and semantic variant PPA [svPPA]) were collected for up to 52 months since initial evaluation.
Differential rates of decline were noted in that MMSE scores declined more precipitously for AD and svPPA compared to bvFTD and nfaPPA patients (p=0.001). The absolute 4-year MMSE decline given median baseline MMSE for bvFTD (14.67, 95% confidence interval [CI]: 14.63-14.71) and nfaPPA (11.02, 95% CI: 10.98-11.06) were lower than svPPA (22.32, 95% CI: 22.29-22.34) or AD (22.24, 95% CI: 22.22-22.26).
These data suggest that within-group AD and FTLD phenotypes present distinct patterns of longitudinal decline on the MMSE. MMSE may not be adequately sensitive to track disease progression in some phenotypes of FTLD.
PMCID: PMC3648632  PMID: 23314064
MMSE; Alzheimer's disease; frontotemporal lobe dementia; longitudinal assessment
14.  Relating brain anatomy and cognitive ability using a multivariate multimodal framework 
NeuroImage  2014;99:477-486.
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.
PMCID: PMC4151353  PMID: 24830834
Language; Verbal fluency; Multimodal; FTD
15.  Qualification of a Surrogate Matrix-Based Absolute Quantification Method for Amyloid-β42 in Human Cerebrospinal Fluid Using 2D UPLC-Tandem Mass Spectrometry 
The primary aims of this work were to: 1) establish a calibrator surrogate matrix for quantification of amyloid-β (Aβ)42 in human cerebrospinal fluid (CSF) and preparation of quality control samples for LC-MS-MS methodology, 2) validate analytical performance of the assay, and 3) evaluate its diagnostic utility and compare it with the AlzBio3 immunoassay. The analytical methodology was based on a 2D-UPLC-MS-MS platform. Sample pretreatment used 5 M guanidine hydrochloride and extraction on μElution SPE columns as previously described. A column cleaning procedure involved gradual removal of aqueous solvents by acetonitrile assured consistent long-term chromatography performance. Receiver-operator characteristic (ROC) curve and correlation analyses evaluated the diagnostic utility of UPLC-MS-MS compared to AlzBio3 immunoassay for detection of Alzheimer’s disease (AD). The surrogate matrix, artificial CSF containing 4 mg/mL of BSA, provides linear and reproducible calibration comparable to human pooled CSF as calibration matrix. Appropriate cleaning of the trapping and analytical columns provided every-day, trouble-free runs. Analyses of CSF Aβ42 showed that UPLC-MS-MS distinguished neuropathologically-diagnosed AD subjects from healthy controls with at least equivalent diagnostic utility to AlzBio3. Comparison of ROC curves for these two assays showed no statistically significant difference (p = 0.2229). Linear regression analysis of Aβ42 concentrations measured by this mass spectrometry-based method compared to the AlzBio3 immunoassay showed significantly higher but highly correlated results. In conclusion, the newly established surrogate matrix for 2D-UPLC-MS-MS measurement of Aβ42 provides selective, reproducible, and accurate results. The documented analytical performance and diagnostic performance for AD versus controls supports consideration as a candidate reference method.
PMCID: PMC4159707  PMID: 24625802
Alzheimer’s disease; amyloid-β42; cerebrospinal fluid; mass spectrometry
16.  Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre 
Brain  2013;136(9):2697-2706.
Cerebrovascular disease and vascular risk factors are associated with Alzheimer’s disease, but the evidence for their association with other neurodegenerative disorders is limited. Therefore, we compared the prevalence of cerebrovascular disease, vascular pathology and vascular risk factors in a wide range of neurodegenerative diseases and correlate them with dementia severity. Presence of cerebrovascular disease, vascular pathology and vascular risk factors was studied in 5715 cases of the National Alzheimer’s Coordinating Centre database with a single neurodegenerative disease diagnosis (Alzheimer’s disease, frontotemporal lobar degeneration due to tau, and TAR DNA-binding protein 43 immunoreactive deposits, α-synucleinopathies, hippocampal sclerosis and prion disease) based on a neuropathological examination with or without cerebrovascular disease, defined neuropathologically. In addition, 210 ‘unremarkable brain’ cases without cognitive impairment, and 280 cases with pure cerebrovascular disease were included for comparison. Cases with cerebrovascular disease were older than those without cerebrovascular disease in all the groups except for those with hippocampal sclerosis. After controlling for age and gender as fixed effects and centre as a random effect, we observed that α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease showed a lower prevalence of coincident cerebrovascular disease than patients with Alzheimer’s disease, and this was more significant in younger subjects. When cerebrovascular disease was also present, patients with Alzheimer’s disease and patients with α-synucleinopathy showed relatively lower burdens of their respective lesions than those without cerebrovascular disease in the context of comparable severity of dementia at time of death. Concurrent cerebrovascular disease is a common neuropathological finding in aged subjects with dementia, is more common in Alzheimer’s disease than in other neurodegenerative disorders, especially in younger subjects, and lowers the threshold for dementia due to Alzheimer’s disease and α-synucleinopathies, which suggests that these disorders should be targeted by treatments for cerebrovascular disease.
PMCID: PMC3858112  PMID: 23842566
Alzheimer’s disease; frontotemporal lobar degeneration; vascular disease; dementia; epidemiology; neuropathology
17.  Comparative semantic profiles in semantic dementia and Alzheimer’s disease 
Brain  2013;136(8):2497-2509.
Patients with the semantic variant of primary progressive aphasia, also known as semantic dementia, and Alzheimer’s disease have deficits in semantic memory. However, few comparative studies have been performed to determine whether these patient groups have distinct semantic memory impairments. We asked 15 patients with semantic variant primary progressive aphasia and 57 patients with Alzheimer’s disease to judge semantic category membership of coloured photos and printed words that are members of familiar natural and manufactured categories, and we related performance to grey matter atrophy. We found that both semantic variant primary progressive aphasia and Alzheimer’s disease are significantly impaired on this task. Moreover, patients with semantic variant primary progressive aphasia had a significantly more prominent deficit for natural objects than their own deficit judging manufactured objects. Both semantic variant primary progressive aphasia and Alzheimer’s disease had atrophy that included portions of the left temporal lobe. Regression analyses related performance in semantic variant primary progressive aphasia to ventral and medial portions of the left temporal lobe, while regression analyses in Alzheimer’s disease related performance to these ventral and medial temporal areas as well as lateral temporal-parietal regions in the left hemisphere. We conclude that both semantic variant primary progressive aphasia and Alzheimer’s disease are significantly impaired in a simple category membership judgement task and the selective impairment for natural kinds in semantic variant primary progressive aphasia is related in part to disease in visual association cortex in ventral–medial portions of the left temporal lobe. We discuss factors that may contribute to the semantic memory deficit in semantic variant primary progressive aphasia.
PMCID: PMC3722350  PMID: 23824492
semantic memory; Alzheimer’s disease; semantic dementia; temporal lobe; category-specific
18.  Differentiating primary progressive aphasias in a brief sample of connected speech 
Neurology  2013;81(4):329-336.
A brief speech expression protocol that can be administered and scored without special training would aid in the differential diagnosis of the 3 principal forms of primary progressive aphasia (PPA): nonfluent/agrammatic PPA, logopenic variant PPA, and semantic variant PPA.
We used a picture-description task to elicit a short speech sample, and we evaluated impairments in speech-sound production, speech rate, lexical retrieval, and grammaticality. We compared the results with those obtained by a longer, previously validated protocol and further validated performance with multimodal imaging to assess the neuroanatomical basis of the deficits.
We found different patterns of impaired grammar in each PPA variant, and additional language production features were impaired in each: nonfluent/agrammatic PPA was characterized by speech-sound errors; logopenic variant PPA by dysfluencies (false starts and hesitations); and semantic variant PPA by poor retrieval of nouns. Strong correlations were found between this brief speech sample and a lengthier narrative speech sample. A composite measure of grammaticality and other measures of speech production were correlated with distinct regions of gray matter atrophy and reduced white matter fractional anisotropy in each PPA variant.
These findings provide evidence that large-scale networks are required for fluent, grammatical expression; that these networks can be selectively disrupted in PPA syndromes; and that quantitative analysis of a brief speech sample can reveal the corresponding distinct speech characteristics.
PMCID: PMC3772830  PMID: 23794681
19.  A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank 
Neurodegenerative diseases (NDs) are defined by the accumulation of abnormal protein deposits in the central nervous system (CNS), and only neuropathological examination enables a definitive diagnosis. Brain banks and their associated scientific programs have shaped the actual knowledge of NDs, identifying and characterizing the CNS deposits that define new diseases, formulating staging schemes, and establishing correlations between neuropathological changes and clinical features. However, brain banks have evolved to accommodate the banking of biofluids as well as DNA and RNA samples. Moreover, the value of biobanks is greatly enhanced if they link all the multidimensional clinical and laboratory information of each case, which is accomplished, optimally, using systematic and standardized operating procedures, and in the framework of multidisciplinary teams with the support of a flexible and user-friendly database system that facilitates the sharing of information of all the teams in the network. We describe a biobanking system that is a platform for discovery research at the Center for Neurodegenerative Disease Research at the University of Pennsylvania.
PMCID: PMC3933464  PMID: 23978324
Cerebrospinal fluid; Plasma; Serum; Autopsy; Neurodegeneration; Alzheimer’s Disease; Dementia; Genetics; Parkinson’s Disease; Frontotemporal lobar degeneration
20.  Stages of pTDP-43 pathology in amyotrophic lateral sclerosis 
Annals of neurology  2013;74(1):20-38.
To see if the distribution patterns of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of neuropathological stages.
pTDP-43 immunohistochemistry was performed on 70 μm sections from ALS autopsy cases (N=76) classified by clinical phenotype and genetic background.
ALS cases with the lowest burden of pTDP-43 pathology were characterized by lesions in the agranular motor cortex, brainstem motor nuclei of cranial nerves XII-X, VII, V, and spinal cord α-motoneurons (stage 1). Increasing burdens of pathology showed involvement of the prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei, and the red nucleus (stage 2). In stage 3, pTDP-43 pathology involved the prefrontal (gyrus rectus and orbital gyri) and then postcentral neocortex and striatum. Cases with the greatest burden of pTDP-43 lesions showed pTDP-43 inclusions in anteromedial portions of the temporal lobe, including the hippocampus (stage 4). At all stages, these lesions were accompanied by pTDP-43 oligodendroglial aggregates. Ten cases with C9orf72 repeat expansion displayed the same sequential spreading pattern as non-expansion cases but a greater regional burden of lesions, indicating a more fulminant dissemination of pTDP-43 pathology.
pTDP-43 pathology in ALS possibly disseminates in a sequential pattern that permits recognition of four neuropathological stages consistent with the hypothesis that pTDP-43 pathology is propagated along axonal pathways. Moreover, the fact that pTDP-43 pathology develops in the prefrontal cortex as part of an ongoing disease process could account for the development of executive cognitive deficits in ALS.
PMCID: PMC3785076  PMID: 23686809
21.  Action verb comprehension in amyotrophic lateral sclerosis and Parkinson’s disease 
Journal of neurology  2014;261(6):1073-1079.
Patients with amyotrophic lateral sclerosis (ALS) have a motor disorder and cognitive difficulties, including difficulty with action verbs. However, the basis for the action verb impairment is unknown. Thirty-six participants with ALS and 22 with Parkinson’s disease (PD) were assessed on a simple, two-alternative forced-choice associativity judgment task, where performance was untimed and did not depend on motor functioning. We probed 120 frequency-matched action verbs, cognition verbs, concrete nouns and abstract nouns. Performance was related to T1 MRI imaging of gray matter atrophy. Patients with ALS were significantly impaired relative to healthy senior control participants only for action verbs. Patients with PD did not differ from controls for all word categories. Regression analyses related action verb performance in ALS to motor-associated cortices, but action verb judgments in PD were not related to cortical atrophy. These findings are consistent with the hypothesis that action verb difficulty in ALS is related in part to the degradation of action-related conceptual knowledge represented in motor-associated cortex.
PMCID: PMC4074280  PMID: 24676939
Comprehension; Amyotrophic lateral sclerosis; Parkinson’s disease
22.  Genetic & Neuronanatomic Associations in Sporadic Frontotemporal Lobar Degeneration 
Neurobiology of aging  2013;35(6):1473-1482.
Genome-wide association studies have identified SNPs that are sensitive for tau or TDP-43 pathology in frontotemporal lobar degeneration (FTLD). Neuroimaging analyses have revealed distinct distributions of disease in FTLD patients with genetic mutations. However, genetic influences on neuroanatomical structure in sporadic FTLD have not been assessed. In this report we use novel multivariate tools, eigenanatomy and sparse canonical correlation analysis (SCCAN), to identify associations between SNPs and neuroanatomical structure in sporadic FTLD. MRI analyses revealed that rs8070723 (MAPT) was associated with grey matter variance in the temporal cortex. DTI analyses revealed that rs1768208 (MOBP), rs646776 (near SORT1) and rs5848 (PGRN) were associated with white matter variance in the midbrain and superior longitudinal fasciculus. In an independent autopsy series we observed that rs8070723 and rs1768208 conferred significant risk of tau pathology relative to TDP-43, and rs646776 conferred increased risk of TDP-43 pathology relative to tau. Identified brain regions and SNPs may help provide an in vivo screen for underlying pathology in FTLD and contribute to our understanding of sporadic FTLD.
PMCID: PMC3961542  PMID: 24373676
Frontotemporal lobar degeneration; Neuroimaging; Genetics; Biomarkers
23.  Heteromodal conceptual processing in the angular gyrus 
NeuroImage  2013;71:175-186.
Concepts bind together the features commonly associated with objects and events to form networks in long-term semantic memory. These conceptual networks are the basis of human knowledge and underlie perception, imagination, and the ability to communicate about experiences and the contents of the environment. Although it is often assumed that this distributed semantic information is integrated in higher-level heteromodal association cortices, open questions remain about the role and anatomic basis of heteromodal representations in semantic memory. Here we used combined neuroimaging evidence from functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to characterize the cortical networks underlying concept representation. Using a lexical decision task, we examined the processing of concepts in four semantic categories that varied on their sensory-motor feature associations (sight, sound, manipulation, and abstract). We found that the angular gyrus was activated across all categories regardless of their modality-specific feature associations, consistent with a heteromodal account for the angular gyrus. Exploratory analyses suggested that categories with weighted sensory-motor features additionally recruited modality-specific association cortices. Furthermore, DTI tractography identified white matter tracts connecting these regions of modality-specific functional activation with the angular gyrus. These findings are consistent with a distributed semantic network that includes a heteromodal, integrative component in the angular gyrus in combination with sensory-motor feature representations in modality-specific association cortices.
PMCID: PMC3594130  PMID: 23333416
DTI; fMRI; language; semantic memory; sensory-motor; heteromodal
24.  TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions 
Acta neuropathologica  2014;127(3):407-418.
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA binding protein of 43kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n=14), with the major allele correlated with later age at death (p=0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n=75), again finding that the major allele associates with later age at death (p=0.016), as well as later age at onset (p=0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
PMCID: PMC4003885  PMID: 24442578
TMEM106B; C9orf72; frontotemporal dementia; frontotemporal lobar degeneration; amyotrophic lateral sclerosis; genetic modifier
JAMA neurology  2014;71(4):442-448.
An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility is necessary.
We sought to develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS.
Case-control study.
Academic medical center.
51 individuals with ALS and 23 individuals with a disorder associated with a four-repeat tauopathy (4R-tau).
CSF level of tau phosophorylated at threonine 181 (ptau), and ratio of ptau to total tau (ttau).
Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and ptau:ttau in ALS relative to 4R-tau and to controls. In the validation cohort, the receiver operating characteristic area under the curve for the ptau:ttau ratio was 0.916, and the comparison of ALS to 4R-tau showed sensitivity=92% and specificity=91.7%. Correct classification based on low CSF ptau:ttau was confirmed in 18 (85.7%) of 21 cases with autopsy-proven or genetically-determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity such as Mini Mental State Exam (n=51) and ALS Functional Rating Scale-Revised (n=42), and regression analyses related ptau:ttau to MRI (n=10) evidence of disease in the corticospinal tract and white matter projections involving prefrontal cortex.
CSF ptau:ttau may be a candidate biomarker to provide objective support for the diagnosis of ALS.
PMCID: PMC3989393  PMID: 24492862
amyotrophic lateral sclerosis; cerebrospinal fluid; phosphorylated tau; biomarker

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