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1.  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.
doi:10.1016/j.jalz.2013.06.003
PMCID: PMC3933464  PMID: 23978324
Cerebrospinal fluid; Plasma; Serum; Autopsy; Neurodegeneration; Alzheimer’s Disease; Dementia; Genetics; Parkinson’s Disease; Frontotemporal lobar degeneration
2.  Stages of pTDP-43 pathology in amyotrophic lateral sclerosis 
Annals of neurology  2013;74(1):20-38.
Objective
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.
Methods
pTDP-43 immunohistochemistry was performed on 70 μm sections from ALS autopsy cases (N=76) classified by clinical phenotype and genetic background.
Results
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.
Interpretation
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.
doi:10.1002/ana.23937
PMCID: PMC3785076  PMID: 23686809
3.  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.
doi:10.1007/s00415-014-7314-y
PMCID: PMC4074280  PMID: 24676939
Comprehension; Amyotrophic lateral sclerosis; Parkinson’s disease
4.  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.
doi:10.1016/j.neurobiolaging.2013.11.029
PMCID: PMC3961542  PMID: 24373676
Frontotemporal lobar degeneration; Neuroimaging; Genetics; Biomarkers
5.  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.
doi:10.1016/j.neuroimage.2013.01.006
PMCID: PMC3594130  PMID: 23333416
DTI; fMRI; language; semantic memory; sensory-motor; heteromodal
6.  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.
doi:10.1007/s00401-013-1239-x
PMCID: PMC4003885  PMID: 24442578
TMEM106B; C9orf72; frontotemporal dementia; frontotemporal lobar degeneration; amyotrophic lateral sclerosis; genetic modifier
7.  PHOSPHORYLATED TAU: CANDIDATE BIOMARKER FOR AMYOTROPHIC LATERAL SCLEROSIS 
JAMA neurology  2014;71(4):442-448.
IMPORTANCE
An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility is necessary.
OBJECTIVE
We sought to develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS.
DESIGN
Case-control study.
SETTING
Academic medical center.
PARTICIPANTS
51 individuals with ALS and 23 individuals with a disorder associated with a four-repeat tauopathy (4R-tau).
MAIN OUTCOME MEASURE
CSF level of tau phosophorylated at threonine 181 (ptau), and ratio of ptau to total tau (ttau).
RESULTS
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.
CONCLUSIONS AND RELEVANCE
CSF ptau:ttau may be a candidate biomarker to provide objective support for the diagnosis of ALS.
doi:10.1001/jamaneurol.2013.6064
PMCID: PMC3989393  PMID: 24492862
amyotrophic lateral sclerosis; cerebrospinal fluid; phosphorylated tau; biomarker
8.  Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD) 
Acta neuropathologica  2014;127(3):423-439.
We examined regional distribution patterns of phosphorylated 43-kDa TAr DNA-binding protein (pTDP-43) intraneuronal inclusions in frontotemporal lobar degeneration (FTLD). Immunohistochemistry was performed on 70 μm sections from FTLD-TDP autopsy cases (n = 39) presenting with behavioral variant frontotemporal dementia. Two main types of cortical pTDP-43 pathology emerged, characterized by either predominantly perikaryal pTDP-43 inclusions (cytoplasmic type, cFTLD) or long aggregates in dendrites (neuritic type, nFTLD). Cortical involvement in nFTLD was extensive and frequently reached occipital areas, whereas cases with cFTLD often involved bulbar somatomotor neurons and the spinal cord. We observed four patterns indicative of potentially sequential dissemination of pTDP-43: cases with the lowest burden of pathology (pattern I) were characterized by widespread pTDP-43 lesions in the orbital gyri, gyrus rectus, and amygdala. With increasing burden of pathology (pattern II) pTDP-43 lesions emerged in the middle frontal and anterior cingulate gyrus as well as in anteromedial temporal lobe areas, the superior and medial temporal gyri, striatum, red nucleus, thalamus, and precerebellar nuclei. More advanced cases showed a third pattern (III) with involvement of the motor cortex, bulbar somatomotor neurons, and the spinal cord anterior horn, whereas cases with the highest burden of pathology (pattern IV) were characterized by pTDP-43 lesions in the visual cortex. We interpret the four neuropathological patterns in bvFTD to be consistent with the hypothesis that pTDP-43 pathology can spread sequentially and may propagate along axonal pathways.
doi:10.1007/s00401-013-1238-y
PMCID: PMC3971993  PMID: 24407427
ALS, amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; FTLD, frontotemporal dementia; FTD; Neurodegeneration; Proteinopathies; TDP-43
9.  Frontotemporal neural systems supporting semantic processing in Alzheimer’s disease 
We hypothesize that semantic memory for object concepts involves both representations of visual feature knowledge in modality-specific association cortex and heteromodal regions that are important for integrating and organizing this semantic knowledge so it can be used in a flexible, contextually appropriate manner. We examined this hypothesis in an fMRI study of mild Alzheimer’s disease (AD). Participants were presented with pairs of printed words and asked whether the words match on a given visual-perceptual feature (e.g. guitar, violin: SHAPE). Stimuli probed natural kinds and manufactured objects, and judgments involved shape or color. We found activation of bilateral ventral temporal cortex and left dorsolateral prefrontal cortex during semantic judgments, with AD patients showing less activation of these regions than healthy seniors. Moreover, AD patients showed less ventral temporal activation relative to healthy seniors for manufactured objects but not natural kinds. We also used diffusion-weighted MRI of white matter to examine fractional anisotropy (FA). Patients with AD showed significantly reduced FA in the superior longitudinal fasciculus and inferior frontal-occipital fasciculus that carry projections linking temporal and frontal regions of this semantic network. Our results are consistent with the hypothesis that semantic memory is supported in part by a large-scale neural network involving modality-specific association cortex, heteromodal association cortex and projections between these regions. The semantic deficit in AD thus arises from gray matter disease that affects the representation of feature knowledge and processing its content, as well as white matter disease that interrupts the integrated functioning of this large-scale network.
doi:10.3758/s13415-013-0239-6
PMCID: PMC3972309  PMID: 24425352
10.  Impairment of script comprehension in Lewy body spectrum disorders 
Brain and language  2013;125(3):330-343.
A disabling impairment of higher-order language function can be seen in patients with Lewy body spectrum disorders such as Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). We focus on script comprehension in patients with Lewy body spectrum disorders. While scripts unfold sequentially, constituent events are thought to contain an internal organization. Executive dysfunction in patients with Lewy body spectrum disorders may interfere with comprehension of this internal structure. We examined 42 patients (30 non-demented PD and 12 mildly demented PDD/DLB patients) and 12 healthy seniors. We presented 22 scripts (e.g., “going fishing”), each consisting of six events. Pilot data from young controls provided the basis for organizing associated events into clusters and arranging them hierarchically into scripts. We measured accuracy and latency to judge the order of adjacent events in the same cluster versus adjacent events in different clusters. PDD/DLB patients were less accurate in their ordering judgments than PD patients and controls. Healthy seniors and PD patients were significantly faster to judge correctly the order of highly associated within-cluster event pairs relative to less closely associated different-cluster event pairs, while PDD/DLB patients did not consistently distinguish between these event-pair types. This relative insensitivity to the clustered-hierarchical organization of events was related to executive impairment and to frontal atrophy as measured by volumetric MRI. These findings extend prior work on script processing to patients with Lewy body spectrum disorders and highlight the potential impact of frontal/executive dysfunction on the daily lives of affected patients.
doi:10.1016/j.bandl.2013.02.006
PMCID: PMC3940934  PMID: 23566691
Parkinson's disease; Parkinson's disease dementia; Dementia with Lewy bodies; Frontal cortex; Executive function; Scripts; Organization; Discourse; Volumetric MRI
11.  CATEGORY-SPECIFIC SEMANTIC MEMORY: CONVERGING EVIDENCE FROM BOLD fMRI AND ALZHEIMER’S DISEASE 
NeuroImage  2012;68:263-274.
Patients with Alzheimer’s disease have category-specific semantic 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, and prefrontal cortex (PFC) which may contribute to feature selection. Tractography revealed dorsal 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 correlated with natural kinds in patients and fMRI activation in healthy adults for natural than manufactured artifacts, and the dorsal WM projection between PFC and TOC in patients correlated only with judgments of natural kinds. Patients thus remained 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.
doi:10.1016/j.neuroimage.2012.11.057
PMCID: PMC3557551  PMID: 23220494
semantic; fMRI; DTI; Alzheimer’s; temporal; prefrontal
12.  The Advantages of FTD Drug Development (Part 2 of FTD: The Next Therapeutic Frontier) 
Frontotemporal Degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language and motor phenotypes for which there are currently no effective therapies. This manuscript is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Dementia Treatment Study Group (FTSG), a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This manuscript discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared to other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease (AD). Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw upon this experience to create a roadmap for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.
doi:10.1016/j.jalz.2012.03.003
PMCID: PMC3562382  PMID: 23062850
13.  Grammatical comprehension deficits in non-fluent/agrammatic primary progressive aphasia 
Importance
Grammatical comprehension difficulty is an essential supporting feature of the non-fluent/agrammatic variant of primary progressive aphasia (naPPA), but well-controlled clinical measures of grammatical comprehension are unavailable.
Objective
To develop a measure of grammatical comprehension and examine this comparatively in PPA variants and behavioural-variant frontotemporal degeneration (bvFTD) and to assess the neuroanatomic basis for these deficits with volumetric grey matter atrophy and whole-brain fractional anisotropy (FA) in white matter tracts.
Design
Case–control study.
Setting
Academic medical centre.
Participants
39 patients with variants of PPA (naPPA=12, lvPPA=15 and svPPA=12), 27 bvFTD patients without aphasia and 12 healthy controls.
Main outcome measure
Grammatical comprehension accuracy.
Results
Patients with naPPA had selective difficulty understanding cleft sentence structures, while all PPA variants and patients with bvFTD were impaired with sentences containing a centre-embedded subordinate clause. Patients with bvFTD were also impaired understanding sentences involving short-term memory. Linear regressions related grammatical comprehension difficulty in naPPA to left anterior-superior temporal atrophy and reduced FA in corpus callosum and inferior frontal-occipital fasciculus. Difficulty with centre-embedded sentences in other PPA variants was related to other brain regions.
Conclusions and relevance
These findings emphasise a distinct grammatical comprehension deficit in naPPA and associate this with interruption of a frontal-temporal neural network.
doi:10.1136/jnnp-2013-305749
PMCID: PMC3925677  PMID: 24039027
14.  Sparse canonical correlation analysis relates network-level atrophy to multivariate cognitive measures in a neurodegenerative population 
NeuroImage  2013;84:698-711.
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, nonfluent/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.
doi:10.1016/j.neuroimage.2013.09.048
PMCID: PMC3911786  PMID: 24096125
Alzheimer disease; Frontotemporal lobar degeneration; Philadelphia Brief Assessment of Cognition; PBAC; MRI; Sparse canonical correlation analysis
15.  Cognitive decline and reduced survival in C9orf72 expansion Frontotemporal degeneration and Amyotrophic lateral sclerosis 
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 TDP-43 proteinopathy.
Methods
A retrospective-cohort study 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 deceased patients, 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-rankλ2=4.183,p=0.041), and C9P FTLD showed a significantly greater annualized rate of decline in letter fluency (4.5±1.3words/year) than C9N FTLD (1.4±0.8words/year, p=0.023). VBM revealed greater atrophy in the right fronto-insular, 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. Neuropathologic 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 ALS and FTLD patients.
doi:10.1136/jnnp-2012-303507
PMCID: PMC3543474  PMID: 23117491
Frontotemporal dementia; Amyotrophic lateral sclerosis; C9orf72; neuropsychological tests; neuroimaging
16.  Development and Validation of Pedigree Classification Criteria for Frontotemporal Lobar Degeneration 
JAMA neurology  2013;70(11):1411-1417.
IMPORTANCE
A significant portion of frontotemporal lobar degeneration (FTLD) is due to inherited gene mutations, and we are unaware of a large sequential series that includes a recently discovered inherited cause of FTLD. There is also great need to develop clinical tools and approaches that will assist clinicians in the identification and counseling of patients with FTLD and their families regarding the likelihood of an identifiable genetic cause.
OBJECTIVES
To ascertain the frequency of inherited FTLD and develop validated pedigree classification criteria for FTLD that provide a standardized means to evaluate pedigree information and insight into the likelihood of mutation-positive genetic test results for C9orf72, MAPT, and GRN.
DESIGN
Information about pedigrees and DNA was collected from 306 serially assessed patients with a clinical diagnosis of FTLD. This information included gene test results for C9orf72, MAPT, and GRN. Pedigree classification criteria were developed based on a literature review of FTLD genetics and pedigree tools and then refined by reviewing mutation-positive and -negative pedigrees to determine differentiating characteristics.
SETTING
Academic medical center.
PARTICIPANTS
Patients with FTLD.
MAIN OUTCOMES AND MEASURES
Familial risk.
RESULTS
The rate of C9orf72, MAPT, or GRN mutation–positive FTLD in this series was 15.4%. Categories designating the risk level for hereditary cause were termed high, medium, low, apparent sporadic, and unknown significance. Thirty-nine pedigrees (12.7%)met criteria for high, 31 (10.1%) for medium, 46 (15.0%) for low, 91 (29.7%) for apparent sporadic, and 99 (32.4%) for unknown significance. The mutation-detection rates were as follows: high, 64.1%; medium, 29%; low, 10.9%; apparent sporadic, 1.1%; and unknown significance, 7.1%. Mutation-detection rates differed significantly between the high and other categories.
CONCLUSIONS AND RELEVANCE
Mutation rates are high in FTLD spectrum disorders, and the proposed criteria provide a validated standard for the classification of FTLD pedigrees. The combination of pedigree criteria and mutation-detection rates has important implications for genetic counseling and testing in clinical settings.
doi:10.1001/jamaneurol.2013.3956
PMCID: PMC3906581  PMID: 24081456
17.  Clinical diagnostic criteria and classification controversies in frontotemporal lobar degeneration 
Frontotemporal lobar degeneration (FTLD) can manifest as a spectrum of clinical syndromes, ranging from behavioural impairment to language or motor dysfunction. Recently, revised diagnostic criteria have been proposed for the behavioural and progressive aphasia syndromes associated with frontotemporal degeneration. The present review will summarize these diagnostic guidelines and highlight some lingering controversies in the classification of FTLD clinical syndromes. We will discuss common tools and methods used to identify the insidious changes of behavioural variant frontotemporal dementia (bvFTD), the value of new, patient-based tasks of orbitofrontal function, and the issue of a benign or ‘phenocopy’ variant of bvFTD. With regard to primary progressive aphasia (PPA), we will discuss the scope of the semantic disorder in semantic-variant PPA, the nature of the speech disorder in non-fluent, agrammatic PPA, and the preliminary utility of a logopenic PPA classification.
doi:10.3109/09540261.2013.763341
PMCID: PMC3906583  PMID: 23611345
18.  Criteria for the diagnosis of corticobasal degeneration 
Neurology  2013;80(5):496-503.
Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.
doi:10.1212/WNL.0b013e31827f0fd1
PMCID: PMC3590050  PMID: 23359374
19.  Can MRI screen for CSF biomarkers in neurodegenerative disease? 
Neurology  2013;80(2):132-138.
Objective:
Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) may have overlapping clinical presentations despite distinct underlying neuropathologies, thus making in vivo diagnosis challenging. In this study, we evaluate the utility of MRI as a noninvasive screening procedure for the differential diagnosis of AD and FTLD.
Methods:
We recruited 185 patients with a clinically diagnosed neurodegenerative disease consistent with AD or FTLD who had a lumbar puncture and a volumetric MRI. A subset of 32 patients had genetic or autopsy-confirmed AD or FTLD. We used singular value decomposition to decompose MRI volumes and linear regression and cross-validation to predict CSF total tau (tt) and β-amyloid (Aβ1-42) ratio (tt/Aβ) in patients with AD and patients with FTLD. We then evaluated accuracy of MRI-based predicted tt/Aβ using 4 converging sources including neuroanatomic visualization and categorization of a subset of patients with genetic or autopsy-confirmed AD or FTLD.
Results:
Regression analyses showed that MRI-predicted tt/Aβ is highly related to actual CSF tt/Aβ. In each group, both predicted and actual CSF tt/Aβ have extensively overlapping neuroanatomic correlates: low tt/Aβ consistent with FTLD is related to ventromedial prefrontal regions while high tt/Aβ consistent with AD is related to posterior cortical regions. MRI-predicted tt/Aβ is 75% accurate at identifying underlying diagnosis in patients with known pathology and in clinically diagnosed patients with known CSF tt/Aβ levels.
Conclusion:
MRI may serve as a noninvasive procedure that can screen for AD and FTLD pathology as a surrogate for CSF biomarkers.
doi:10.1212/WNL.0b013e31827b9147
PMCID: PMC3589187  PMID: 23269595
20.  White Matter Disease Correlates with Lexical Retrieval Deficits in Primary Progressive Aphasia 
Objective: To relate fractional anisotropy (FA) changes associated with the semantic and logopenic variants of primary progressive aphasia (PPA) to measures of lexical retrieval.
Methods: We collected neuropsychological testing, volumetric magnetic resonance imaging, and diffusion-weighted imaging on semantic variant PPA (svPPA) (n = 11) and logopenic variant PPA (lvPPA) (n = 13) patients diagnosed using published criteria. We also acquired neuroimaging data on a group of demographically comparable healthy seniors (n = 34). FA was calculated and analyzed using a white matter (WM) tract-specific analysis approach. This approach utilizes anatomically guided data reduction to increase sensitivity and localizes results within canonically defined tracts. We used non-parametric, cluster-based statistical analysis to relate language performance to FA and determine regions of reduced FA in patients.
Results: We found widespread FA reductions in WM for both variants of PPA. FA was related to both confrontation naming and category naming fluency performance in left uncinate fasciculus and corpus callosum in svPPA and left superior and inferior longitudinal fasciculi in lvPPA.
Conclusion: SvPPA and lvPPA are associated with distinct disruptions of a large-scale network implicated in lexical retrieval, and the WM disease in each phenotype may contribute to language impairments including lexical retrieval.
doi:10.3389/fneur.2013.00212
PMCID: PMC3873600  PMID: 24409166
frontotemporal dementia; primary progressive aphasia; diffusion-weighted MRI; magnetic resonance imaging; neuropsychology
21.  The neural basis for establishing a focal point in pure coordination games 
When making a decision, humans often have to ‘coordinate’—reach the same conclusion—as another individual without explicitly communicating. Relatively, little is known about the neural basis for coordination. Moreover, previous fMRI investigations have supported conflicting hypotheses. One account proposes that individuals coordinate using a ‘gut feeling’ and that this is supported by insula recruitment. Another account proposes that individuals recruit strategic decision-making mechanisms in prefrontal cortex in order to coordinate. We investigate the neural basis for coordination in individuals with behavioral-variant frontotemporal dementia (bvFTD) who have limitations in social decision-making associated with disease in prefrontal cortex. We demonstrate that bvFTD are impaired at establishing a focal point in a semantic task (e.g. ‘Tell me any boy's name’) that requires coordination relative to a similar, control semantic task that does not. Additionally, coordination limitations in bvFTD are related to cortical thinning in prefrontal cortex. These findings are consistent with behavioral economic models proposing that, beyond a ‘gut feeling’, strategic decision-making contributes to the coordination process, including a probabilistic mechanism that evaluates the salience of a response (e.g. is ‘John’ a frequent boy's name), a hierarchical mechanism that iteratively models an opponent's likely response and a mechanism involved in social perspective taking.
doi:10.1093/scan/nsr070
PMCID: PMC3501702  PMID: 22009019
coordination; frontotemporal dementia; MRI; decision making; game theory
22.  White Matter Imaging Helps Dissociate Tau from TDP-43 in Frontotemporal Lobar Degeneration 
Background
Frontotemporal lobar degeneration (FTLD) is most commonly associated with TAR-DNA binding protein (TDP-43) or tau pathology at autopsy, but there are no in vivo biomarkers reliably discriminating between sporadic cases. As disease-modifying treatments emerge, it is critical to accurately identify underlying pathology in living patients so that they can be entered into appropriate etiology-directed clinical trials. Patients with tau inclusions (FTLD-TAU) appear to have relatively greater white matter (WM) disease at autopsy than those patients with TDP-43 (FTLD-TDP). In this paper, we investigate the ability of white matter (WM) imaging to help discriminate between FTLD-TAU and FTLD-TDP during life using diffusion tensor imaging (DTI).
Methods
Patients with autopsy-confirmed disease or a genetic mutation consistent with FTLD-TDP or FTLD-TAU underwent multimodal T1 volumetric MRI and diffusion weighted imaging scans. We quantified cortical thickness in GM and fractional anisotropy (FA) in WM. We performed Eigenanatomy, a statistically robust dimensionality reduction algorithm, and used leave-one-out cross-validation to predict underlying pathology. Neuropathological assessment of GM and WM disease burden was performed in the autopsy-cases to confirm our findings of an ante-mortem GM and WM dissociation in the neuroimaging cohort.
Results
ROC curve analyses evaluated classification accuracy in individual patients and revealed 96% sensitivity and 100% specificity for WM analyses. FTLD-TAU had significantly more WM degeneration and inclusion severity at autopsy relative to FTLD-TDP.
Conclusions
These neuroimaging and neuropathological investigations provide converging evidence for greater WM burden associated with FTLD-TAU, and emphasize the role of WM neuroimaging for in vivo discrimination between FTLD-TAU and FTLD-TDP.
doi:10.1136/jnnp-2012-304418
PMCID: PMC3737288  PMID: 23475817
23.  Memantine in frontotemporal lobar degeneration: A multicenter, randomised, double-blind, placebo-controlled trial 
Lancet neurology  2013;12(2):149-156.
Background
Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26 week open label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI).
Methods
We performed a randomized, parallel group, double blind, placebo controlled trial of 20 mg memantine taken orally daily for 26 weeks in FTD. Participants met Neary criteria for behavioral variant (bvFTD) or semantic dementia (SD) and had characteristic brain atrophy. Use of cholinesterase inhibitors was prohibited. The objective of the study was to determine whether memantine is an effective treatment for FTD. Individuals were randomized to memantine or matched placebo tablets in blocks of two and four. Primary endpoints were the change in total NPI score and Clinical Global Impression of Change (CGIC) scores after 26 weeks. Secondary outcomes included a neuropsychological battery, and other cognitive, global and activity of daily living measures. Clinicaltrials.gov identifier: NCT00545974
Findings
100 subjects were screened, 81 were randomized, 5 (6%) discontinued and 76 completed all visits. Enrollment numbers were lower than planned due to many subjects’ preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. 39 memantine and 42 placebo subjects entered the primary intent to treat analysis. There was no effect of memantine treatment on either the NPI (mean difference [MD] 2.2, 95%CI: −3.9, 8.3, p = 0.47) or CGIC (MD 0, 95%CI: −0.4, 0.4, p = 0.90) after 26 weeks of treatment. Memantine was generally well tolerated, however there were more frequent cognitive adverse events in the memantine group.
Interpretation
There was no benefit of memantine treatment in bvFTD or SD. These data do not support memantine use in FTD.
Funding
Forest Research Institute
doi:10.1016/S1474-4422(12)70320-4
PMCID: PMC3756890  PMID: 23290598
24.  Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease 
Neurology  2012;79(9):897-905.
Objectives:
While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI).
Methods:
Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide.
Conclusion:
Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.
doi:10.1212/WNL.0b013e318266fa70
PMCID: PMC3425844  PMID: 22855860
25.  Frontal lobe abnormalities on MRS correlate with poor letter fluency in ALS 
Neurology  2012;79(6):583-588.
Objective:
To examine whether frontal lobe abnormalities on magnetic resonance spectroscopy (MRS) in amyotrophic lateral sclerosis (ALS) correlate with poor letter fluency (LF).
Methods:
Twenty-five patients with ALS (20 with definite, probable, or possible ALS and 5 with progressive muscular atrophy) performed an LF task, involving F word generation in 1 minute, and underwent MRS. Comparisons were made between patients with ALS with impaired LF and unimpaired LF based on an empirically derived cutoff score. A Spearman correlation was performed between the patient's N-acetyl acetate/creatinine-phosphocreatinine ratio (NAA/Cr) and the number of F words generated.
Results:
LF was impaired in 50% of patients with ALS. Patients with impaired LF had reduced NAA/Cr in the DLPFC compared with those with unimpaired LF (p = 0.007). There was a significant correlation between LF and NAA/Cr in the DLPFC (r = 0.51, p = 0.0009). The ALS Functional Rating Scale score, clinical region of motor onset, and disease category had no effect on LF or NAA/Cr in the DLPFC.
Conclusions:
A reduced NAA/Cr in the DLPFC of patients with ALS is a marker of neuronal dysfunction and correlates with impaired performance on a clinical measure of executive function.
doi:10.1212/WNL.0b013e3182635720
PMCID: PMC3413764  PMID: 22843269

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