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1.  Anterior temporal lobe degeneration produces widespread network-driven dysfunction 
Brain  2013;136(10):2979-2991.
The neural organization of semantic memory remains much debated. A ‘distributed-only’ view contends that semantic knowledge is represented within spatially distant, modality-selective primary and association cortices. Observations in semantic variant primary progressive aphasia have inspired an alternative model featuring the anterior temporal lobe as an amodal hub that supports semantic knowledge by linking distributed modality-selective regions. Direct evidence has been lacking, however, to support intrinsic functional interactions between an anterior temporal lobe hub and upstream sensory regions in humans. Here, we examined the neural networks supporting semantic knowledge by performing a multimodal brain imaging study in healthy subjects and patients with semantic variant primary progressive aphasia. In healthy subjects, the anterior temporal lobe showed intrinsic connectivity to an array of modality-selective primary and association cortices. Patients showed focal anterior temporal lobe degeneration but also reduced physiological integrity throughout distributed modality-selective regions connected with the anterior temporal lobe in healthy controls. Physiological deficits outside the anterior temporal lobe correlated with scores on semantic tasks and with anterior temporal subregion atrophy, following domain-specific and connectivity-based predictions. The findings provide a neurophysiological basis for the theory that semantic processing is orchestrated through interactions between a critical anterior temporal lobe hub and modality-selective processing nodes.
doi:10.1093/brain/awt222
PMCID: PMC3857932  PMID: 24072486
anterior temporal lobe; semantic dementia; cognition; semantics; functional neuroimaging
2.  Intrinsic connectivity network disruption in progressive supranuclear palsy 
Annals of neurology  2013;73(5):603-616.
Objective
Progressive supranuclear palsy (PSP) has been conceptualized as a large-scale network disruption, but the specific network targeted has not been fully characterized. We sought to delineate the affected network in patients with clinical PSP.
Methods
Using task-free fMRI, we mapped intrinsic connectivity to the dorsal midbrain tegmentum (dMT), a region which shows focal atrophy in PSP. Two healthy control groups (1 young, 1 older) were used to define and replicate the normal connectivity pattern, and patients with PSP were compared to an independent matched healthy control group on measures of network connectivity.
Results
Healthy young and older subjects showed a convergent pattern of connectivity to the dMT, including brainstem, cerebellar, diencephalic, basal ganglia, and cortical regions involved in skeletal, oculomotor, and executive control. Patients with PSP showed significant connectivity disruptions within this network, particularly within cortico-subcortical and cortico-brainstem interactions. Patients with more severe functional impairment showed lower mean dMT network connectivity scores.
Interpretation
This study defines a PSP-related intrinsic connectivity network in the healthy brain and demonstrates the sensitivity of network-based imaging methods to PSP-related physiological and clinical changes.
doi:10.1002/ana.23844
PMCID: PMC3732833  PMID: 23536287
3.  Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation 
Acta neuropathologica  2013;125(4):581-593.
Post-translational modifications play a key role in tau protein aggregation and related neurodegeneration. Because hyperphosphorylation alone does not necessarily cause tau aggregation, other post-translational modifications have been recently explored. Tau acetylation promotes aggregation and inhibits tau’s ability to stabilize microtubules. Recent studies have shown co-localization of acetylated and phosphorylated tau in AD and some 4R tauopathies. We developed a novel monoclonal antibody against acetylated tau at lysine residue 274, which recognizes both 3R and 4R tau, and used immunohistochemistry and immunofluorescence to probe 22 cases, including AD and another eight familial or sporadic tauopathies. Acetylated tau was identified in all tauopathies except argyrophilic grain disease (AGD). AGD is an age-associated, common but atypical 4R tauopathy, not always associated with clinical progression. Pathologically, AGD is characterized by neuropil grains, pre-neurofibrillary tangles, and oligodendroglial coiled bodies, all recognized by phospho-tau antibodies. The lack of acetylated tau in these inclusions suggests that AGD represents a distinctive tauopathy. Our data converge with previous findings to raise the hypothesis that AGD could play a protective role against the spread of AD-related tau pathology. Tau acetylation as a key modification for the propagation tau toxicity deserves further investigation.
doi:10.1007/s00401-013-1080-2
PMCID: PMC3692283  PMID: 23371364
tau; pathology; autopsy; acetylation; immunohistochemistry; human
4.  One-year test-retest reliability of intrinsic connectivity network fMRI in older adults 
NeuroImage  2012;61(4):1471-1483.
“Resting-state” or task-free fMRI can assess intrinsic connectivity network (ICN) integrity in health and disease, suggesting a potential for use of these methods as disease-monitoring biomarkers. Numerous analytical options are available, including model-driven ROI-based correlation analysis and model-free, independent component analysis (ICA). High test-retest reliability will be a necessary feature of a successful ICN biomarker, yet available reliability data remains limited. Here, we examined ICN fMRI test-retest reliability in 24 healthy older subjects scanned roughly one year apart. We focused on the salience network, a disease-relevant ICN not previously subjected to reliability analysis. Most ICN analytical methods proved reliable (intraclass coefficients > 0.4) and could be further improved by wavelet analysis. Seed-based ROI correlation analysis showed high map-wise reliability, whereas graph theoretical measures and temporal concatenation group ICA produced the most reliable individual unit-wise outcomes. Including global signal regression in ROI-based correlation analyses reduced reliability. Our study provides a direct comparison between the most commonly used ICN fMRI methods and potential guidelines for measuring intrinsic connectivity in aging control and patient populations over time.
doi:10.1016/j.neuroimage.2012.03.027
PMCID: PMC4226138  PMID: 22446491
5.  Neurodegenerative disease phenotypes in carriers of MAPT p.A152T, a risk factor for frontotemporal dementia spectrum disorders and Alzheimer's disease 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31828cc357.
Recently, Coppola and colleagues demonstrated that a rare MAPT sequence variant, c.454G>A (p.A152T), significantly increases the risk of frontotemporal dementia (FTD) spectrum disorders and Alzheimer's disease (AD) in a screen of 15,369 subjects1. We describe clinical features of 9 patients with neurodegenerative disease (4 women) harboring p.A152T, aged 51 to 79 years at symptom onset. Seven developed FTD spectrum clinical syndromes, including progressive supranuclear palsy syndrome (PSP, n=2), behavioral variant FTD (bvFTD, n=1), nonfluent variant primary progressive aphasia (nfvPPA, n=2), and corticobasal syndrome (CBS, n=2); two patients were diagnosed with clinical AD. Thus, MAPT p.A152T is associated with a variety of FTD spectrum clinical presentations, although patients with clinical AD are also identified. These data warrant larger studies with clinicopathological correlation to elucidate the influence of this genetic variant on neurodegenerative disease.
doi:10.1097/WAD.0b013e31828cc357
PMCID: PMC3796183  PMID: 23518664
All Cognitive Disorders/Dementia; Alzheimer's disease; Frontotemporal Dementia; Corticobasal degeneration; Progressive Supranuclear Palsy
6.  Patterns of striatal degeneration in frontotemporal dementia 
Behavioral variant frontotemporal dementia and semantic dementia have been associated with striatal degeneration, but few studies have delineated striatal subregion volumes in vivo or related them to clinical phenotype. We traced caudate, putamen, and nucleus accumbens on MR images to quantify volumes of these structures in behavioral variant frontotemporal dementia, semantic dementia, Alzheimer’s disease, and healthy controls (n = 12 per group). We further related these striatal volumes to clinical deficits and neuropathological findings in a subset of patients. Behavioral variant frontotemporal dementia and semantic dementia showed significant overall striatal atrophy compared with controls. Moreover, behavioral variant frontotemporal dementia showed panstriatal degeneration whereas semantic dementia featured a more focal pattern involving putamen and accumbens. Right-sided striatal atrophy, especially in the putamen, correlated with overall behavioral symptom severity and with specific behavioral domains. At autopsy, patients with behavioral variant frontotemporal dementia and semantic dementia showed striking and severe tau or TAR DNA-binding protein of 43 kDa pathology, especially in ventral parts of the striatum. These results demonstrate that ventral striatum degeneration is a prominent shared feature in behavioral variant frontotemporal dementia and semantic dementia and may contribute to social-emotional deficits common to both disorders.
doi:10.1097/WAD.0b013e31824a7df4
PMCID: PMC3389579  PMID: 22367382
7.  Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene 
Background
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.
Results
We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]).
Conclusions
Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-38) contains supplementary material, which is available to authorized users.
doi:10.1186/1750-1326-9-38
PMCID: PMC4190282  PMID: 25239657
C9ORF72; Frontotemporal dementia; Motor neuron disease; Genetic modifier; Repeat expansion
8.  Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS 
Neurobiology of aging  2013;34(9):2235.e11-2235.e13.
The nuclear protein fused in sarcoma (FUS) is found in cytoplasmic inclusions in a subset of patients with the neurodegenerative disorder frontotemporal lobar degeneration (FTLD-FUS). FUS contains a methylated arginine-glycine-glycine domain which is required for transport into the nucleus. Recent findings have shown that this domain is hypomethylated in patients with FTLD-FUS. To determine if the cause of hypomethylation is the result of mutations in protein N-arginine methyltransferases (PRMTs), we selected 3 candidate genes (PRMT1, PRMT3 and PRMT8) and performed complete sequencing analysis and real-time PCR mRNA expression analysis in 20 FTLD-FUS cases. No mutations or statistically significant changes in expression were observed in our patient samples, suggesting that defects in PRMTs are not the cause of FTLD-FUS.
doi:10.1016/j.neurobiolaging.2013.04.004
PMCID: PMC3683824  PMID: 23635657
9.  TDP-43 Frontotemporal Lobar Degeneration and Autoimmune Disease 
Journal of neurology, neurosurgery, and psychiatry  2013;84(9):10.1136/jnnp-2012-304644.
Background
The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored.
Objective
To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared to neurologically healthy normal controls (NC) and Alzheimer’s disease (AD) as dementia controls.
Design
Case control.
Setting
Academic medical centres.
Participants
129 svPPA, 39 PGRN, 186 NC, and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN, and NC cohorts underwent serum analysis for tumor necrosis factor α (TNF-α) levels.
Outcome Measures
Chi-square comparison of autoimmune prevalence and follow up logistic regression.
Results
There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders, and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared to NC.
Conclusions
svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared to NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 (TDP-43) aggregation.
doi:10.1136/jnnp-2012-304644
PMCID: PMC3840954  PMID: 23543794
10.  Rivastigmine is Associated with Restoration of Left Frontal Brain Activity in Parkinson’s Disease 
Objective
To investigate how acetylcholinesterase inhibitor (ChEI) treatment impacts brain function in Parkinson’s disease (PD).
Methods
Twelve patients with PD and either dementia or mild cognitive impairment underwent task-free functional magnetic resonance imaging before and after three months of ChEI treatment and were compared to 15 age and sex matched neurologically healthy controls. Regional spontaneous brain activity was measured using the fractional amplitude of low frequency fluctuations.
Results
At baseline, patients showed reduced spontaneous brain activity in regions important for motor control (e.g., caudate, supplementary motor area, precentral gyrus, thalamus), attention and executive functions (e.g., lateral prefrontal cortex), and episodic memory (e.g., precuneus, angular gyrus, hippocampus). After treatment, the patients showed a similar but less extensive pattern of reduced spontaneous brain activity relative to controls. Spontaneous brain activity deficits in the left premotor cortex, inferior frontal gyrus, and supplementary motor area were restored such that the activity was increased post-treatment compared to baseline and was no longer different from controls. Treatment-related increases in left premotor and inferior frontal cortex spontaneous brain activity correlated with parallel reaction time improvement on a test of controlled attention.
Conclusions
PD patients with cognitive impairment show numerous regions of decreased spontaneous brain function compared to controls, and rivastigmine is associated with performance-related normalization in left frontal cortex function.
doi:10.1002/mds.25575
PMCID: PMC4001926  PMID: 23847120
acetylcholine (D02.092.211.111); magnetic resonance imaging functional (E01.370.350.825.500); attention (F02.830.104.214); Acetylcholinesterase Inhibitors (D27.505.519.389.275) executive control (F02.463.217)
11.  ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease 
Neurocase  2012;19(3):295-301.
Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is characterized by neuronal cytoplasmic inclusions containing TDP-43. Apolipoprotein E4 (apoE4), derived from the apoE ε4 allele, enhances brain atrophy in FTLD through unknown mechanisms. Here, we studied two siblings with C9ORF72-linked familial FTLD-MND, an apoE ε4 homozygote and an apoE ε3 homozygote. The apoE ε4 homozygote had more cognitive-behavioral symptoms, fronto-insulo-temporal atrophy, and apoE fragments and aggregates in the anterior cingulate cortex. ApoE formed complexes with TDP-43 that were more abundant in the apoE ε4 homozygote. Although differences seen in a sibling pair could arise due to chance, these findings raise the possibility that apoE4 exacerbates brain pathology in FTLD through formation of neurotoxic apoE fragments and interactions with TDP-43.
doi:10.1080/13554794.2012.667124
PMCID: PMC3655113  PMID: 22512241
Apolipoprotein E; TDP-43; Frontotemporal dementia; Motor neuron disease; Neuropathology
12.  The salience network causally influences default mode network activity during moral reasoning 
Brain  2013;136(6):1929-1941.
Large-scale brain networks are integral to the coordination of human behaviour, and their anatomy provides insights into the clinical presentation and progression of neurodegenerative illnesses such as Alzheimer’s disease, which targets the default mode network, and behavioural variant frontotemporal dementia, which targets a more anterior salience network. Although the default mode network is recruited when healthy subjects deliberate about ‘personal’ moral dilemmas, patients with Alzheimer’s disease give normal responses to these dilemmas whereas patients with behavioural variant frontotemporal dementia give abnormal responses to these dilemmas. We hypothesized that this apparent discrepancy between activation- and patient-based studies of moral reasoning might reflect a modulatory role for the salience network in regulating default mode network activation. Using functional magnetic resonance imaging to characterize network activity of patients with behavioural variant frontotemporal dementia and healthy control subjects, we present four converging lines of evidence supporting a causal influence from the salience network to the default mode network during moral reasoning. First, as previously reported, the default mode network is recruited when healthy subjects deliberate about ‘personal’ moral dilemmas, but patients with behavioural variant frontotemporal dementia producing atrophy in the salience network give abnormally utilitarian responses to these dilemmas. Second, patients with behavioural variant frontotemporal dementia have reduced recruitment of the default mode network compared with healthy control subjects when deliberating about these dilemmas. Third, a Granger causality analysis of functional neuroimaging data from healthy control subjects demonstrates directed functional connectivity from nodes of the salience network to nodes of the default mode network during moral reasoning. Fourth, this Granger causal influence is diminished in patients with behavioural variant frontotemporal dementia. These findings are consistent with a broader model in which the salience network modulates the activity of other large-scale networks, and suggest a revision to a previously proposed ‘dual-process’ account of moral reasoning. These findings also characterize network interactions underlying abnormal moral reasoning in frontotemporal dementia, which may serve as a model for the aberrant judgement and interpersonal behaviour observed in this disease and in other disorders of social function. More broadly, these findings link recent work on the dynamic interrelationships between large-scale brain networks to observable impairments in dementia syndromes, which may shed light on how diseases that target one network also alter the function of interrelated networks.
doi:10.1093/brain/awt066
PMCID: PMC3673466  PMID: 23576128
moral reasoning; frontotemporal dementia; salience network; default mode network; functional neuroimaging
13.  Progranulin mutations as a risk factor for Alzheimer’s Disease 
JAMA neurology  2013;70(6):774-778.
Objective
To describe patients with progranulin gene (GRN) mutations and evidence of Alzheimer’s disease (AD) pathology
Design
Two case reports and literature review
Setting
University of California San Francisco Memory and Aging Center
Patients
Two unrelated patients with GRN mutations
Results
One patient presented at age 65 with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 with logopenic progressive aphasia and at autopsy showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD.
Conclusions
In addition to autosomal-dominant frontotemporal lobar degeneration, mutations in GRN may be a risk factor for AD clinical phenotypes and neuropathology.
doi:10.1001/2013.jamaneurol.393
PMCID: PMC3743672  PMID: 23609919
14.  Predicting regional neurodegeneration from the healthy brain functional connectome 
Neuron  2012;73(6):1216-1227.
Summary
Neurodegenerative diseases target large-scale neural networks. Four competing mechanistic hypotheses have been proposed to explain network-based disease patterning: nodal stress, transneuronal spread, trophic failure, and shared vulnerability. Here, we used task-free fMRI to derive the healthy intrinsic connectivity patterns seeded by brain regions vulnerable to any of five distinct neurodegenerative diseases. These data enabled us to investigate how intrinsic connectivity in health predicts region-by-region vulnerability to disease. For each illness, specific regions emerged as critical network “epicenters” whose normal connectivity profiles most resembled the disease-associated atrophy pattern. Graph theoretical analyses in healthy subjects revealed that regions with higher total connectional flow and, more consistently, shorter functional paths to the epicenters, showed greater disease-related vulnerability. These findings best fit a transneuronal spread model of network-based vulnerability. Molecular pathological approaches may help clarify what makes each epicenter vulnerable to its targeting disease and how toxic protein species travel between networked brain structures.
doi:10.1016/j.neuron.2012.03.004
PMCID: PMC3361461  PMID: 22445348
fMRI; neurodegeneration; network; functional connectivity; Alzheimer’s disease; frontotemporal dementia
15.  Seizures and Epileptiform Activity in the Early Stages of Alzheimer Disease 
JAMA neurology  2013;70(9):1158-1166.
IMPORTANCE
Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness. We report key features of AD-related seizures and epileptiform activity that are instructive for clinical practice and highlight similarities between AD and transgenic animal models of the disease.
OBJECTIVE
To describe common clinical characteristics and treatment outcomes of patients with amnestic mild cognitive impairment (aMCI) or early AD who also have epilepsy or subclinical epileptiform activity.
DESIGN
Retrospective observational study from 2007 to 2012.
SETTING
Memory and Aging Center, University of California, San Francisco.
PATIENTS
We studied 54 patients with a diagnosis of aMCI plus epilepsy (n = 12), AD plus epilepsy (n = 35), and AD plus subclinical epileptiform activity (n = 7).
MAIN OUTCOMES AND MEASURES
Clinical and demographic data, electroencephalogram (EEG) readings, and treatment responses to antiepileptic medications.
RESULTS
Patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs 71.1 years; P = .02). Patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; P = .001). Patients with AD who had subclinical epileptiform activity also had an early onset of cognitive decline (58.9 years). The timing of seizure onset in patients with aMCI and AD was nonuniform (P < .001), clustering near the onset of cognitive decline. Epilepsies were most often complex partial seizures (47%) and more than half were nonconvulsive (55%). Serial or extended EEG monitoring appeared to be more effective than routine EEG at detecting interictal and subclinical epileptiform activity. Epileptic foci were predominantly unilateral and temporal. Of the most commonly prescribed antiepileptics, treatment outcomes appeared to be better for lamotrigine and levetiracetam than for phenytoin.
CONCLUSIONS AND RELEVANCE
Common clinical features of patients with aMCI- or AD-associated epilepsy at our center included early age at onset of cognitive decline, early incidence of seizures in the disease course, unilateral temporal epileptic foci detected by serial/extended EEG, transient cognitive dysfunction, and good seizure control and tolerability with lamotrigine and levetiracetam. Careful identification and treatment of epilepsy in such patients may improve their clinical course.
doi:10.1001/jamaneurol.2013.136
PMCID: PMC4013391  PMID: 23835471
16.  Selective Frontoinsular von Economo Neuron and Fork Cell Loss in Early Behavioral Variant Frontotemporal Dementia 
Cerebral Cortex (New York, NY)  2011;22(2):251-259.
Behavioral variant frontotemporal dementia (bvFTD) erodes complex social–emotional functions as the anterior cingulate cortex (ACC) and frontoinsula (FI) degenerate, but the early vulnerable neuron within these regions has remained uncertain. Previously, we demonstrated selective loss of ACC von Economo neurons (VENs) in bvFTD. Unlike ACC, FI contains a second conspicuous layer 5 neuronal morphotype, the fork cell, which has not been previously examined. Here, we investigated the selectivity, disease-specificity, laterality, timing, and symptom relevance of frontoinsular VEN and fork cell loss in bvFTD. Blinded, unbiased, systematic sampling was used to quantify bilateral FI VENs, fork cells, and neighboring neurons in 7 neurologically unaffected controls (NC), 5 patients with Alzheimer's disease (AD), and 9 patients with bvFTD, including 3 who died of comorbid motor neuron disease during very mild bvFTD. bvFTD showed selective FI VEN and fork cell loss compared with NC and AD, whereas in AD no significant VEN or fork cell loss was detected. Although VEN and fork cell losses in bvFTD were often asymmetric, no group-level hemispheric laterality effects were identified. Right-sided VEN and fork cell losses, however, correlated with each other and with anatomical, functional, and behavioral severity. This work identifies region-specific neuronal targets in early bvFTD.
doi:10.1093/cercor/bhr004
PMCID: PMC3256403  PMID: 21653702
Alzheimer's disease; behavioral variant frontotemporal dementia; fork cell; frontoinsula; von Economo neuron
17.  Role of right pregenual anterior cingulate cortex in self-conscious emotional reactivity 
Self-conscious emotions such as embarrassment arise when one’s actions fail to meet salient social expectations and are accompanied by marked physiological and behavioral activation. We investigated the neural correlates of self-conscious emotional reactivity in 27 patients with behavioral variant frontotemporal dementia (bvFTD), a neurodegenerative disease that disrupts self-conscious emotion and targets brain regions critical for emotional functioning early in the disease course, and in 33 healthy older controls. Subjects participated in an embarrassing karaoke task in which they watched a video clip of themselves singing. They also watched a sad film clip; these data were used to control for non-self-conscious emotional reactivity in response to audiovisual stimuli. Using Freesurfer to quantify regional brain volumes from structural magnetic resonance imaging, right pregenual anterior cingulate cortex (pACC) gray matter volume was the only brain region that was a significant predictor of self-conscious emotion. Smaller pACC volume was associated with attenuated physiological and behavioral self-conscious emotional reactivity, and this relationship was not specific to diagnosis. We argue that these results reflect the significant role that right pACC plays in the visceromotor responding that accompanies self-conscious emotion and that neurodegeneration in this region may underlie the self-conscious emotional decline seen in bvFTD.
doi:10.1093/scan/nss023
PMCID: PMC3624960  PMID: 22345371
emotion; cingulate; autonomic nervous system; behavior; neurodegenerative disease
18.  Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer’s disease 
Brain  2013;136(3):844-858.
The factors driving clinical heterogeneity in Alzheimer’s disease are not well understood. This study assessed the relationship between amyloid deposition, glucose metabolism and clinical phenotype in Alzheimer’s disease, and investigated how these relate to the involvement of functional networks. The study included 17 patients with early-onset Alzheimer’s disease (age at onset <65 years), 12 patients with logopenic variant primary progressive aphasia and 13 patients with posterior cortical atrophy [whole Alzheimer’s disease group: age = 61.5 years (standard deviation 6.5 years), 55% male]. Thirty healthy control subjects [age = 70.8 (3.3) years, 47% male] were also included. Subjects underwent positron emission tomography with 11C-labelled Pittsburgh compound B and 18F-labelled fluorodeoxyglucose. All patients met National Institute on Ageing–Alzheimer’s Association criteria for probable Alzheimer’s disease and showed evidence of amyloid deposition on 11C-labelled Pittsburgh compound B positron emission tomography. We hypothesized that hypometabolism patterns would differ across variants, reflecting involvement of specific functional networks, whereas amyloid patterns would be diffuse and similar across variants. We tested these hypotheses using three complimentary approaches: (i) mass-univariate voxel-wise group comparison of 18F-labelled fluorodeoxyglucose and 11C-labelled Pittsburgh compound B; (ii) generation of covariance maps across all subjects with Alzheimer’s disease from seed regions of interest specifically atrophied in each variant, and comparison of these maps to functional network templates; and (iii) extraction of 11C-labelled Pittsburgh compound B and 18F-labelled fluorodeoxyglucose values from functional network templates. Alzheimer’s disease clinical groups showed syndrome-specific 18F-labelled fluorodeoxyglucose patterns, with greater parieto-occipital involvement in posterior cortical atrophy, and asymmetric involvement of left temporoparietal regions in logopenic variant primary progressive aphasia. In contrast, all Alzheimer’s disease variants showed diffuse patterns of 11C-labelled Pittsburgh compound B binding, with posterior cortical atrophy additionally showing elevated uptake in occipital cortex compared with early-onset Alzheimer’s disease. The seed region of interest covariance analysis revealed distinct 18F-labelled fluorodeoxyglucose correlation patterns that greatly overlapped with the right executive-control network for the early-onset Alzheimer’s disease region of interest, the left language network for the logopenic variant primary progressive aphasia region of interest, and the higher visual network for the posterior cortical atrophy region of interest. In contrast, 11C-labelled Pittsburgh compound B covariance maps for each region of interest were diffuse. Finally, 18F-labelled fluorodeoxyglucose was similarly reduced in all Alzheimer’s disease variants in the dorsal and left ventral default mode network, whereas significant differences were found in the right ventral default mode, right executive-control (both lower in early-onset Alzheimer’s disease and posterior cortical atrophy than logopenic variant primary progressive aphasia) and higher-order visual network (lower in posterior cortical atrophy than in early-onset Alzheimer’s disease and logopenic variant primary progressive aphasia), with a trend towards lower 18F-labelled fluorodeoxyglucose also found in the left language network in logopenic variant primary progressive aphasia. There were no differences in 11C-labelled Pittsburgh compound B binding between syndromes in any of the networks. Our data suggest that Alzheimer’s disease syndromes are associated with degeneration of specific functional networks, and that fibrillar amyloid-β deposition explains at most a small amount of the clinico-anatomic heterogeneity in Alzheimer’s disease.
doi:10.1093/brain/aws327
PMCID: PMC3580269  PMID: 23358601
Alzheimer’s disease; posterior cortical atrophy; logopenic variant of PPA; positron emission tomography (PET); functional networks
19.  Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia 
Neurology  2013;80(9):814-823.
Objective:
We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of microtubule-associated protein tau and progranulin mutations.
Methods:
In this case-control study, 75 healthy individuals (aged 20–70 years) with 50% risk for frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, and structural and functional MRI. We used voxel-based morphometry and tract-based spatial statistics for voxelwise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsula, anterior midcingulate cortex (aMCC), and posterior cingulate cortex.
Results:
Although carriers (n = 37) and noncarriers (n = 38) had similar neuropsychological performance, worse performance on Stroop III, Ekman faces, and Happé cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy and increased radial diffusivity throughout frontotemporal white matter tracts were found in carriers and correlated with higher age. Reductions in functional aMCC connectivity were found in carriers compared with controls, and connectivity between frontoinsula and aMCC seeds and several brain regions significantly decreased with higher age in carriers but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found.
Conclusions:
This study convincingly demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.
doi:10.1212/WNL.0b013e31828407bc
PMCID: PMC3598452  PMID: 23390180
20.  Frontotemporal Dementia in Eight Chinese Individuals 
Neurocase  2012;19(1):76-84.
Frontotemporal dementia (FTD) has rarely been reported in Chinese populations. There are many potential reasons for this, including possible hesitancy on the part of patients or families to bring FTD-related symptoms to medical attention. Here, we present data on eight Chinese individuals, all of whom met criteria for the behavioral variant of FTD or the semantic variant of primary progressive aphasia. These patients presented for neurological evaluation at a relatively advanced stage. The mean MMSE score at initial presentation was 15. Behavioral symptoms were common and usually elicited during the medical history only after direct questioning. Delay in presentation was attributed to a variety of issues, including family disagreements about whether the symptoms represented a disease and lack of medical insurance. These cases illustrate that the symptoms of FTD in Chinese Americans are similar to those in Caucasians but various factors, some potentially culturally-relevant, may influence the likelihood and timing of clinical presentation for FTD, as well as other dementias. Additional study of FTD in diverse ethnic groups needs to address barriers to clinical presentation, including factors that may be culturally specific.
doi:10.1080/13554794.2011.654218
PMCID: PMC3545415  PMID: 23311888
Frontotemporal dementia; Chinese; ethnic culture; pathology; cognitive impairment; behavior changes
21.  Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype 
Neurobiology of aging  2012;33(12):2950.e5-2950.e7.
Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers.
doi:10.1016/j.neurobiolaging.2012.07.005
PMCID: PMC3617405  PMID: 22840558
Amyotrophic lateral sclerosis; Frontotemporal Dementia; C9ORF72; Repeat-expansion disease; Association study
22.  Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease 
Brain  2010;133(5):1352-1367.
Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer’s disease cause atrophy within two major networks, an anterior ‘Salience Network’ (atrophied in behavioural variant frontotemporal dementia) and a posterior ‘Default Mode Network’ (atrophied in Alzheimer’s disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer’s disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer’s disease) and the Default Mode Network (disrupted in Alzheimer’s disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer’s disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer’s disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic connectivity enhancement within the reciprocal network. In behavioural variant frontotemporal dementia, clinical severity correlated with loss of right frontoinsular Salience Network connectivity and with biparietal Default Mode Network connectivity enhancement. Based on these results, we explored whether a combined index of Salience Network and Default Mode Network connectivity might discriminate between the three groups. Linear discriminant analysis achieved 92% clinical classification accuracy, including 100% separation of behavioural variant frontotemporal dementia and Alzheimer’s disease. Patients whose clinical diagnoses were supported by molecular imaging, genetics, or pathology showed 100% separation using this method, including four diagnostically equivocal ‘test’ patients not used to train the algorithm. Overall, the findings suggest that behavioural variant frontotemporal dementia and Alzheimer’s disease lead to divergent network connectivity patterns, consistent with known reciprocal network interactions and the strength and deficit profiles of the two disorders. Further developed, intrinsic connectivity network signatures may provide simple, inexpensive, and non-invasive biomarkers for dementia differential diagnosis and disease monitoring.
doi:10.1093/brain/awq075
PMCID: PMC2912696  PMID: 20410145
functional magnetic resonance imaging; frontotemporal dementia; Alzheimer’s disease; functional connectivity; biomarker
23.  Genetic Correction of Tauopathy Phenotypes in Neurons Derived from Human Induced Pluripotent Stem Cells 
Stem Cell Reports  2013;1(3):226-234.
Summary
Tauopathies represent a group of neurodegenerative disorders characterized by the accumulation of pathological TAU protein in brains. We report a human neuronal model of tauopathy derived from induced pluripotent stem cells (iPSCs) carrying a TAU-A152T mutation. Using zinc-finger nuclease-mediated gene editing, we generated two isogenic iPSC lines: one with the mutation corrected, and another with the homozygous mutation engineered. The A152T mutation increased TAU fragmentation and phosphorylation, leading to neurodegeneration and especially axonal degeneration. These cellular phenotypes were consistent with those observed in a patient with TAU-A152T. Upon mutation correction, normal neuronal and axonal morphologies were restored, accompanied by decreases in TAU fragmentation and phosphorylation, whereas the severity of tauopathy was intensified in neurons with the homozygous mutation. These isogenic TAU-iPSC lines represent a critical advancement toward the accurate modeling and mechanistic study of tauopathies with human neurons and will be invaluable for drug-screening efforts and future cell-based therapies.
Highlights
•A human neuron model of tauopathy using TAU-A152T-iPSCs•Correction of TAU-A152T mutation eliminates tauopathy•Engineered homozygous TAU-A152T mutation intensifies tauopathy•A152T mutation increases TAU proteolysis, leading to tauopathy
doi:10.1016/j.stemcr.2013.08.001
PMCID: PMC3849235  PMID: 24319659
24.  Sporadic Corticobasal Syndrome due to FTLD-TDP 
Acta neuropathologica  2009;119(3):365-374.
Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau (MAPT) or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for sporadic CBS.
doi:10.1007/s00401-009-0605-1
PMCID: PMC2832091  PMID: 19876635
corticobasal degeneration; TDP-43; frontotemporal lobar degeneration; progranulin
25.  Clinical characterization of bvFTD due to FUS neuropathology 
Neurocase  2011;18(4):305-317.
In 2009, inclusions containing the fused in sarcoma (FUS) protein were identified as a third major molecular class of pathology underlying the behavioral variant frontotemporal dementia (bvFTD) syndrome. Due to the low prevalence of FUS pathology, few clinical descriptions have been published and none provides information about specific social-emotional deficits despite evidence for severe behavioral manifestations in this disorder. We evaluated a patient with bvFTD due to FUS pathology using a comprehensive battery of cognitive and social-emotional tests. A structural MRI scan and genetic tests for tau, progranulin, and FUS mutations were also performed. The patient showed preserved general cognitive functioning and superior working memory, but severe deficits in emotion attribution, sensitivity to punishment, and the capacity for interpersonal warmth and empathy. The gray matter atrophy pattern corresponded to this focal deficit profile, with preservation of dorsolateral fronto-parietal regions associated with executive functioning but severe damage to right worse than left frontoinsula, temporal pole, subgenual anterior cingulate, medial orbitofrontal cortex, amygdala, and caudate. This patient demonstrates the striking focality associated with FUS neuropathology in patients with bvFTD.
doi:10.1080/13554794.2011.604637
PMCID: PMC3288419  PMID: 22060063
behavioral variant frontotemporal dementia; FTLD-FUS; social emotional testing; voxel-based morphometry; FUS neuropathology

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