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.
emotion; cingulate; autonomic nervous system; behavior; neurodegenerative disease
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.
tau; pathology; autopsy; acetylation; immunohistochemistry; human
Little is known about how changes in DNA methylation mediate risk for human diseases including dementia. Analysis of genome-wide methylation patterns in patients with two forms of tau-related dementia – progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) – revealed significant differentially methylated probes (DMPs) in patients versus unaffected controls. Remarkably, DMPs in PSP were clustered within the 17q21.31 region, previously known to harbor the major genetic risk factor for PSP. We identified and replicated a dose-dependent effect of the risk-associated H1 haplotype on methylation levels within the region in blood and brain. These data reveal that the H1 haplotype increases risk for tauopathy via differential methylation at that locus, indicating a mediating role for methylation in dementia pathophysiology.
Progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) are two neurodegenerative diseases linked, at the pathologic and genetic level, to the microtubule associated protein tau. We studied epigenetic changes (DNA methylation levels) in peripheral blood from patients with PSP, FTD, and unaffected controls. Analysis of genome-wide methylation patterns revealed significant differentially methylated probes in patients versus unaffected controls. Remarkably, differentially methylated probes in PSP vs. controls were preferentially clustered within the 17q21.31 region, previously known to harbor the major genetic risk factor for PSP. We identified and replicated a dose-dependent effect of the risk-associated H1 haplotype on methylation levels within the region in independent datasets in blood and brain. These data reveal that the H1 haplotype increases risk for tauopathy via differential methylation, indicating a mediating role for methylation in dementia pathophysiology.
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.
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.
Alzheimer’s disease; posterior cortical atrophy; logopenic variant of PPA; positron emission tomography (PET); functional networks
Neuroimaging studies examining neural substrates of impaired self-awareness in patients with neurodegenerative diseases have shown divergent results depending on the modality (cognitive, emotional, behavioral) of awareness. Evidence is accumulating to suggest that self-awareness arises from a combination of modality-specific and large-scale supramodal neural networks.
We investigated the structural substrates of patients' tendency to overestimate or underestimate their own capacity to demonstrate empathic concern for others. Subjects' level of empathic concern was measured using the Interpersonal Reactivity Index, and subject-informant discrepancy scores were used to predict regional atrophy pattern, using voxel-based morphometry analysis. Of the 102 subjects, 83 were patients with neurodegenerative diseases such as behavioral variant frontotemporal dementia (bvFTD) or semantic variant primary progressive aphasia (svPPA); the other 19 were healthy older adults.
bvFTD and svPPA patients typically overestimated their level of empathic concern compared to controls, and overestimating one's empathic concern predicted damage to predominantly right-hemispheric anterior infero-lateral temporal regions, whereas underestimating one's empathic concern showed no neuroanatomical basis.
These findings suggest that overestimation and underestimation of one's capacity for empathic concern cannot be interpreted as varying degrees of the same phenomenon, but may arise from different pathophysiological processes. Damage to anterior infero-lateral temporal regions has been associated with semantic self-knowledge, emotion processing, and social perspective taking; neuropsychological functions partly associated with empathic concern itself. These findings support the hypothesis that—at least in the socioemotional domain—neural substrates of self-awareness are partly modality-specific.
Affective perspective taking; dementia; empathy; infero-lateral temporal cortex; neurodegeneration; semantic self-knowledge; unawareness; voxel-based morphometry
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.
Frontotemporal dementia; Chinese; ethnic culture; pathology; cognitive impairment; behavior changes
► Patterns of cell loss in lvPPA remain asymmetrical over time. ► More anterior left hemisphere areas become involved over time. ► Right hemisphere regions become affected that mirror early left hemisphere change. ► Left hemisphere atrophy rates are greater than right hemisphere. ► Over time patients with lvPPA develop single word level processing deficits.
The logopenic variant of primary progressive aphasia (PPA) is characterised by impaired sentence repetition and word retrieval difficulties. Post mortem studies, amyloid imaging and CSF tau/Aβ measurements suggest Alzheimer’s disease (AD) pathology as the underlying cause. Relatively little is known about patterns of progression in patients with the logopenic variant of PPA. 21 patients (3 with post mortem confirmation of AD and 5 with positive amyloid PIB-PET scans) were studied with longitudinal T1-weighted MR imaging (mean interscan interval 1.2 years) using volumetric analysis and voxel-based morphometry (VBM). Baseline imaging showed asymmetrical (left greater than right) involvement of the posterior superior temporal and inferior parietal lobes as well as posterior cingulate and medial temporal lobes. The whole brain rate of volume loss was 2.0% per year with a greater rate of left hemisphere atrophy (2.3%/year) than right hemisphere (1.6%/year). Longitudinal VBM analysis showed increasing involvement of other areas in the left hemisphere (temporal, parietal, frontal and caudate) and atrophy of areas in the right hemisphere that had been involved earlier in the disease in the left hemisphere, particularly posterior cingulate/precuneus. With disease progression there was worsening of anomia, sentence repetition and sentence comprehension but consistent with the spread of imaging changes also deficits in single word comprehension, single word repetition and verbal memory. This study shows that the logopenic variant of PPA remains an asymmetrical disease, with spread through the left hemisphere language network but also involvement to a lesser degree of regions in the right hemisphere that mirror the earlier left hemisphere changes.
Primary progressive aphasia; Logopenic aphasia
Brain magnetic resonance imaging (MRI) studies have demonstrated regional patterns of brain macrostructural atrophy and white matter microstructural alterations separately in the three major subtypes of frontotemporal lobar degeneration (FTLD), which includes behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). This study was to investigate to what extent the pattern of white matter microstructural alterations in FTLD subtypes mirrors the pattern of brain atrophy, and to compare the ability of various diffusion tensor imaging (DTI) indices in characterizing FTLD patients, as well as to determine whether DTI measures provide greater classification power for FTLD than measuring brain atrophy. Twenty-five patients with FTLD (13 with bvFTD, 6 with SD, and 6 with PNFA) and 19 healthy age-matched control subjects underwent both structural MRI and DTI scans. Measurements of regional brain atrophy were based on T1-weighted MRI data and voxel-based morphometry. Measurements of regional white matter degradation were based on voxelwise as well as regions-of-interest tests of DTI variations, expressed as fractional anisotropy, axial diffusivity, and radial diffusivity. Compared to controls, bvFTD, SD, and PNFA patients each exhibited characteristic regional patterns of brain atrophy and white matter damage. DTI overall provided significantly greater accuracy for FTLD classification than brain atrophy. Moreover, radial diffusivity was more sensitive in assessing white matter damage in FTLD than other DTI indices. The findings suggest that DTI in general and radial diffusivity in particular are more powerful measures for the classification of FTLD patients from controls than brain atrophy.
Behavioral variant frontotemporal dementia; diffusion tensor imaging; frontotemporal lobar degeneration; multimodality MRI; progressive nonfluent aphasia; semantic dementia
The aim of the study was to evaluate the value of assessing white matter integrity using diffusion tensor imaging (DTI) for classification of mild cognitive impairment (MCI) and prediction of cognitive impairments in comparison to brain atrophy measurements using structural MRI. Fifty-one patients with MCI and 66 cognitive normal controls (CN) underwent DTI and T1-weighted structural MRI. DTI measures included fractional anisotropy (FA) and radial diffusivity (DR) from 20 predetermined regions-of-interest (ROIs) in the commissural, limbic and association tracts, which are thought to be involved in Alzheimer's disease; measures of regional gray matter (GM) volume included 21 ROIs in medial temporal lobe, parietal cortex, and subcortical regions. Significant group differences between MCI and CN were detected by each MRI modality: In particular, reduced FA was found in splenium, left isthmus cingulum and fornix; increased DR was found in splenium, left isthmus cingulum and bilateral uncinate fasciculi; reduced GM volume was found in bilateral hippocampi, left entorhinal cortex, right amygdala and bilateral thalamus; and thinner cortex was found in the left entorhinal cortex. Group classifications based on FA or DR was significant and better than classifications based on GM volume. Using either DR or FA together with GM volume improved classification accuracy. Furthermore, all three measures, FA, DR and GM volume were similarly accurate in predicting cognitive performance in MCI patients. Taken together, the results imply that DTI measures are as accurate as measures of GM volume in detecting brain alterations that are associated with cognitive impairment. Furthermore, a combination of DTI and structural MRI measurements improves classification accuracy.
Hexanucleotide expansion intronic to chromosome 9 open reading frame 72 (C9ORF72) has recently been identified as the most common genetic cause of both familial and sporadic amyotrophic lateral sclerosis and of frontotemporal dementia with or without concomitant motor neuron disease. Given the common frequency of this genetic aberration, clinicians seek to identify neuroimaging hallmarks characteristic of C9ORF72-associated disease, both to provide a better understanding of the underlying degenerative patterns associated with this mutation and to enable better identification of patients for genetic screening and diagnosis. A survey of the literature describing C9ORF72 neuroimaging thus far suggests that patients with this mutation may demonstrate symmetric frontal and temporal lobe, insular, and posterior cortical atrophy, although temporal involvement may be less than that seen in other mutations. Some studies have also suggested cerebellar and thalamic involvement in C9ORF72-associated disease. Diffuse cortical atrophy that includes anterior as well as posterior structures and subcortical involvement thus may represent unique features of C9ORF72.
On tests of design fluency, an examinee draws as many different designs as possible in a specified time limit while avoiding repetition. The neuroanatomical substrates and diagnostic group differences of design fluency repetition errors and total correct scores were examined in 110 individuals diagnosed with dementia, 53 with mild cognitive impairment (MCI), and 37 neurologically healthy controls. The errors correlated significantly with volumes in the right and left orbitofrontal cortex (OFC), the right and left superior frontal gyrus, the right inferior frontal gyrus, and the right striatum, but did not correlate with volumes in any parietal or temporal lobe regions. Regression analyses indicated that the lateral OFC may be particularly crucial for preventing these errors, even after excluding patients with behavioral variant frontotemporal dementia (bvFTD) from the analysis. Total correct correlated more diffusely with volumes in the right and left frontal and parietal cortex, the right temporal cortex, and the right striatum and thalamus. Patients diagnosed with bvFTD made significantly more repetition errors than patients diagnosed with MCI, Alzheimer’s disease, semantic dementia, progressive supranuclear palsy or corticobasal syndrome. In contrast, total correct design scores did not differentiate the dementia patients. These results highlight the frontal-anatomic specificity of design fluency repetitions. In addition, the results indicate that the propensity to make these errors supports the diagnosis of bvFTD.
Perseveration; Orbitofrontal; Neuropsychology; Executive Function; Dementia; Process Approach
Successful navigation of the social world requires the ability to recognize and track emotions as they unfold and change dynamically. Neuroimaging and neurological studies of emotion recognition have primarily focused on the ability to identify the emotion shown in static photographs of facial expressions, showing correlations with the amygdala as well as temporal and frontal brain regions. In the current study we examined the neural correlates of continuously tracking dynamically-changing emotions. Fifty-nine patients with diverse neurodegenerative diseases used a rating dial to track continuously how positive or how negative the character in a film clip felt. Tracking accuracy was determined by comparing participants’ ratings with the ratings of 10 normal control participants. The relationship between tracking accuracy and regional brain tissue content was examined using voxel-based morphometry. Low tracking accuracy was primarily associated with gray matter loss in the right lateral orbitofrontal cortex (OFC). Our finding that the right OFC is critical to the ability to track dynamically-changing emotions is consistent with previous research showing right OFC involvement in both socioemotional understanding and modifying responding in changing situations.
emotion; emotion perception; empathic accuracy; voxel-based-morphometry; orbitofrontal region; dementia
Accurate appraisal of one’s own abilities is one metacognitive skill considered to be an important factor affecting learning and behavior in childhood. The present study measured self-appraisal accuracy in children using tasks of executive function, and investigated relations between self-appraisal and informant ratings of real world behaviors measured by the BRIEF. We examined self-appraisal accuracy on fluency tasks in 91 children ages 10-17. More accurate self-appraisal was correlated with fewer informant ratings of real world behavior problems in inhibition and shifting, independent of actual performance. Findings suggest that self-appraisal represents cognitive processes that are at least partially independent of other functions putatively dependent on the frontal lobes, and these self-appraisal-specific processes have unique implications for optimal daily function.
Self Assessment; Self Concept; Awareness; Child Behavior; Executive Function; Meta-cognition
Magnetic Resonance Imaging (MRI) provides various imaging modes to study the brain. We tested the benefits of a joint analysis of multimodality MRI data in combination with a large-scale analysis that involved simultaneously all image voxels using joint independent components analysis (jICA) and compared the outcome to results using conventional voxel-by-voxel unimodality tests. Specifically, we designed a jICA to decompose multimodality MRI data into independent components that explain joint variations between the image modalities as well as variations across brain regions. We tested the jICA design on structural and perfusion-weighted MRI data from 12 patients diagnosed with behavioral variant frontotemporal dementia (bvFTD) and 12 cognitively normal elderly individuals. While unimodality analyses showed widespread brain atrophy and hypoperfusion in the patients, jICA further revealed two significant joint components of variations between atrophy and hypoperfusion across brain regions. The 1st joint component revealed associated brain atrophy and hypoperfusion predominantly in the right brain hemisphere in behavioral variant frontotemporal dementia, and the 2nd joint component revealed greater atrophy relative to hypoperfusion affecting predominantly the left hemisphere in behavioral variant frontotemporal dementia. The patterns are consistent with the clinical symptoms of behavioral variant frontotemporal dementia that relate to asymmetric compromises of the left and right brain hemispheres. The joint components also revealed that that structural alterations can be associated with physiological alterations in spatially separated but potentially connected brain regions. Finally, jICA outperformed voxel-by-voxel unimodal tests significantly in terms of an effect size, separating the behavioral variant frontotemporal dementia patients from the controls. Taken together, the results demonstrate the benefit of multimodality MRI in conjunction with jICA for mapping neurodegeneration, which may lead ultimately to an improved diagnosis of behavioral variant frontotemporal dementia and other forms of neurodegenerative diseases.
Brain atrophy; Brain hypoperfusion; Dementia; Neurodegenerative diseases; Joint ICA; Multimodality MRI
We examined whether the effect of APOE genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared to ε3 homozygotes. More importantly, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared to either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer’s disease, i.e. spinal fluid levels of tau, provided corresponding evidence for this gender by APOE interaction. Taken together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer’s disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.
Pathological laughing and crying is a disorder of emotional expression seen in a number of neurological diseases. The aetiology is poorly understood, but clinical descriptions suggest a disorder of emotion regulation. The goals of this study were: (i) to characterize the subjective, behavioural and physiological emotional reactions that occur during episodes of pathological laughing and crying; (ii) to compare responses during these episodes to those that occur when emotions are elicited under standard conditions (watching sad and amusing emotional films, being startled); and (iii) to examine the ability of patients with this disorder to regulate their emotions under standardized conditions. Twenty-one patients with pathological laughing and crying due to amyotrophic lateral sclerosis and 14 with amyotrophic lateral sclerosis but no pathological laughing and crying were studied. Emotional measures included self-reported emotional experience, video recordings of facial reactivity and peripheral physiological responses (skin conductance, heart rate and somatic activity). Nineteen of the 21 patients with histories of pathological laughing and crying had at least one episode in the laboratory that they agreed constituted pathological laughing or crying (a total of 56 episodes were documented). Compared with viewing sad and amusing films, the episodes were associated with greater facial and physiological activation. Contrary to many clinical descriptions, episodes were often induced by contextually appropriate stimuli and associated with strong experiences of emotion that were consistent with the display. When instructed to regulate their facial responses to emotion-eliciting films, patients with pathological laughing and crying showed impairments compared with patients who did not have a history of this disorder. These findings support the idea that pathological laughing and crying represents activation of all channels of emotional responding (i.e. behavioural, physiological and subjective). Furthermore, they support previously advanced theories that, rather than being associated with general emotional hyperreactivity, this disorder may be due to dysfunction in frontal neural systems that support voluntary regulation of emotion.
behavioural neurology; pseudobulbar affect; affective neuroscience; amyotrophic lateral sclerosis
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology
Some patients meeting behavioral variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy, and have thus been referred to as bvFTD “phenocopies” or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have found no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, we describe two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions.
Three hundred and eighty-four patients with FTD clinical spectrum and Alzheimer’s disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns assessed using voxel-based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls.
Both patients were age 48 at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over seven years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over two years, her neuropsychological and functional scores as well as brain atrophy remained stable.
C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.
C9ORF72; C9FTD/ALS; frontotemporal dementia; genetics; dementia
Purpose: To describe the results of efforts to recruit Asian Americans into longitudinal research on cognitive decline in aging. Design and
Methods: Recruitment strategies include clinics for assessment of cognitive impairment at the University of California, San Francisco campus and San Francisco’s Chinatown, lectures to local health care providers and community members, participation in community events, and publications in mass media. Results: Over 200 Chinese patients were evaluated in our outreach clinic. Many were primarily Chinese speaking with low levels of education. One hundred and twenty-five participants enrolled, and annual follow-up has been 88%. Among enrollees, 36% were recruited from our clinical service; 30% via word of mouth; and the rest from community lectures and events, flyers, and mass media. Participants who enrolled were relatively highly educated, tended to be interested in learning about their cognitive abilities, and were supportive of the goals of research. Implications: Despite the significant cultural and linguistic barriers, Chinese Americans can be successfully recruited into longitudinal studies of aging and cognitive impairment. Clinical services are a critical component of such an effort, and low education and other factors that may be associated with it are clear barriers to research participation.
Alzheimer’s disease; Asian and Pacific Rim Older Adults; Attitudes and perceptions toward aging/aged; Cognition; Cross-cultural studies; Dementia; Ethics (research, practice, policy, individual choices)
To determine if socioemotional disinhibition and executive dysfunction are related to dissociable patterns of brain atrophy in neurodegenerative disease. Previous studies have indicated that behavioral and cognitive dysfunction in neurodegenerative disease are linked to atrophy in different parts of the frontal lobe, but these prior studies did not establish that these relationships were specific, which would best be demonstrated by a double dissociation.
Subjects included 157 patients with neurodegenerative disease. A semi-automated parcellation program (Freesurfer) was used to generate regional cortical volumes from structural MRI scans. Regions of interest (ROIs) included anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), middle frontal gyrus (MFG) and inferior frontal gyrus (IFG). Socioemotional disinhibition was measured using the Neuropsychiatric Inventory. Principal component analysis including three tasks of executive function (EF; verbal fluency, Stroop Interference, modified Trails) was used to generate a single factor score to represent EF.
Partial correlations between ROIs, disinhibition, and EF were computed after controlling for total intracranial volume, MMSE, diagnosis, age, and education. Brain regions significantly correlated with disinhibition (ACC, OFC, IFG, and temporal lobes) and EF (MFG) were entered into separate hierarchical regressions to determine which brain regions predicted disinhibition and EF. OFC was the only brain region to significantly predict disinhibition and MFG significantly predicted executive functioning performance. A multivariate general linear model demonstrated a significant interaction between ROIs and cognitive-behavioral functions.
These results support a specific association between orbitofrontal areas and behavioral management as compared to dorsolateral areas and EF.
Brain behaviour and relationships; prefrontal; emotion regulation; executive control
Frontotemporal lobar degeneration (FTLD) often presents with asymmetric atrophy. We assessed whether premorbid occupations in FTLD patients were associated with these hemispheric asymmetries. In a multi-center chart review of 588 patients, occupation information was related to location of tissue loss or dysfunction. Patients with atrophy lateralized to the right had professions more dependent on verbal abilities than patients with left-lateralized or symmetrical atrophy. In a subgroup of 96 well-characterized patients with quantified neuroimaging data, the lateralization effect was localized to the temporal lobes and included verbal and mathematical ability. Patients whose professions placed high demands on language and mathematics had relatively preserved left temporal relative to right temporal volumes. Thus, occupation selection occurring in early adulthood is related to lateralized brain asymmetry in patients who develop FTLD decades later in the relatively deficient hemisphere. The finding suggests that verbal and mathematical occupations may have been pursued due to developmental right-lateralized functional impairment that precedes the neurodegenerative process. Alternatively, long-term engagement of activities associated with these occupations contributed to left-lateralized reserve, right-lateralized dysfunction, or both.
Frontotemporal dementia; laterality; reserve
Most MRI studies of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have assessed structural, perfusion and diffusion abnormalities separately while ignoring the relationships across imaging modalities. This paper aimed to assess brain gray (GM) and white matter (WM) abnormalities jointly to elucidate differences in abnormal MRI patterns between the diseases. Twenty AD, 20 FTD patients, and 21 healthy control subjects were imaged using a 4 Tesla MRI. GM loss and GM hypoperfusion were measured using high-resolution T1 and arterial spin labeling MRI (ASL-MRI). WM degradation was measured with diffusion tensor imaging (DTI). Using a new analytical approach, the study found greater WM degenerations in FTD than AD at mild abnormality levels. Furthermore, the GM loss and WM degeneration exceeded the reduced perfusion in FTD whereas, in AD, structural and functional damages were similar. Joint assessments of multimodal MRI have potential value to provide new imaging markers for improved differential diagnoses between FTD and AD.
Patients with early age-of-onset Alzheimer’s disease show more rapid progression, more generalized cognitive deficits and greater cortical atrophy and hypometabolism compared to late-onset patients at a similar disease stage. The biological mechanisms that underlie these differences are not well understood. The purpose of this study was to examine in vivo whether metabolic differences between early-onset and late-onset Alzheimer’s disease are associated with differences in the distribution and burden of fibrillar amyloid-β. Patients meeting criteria for probable Alzheimer’s disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's; Disease and Related Disorders Association criteria) were divided based on estimated age at first symptom (less than or greater than 65 years) into early-onset (n = 21, mean age-at-onset 55.2 ± 5.9 years) and late-onset (n = 18, 72.0 ± 4.7 years) groups matched for disease duration and severity. Patients underwent positron emission tomography with the amyloid-β-ligand [11C]-labelled Pittsburgh compound-B and the glucose analogue [18F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 ± 6.4) was studied for comparison. [11C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [18F]-labelled fluorodeoxyglucose images were normalized to mean activity in the pons. Group differences in tracer uptake were assessed on a voxel-wise basis using statistical parametric mapping, and by comparing mean values in regions of interest. To account for brain atrophy, analyses were repeated after applying partial volume correction to positron emission tomography data. Compared to normal controls, both early-onset and late-onset Alzheimer’s disease patient groups showed increased [11C]-labelled Pittsburgh compound-B uptake throughout frontal, parietal and lateral temporal cortices and striatum on voxel-wise and region of interest comparisons (P < 0.05). However, there were no significant differences in regional or global [11C]-labelled Pittsburgh compound-B binding between early-onset and late-onset patients. In contrast, early-onset patients showed significantly lower glucose metabolism than late-onset patients in precuneus/posterior cingulate, lateral temporo–parietal and occipital corticies (voxel-wise and region of interest comparisons, P < 0.05). Similar results were found for [11C]-labelled Pittsburgh compound-B and [18F]-labelled fluorodeoxyglucose using atrophy-corrected data. Age-at-onset correlated positively with glucose metabolism in precuneus, lateral parietal and occipital regions of interest (controlling for age, education and Mini Mental State Exam, P < 0.05), while no correlations were found between age-at-onset and [11C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-β was associated with greater posterior cortical hypometabolism in early-onset Alzheimer’s disease. Our data are consistent with a model in which both early amyloid-β accumulation and increased vulnerability to amyloid-β pathology play critical roles in the pathogenesis of Alzheimer’s disease in young patients.
Alzheimer’s disease; age of onset; amyloid-β; [18F]-labelled fluorodeoxyglucose; [11C]-labelled Pittsburgh compound-B
Diminished ability to perceive one’s own impairments, whether cognitive or social, is common in dementia, in particular frontotemporal dementia (FTD), where “lack of insight” is listed as a core diagnostic feature. Yet, there is no currently accepted method for measuring insight in dementia. The most commonly used methods, which involve comparing patients’ opinions of their level of impairment with the opinions of caregivers or close family members, are subjective and require the participation of a knowledgeable informant. Here, we introduce a new method that allows objective quantification of an individual’s awareness of their cognitive abilities and relies upon objective bedside testing.
We administered several tests of everyday, real-world functions to patients with FTD (n=10), Alzheimer’s disease (AD, n=10) and to control subjects (n=10). Prior to the tasks, participants were asked to predict their performance using a percentile-based rating system. They were also asked to estimate their performance after task completion. Differences between their self-rated and actual performances were calculated.
Whereas the control group showed very little discrepancy between pre-test predictions, post-task estimates and actual performance (mean difference of 3.9 percentile points for prediction /3.0 percentile points for post-task estimate), both patient groups over-predicted and overestimated their performance, with a significantly greater discrepancy for FTD (49.0/54.3 percentile points) than AD (27.2/28.3 percentile points).
Failures of insight and self-awareness of cognitive dysfunction can be objectively measured in dementia without the assistance of an informant, which will facilitate further study of this key component of higher cognitive functioning.
Frontotemporal lobar degeneration; Alzheimer’s disease; Self-awareness; Insight