[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms.
FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis.
INTERPRETATION: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD
The Lancet Neurology 07/2014; 3(7):686-99. · 23.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accurate self-awareness is essential for adapting one's tasks and goals to one's actual abilities. Patients with neurodegenerative diseases, particularly those with right frontal involvement, often present with poor self-awareness of their functional limitations that may exacerbate their already jeopardized decision-making and behaviour. We studied the structural neuroanatomical basis for impaired self-awareness among patients with neurodegenerative disease and healthy older adults. One hundred and twenty-four participants (78 patients with neurodegenerative diseases including Alzheimer's disease, behavioural variant frontotemporal dementia, right-temporal frontotemporal dementia, semantic variant and non-fluent variant primary progressive aphasia, and 46 healthy controls) described themselves on the Patient Competency Rating Scale, rating observable functioning across four domains (daily living activities, cognitive, emotional control, interpersonal). All participants underwent structural magnetic resonance imaging. Informants also described subjects' functioning on the same scale. Self-awareness was measured by comparing self and informant ratings. Group differences in discrepancy scores were analysed using general linear models, controlling for age, sex and disease severity. Compared with controls, patients with behavioural variant frontotemporal dementia overestimated their functioning in all domains, patients with Alzheimer's disease overestimated cognitive and emotional functioning, patients with right-temporal frontotemporal dementia overestimated interpersonal functioning, and patients with non-fluent aphasia overestimated emotional and interpersonal functioning. Patients with semantic variant aphasia did not overestimate functioning on any domain. To examine the neuroanatomic correlates of impaired self-awareness, discrepancy scores were correlated with brain volume using voxel-based morphometry. To identify the unique neural correlates of overlooking versus exaggerating deficits, overestimation and underestimation scores were analysed separately, controlling for age, sex, total intracranial volume and extent of actual functional decline. Atrophy related to overestimating one's functioning included bilateral, right greater than left frontal and subcortical regions, including dorsal superior and middle frontal gyri, lateral and medial orbitofrontal gyri, right anterior insula, putamen, thalamus, and caudate, and midbrain and pons. Thus, our patients' tendency to under-represent their functional decline was related to degeneration of domain-general dorsal frontal regions involved in attention, as well as orbitofrontal and subcortical regions likely involved in assigning a reward value to self-related processing and maintaining accurate self-knowledge. The anatomic correlates of underestimation (right rostral anterior cingulate cortex, uncorrected significance level) were distinct from overestimation and had a substantially smaller effect size. This suggests that underestimation or 'tarnishing' may be influenced by non-structural neurobiological and sociocultural factors, and should not be considered to be on a continuum with overestimation or 'polishing' of functional capacity, which appears to be more directly mediated by neural circuit dysfunction.
[Show abstract][Hide abstract] ABSTRACT: Elevated CSF τ is considered a biomarker of neuronal injury in newly developed Alzheimer's disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of τ species in other primary tauopathies. We assessed CSF τ protein abnormalities in AD, a tauopathy with prominent Aβ pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterised by deposition of four microtubule-binding repeat (4R) τ with minimal Aβ pathology.
Journal of neurology, neurosurgery, and psychiatry. 06/2014;
[Show abstract][Hide abstract] ABSTRACT: Behavioural variant frontotemporal dementia is characterized by abnormal responses to primary reward stimuli such as food, sex and intoxicants, suggesting abnormal functioning of brain circuitry mediating reward processing. The goal of this analysis was to determine whether abnormalities in reward-seeking behaviour in behavioural variant frontotemporal dementia are correlated with atrophy in regions known to mediate reward processing. Review of case histories in 103 patients with behavioural variant frontotemporal dementia identified overeating or increased sweet food preference in 80 (78%), new or increased alcohol or drug use in 27 (26%), and hypersexuality in 17 (17%). For each patient, a primary reward-seeking score of 0-3 was created with 1 point given for each target behaviour (increased seeking of food, drugs, or sex). Voxel-based morphometry performed in 91 patients with available imaging revealed that right ventral putamen and pallidum atrophy correlated with higher reward-seeking scores. Each of the reward-related behaviours involved partially overlapping right hemisphere reward circuit regions including putamen, globus pallidus, insula and thalamus. These findings indicate that in some patients with behavioural variant frontotemporal dementia, low volume of subcortical reward-related structures is associated with increased pursuit of primary rewards, which may be a product of increased thalamocortical feedback.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Background: 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. Methods: 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. Results: 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. Conclusions: 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.
[Show abstract][Hide abstract] ABSTRACT: Biomarkers derived from brain magnetic resonance (MR) imaging have promise in being able to assist in the clinical diagnosis of brain pathologies. These have been used in many studies in which the goal has been to distinguish between pathologies such as Alzheimer's disease and healthy aging. However, other dementias, in particular, frontotemporal dementia, also present overlapping pathological brain morphometry patterns. Hence, a classifier that can discriminate morphometric features from a brain MRI from the three classes of normal aging, Alzheimer's disease (AD), and frontotemporal dementia (FTD) would offer considerable utility in aiding in correct group identification. Compared to the conventional use of multiple pair-wise binary classifiers that learn to discriminate between two classes at each stage, we propose a single three-way classification system that can discriminate between three classes at the same time. We present a novel classifier that is able to perform a three-class discrimination test for discriminating among AD, FTD, and normal controls (NC) using volumes, shape invariants, and local displacements (three features) of hippocampi and lateral ventricles (two structures times two hemispheres individually) obtained from brain MR images. In order to quantify its utility in correct discrimination, we optimize the three-class classifier on a training set and evaluate its performance using a separate test set. This is a novel, first-of-its-kind comparative study of multiple individual biomarkers in a three-class setting. Our results demonstrate that local atrophy features in lateral ventricles offer the potential to be a biomarker in discriminating among AD, FTD, and NC in a three-class setting for individual patient classification.
[Show abstract][Hide abstract] ABSTRACT: Diffusion Weighted Imaging is extremely important for the diagnosis of probable sporadic Jakob-Creutzfeldt disease, the most common human prion disease. Although visual assessment of DWI MRI is critical diagnostically, a more objective, quantifiable approach might more precisely identify the precise pattern of brain involvement. Furthermore, a quantitative, systematic tracking of MRI changes occurring over time might provide insights regarding the underlying histopathological mechanisms of human prion disease and provide information useful for clinical trials. The purposes of this study were: 1) to describe quantitatively the average cross-sectional pattern of reduced mean diffusivity, fractional anisotropy, atrophy and T1 relaxation in the gray matter (GM) in sporadic Jakob-Creutzfeldt disease, 2) to study changes in mean diffusivity and atrophy over time and 3) to explore their relationship with clinical scales. Twenty-six sporadic Jakob-Creutzfeldt disease and nine control subjects had MRIs on the same scanner; seven sCJD subjects had a second scan after approximately two months. Cortical and subcortical gray matter regions were parcellated with Freesurfer. Average cortical thickness (or subcortical volume), T1-relaxiation and mean diffusivity from co-registered diffusion maps were calculated in each region for each subject. Quantitatively on cross-sectional analysis, certain brain regions were preferentially affected by reduced mean diffusivity (parietal, temporal lobes, posterior cingulate, thalamus and deep nuclei), but with relative sparing of the frontal and occipital lobes. Serial imaging, surprisingly showed that mean diffusivity did not have a linear or unidirectional reduction over time, but tended to decrease initially and then reverse and increase towards normalization. Furthermore, there was a strong correlation between worsening of patient clinical function (based on modified Barthel score) and increasing mean diffusivity.
[Show abstract][Hide abstract] ABSTRACT: Objective: Impaired self-awareness is characteristic of nearly all dementias, including Alzheimer’s disease (AD), but the deficit is most severe in the behavioral variant of frontotemporal dementia (bvFTD). The prominence of frontal pathology in bvFTD suggests that failure of online monitoring, the process by which individuals monitor their own cognitive processing in real time, is an important contributor. Metacognitive research offers several approaches to measure self-assessment, some more and others less sensitive to online monitoring. The goal of this study was to assess metacognition in bvFTD using several approaches, and to compare the results with those in AD. Method: We examined metacognition in 12 patients with bvFTD, 14 with AD, and 35 healthy controls using feeling of knowing (FOK), ease of learning (EOL), judgment of learning (JOL), and retrospective confidence rating (CR) tasks, as well as response to feedback about performance. Results: BvFTD and AD were both impaired at FOK compared with controls, although AD showed some sparing. Both groups were similarly impaired at CR and neither group was impaired at JOL after accounting for memory performance. Most striking, bvFTD patients failed to appropriately adjust their predictions about future memory performance even after receiving explicit feedback that they had performed worse than they expected. Conclusions: Both bvFTD and AD show deficits in online monitoring, although the deficit appears more severe in bvFTD. The insensitivity of bvFTD patients to overt feedback may point to unique mechanisms, possibly frontally mediated, that add to their severe lack of self-awareness. (PsycINFO Database Record (c) 2014 APA, all rights reserved)
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effect of amyloid imaging on clinical decision making.
We conducted a retrospective analysis of 140 cognitively impaired patients (mean age 65.0 years, 46% primary β-amyloid (Aβ) diagnosis, mean Mini-Mental State Examination 22.3) who underwent amyloid (Pittsburgh compound B [PiB]) PET as part of observational research studies and were evaluated clinically before and after the scan. One hundred thirty-four concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed for changes between the pre- and post-PET clinical diagnosis (from Aβ to non-Aβ diagnosis or vice versa) and Alzheimer disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ(2) and multivariate logistic regression. Postmortem diagnosis was available for 24 patients (17%).
Concordance between scan results and baseline diagnosis was high (PiB 84%, FDG 82%). The primary diagnosis changed after PET in 13/140 patients (9%) overall but in 5/13 (38%) patients considered pre-PET diagnostic dilemmas. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (unadjusted p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (adjusted p = 0.00013). Changes in treatment were associated with discordant PiB in patients with non-Aβ diagnoses (adjusted p = 0.028), while FDG had no effect on therapy. Both PiB (96%) and FDG (91%) showed high agreement with autopsy diagnosis.
PET had a moderate effect on clinical outcomes. Discordant PiB had a greater effect than discordant FDG, and influence on diagnosis was greater than on treatment. Prospective studies are needed to better characterize the clinical role of amyloid PET.
[Show abstract][Hide abstract] ABSTRACT: Executive functioning is widely targeted when human cognition is assessed, but there is little consensus on how it should be operationalized and measured. Recognizing the difficulties associated with establishing standard operational definitions of executive functioning, the National Institute of Neurological Disorders and Stroke entered into a contract with the University of California-San Francisco to develop psychometrically robust executive measurement tools that would be accepted by the neurology clinical trials and clinical research communities. This effort, entitled Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER), resulted in a series of tasks targeting working memory, inhibition, set shifting, fluency, insight, planning, social cognition and behavior. We describe battery conceptualization and development, data collection, scale construction based on item response theory, and lay the foundation for studying the battery's utility and validity for specific assessment and research goals. (JINS, 2013, 19, 1-9).
Journal of the International Neuropsychological Society 10/2013; · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the prevalence of depressive symptoms and frequency of antidepressant use between a group of elderly Chinese-American subjects with and without cognitive impairment and a group of matched white subjects. A secondary aim was to examine the clinical and demographic predictors of depressive symptoms across these groups.
The study was conducted at an academic neurology subspecialty clinic. This was a case-control study with 140 Chinese-American subjects and 140 demographically and cognitively matched white subjects. In each group, there were 48 cognitively normal and 92 cognitively impaired participants (49 with mild cognitive impairment, 43 with Alzheimer disease). The proportion of individuals with significant depressive symptoms, as indicated by a Geriatric Depression Scale score ≥6 of 15, and frequency of antidepressant use were compared across groups by using χ(2) analysis. Factors predicting depressive symptoms, including racial and diagnostic group, age, gender, Mini-Mental State Examination score, level of functional impairment, education level, and medical comorbidities, were assessed by using linear regression analysis.
Significant depressive symptoms were more common in cognitively impaired Chinese-American (35%) than cognitively impaired white (15%; χ(2) = 9.4; p = 0.004) subjects. Chinese-American subjects with cognitive impairment were less likely to be receiving treatment for depression (12%) than white subjects with cognitive impairment (37%; χ(2) = 15.6; p = 0.002). Racial and diagnostic group, age, level of functional impairment, Mini-Mental State Examination score, and education level were all statistically significant independent predictors of Geriatric Depression Scale score.
Elderly Chinese-American subjects with cognitive impairment are at increased risk for unrecognized and untreated depressive symptoms compared with elderly white subjects with cognitive impairment. Education level may contribute to this risk or it may be a surrogate marker for other factors contributing to depressive symptoms in this group.
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 09/2013; · 3.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE Mutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review. OBSERVATIONS This study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD. CONCLUSIONS AND RELEVANCE In addition to autosomal-dominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.
[Show abstract][Hide abstract] ABSTRACT: Financial errors by patients with dementia can have devastating personal and family consequences. We developed and evaluated a neuroeconomic conceptual framework for understanding financial errors across different dementia syndromes, using a systematic, retrospective, blinded chart review of demographically-balanced cohorts of patients with Alzheimer's disease (AD, n=100) and behavioral variant frontotemporal dementia (bvFTD, n=50). Reviewers recorded specific reports of financial errors according to a conceptual framework identifying patient cognitive and affective characteristics, and contextual influences, conferring susceptibility to each error. Specific financial errors were reported for 49% of AD and 70% of bvFTD patients (p = 0.012). AD patients were more likely than bvFTD patients to make amnestic errors (p < 0.001), while bvFTD patients were more likely to spend excessively (p = 0.004) and to exhibit other behaviors consistent with diminished sensitivity to losses and other negative outcomes (p < 0.001). Exploratory factor analysis identified a social/affective vulnerability factor associated with errors in bvFTD, and a cognitive vulnerability factor associated with errors in AD. Our findings highlight the frequency and functional importance of financial errors as symptoms of AD and bvFTD. A conceptual model derived from neuroeconomic literature identifies factors that influence vulnerability to different types of financial error in different dementia syndromes, with implications for early diagnosis and subsequent risk prevention.
[Show abstract][Hide abstract] ABSTRACT: Abstract The term frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders that are associated with atrophy of the frontal and temporal lobes, and present clinically with impairments of behaviour or language. Three main subtypes are described, behavioural variant FTD (bvFTD) and two subtypes of the language presentation (known as primary progressive aphasia or PPA) called semantic variant of PPA and non-fluent variant of PPA. Most imaging studies of FTD have used volumetric T1 magnetic resonance imaging (MRI) or positron emissions tomography imaging to identify patterns of grey matter atrophy or hypometabolism in these different subtypes, but more recently newer imaging techniques have been used to help define abnormalities in structural connectivity (white matter tract integrity using diffusion tensor imaging), functional connectivity (resting state networks using resting state functional MRI) and perfusion (using arterial spin labelling perfusion MRI) in FTD. These techniques have the potential to improve the differential diagnosis of FTD from other disorders and to provide more informative imaging signatures of FTD syndromes.
International Review of Psychiatry 04/2013; 25(2):221-9. · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 with 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 tumour necrosis factor α (TNF-α) levels. OUTCOME MEASURES: χ(2) 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 with NC. CONCLUSIONS: svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared with 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 aggregation.
Journal of neurology, neurosurgery, and psychiatry 03/2013; · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A recent national survey of HIV+ adults noted that nearly three-quarters of cognitively impaired individuals are categorized as having Asymptomatic Neurocognitive Impairment (ANI), lacking documented compromise of everyday function. The clinical impact and long-term consequences of ANI are unknown and the importance of this asymptomatic diagnosis has raised concerns in clinical care settings where competing priorities often exist. In this study, we conducted structured tests of everyday functioning in a sample of HIV+ subjects over 60 years of age and asked subjects to rate their performance relative to peers. We demonstrate that individuals with neuropsychological testing impairment often lack self-awareness of functional performance deficits. Specifically, ANI subjects rated functional performance similar to that of HIV-negative control subjects, despite noted deficits in objective measures of function. These findings have important implications for use of self-report of function in the diagnosis of HIV-associated Neurocognitive Disorders (HAND), likely underestimating symptomatic impairment.
AIDS research and human retroviruses 02/2013; · 2.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 1.2years) 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.