Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD.
Differentiation of logopenic (lvPPA) and nonfluent/agrammatic (nfvPPA) variants of Primary Progressive Aphasia is important yet remains challenging since it hinges on expert based evaluation of speech and language production. In this study acoustic measures of speech in conjunction with voxel-based morphometry were used to determine the success of the measures as an adjunct to diagnosis and to explore the neural basis of apraxia of speech in nfvPPA. Forty-one patients (21 lvPPA, 20 nfvPPA) were recruited from a consecutive sample with suspected frontotemporal dementia. Patients were diagnosed using the current gold-standard of expert perceptual judgment, based on presence/absence of particular speech features during speaking tasks. Seventeen healthy age-matched adults served as controls. MRI scans were available for 11 control and 37 PPA cases; 23 of the PPA cases underwent amyloid ligand PET imaging. Measures, corresponding to perceptual features of apraxia of speech, were periods of silence during reading and relative vowel duration and intensity in polysyllable word repetition. Discriminant function analyses revealed that a measure of relative vowel duration differentiated nfvPPA cases from both control and lvPPA cases (r2 = 0.47) with 88% agreement with expert judgment of presence of apraxia of speech in nfvPPA cases. VBM analysis showed that relative vowel duration covaried with grey matter intensity in areas critical for speech motor planning and programming: precentral gyrus, supplementary motor area and inferior frontal gyrus bilaterally, only affected in the nfvPPA group. This bilateral involvement of frontal speech networks in nfvPPA potentially affects access to compensatory mechanisms involving right hemisphere homologues. Measures of silences during reading also discriminated the PPA and control groups, but did not increase predictive accuracy. Findings suggest that a measure of relative vowel duration from of a polysyllable word repetition task may be sufficient for detecting most cases of apraxia of speech and distinguishing between nfvPPA and lvPPA.
Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer’s disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures.
Frontotemporal dementia (FTD) is associated with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Together, this group of disorders constitutes a major cause of young-onset dementia. One of the three clinical variants of FTD is progressive nonfluent aphasia (PNFA), which is focused on in this study. The steroid hormone progesterone (PROG) is known to have an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum samples (39 FTD, 91 controls), low serum PROG was associated with FTD overall. In subgroup analysis, low PROG levels were significantly associated with FTD-MND and CBS, but not with PSPS or PNFA. PROG levels of >195 pg/ml were significantly correlated with lower disease severity (frontotemporal dementia rating scale) for individuals with CBS. In the human neuroblastoma SK-N-MC cell line, exogenous PROG (9300–93,000 pg/ml) had a significant effect on overall Tau and nuclear TDP-43 levels, reducing total Tau levels by ∼1.5-fold and increasing nuclear TDP-43 by 1.7- to 2.0-fold. Finally, elevation of plasma PROG to a mean concentration of 5870 pg/ml in an Ala315Thr (A315T) TARDBP transgenic mouse model significantly reduced the rate of loss of locomotor control in PROG-treated, compared with placebo, mice. The PROG treatment did not significantly increase survival of the mice, which might be due to the limitation of the transgenic mouse to accurately model TDP-43-mediated neurodegeneration. Together, our clinical, cellular and animal data provide strong evidence that PROG could be a valid therapy for specific related disorders of FTD.
The recently discovered hexanucleotide repeat expansion, C9ORF72, has been shown to be among the most common cause of familial behavioural variant frontotemporal dementia (bvFTD) and to be present in a significant minority of apparently sporadic cases. While mounting evidence points to prominent episodic memory dysfunction in bvFTD cases, recent reports have also suggested an amnestic profile in C9ORF72 mutation carriers. No study to date, however, has formally characterised the extent to which episodic memory is impaired in C9ORF72 mutation versus sporadic cases, or the underlying neural substrates of such deficits. We conducted a comparison of C9ORF72 (n = 8) and sporadic (n = 15) bvFTD cases using a battery of verbal and visual episodic memory tasks, and contrasted their performance with that of Alzheimer's disease (AD, n = 15) and healthy older control (n = 15) participants. Behaviourally, the two bvFTD groups displayed comparable episodic memory profiles, irrespective of task administered, with prominent impairments evident relative to Controls. Whole-brain voxel-based morphometry analyses revealed distinct neural correlates of episodic memory dysfunction in each patient group. Widespread atrophy in medial prefrontal, medial and lateral temporal cortices correlated robustly with episodic memory dysfunction in sporadic bvFTD cases. In contrast, atrophy in a distributed set of regions in the frontal, temporal, and parietal lobes including the posterior cingulate cortex, was implicated in episodic memory dysfunction in C9ORF72 cases. Our results demonstrate that while episodic memory is disrupted to the same extent irrespective of genetic predisposition in bvFTD, distinct neural changes specific to each patient group are evident. The involvement of medial and lateral parietal regions in episodic memory dysfunction in C9ORF72 cases is of particular significance and represents an avenue of considerable interest for future studies.
•We assessed episodic memory in bvFTD patients with and without C9ORF72 mutations.•Episodic memory deficits were present in C9ORF72 cases relative to Controls.•C9ORF72 and sporadic bvFTD cases showed equivalent episodic memory profiles.•Neural substrates of memory disruption differed contingent on mutation status.•Medial and lateral parietal involvement in C9ORF72 memory deficits is notable.
Episodic memory; Frontotemporal dementia; Alzheimer's disease; C9ORF72 mutation; Neuroimaging
Patients with frontotemporal dementia have pervasive changes in emotion recognition and social cognition, yet the neural changes underlying these emotion processing deficits remain unclear. The multimodal system model of emotion proposes that basic emotions are dependent on distinct brain regions, which undergo significant pathological changes in frontotemporal dementia. As such, this syndrome may provide important insight into the impact of neural network degeneration upon the innate ability to recognise emotions. This study used voxel-based morphometry to identify discrete neural correlates involved in the recognition of basic emotions (anger, disgust, fear, sadness, surprise and happiness) in frontotemporal dementia. Forty frontotemporal dementia patients (18 behavioural-variant, 11 semantic dementia, 11 progressive nonfluent aphasia) and 27 healthy controls were tested on two facial emotion recognition tasks: The Ekman 60 and Ekman Caricatures. Although each frontotemporal dementia group showed impaired recognition of negative emotions, distinct associations between emotion-specific task performance and changes in grey matter intensity emerged. Fear recognition was associated with the right amygdala; disgust recognition with the left insula; anger recognition with the left middle and superior temporal gyrus; and sadness recognition with the left subcallosal cingulate, indicating that discrete neural substrates are necessary for emotion recognition in frontotemporal dementia. The erosion of emotion-specific neural networks in neurodegenerative disorders may produce distinct profiles of performance that are relevant to understanding the neurobiological basis of emotion processing.
Neurodegenerative patients show often severe everyday decision making problems. Currently it is however not clear which brain atrophy regions are implicated in such decision making problems. We investigated the atrophy correlates of gambling decision making in a sample of 63 participants, including two neurodegenerative conditions (behavioural variant frontotemporal dementia — bvFTD; Alzheimer's disease — AD) as well as healthy age-matched controls. All participants were tested on the Iowa Gambling Task (IGT) and the behavioural IGT results were covaried against the T1 MRI scans of all participants to identify brain atrophy regions implicated in gambling decision making deficits. Our results showed a large variability in IGT performance for all groups with both patient groups performing especially poor on the task. Importantly, bvFTD and AD groups did not differ significantly on the behavioural performance of the IGT. However, by contrast, the atrophy gambling decision making correlates differed between bvFTD and AD, with bvFTD showing more frontal atrophy and AD showing more parietal and temporal atrophy being implicated in decision making deficits, indicating that both patient groups fail the task on different levels. Frontal (frontopolar, anterior cingulate) and parietal (retrosplenial) cortex atrophy covaried with poor performance on the IGT. Taken together, the atrophy correlates of gambling decision making show that such deficits can occur due to a failure of different neural structures, which will inform future diagnostics and treatment options to alleviate these severe everyday problems in neurodegenerative patients.
► bvFTD and AD patients are both impaired in gambling decision making. ► However, atrophy correlates for gambling decision making differ between groups. ► Poor performance in decision making covaried with frontal atrophy in bvFTD. ► Poor performance in decision making covaried with parietal/temporal atrophy in AD. ► Gambling decision deficits can occur due to atrophy in different brain regions.
Behavioural variant frontotemporal dementia; Alzheimer's disease; Voxel-based morphometry; Gambling decision making; Iowa Gambling Task
Behavioral changes in patients with amyotrophic lateral sclerosis (ALS) mirror those found in frontotemporal dementia (FTD). Considering the high rate of neuropsychiatric symptoms found in ALS patients, this paper examines whether caregiver burden is associated with behavioral changes over and above the physical disability of patients with ALS, and if the presence of caregivers’ depression, anxiety and stress also impacts on caregiver burden.
140 caregivers of patients with ALS participated in a postal survey investigating patients’ neuropsychiatric symptoms (Cambridge Behaviour Inventory Revised CBI-R), motor function (Amyotrophic Lateral Sclerosis Functional Rating Scale Revised - ALSFRS-R), caregiver burden (Zarit Burden Interview), and caregiver mood (Depression, Anxiety and Stress Scale- DASS21). Seventy four percent of them were caregivers of patients with limb onset and 25.7% were caregivers of patients with bulbar onset.
Moderate to severe behavioral changes were reported in 10-40% of patients with ALS. The levels of depression, anxiety and stress in the caregivers reached 20%. Burden was high in 48% of the caregivers. The strongest predictor of high caregiver burden was ALS patients’ abnormal behavior rather than physical disability, with an odds ratio of 1.4, followed by caregivers’ stress.
Our study has identified that behavioral changes (e.g. disinhibition, impulsivity) and caregiver stress have greater impact on caregiver burden than level and pattern of physical disability.
ALS; Behavioral changes; FTD; Caregiver burden
Frontotemporal dementia (FTD) is classically considered to be a neurodegenerative disease with cortical changes. Recent structural imaging findings, however, highlight that subcortical and in particular striatal regions are also affected in the FTD syndrome. The influence of striatal pathology on cognitive and behavioural changes in FTD is virtually unexplored. In the current study we employ the Weather Prediction Task (WPT), a probabilistic learning task which taps into striatal dysfunction, in a group of FTD patients. We also regressed the patients' behavioural performance with their grey matter atrophy via voxel-based morphometry (VBM) to identify the grey matter contributions to WPT performance in FTD. Based on previous studies we expected to see striatal and frontal atrophy to be involved in impaired probabilistic learning. Our behavioural results show that patients performed on a similar level to controls overall, however, there was a large variability of patient performance in the first 30 trials of the task, which are critical in the acquisition of the probabilistic learning rules. A VBM analysis covarying the performance for the first 30 trials across participants showed that atrophy in striatal but also frontal brain regions correlated with WPT performance in these trials. Closer inspection of performance across the first 30 trials revealed a subgroup of FTD patients that performed significantly poorly than the remaining patients and controls on the WPT, despite achieving the same level of probabilistic learning as the other groups in later trials. Additional VBM analyses revealed that the subgroup of FTD patients with poor early probabilistic learning in the first 30 trials showed greater striatal atrophy compared to the remaining FTD patients and controls. These findings suggest that the integrity of fronto-striatal regions is important for probabilistic learning in FTD, with striatal integrity in particular, determining the acquisition learning rate. These findings will therefore have implications for developing an easily administered version of the probabilistic learning task which can be used by clinicians to assess striatal functioning in neurodegenerative syndromes.
► Probabilistic association memory was investigated in FTD patients. ► FTD patients with slow acquisition rates showed greater striatal atrophy. ► Striatal dysfunction in FTD can be functionally assessed via such tests.
Frontotemporal dementia; Probabilistic learning; Weather Prediction Task; Striatum; Orbitofrontal cortex; Voxel-based morphometry
Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.
Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination – Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM.
In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/− 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices.
Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy.
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
There is increasing evidence that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) lie on a clinical, pathological and genetic continuum with patients of one disease exhibiting features of the other. Nevertheless, to date, the underlying grey matter and white matter changes across the ALS-FTD disease continuum have not been explored. In this study fifty-three participants with ALS (n = 10), ALS-FTD (n = 10) and behavioural variant FTD (bvFTD; n = 15) as well as controls (n = 18), underwent detailed clinical assessment plus structural imaging using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analysis of magnetic resonance brain imaging to examine grey and white matter differences and commonalities across the continuum. Importantly, patient groups were matched for age, education, gender and disease duration. VBM and DTI results showed that changes in the ALS group were confined mainly to the motor cortex and anterior cingulate as well as their underlying white matter tracts. ALS-FTD and bvFTD showed widespread grey matter and white matter changes involving frontal and temporal lobes. Extensive prefrontal cortex changes emerged as a marker for bvFTD compared to other subtypes, while ALS-FTD could be distinguished from ALS by additional temporal lobe grey and white matter changes. Finally, ALS could be mainly distinguished from the other two groups by corticospinal tract degeneration. The present study shows for the first time that FTD and ALS overlap in anterior cingulate, motor cortex and related white matter tract changes across the whole continuum. Nevertheless, frontal and temporal atrophy as well as corticospinal tract degeneration emerged as marker for subtype classification, which will inform future diagnosis and target disease management across the continuum.
Although progressive supranuclear palsy is defined by its akinetic rigidity, vertical supranuclear gaze palsy and falls, cognitive impairments are an important determinant of patients’ and carers’ quality of life. Here, we investigate whether there is a broad deficit of modality-independent social cognition in progressive supranuclear palsy and explore the neural correlates for these. We recruited 23 patients with progressive supranuclear palsy (using clinical diagnostic criteria, nine with subsequent pathological confirmation) and 22 age- and education-matched controls. Participants performed an auditory (voice) emotion recognition test, and a visual and auditory theory of mind test. Twenty-two patients and 20 controls underwent structural magnetic resonance imaging to analyse neural correlates of social cognition deficits using voxel-based morphometry. Patients were impaired on the voice emotion recognition and theory of mind tests but not auditory and visual control conditions. Grey matter atrophy in patients correlated with both voice emotion recognition and theory of mind deficits in the right inferior frontal gyrus, a region associated with prosodic auditory emotion recognition. Theory of mind deficits also correlated with atrophy of the anterior rostral medial frontal cortex, a region associated with theory of mind in health. We conclude that patients with progressive supranuclear palsy have a multimodal deficit in social cognition. This deficit is due, in part, to progressive atrophy in a network of frontal cortical regions linked to the integration of socially relevant stimuli and interpretation of their social meaning. This impairment of social cognition is important to consider for those managing and caring for patients with progressive supranuclear palsy.
progressive supranuclear palsy; voxel-based morphometry; social cognition; theory of mind; emotion perception
The network activated during normal route learning shares considerable homology with the network of degeneration in the earliest symptomatic stages of Alzheimer's disease (AD). This inspired the virtual route learning test (VRLT) in which patients learn routes in a virtual reality environment. This study investigated the neural basis of VRLT performance in AD to test whether impairment was underpinned by a network or by the widely held explanation of hippocampal degeneration. VRLT score in a mild AD cohort was regressed against gray matter (GM) density and diffusion tensor metrics of white matter (WM) (n = 30), and, cerebral glucose metabolism (n = 26), using a mass univariate approach. GM density and cerebral metabolism were then submitted to a multivariate analysis [support vector regression (SVR)] to examine whether there was a network associated with task performance. Univariate analyses of GM density, metabolism and WM axial diffusion converged on the vicinity of the retrosplenial/posterior cingulate cortex, isthmus and, possibly, hippocampal tail. The multivariate analysis revealed a significant, right hemisphere-predominant, network level correlation with cerebral metabolism; this comprised areas common to both activation in normal route learning and early degeneration in AD (retrosplenial and lateral parietal cortices). It also identified right medio-dorsal thalamus (part of the limbic-diencephalic hypometabolic network of early AD) and right caudate nucleus (activated during normal route learning). These results offer strong evidence that topographical memory impairment in AD relates to damage across a network, in turn offering complimentary lesion evidence to previous studies in healthy volunteers for the neural basis of topographical memory. The results also emphasize that structures beyond the mesial temporal lobe (MTL) contribute to memory impairment in AD—it is too simplistic to view memory impairment in AD as a synonym for hippocampal degeneration.
topographical memory; Alzheimer's; MRI; PET; multivariate; support vector; retrosplenial cortex
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
Behavioural variant frontotemporal dementia is a neurodegenerative disorder with dysfunction and atrophy of the frontal lobes leading to changes in personality, behaviour, empathy, social conduct and insight, with relative preservation of language and memory. As novel treatments begin to emerge, biomarkers of frontotemporal dementia will become increasingly important, including functionally relevant neuroimaging indices of the neurophysiological basis of cognition. We used magnetoencephalography to examine behavioural variant frontotemporal dementia using a semantic decision task that elicits both frontal and temporal activity in healthy people. Twelve patients with behavioural variant frontotemporal dementia (age 50–75) and 16 matched controls made categorical semantic judgements about 400 pictures during continuous magnetoencephalography. Distributed source analysis was used to compare patients and controls. The patients had normal early responses to picture confrontation, indicating intact visual processing. However, a predominantly posterior set of regions including temporoparietal cortex showed reduced source activity 250–310 ms after stimulus onset, in proportion to behavioural measures of semantic association. In contrast, a left frontoparietal network showed reduced source activity at 550–650 ms, proportional to patients’ deficits in attention and orientation. This late deficit probably reflects impairment in the neural substrate of goal-oriented decision making. The results demonstrate behaviourally relevant neural correlates of semantic processing and decision making in behavioural variant frontotemporal dementia, and show for the first time that magnetoencephalography can be used to study cognitive systems in the context of frontotemporal dementia.
frontotemporal; dementia; semantic decision; picture categorization; magnetoencephalography
Frontotemporal lobar degeneration (FTLD) is the umbrella term encompassing a heterogeneous group of pathological disorders. With recent discoveries, the FTLDs have been show to classify nicely into three main groups based on the major protein deposited in the brain: FTLD-tau, FTLD-TDP and FTLD-FUS. These pathological groups, and their specific pathologies, underlie a number of well-defined clinical syndromes, including three frontotemporal dementia (FTD) variants [behavioral variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia, and semantic dementia (SD)], progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS). Understanding the neuropathological background of the phenotypic variability in FTD, PSPS and CBS requires large clinicopathological studies. We review current knowledge on the relationship between the FTLD pathologies and clinical syndromes, and pool data from a number of large clinicopathological studies that collectively provide data on 544 cases. Strong relationships were identified as follows: FTD with motor neuron disease and FTLD-TDP; SD and FTLD-TDP; PSPS and FTLD-tau; and CBS and FTLD-tau. However, the relationship between some of these clinical diagnoses and specific pathologies is not so clear cut. In addition, the clinical diagnosis of bvFTD does not have a strong relationship to any FTLD subtype or specific pathology and therefore remains a diagnostic challenge. Some evidence suggests improved clinicopathological association of bvFTD by further refining clinical characteristics. Unlike FTLD-tau and FTLD-TDP, FTLD-FUS has been less well characterized, with only 69 cases reported. However, there appears to be some associations between clinical phenotypes and FTLD-FUS pathologies. Clinical diagnosis is therefore promising in predicting molecular pathology.
Frontotemporal lobar degeneration; Progressive supranuclear palsy; Tau; TDP-43; FUS
Frontotemporal dementia (FTD) syndromes comprise a heterogeneous group of neurodegenerative conditions characterized by atrophy in the frontal and temporal lobes. Three main clinical variants are recognized: Behavioral variant (bv-FTD), Semantic dementia (SD), and Progressive nonfluent aphasia (PNFA). However, logopenic/phonological (LPA) variant has been recently described, showing a distinctive pattern of brain atrophy and often associated to Alzheimer’s disease pathology. The diagnosis of FTD is challenging, since there is clinical, pathological, and genetic overlap between the variants and other neurodegenerative diseases, such as motoneuron disease (MND) and corticobasal degeneration (CBD). In addition, patients with gene mutations (tau and progranulin) display an inconsistent clinical phenotype and the correspondence between the clinical variant and its pathology is unpredictable. New cognitive tests based on social cognition and emotional recognition together with advances in molecular pathology and genetics have contributed to an improved understanding. There is now a real possibility of accurate biomarkers for early diagnosis. The present review concentrates on new insights and debates in FTD.
Frontotemporal dementia; progressive nonfluent aphasia; semantic dementia; taupathies; TDP-43
The speech of patients with progressive non-fluent aphasia (PNFA) has often been described clinically, but these descriptions lack support from quantitative data. The clinical classification of the progressive aphasic syndromes is also debated. This study selected 15 patients with progressive aphasia on broad criteria, excluding only those with clear semantic dementia. It aimed to provide a detailed quantitative description of their conversational speech, along with cognitive testing and visual rating of structural brain imaging, and to examine which, if any features were consistently present throughout the group; as well as looking for sub-syndromic associations between these features. A consistent increase in grammatical and speech sound errors and a simplification of spoken syntax relative to age-matched controls were observed, though telegraphic speech was rare; slow speech was common but not universal. Almost all patients showed impairments in picture naming, syntactic comprehension and executive function. The degree to which speech was affected was independent of the severity of the other cognitive deficits. A partial dissociation was also observed between slow speech with simplified grammar on the one hand, and grammatical and speech sound errors on the other. Overlap between these sets of impairments was however, the rule rather than the exception, producing continuous variation within a single consistent syndrome. The distribution of atrophy was remarkably variable, with frontal, temporal and medial temporal areas affected, either symmetrically or asymmetrically. The study suggests that PNFA is a coherent, well-defined syndrome and that varieties such as logopaenic progressive aphasia and progressive apraxia of speech may be seen as points in a space of continuous variation within progressive non-fluent aphasia.
progressive aphasia; frontotemporal dementia; language; cortical atrophy; neuropsychology
The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5′ end of the BDNF gene. The patient’s genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyper-activity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior.
We compared demographics of subjects diagnosed with frontotemporal degeneration (FTD) at a group of 5 clinics specializing in this non-Alzheimer dementia against those subjects diagnosed at standard Alzheimer disease centers, to determine any differences in referral patterns between such clinics.
Of the two major phenotypes of FTD, behavior and language, the latter more frequently presented to the specialty clinics (46% of FTD diagnoses versus 19%, P < 0.001). Mean age at onset for the behavioral presentation phenotype was one year younger at the specialty clinics (P < 0.01). Mean age at onset for the language phenotype was 3 years older (P < 0.001) than for the behavioral phenotype at standard centers but did not differ between the two evaluating groups.
Cases with FTD referred to all of the dementia evaluation sites in this study did not differ significantly from those previously reported in the literature. Clinics specializing in FTD recruit more language presentation cases. There were statistical but not clinically significant differences in ages at onset.
frontotemporal degeneration; gender; referral onset age
To determine the frequency of a hexanucleotide repeat expansion in C9ORF72, a gene of unknown function implicated in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), in Australian FTD patient cohorts and to examine the clinical and neuropathologic phenotypes associated with this expansion.
We examined a clinically ascertained FTD cohort (n = 89) and a neuropathologically ascertained cohort of frontotemporal lobar degeneration cases with TDP-43 pathology (FTLD-TDP) (n = 22) for the C9ORF72 hexanucleotide repeat expansion using a repeat primed PCR assay. All expansion-positive patients were genotyped for rs3849942, a surrogate marker for the chromosome 9p21 risk haplotype previously associated with FTD and ALS.
The C9ORF72 repeat expansion was detected in 10% of patients in the clinically diagnosed cohort, rising to 29% in those with a positive family history of early-onset dementia or ALS. The prevalence of psychotic features was significantly higher in expansion-positive cases (56% vs 14%). In the pathology cohort, 41% of TDP-43-positive cases harbored the repeat expansion, and all exhibited type B pathology. One of the 17 expansion-positive probands was homozygous for the “nonrisk” G allele of rs3849942.
The C9ORF72 repeat expansion is a relatively common cause of FTD in Australian populations, and is especially common in those with FTD-ALS, psychotic features, and a strong family history. Detection of a repeat expansion on the 9p21 putative “nonrisk” haplotype suggests that not all mutation carriers are necessarily descended from a common founder and indicates that the expansion may have occurred on multiple haplotype backgrounds.
The frontal variant of frontotemporal dementia is a significant neurological condition worldwide. There exist few treatments available for the cognitive and behavioural sequelae of fvFTD. Previous research has shown that these patients display risky decision-making, and numerous studies have now demonstrated pathology affecting the orbitofrontal cortex. The present study uses a within-subjects, double-blind, placebo-controlled procedure to investigate the effects of a single dose of methylphenidate (40 mg) upon a range of different cognitive processes including those assessing prefrontal cortex integrity. Methylphenidate was effective in ‘normalizing’ the decision-making behavior of patients, such that they became less risk taking on medication, although there were no significant effects on other aspects of cognitive function, including working memory, attentional set shifting, and reversal learning. Moreover, there was an absence of the normal subjective and autonomic responses to methylphenidate seen in elderly subjects. The results are discussed in terms of the ‘somatic marker’ hypothesis of impaired decision-making following orbitofrontal dysfunction.
orbitofrontal cortex; methylphenidate; risk-taking; decision-making; frontal variant frontotemporal dementia
Corticobasal syndrome (CBS) is a multifaceted neurodegenerative disorder characterized by a combination of motor and cognitive deficits. Several different pathological entities, including Alzheimer’s pathology, have been described in association with CBS. The present study aimed to establish clinical, neuropsychological, and neuroimaging features that could be useful in the distinction of CBS due to AD pathology from other CBS cases in life based on [11C] Pittsburgh Compound B positron emission tomography (PiB-PET) status.
Patients with CBS were prospectively recruited from a specialized cognitive disorders clinic. All patients underwent detailed clinical and neuropsychological assessment, with structural imaging using voxel-based analysis of magnetic resonance imaging. Alzheimer’s pathology was detected using PiB-PET imaging, and PiB-positive and PiB-negative groups were compared.
Fourteen CBS patients meeting defined criteria were included (7 male, 7 female; mean age 66.1+/−6.9 years; median symptom duration was 35.5+/−22.6 months) and compared to 20 matched control subjects. Of the 14 patients, 4 were PiB-positive and 10 PiB-negative. There were no significant differences between PiB-positive and PiB-negative CBS patients in age, gender, education, symptom duration, or motor features. PiB-positive patients had greater visuospatial deficits, a higher rate of sentence repetition impairment, and more functional decline. Voxel-based morphometry analyses demonstrated extensive peri-insular and post-central atrophy in both groups, but PiB-positive patients had atrophy that extended to include the posterior part of the left superior temporal gyrus.
Visuospatial function, aspects of language, and the pattern of cerebral atrophy may be useful in distinguishing patients with CBS due to underlying AD pathology.