Can MRI Visual Assessment Differentiate the Variants of Primary-Progressive Aphasia?

BACKGROUND AND PURPOSE: Primary-progressive aphasia is a clinically and pathologically heterogeneous condition. Nonfluent, semantic, and logopenic are the currently recognized clinical variants. The recommendations for the classification of primary-progressive aphasia have advocated variant-specific patterns of atrophy. The aims of the present study were to evaluate the sensitivity and specificity of the proposed imaging criteria and to assess the intra- and interrater reporting agreements. MATERIALS AND METHODS: The cohort comprised 51 patients with a root diagnosis of primary-progressive aphasia, 25 patients with typical Alzheimer disease, and 26 matched control participants. Group-level analysis (voxel-based morphometry) confirmed the proposed atrophy patterns for the 3 syndromes. The individual T1-weighted anatomic images were reported by 3 senior neuroradiologists. RESULTS: We observed a dichotomized pattern of high sensitivity (92%) and specificity (93%) for the proposed atrophy pattern of semantic-variant primary-progressive aphasia and low sensitivity (21% for nonfluent-variant primary-progressive aphasia and 43% for logopenic-variant primary-progressive aphasia) but high specificity (91% for nonfluent-variant primary-progressive aphasia and 95% for logopenic-variant primary-progressive aphasia) in other primary-progressive aphasia variants and Alzheimer disease (sensitivity 43%, specificity 92%). MR imaging was least sensitive for the diagnosis of nonfluent-variant primary-progressive aphasia. Intrarater agreement analysis showed mean κ values above the widely accepted threshold of 0.6 (mean, 0.63 ± 0.16). Pair-wise interobserver agreement outcomes, however, were well below this threshold in 5 of the 6 possible interrater contrasts (mean, 0.41 ± 0.09). CONCLUSIONS: While the group-level results were in precise agreement with the recommendations, semantic-variant primary-progressive aphasia was the only subtype for which the proposed recommendations were both sensitive and specific at an individual level.

CADASIL presenting with a behavioural variant frontotemporal dementia phenotype.

The behavioural variant of frontotemporal dementia (bvFTD) is characterised by personality change with a decline in cognition. We describe two patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) who presented with behavioural phenotypes similar to bvFTD. The first patient presented with progressive personality and behavioural change, had florid white matter hyperintensity, and had a novel missense mutation C366W in exon 7 of the Notch3 gene. The second patient presented with progressive memory impairment and marked personality changes after a transient ischaemic attack. In this second patient, the radiological features were subtle and only the family history of stroke prompted testing for CADASIL using Notch3 genotyping. We present these patients to demonstrate that CADASIL may mimic bvFTD, with little clinical or radiological evidence to distinguish the two. CADASIL may be an under-recognised diagnosis in apparent bvFTD. Screening Notch3 in a substantial and unselected cohort of frontotemporal dementia patients might be appropriate to investigate this possibility.

EFNS task force: the use of neuroimaging in the diagnosis of dementia.

BACKGROUND AND PURPOSE: The European Federation of the Neurological Societies (EFNS) guidelines on the use of neuroimaging in the diagnosis and management of dementia are designed to revise and expand previous EFNS recommendations for the diagnosis and management of patients with Alzheimer's disease (AD) and to provide an overview of the evidence for the use of neuroimaging techniques in non-AD dementias, as well as general recommendations that apply to all types of dementia in clinical practice. METHODS: The task force working group reviewed evidence from original research articles, meta-analyses and systematic reviews, published before April 2012. The evidence was classified, and consensus recommendations were given and graded according to the EFNS guidance regulations. RESULTS: Structural imaging, which should be performed at least once in the diagnostic work-up of patients with cognitive impairment, serves to exclude other potentially treatable diseases, to recognize vascular lesions and to identify specific findings to help distinguish different forms of neurodegenerative types of dementia. Although typical cases of dementia may not benefit from routine functional imaging, these tools are recommended in those cases where diagnosis remains in doubt after clinical and structural imaging work-up and in particular clinical settings. Amyloid imaging is likely to find clinical utility in several fields, including the stratification of patients with mild cognitive impairment into those with and without underlying AD and the evaluation of atypical AD presentations. CONCLUSIONS: A number of recommendations and good practice points are made to improve the diagnosis of AD and other dementias.

Primary progressive aphasia: a tale of two syndromes and the rest.

OBJECTIVE: Primary progressive aphasia (PPA) has been proposed to comprise 3 discrete clinical subtypes: semantic, agrammatic/nonfluent, and logopenic. Recent consensus recommendations suggest a diagnostic framework based primarily on clinical and neuropsychological findings to classify these variants. Our objective was to evaluate the extent to which patients with PPA would conform to the proposed tripartite system and whether the clustering pattern of elements of the linguistic profile suggests discrete clinical syndromes. METHODS: A total of 46 patients with PPA were prospectively recruited to the Cambridge Longitudinal Study of PPA. Sufficient data were collected to assess all consensus-proposed diagnostic domains. By comparing patients' performances against those of 30 age- and education-matched healthy volunteers, z scores were calculated, and values of 1.5 SDs outside control participants' means were considered abnormal. Raw test scores were used to undertake a principal factor analysis to identify the clustering pattern of individual measures. RESULTS: Of the patients, 28.3%, 26.1%, and 4.3% fitted semantic, nonfluent/agrammatic, and logopenic categories respectively, and 41.3% did not fulfill the diagnostic recommendations for any of the 3 proposed variants. There was no significant between-group difference in age, education, or disease duration. Furthermore, the outcome of the factor analysis was in keeping with discrete semantic and nonfluent/agrammatic syndromes but did not support a logopenic variant. CONCLUSION: Taken together, the results of this prospective data-driven study suggest that although a substantial proportion of patients with PPA have neither the semantic nor the nonfluent variants, they do not necessarily conform to a discrete logopenic variant.

Profiles of recent autobiographical memory retrieval in semantic dementia, behavioural-variant frontotemporal dementia, and Alzheimer's disease.

Episodic autobiographical memory (ABM) comprises recollection for events that are grounded within a specific spatiotemporal context, and usually accompanied by perceptual and emotional information. The neural substrates mediating ABM retrieval are those harbouring significant pathology in semantic dementia (SD) and behavioural-variant frontotemporal dementia (bvFTD), the most common subtypes of FTD. Relatively little is known, however, regarding the differential patterns of contextual details during episodic ABM retrieval across these dementia syndromes. This study investigated episodic ABM retrieval under free and probed recall conditions from 4 time periods with the aim to identify disease-specific profiles of episodic ABM contextual details. Episodic ABM was measured in 25 SD and 15 bvFTD patients and their performance contrasted to that of 17 Alzheimer's disease (AD) patients and 19 age-matched controls. Critically, SD patients showed relatively preserved recent ABM in comparison with remote epochs. In contrast, bvFTD and AD patients showed a reduced capacity to recall specific and contextually rich ABMs across all life epochs, in both free and probed recall conditions. Analyses of the recent period (last 12 months) provided evidence for different profiles of contextual episodic details recalled in dementia syndromes. Following probing, SD patients' recall deficits emanated exclusively from compromised Emotion/Thoughts and Spatiotemporal details. In contrast, bvFTD patients were significantly impaired across all categories of contextual details whereas AD patients showed deficits for Event and Emotion/Thoughts details only. As the largest study of ABM in FTD to date, these findings emphasise the differential impairment of recent ABM contextual details contingent on the underlying disease pathology. In addition, these results point towards the importance of investigating the constituent elements of emotion processing and strategic retrieval processes as potential variables mediating recent episodic ABM retrieval.

How preserved is episodic memory in behavioral variant frontotemporal dementia?

OBJECTIVE: Studies have shown variable memory performance in patients with behavioral variant frontotemporal dementia (bvFTD). Our study investigated whether this variability is due to the admixture of patients with true bvFTD and phenocopy patients. We also sought to compare performance of patients with bvFTD and patients with Alzheimer disease (AD). METHODS: We analyzed neuropsychological memory performance in patients with a clinical diagnosis of bvFTD divided into those who progressed (n = 50) and those who remained stable (n = 39), patients with AD (n = 64), and healthy controls (n = 64). RESULTS: Patients with progressive bvFTD were impaired on most memory tests to a similar level to that of patients with early AD. Findings from a subset of patients with progressive bvFTD with confirmed FTLD pathology (n = 10) corroborated these findings. By contrast, patients with phenocopy bvFTD performed significantly better than progressors and patients with AD. Logistic regression revealed that patients with bvFTD can be distinguished to a high degree (85%) on the immediate recall score of a word list learning test (Rey Auditory Verbal Learning Test). CONCLUSIONS: Our results provide evidence for an underlying memory deficit in "real" or progressive behavioral variant frontotemporal dementia (bvFTD) similar to Alzheimer disease, though the groups differ in orientation scores, with patients with bvFTD being intact. Exclusion solely based on impaired neuropsychological memory performance can potentially lead to an underdiagnosis of FTD.

Registration accuracy for VBM studies varies according to region and degenerative disease grouping.

Voxel-based morphometry studies are frequently cited as having the advantage of being objective compared to region-of-interest methods. This statement assumes, however, that all regions are treated equally both in controls and diseased cohorts. This study aimed to test whether this statement is correct by analyzing fiducial landmarks in controls, Alzheimer's disease (as a model of mild generalized atrophy model); Frontotemporal Dementia (focal atrophy model) and Semantic Dementia (extreme focal atrophy model). Standard SPM5 and DARTEL were evaluated using either raw or skull-stripped/bias corrected scans. The results indicated that with all methods there was variability in the degree of misregistration across regions and that there was a disease grouping interaction-most severely in the extreme focal atrophy model (Semantic Dementia). Preprocessing improved VBM outputs both with standard SPM and DARTEL. In the latter case, this occurred to an extreme degree-DARTEL using raw data was grossly insensitive to a ground truth (manually verified hippocampal atrophy in AD) whereas DARTEL after preprocessing yielded excellent results with respect to this yardstick.

Determinants of survival in behavioral variant frontotemporal dementia.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is a common cause of younger onset dementia. Little is known about its rate of progression but a recently identified subgroup seems to have an excellent prognosis. Other determinants of survival are unclear. METHODS: We analyzed survival in a large group of clinically diagnosed bvFTD patients (n = 91) with particular attention to demographic and clinical features at presentation. Of the 91 cases, 50 have died, with pathologic confirmation in 28. RESULTS: Median survival in the whole group was 9.0 years from symptom onset, and 5.4 years from diagnosis. After the exclusion of 24 "phenocopy" cases, the analysis was repeated in a subgroup of 67 patients. The mean age at symptom onset of the pathologic group was 58.5 years and 16% had a positive family history. Their median survival was 7.6 years (95% confidence interval [CI] 6.6-8.6) from symptom onset and 4.2 years (95% CI 3.4-5.0) from diagnosis. The only factor associated with shorter survival was the presence of language impairment at diagnosis. CONCLUSIONS: Patients with definite frontotemporal dementia have a poor prognosis which is worse if language deficits are also present. This contrasts with the extremely good outcome in those with the phenocopy syndrome: of our 24 patients only 1 has died (of coincident pathology) despite, in some cases, many years of follow-up.

Atrophy patterns in histologic vs clinical groupings of frontotemporal lobar degeneration.

OBJECTIVE: Predictable patterns of atrophy are associated with the clinical subtypes of frontotemporal dementia (FTD): behavioral variant (bvFTD), semantic dementia (SEMD), and progressive nonfluent aphasia (PNFA). Some studies of pathologic subtypes have also suggested specific atrophy patterns; however, results are inconsistent. Our aim was to test the hypothesis that clinical, but not pathologic, classification (FTD with ubiquitin inclusions [FTD-U] and FTD with tau inclusions [FTD-T]) is associated with predictable patterns of regional atrophy. METHODS: Magnetic resonance scans of nine FTD-U and six FTD-T patients (histologically confirmed) were compared with 25 controls using voxel-based morphometry (VBM). Analyses were conducted with the patient group classified according to histologic or clinical variant. Additionally, three Alzheimer pathology patients who had the syndrome of SEMD in life (FTD-A) were analyzed. RESULTS: The VBM studies in clinical variants confirmed established patterns of atrophy (SEMD, rostral temporal; bvFTD, mesial frontal; PNFA, left insula). FTD-U and FTD-T VBM results were very similar, showing severe atrophy in the temporal poles, mesial frontal lobe, and insulae. A conjunction analysis confirmed this similarity. Subgroup analysis found that SEMD associated with either FTD-T or FTD-U was associated with similar rostral temporal atrophy; however, FTD-A had a qualitatively different pattern of left hippocampal atrophy. CONCLUSIONS: While there is predictable atrophy for clinical variants of frontotemporal dementia (FTD), histologic FTD variants show no noticeable differences. Reports of specific atrophy profiles are likely the result of idiosyncrasies in small groups. Semantic dementia associated with Alzheimer pathology, however, presented a distinct atrophy pattern.

Combined magnetic resonance imaging and positron emission tomography brain imaging in behavioural variant frontotemporal degeneration: refining the clinical phenotype.

In patients with the behavioural variant of frontotemporal dementia, prognosis is often surprisingly good when there is normal structural imaging at presentation. Imaging abnormalities are not, however, mandatory for diagnosis, which in the absence of suitable biomarkers, remains entirely clinical. We aimed to test whether cases with normal structural imaging have hypometabolism suggestive of underlying neurodegeneration, or whether it is likely that such patients are false positive diagnoses of behavioural variant frontotemporal dementia. Patients with this disease (n = 24) and age-matched controls (n = 12) underwent both magnetic resonance imaging (MRI) and quantitative fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning, together with clinical and behavioural assessments. Regions of interest were used to calculate metabolic rate in frontotemporal and control regions. Using a semi-quantitative visual rating scale, patients were divided into MRI-abnormal (n = 15) and MRI-normal groups (n = 9). There was definite frontotemporal hypometabolism in the MRI-abnormal group (particularly in the mesial and orbitofrontal regions) even after accounting for brain volume loss, whereas the MRI-normal group was similar to controls in all regions. In contrast, cognitive and behavioural indices did not separate the two behavioural variant frontotemporal dementia patient groups. The results suggest that the clinical syndrome of the behavioural variant of frontotemporal dementia may not be specific for a neurodegenerative disease, and we hypothesize the existence of a phenocopy. A number of alternative neuropsychiatric and developmental explanations are discussed. We advise caution in diagnosing the illness in patients without imaging abnormalities, and propose that imaging findings are included in criteria for diagnosis.

Understanding social dysfunction in the behavioural variant of frontotemporal dementia: the role of emotion and sarcasm processing.

Social interaction is profoundly affected in the behavioural form of frontotemporal dementia (bvFTD) yet there are few means of objectively assessing this. Diagnosis of bvFTD is based on informant report, however a number of individuals with a clinical profile consistent with the disease have no imaging abnormality and seem to remain stable, with doubt about the presence of underlying neurodegenerative pathology. We aimed to quantify aspects of the behavioural disorder and link it to the underlying level of atrophy in socially relevant brain regions. We tested individuals with either bvFTD (N = 26) or Alzheimer's disease (N = 9) and 16 controls using The Awareness of Social Inference Test (TASIT) to assess their ability to identify emotion and sarcasm in video vignettes. A subset of bvFTD patients (N = 21) and controls (N = 12) were scanned using MRI within 6 months of assessment. There was marked impairment in the ability of bvFTD patients whose scans showed abnormalities to recognize sarcastic, but not sincere statements. Their capacity to interpret negative emotion was also impaired, and this appeared to be a major factor underlying the deficit in sarcasm recognition. Clinically diagnosed bvFTD patients whose scans were normal, Alzheimer's disease patients and controls had no difficulty in appreciating both types of statement. In a multivariate imaging analysis it was shown that the sarcasm (and emotion recognition) deficit was dependent on a circuit involving the lateral orbitofrontal cortex, insula, amygdala and temporal pole, particularly on the right. Performance on a more global test of cognitive function, the Addenbrooke's Cognitive Examination did not have a unique association with these regions. The TASIT is an objective test of social dysfunction in bvFTD which indexes the frontotemporal volume loss in bvFTD patients and provides an objective measure for separating behavioural patients who are likely to decline from those who may remain stable. These results provide additional evidence for the role of the orbitofrontal cortex and related structures in the processing of socially relevant signals, particularly those where negative emotion recognition is important.

Transient epileptic amnesia: regional brain atrophy and its relationship to memory deficits.

Transient epileptic amnesia (TEA) is a recently recognised form of epilepsy of which the principle manifestation is recurrent, transient episodes of isolated memory loss. In addition to the amnesic episodes, many patients describe significant interictal memory difficulties. Performance on standard neuropsychological tests is often normal. However, two unusual forms of memory deficit have recently been demonstrated in TEA: (i) accelerated long-term forgetting (ALF): the excessively rapid loss of newly acquired memories over a period of days or weeks and (ii) remote autobiographical memory loss: a loss of memories for salient, personally experienced events of the past few decades. The neuroanatomical bases of TEA and its associated memory deficits are unknown. In this study, we first assessed the relationship between subjective and objective memory performance in 41 patients with TEA. We then analysed MRI data from these patients and 20 matched healthy controls, using manual volumetry and voxel-based morphometry (VBM) to correlate regional brain volumes with clinical and neuropsychological data. Subjective memory estimates were unrelated to performance on standard neuropsychological tests but were partially predicted by mood, ALF and remote autobiographical memory. Manual volumetry identified subtle hippocampal volume loss in the patient group. Both manual volumetry and VBM revealed correlations between medial temporal lobe atrophy and standard anterograde memory scores, but no relation between atrophy and ALF or remote autobiographical memory. These results add weight to the hypothesis that TEA is a syndrome of mesial temporal lobe epilepsy. Furthermore, they suggest that although standard anterograde memory test performance is related to the degree of mesial temporal lobe damage, this is not true for ALF and autobiographical amnesia. It is possible that these unusual memory deficits have a more diffuse physiological basis rather than being a consequence of discrete structural damage.

Measuring progression in frontotemporal dementia: implications for therapeutic interventions.

BACKGROUND: There is a need for instruments which can measure progression of disease in frontotemporal dementia (FTD), particularly with respect to the assessment of potential therapeutic agents. METHODS: The Cambridge Early Onset Dementia Clinic database was reviewed for all prospectively enrolled cases of FTD with documented scores on the Mini-Mental State Examination (MMSE) or Addenbrooke's Cognitive Examination (ACE) on at least two occasions. We identified 50 cases fulfilling these criteria: pathologic confirmation was present in 11 of 16 patients who had died, 12 of the remainder had imaging abnormalities on their initial scans, and 22 had structural scans no different from controls. We compared these groups to a cohort with early AD (n = 25) and healthy controls (n = 10). RESULTS: There was clear cognitive decline (measured by the MMSE and ACE) in patients who had died, and those with documented atrophy on initial MRI scan. In contrast, patients with FTD with normal scans showed no change in cognitive scores over a much longer interval, and serial ACE measurements paralleled those of controls. Power calculations showed that the inclusion of these patients with FTD would significantly increase the number of cases needed in any therapeutic trial. CONCLUSION: Addenbrooke's Cognitive Examination is a simple monitoring tool which can detect progression of disease in frontotemporal dementia over a 1- to 2-year interval without the need for serial imaging. We estimated that a clinical trial that enrolled subjects with abnormal MR scans would require 135 subjects per group to detect a small effect, and 35 for a medium effect.

Behavioural variant frontotemporal dementia: not all it seems?

BACKGROUND: The diagnosis of the behavioural variant of frontotemporal dementia (bvFTD) can be challenging. At present there is a paucity of prospective work addressing the specificity of current diagnostic criteria for bvFTD with respect to long-term outcome (i.e., false positives versus true positives). METHODS: Here we report two individuals who met current clinical criteria for bvFTD and who underwent detailed long-term clinical and neuropsychological follow-up. In addition, both had serial volumetric MRI and functional metabolic (FDG-PET) imaging separated by 5 years. RESULTS: One case had a slow clinical decline as well as both progressive atrophy and hypometabolism in a frontotemporal distribution, consistent with a neurodegenerative FTD syndrome. However, the second developed neither atrophy nor hypometabolism and remained clinically stable, a decade from symptom onset. CONCLUSION: We propose that these cases illustrate that while there may be a slow evolution in bvFTD, it is possible that some cases who meet current criteria may not have a neurodegenerative syndrome. If correct, this hypothesis has important implications for the current diagnostic criteria. A potential hierarchy for diagnostic certainty in bvFTD is suggested.

Semantic dementia and fluent primary progressive aphasia: two sides of the same coin?

Considerable controversy exists regarding the relationship between semantic dementia (SD) and progressive aphasia. SD patients present with anomia and impaired word comprehension. The widely used consensus criteria also include the need for patients to exhibit associative agnosia and/or prosopagnosia: many authors have used the label SD for patients with non-verbal, as well as verbal, semantic deficits on formal testing even if they recognize the objects and people encountered in everyday life; others interpret the criterion of agnosia to require pervasive recognition impairments affecting daily life. According to this latter view, SD patients have pathology that disrupts both a bilateral ventrotemporal-fusiform network (resulting in agnosia) and the left hemisphere language network (resulting in profound aphasia). These authors suggest that this profile is different to that seen in the fluent form of primary progressive aphasia (fPPA), a neurodegenerative disease primarily affecting language function. We present data on seven patients who met the diagnostic criteria for fPPA. All seven showed deficits relative to matched controls on both verbal and non-verbal measures of semantic memory, and these deficits were modulated by degree of anomia, concept familiarity and item typicality. Voxel-based morphometry revealed reduced grey matter density in the temporal lobes bilaterally (more widespread on the left), with the severity of atrophy in the left inferior temporal lobe being significantly related to performance on both the verbal and non-verbal measures. Together these findings suggest that patients who meet the diagnostic criteria for fPPA, can also meet the diagnostic criteria for early-stage SD provided that the impact of concept familiarity and typicality is taken into account. In addition, these findings support a claim that the patients' deficits on both verbal and non-verbal tasks reflect progressive deterioration of an amodal integrative semantic memory system critically involving the rostral temporal lobes, rather than a combination of atrophy in the left language network and a separate bilateral ventrotemporal-fusiform network.

Correlation of visual hallucinations with occipital rCBF changes by donepezil in DLB.

The authors explored the neural substrate of visual hallucinations in dementia with Lewy bodies (DLB) by investigating changes in regional cerebral blood flow (rCBF) and psychiatric symptoms, before and after cholinesterase inhibitor treatment. Twenty subjects with DLB were treated with donepezil for a 12-week period. Hallucinations attenuated while receiving therapy, whereas occipital rCBF focally increased, suggesting that functional visual association cortex deficits may cause visual hallucinations in patients with DLB.

Similar early clinical presentations in familial and non-familial frontotemporal dementia.

BACKGROUND: It is unclear whether there are early clinical features that can distinguish between patients with familial and non-familial frontotemporal dementia (FTD). OBJECTIVE: To compare the clinical features of FTD cases who have tau gene mutations with those of cases with a family history of FTD but no tau gene mutation, and with sporadic cases with neither feature. METHODS AND RESULTS: Comparisons of the behavioural, cognitive, and motor features in 32 FTD patients (five positive for tau gene mutations, nine familial but tau negative, and 18 tau negative sporadic) showed that age of onset and duration to diagnosis did not differ between the groups. Apathy was not observed in tau mutation positive cases, and dysexecutive signs were more frequent in familial tau mutation negative cases. Memory deficits and behavioural changes were common in all groups. CONCLUSIONS: In comparison with other neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, neither tau gene mutations nor strong familial associations confer earlier disease susceptibility.