Lobar atrophy in frontotemporal dementia: diagnostic and prognostic implications

We review the practical importance of lobar atrophy in frontotemporal dementia (FTD), for diagnosis and prognosis. We discuss specific patterns of frontotemporal atrophy that denote clinical and pathological subtypes of FTD (e.g. semantic dementia). We also discuss the unsatisfactory clinical experience of interpreting MRI scans in individual FTD cases, especially the behavioural presentations (without aphasic or motor impairments). This issue is explored by examining the FTD phenocopy concept. Lobar atrophy emerges as a key observation in defining behavioural FTD patients whose symptoms are likely to progress. In a situation where objective clinical data are few, we highlight the importance of applying caution before diagnosing FTD is the absence of visible brain atrophy.</p

Disgust and happiness recognition correlate with anteroventral insula and amygdala volume respectively in preclinical Huntington's disease

Patients with Huntington's disease (HD) can show disproportionate impairments in recognizing facial signals of disgust, but the neural basis of this deficit remains unclear. Functional imaging studies have implicated the anterior insula in the ability to recognize disgust, but have identified other structures as well, including the basal ganglia. In view of variable insula and basal ganglia volume changes in HD, we used voxel-based morphometry to map regional variations in gray matter (GM) volume in participants carrying the mutation for HD, and correlated this with their performance on a test of facial emotion recognition for six basic emotions (disgust, fear, anger, happiness, sadness, surprise). The volume of the anteroventral insula was strongly correlated with performance on the disgust recognition task. The amygdala volume (bilaterally) correlated with the ability to recognize happy facial expressions. There was marked specificity of the regional correlations for the emotion involved. Recognition of other emotion expressions, or more general cognitive or motor performance as measured by a standardized rating scale, did not correlate with regional brain volume in this group. Control participants showed no effect for any measure. The strong linear correlations for disgust and happiness recognition imply direct involvement of the anterior insula in disgust appreciation, and a similar role for the amygdala in recognizing happy facial expressions. The absence of a significant correlation with the basal ganglia suggests a less critical role for these structures in disgust recognition than has previously been suggested. The findings also highlight the role of neurodegenerative diseases combined with statistical imaging techniques in elucidating the brain basis of behavior and cognition

The impact of regional 99mTc-HMPAO single-photon-emission computed tomography (SPECT) imaging on clinician diagnostic confidence in a mixed cognitive impairment sample

AIM:To assess the clinical impact of regional cerebral blood flow (rCBF) single-photon-emission computed tomography (SPECT) imaging on diagnosis and clinician diagnostic confidence in a cohort of individuals with cognitive impairment. MATERIALS AND METHODS:Forty-one clinicians who referred 79 patients for a [99mTc]-hexamethylpropyleneamine oxime (HMPAO) SPECT for cognitive complaints completed a two-part questionnaire to determine the diagnosis and diagnostic confidence (using a 0-100 visual analogue scale [VAS]) before and after imaging. SPECT images were analysed using statistical parametric mapping and interpreted semi-quantitatively. Clinicians were also asked directly for their opinion on whether the imaging contributed to their diagnostic process. RESULTS:Diagnosis changed after imaging in 44% of cases, and confidence was significantly improved (VAS score change= +26.3±22.2) after imaging in cases where the pre-imaging confidence was low (p&lt;0.001). Clinician confidence was not significantly different (VAS score change=-6.6±25.5) after imaging when pre-imaging confidence was moderate to high. Interestingly, a proportion of clinicians with the highest confidence levels became less certain about their diagnosis following imaging results. When asked directly, 96% of clinicians stated that the imaging contributed to the diagnostic process. CONCLUSIONS:In a mixed clinical cognitive impairment cohort, perfusion SPECT is valued by referring clinicians and contributes to diagnostic decision making. Imaging is of particular value when diagnostic confidence is low prior to imagin

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

Neuropsychology of frontotemporal dementia

Frontotemporal dementia (FTD), also known as frontal variant (fv-FTD) or behavioral variant (bv-FTD), presents with disturbed behavior. The chapter describes two language variants: semantic dementia (SD), known also as temporal variant FTD (tv-FTD) and a progressive nonfluent aphasic syndrome (PNFA). A wide range of neuropsychological tests have been applied to patients with FTD in order to characterize their deficits, and to distinguish them from patients who have other neurodegenerative disorders. Symptoms in FTD are related to the underlying structures involved in the pathological process, and not to the nature of the pathology itself. There are reliable symptom clusters which define syndromes, but there is several language and behavioral features that show significant overlap between the different variants of FTLD. Future work needs to continue to delineate the relevant neural substrates of the disturbed cognition in these patients. As the nature of the disease becomes clearer, it is likely that the disease will be recognized in more patients, particularly those over the age of 65 who have previously been given a diagnosis of Alzheimer's disease. Despite substantial progress in delineating the features of this disease, there remains no effective treatment, either symptomatic or curative

Hybrid simulation modelling for dementia care services planning

Dementia is an increasing problem in today’s ageing society, and meeting future demand for care is a major concern for policy-makers and planners. This paper presents a novel hybrid simulation model that simultaneously takes population-level and patient-level perspectives to calculate the numbers of patients at different stages of disease severity over time, and their associated care costs. System Dynamics is used at population level to capture ageing, dementia onset, and all-cause mortality, whereas disease progression is modelled at individual patient level using Agent-Based methods. This enables the model to account for variability between patients in the rate of cognitive decline, dementia-related mortality and response to treatment interventions. Using epidemiological data from the medical literature, disease progression is modelled via a longitudinal clustering method to identify progression type, followed by mixed-effects regression to reflect each individual’s rate of cognitive decline. Results are presented for population data from the south of England, and show that the currently available interventions have only modest effects at population level

Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study

Background and objectives: regional cerebral atrophy occurs in carriers of the Huntington’s disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change.Methods: thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject’s early to late T1 images.Results: over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra.Conclusions: while these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD

Supplementary Material for: Imaging Care Requirements: Use of Functional Neuroimaging to Predict Dementia Caregiver Burden

<b><i>Background:</i></b> Dementia caregivers frequently report high stress, with increased burden associated with worse outcomes for both patients and caregivers. Although many studies relate clinical phenotypes to burden, the relationship between imaging pathology and burden, irrespective of diagnosis, is unknown. This study investigated the relationship between caregiver burden and patient regional cerebral blood flow in dementia. <b><i>Methods:</i></b> Seventy-sev en patients with cognitive impairment undergoing brain perfusion single-photon emission computed tomography imaging in normal clinical care and their caregivers were recruited. Caregiver burden was ranked from “little” to “severe” using the Zarit Burden Interview and perfusion values extracted from the patient images for predefined regions of interest. The associations between burden score and regional function on imaging were tested. <b><i>Results:</i></b> Burden score was significantly higher for caregivers of patients with abnormal perfusion compared to those with normal perfusion in the left and right frontal, right parietal, and right temporal lobes. No difference in burden was found in the left parietal or temporal groups. Correlations showed that a higher caregiver burden was associated with lower patient perfusion scores in the same regions. <b><i>Conclusion:</i></b> Caregiver burden is strongly related to the extent of frontal or right-predominant parietal or temporal lobe dysfunction. Regional abnormality on perfusion imaging can be used to facilitate identification of individuals who are likely to create a high burden on caregivers

Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia

Chromosome 13q14 deletions constitute the most common structural aberration in B-cell chronic lymphocytic leukemia (B-CLL). We constructed a high-resolution physical map covering the critical deleted region in B-CLL at 13q14 and flanking sequences. The order and position of both genomic markers and known genes were determined precisely. Three novel genes, CLLD6, CLLD7, and CLLD8, were isolated and characterized. The predicted protein sequence of CLLD6 revealed no homology with known proteins. However, both CLLD7 and CLLD8 predicted proteins contain known functional domains. CLLD7 has both an RCC1 and a BTB domain, and could thus be involved in cell cycle regulation by chromatin remodeling. CLLD8 contains a methyl-CpG binding, a preSET and a SET domain, suggesting that CLLD8 might be associated with methylation-mediated transcriptional repression. Mutation analysis of hematopoietic tumor cell lines and B-CLL tumor samples revealed no point mutations within the coding region of these three novel genes. The functional domains present within CLLD7 and CLLD8 suggest that the proteins may be involved in critical cellular processes such as cell cycle and transcriptional control and could therefore be directly or indirectly involved in leukemogenesi

Characterization of the 13q14 tumor suppressor locus in CLL: identification of ALT1, an alternative splice variant of the LEU2 gene.

Chromosome 13q14 deletions constitute the most common genetic abnormality in chronic lymphocytic leukemia (CLL). To identify the putative tumor suppressor gene targeted by 13q14 genomic loss, we completely sequenced and characterized a segment of 790 kb at 13q14 spanning the minimal region of loss in CLL. Transcribed sequences in the region were identified through database homology searches and exon-prediction analysis. Two-hundred kb at the centromeric end of the sequence contain five CpG islands, three previously identified genes LEU5/RFP2, LEU2, and LEU1, seven of seven EST clusters composed of >10 ESTs, and a large number of predicted exons. Homology searches against the mouse EST database have allowed us to identify a highly conserved alternative first exon of the LEU2 gene, giving rise to a novel transcript, ALT1 (GenBank accession no. AF380424), which originates within a G+C region in the vicinity of the D13S272 marker. Two novel 3' exons of LEU2 were also identified and are present in both LEU2 and ALT1 transcripts. However, we have not identified any mutations in leukemia cases, or alterations in expression of mRNAs in the region, that might directly implicate these mRNAs in the pathology of CLL. The centromeric end of the sequence, where all reported genes are located, contains twice the expected amount of ALU repeats, whereas the telomeric end is LINE1 rich and contains four LINE1 elements longer than 4 kb, including two full-length LINE1 sequences. This feature of the sequence may favor the occurrence of chromosomal rearrangements and may confer instability to the region, resulting in deletions that may inactivate an as yet unidentified tumor suppressor