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Nick C Fox

Publications and source records attributed to Nick C Fox.

At least 19 recordsLinked to original sources
PubMed2025

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Humans↗
PubMed2012

Clinical and biomarker changes in dominantly inherited Alzheimer's disease.

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

Age of Onset↗
PubMed2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

ATP-Binding Cassette Transporters↗
PubMed2006

Longitudinal stability of MRI for mapping brain change using tensor-based morphometry.

Measures of brain change can be computed from sequential MRI scans, providing valuable information on disease progression, e.g., for patient monitoring and drug trials. Tensor-based morphometry (TBM) creates maps of these brain changes, visualizing the 3D profile and rates of tissue growth or atrophy, but its sensitivity depends on the contrast and geometric stability of the images. As part of the Alzheimer's Disease Neuroimaging Initiative (ADNI), 17 normal elderly subjects were scanned twice (at a 2-week interval) with several 3D 1.5 T MRI pulse sequences: high and low flip angle SPGR/FLASH (from which Synthetic T1 images were generated), MP-RAGE, IR-SPGR (N = 10) and MEDIC (N = 7) scans. For each subject and scan type, a 3D deformation map aligned baseline and follow-up scans, computed with a nonlinear, inverse-consistent elastic registration algorithm. Voxelwise statistics, in ICBM stereotaxic space, visualized the profile of mean absolute change and its cross-subject variance; these maps were then compared using permutation testing. Image stability depended on: (1) the pulse sequence; (2) the transmit/receive coil type (birdcage versus phased array); (3) spatial distortion corrections (using MEDIC sequence information); (4) B1-field intensity inhomogeneity correction (using N3). SPGR/FLASH images acquired using a birdcage coil had least overall deviation. N3 correction reduced coil type and pulse sequence differences and improved scan reproducibility, except for Synthetic T1 images (which were intrinsically corrected for B1-inhomogeneity). No strong evidence favored B0 correction. Although SPGR/FLASH images showed least deviation here, pulse sequence selection for the ADNI project was based on multiple additional image analyses, to be reported elsewhere.

Aged↗
PubMed2006

Longitudinal MRI in progressive supranuclear palsy and multiple system atrophy: rates and regions of atrophy.

The rate of brain atrophy and its relationship to clinical disease progression in progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) is not clear. Twenty-four patients with PSP, 11 with MSA-P (Parkinsonian variant), 12 with Parkinson's disease, and 18 healthy control subjects were recruited for serial MRI scans, clinical assessments and formal neuropsychological evaluations in order to measure brain atrophy during life and its association with disease progression in PSP and MSA-P. Serial scans were registered and rates of whole brain atrophy calculated from the brain-boundary shift integral. Regional rates of atrophy were calculated in the brainstem (midbrain and pons), the cerebellum, the lateral and third ventricles as well as frontal and posterior inferior brain regions, by locally registering to a region of interest in order to derive a local boundary shift integral (BSI). 82% of recruited subjects completed serial MRI scans (17 PSP, 9 MSA-P, 9 Parkinson's disease patients and 18 healthy controls). Mean (SD) annualized rates of whole-brain atrophy were greatest in PSP: 1.2% (1.0%), three times that in controls. Mean (SD) midbrain atrophy rates in PSP, 2.2% (1.5%), were seven times greater than in healthy controls. In MSA-P, atrophy rates were greatest in the pons: 4.5% (3.2%), over 20 times that in controls and three times the rate of pontine atrophy in PSP. Atrophy rates in Parkinson's disease were not significantly different from control rates of atrophy. Variability in the atrophy rates was lower when calculated using the BSI rather than manual measurements. Worsening motor deficit was associated with midbrain atrophy in PSP, and ponto-cerebellar atrophy in MSA-P. Worsening executive dysfunction was associated with increased rates of frontal atrophy in PSP. Cerebellar atrophy rates were better discriminators of MSA-P than cross-sectional volumes. We confirm that serial MRI can be applied to measure whole brain and regional atrophy rates in PSP and MSA-P. Regional rather than whole-brain atrophy rates better discriminate PSP and MSA-P from healthy controls. Clinico-radiological associations suggest these regional atrophy rates have potential as markers of disease progression in trials of novel therapies.

Aged↗
PubMed2006

Atrophy rates of the cingulate gyrus and hippocampus in AD and FTLD.

This study explores the diagnostic utility of atrophy rates of the cingulate gyrus, its subdivisions and the hippocampus in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Regions were manually outlined on MR images of a group of pathologically or genetically confirmed patients with AD (n=19), FTLD (n=8) and age-matched controls (n=11). Mean (S.D.) atrophy rates (%year(-1)) in the cingulate in controls, AD and FTLD were -0.3 (1.2), 5.9 (3.5), and 8.6 (4.1), respectively. Hippocampal atrophy rates in controls, AD and FTLD were -0.1 (0.8), 3.4 (2.2), and 5.2 (5.4), respectively. Atrophy rates were significantly higher in the cingulate and hippocampi in AD and FTLD compared with controls (p<0.01). There was evidence of a difference in trends of atrophy in the cingulate (more anterior in FTLD and more posterior in AD) between the disease groups (p=0.03). Cingulate atrophy rates discriminated perfectly between FTLD and controls. Significantly better discrimination between AD and controls was obtained by hippocampal rather than cingulate rates. In conclusion, cingulate atrophy is as significant a feature of AD and FTLD as hippocampal atrophy.

Alzheimer Disease↗
PubMed2006

Differential regional atrophy of the cingulate gyrus in Alzheimer disease: a volumetric MRI study.

Magnetic resonance imaging-based volumetric measurements provide a useful technique for quantifying in vivo regional cerebral atrophy in Alzheimer disease (AD). Histopathological studies have shown the cingulate cortex, a cytoarchitectonically heterogeneous region, to be severely affected in AD. In this study, we developed and validated a manual segmentation protocol, based on macroscopic characteristics such as gyri and sulci patterns, in order to assess volumetric changes in 4 cingulate regions of interest. Cingulate cortical volumes of 10 familial AD patients were compared with 10 age- and sex-matched controls. Inter- and intrarater reliability coefficients were high for all cingulate regions (91.9-99.4%). All 4 cingulate regions were significantly smaller (P < 0.05) in AD cases compared with controls: rostral anterior cingulate gyrus (22.5% smaller), caudal anterior cingulate gyrus (20.7% smaller), posterior cingulate gyrus (44.1% smaller), and retrosplenial cortex (21.5% smaller). The atrophy in the posterior cingulate region was significantly greater than that in other cingulate regions (P < 0.001), suggesting a higher vulnerability for this region in familial AD. Considering the functional and connectional differences of these 4 cingulate regions, detection and monitoring of their atrophy may provide insights into the natural history of AD and may help in the search for diagnostic markers for early AD.

Alzheimer Disease↗
PubMed2006

Measurements of the amygdala and hippocampus in pathologically confirmed Alzheimer disease and frontotemporal lobar degeneration.

BACKGROUND: Differentiating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) can be difficult, particularly in the earliest stages of the diseases. Patterns of atrophy on magnetic resonance imaging may help distinguish these diseases and aid diagnosis. OBJECTIVE: To assess the diagnostic utility of magnetic resonance imaging-derived amygdala and hippocampal volumes from patients with pathologically proved AD and FTLD. DESIGN: Cross-sectional volumetric magnetic resonance imaging study of the hippocampus and amygdala. SETTING: Specialist cognitive disorders clinic. Subjects Thirty-seven subjects, including 10 patients with pathologically proved AD, 17 patients with pathologically proved FTLD, and 10 age-matched control subjects. MAIN OUTCOME MEASURES: Hippocampal and amygdala volumes. RESULTS: Geometric mean amygdala and hippocampal volumes were, respectively, 15.0% (95% confidence interval [CI], 4.2%-24.5%) and 16.4% (95% CI, 5.9%-25.6%) lower in the AD than in the control group. In FTLD, the equivalent differences were 43.1% (95% CI, 31.9%-52.6%) in the amygdala and 36.1% (95% CI, 27.5%-43.7%) in the hippocampus. Volumes were significantly lower in the FTLD than in the AD group (P<.01 in both regions). Within the FTLD clinical subgroups, there was evidence of a difference in pattern of atrophy with greater asymmetry (left smaller than right) in semantic dementia compared with frontal variant FTLD (P<.001). On average, the left hippocampus was 14% smaller in semantic dementia than in frontal variant FTLD, whereas the right hippocampus was 37% larger. On average, the left amygdala was 39% smaller in semantic dementia than in frontal variant FTLD, whereas the right amygdala was only 1% smaller. CONCLUSIONS: Hippocampal atrophy is not specific to AD or FTLD. However, severe or asymmetrical amygdala atrophy should suggest FTLD. Atrophy patterns follow clinical syndromes rather than pathology.

Adult↗
PubMed2006

Amyloid load and cerebral atrophy in Alzheimer's disease: an 11C-PIB positron emission tomography study.

To determine the relationship between cerebral amyloid plaque load and rates of cerebral atrophy in Alzheimer's disease. (11)C-PIB((11)C-6-OH benzothiazole)PET (positron emission tomography) findings were correlated with volumetric magnetic resonance imaging (MRI) measurements in nine subjects with mild to moderate AD. Analysis revealed a positive correlation between rates of whole brain atrophy and whole brain (p = 0.019) and regional (11)C-PIB uptake. This provides support for the central role of amyloid deposition in the pathogenesis of AD.

Aged↗
PubMed2006

Magnetic resonance imaging measures of brain atrophy in multiple sclerosis.

Magnetic resonance imaging (MRI) has been widely used to diagnose and monitor multiple sclerosis (MS). Although MRI-visible lesions are a key feature of MS, they are thought to correlate poorly with clinical progression. Neurodegeneration is increasingly being recognized as an important factor in the pathogenesis of MS, and MRI measures of brain atrophy have been suggested as surrogate markers of neuroaxonal loss and disease progression. This pathology may be more relevant to the progression of disability than focal inflammation. A number of MRI-based methods have been developed for the measurement of global and regional brain atrophy. Natural-history studies of MS and clinically isolated syndromes suggestive of MS have observed atrophy in these subjects above that seen in controls, over periods ranging from three months to years. Brain atrophy has also been incorporated as an outcome measure in therapeutic trials of disease-modifying treatments. This paper considers neuroaxonal loss and the pathological basis of brain atrophy, methods developed to quantify brain atrophy, the findings of natural-history and therapeutic studies, the relationship of brain atrophy to disability and cognition, and the future research directions and clinical applications of brain atrophy measurements.

Atrophy↗
PubMed2006

Regional brain volumes distinguish PSP, MSA-P, and PD: MRI-based clinico-radiological correlations.

Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are neurodegenerative disorders, each with a prevalence of around 5 per 100,000. Regional brain atrophy patterns differ in the two disorders, however, and magnetic resonance imaging is sometimes helpful in distinguishing them in the later stages. We measured whole brain and regional volumes, including cerebellum, pons, midbrain, superior cerebellar peduncle (SCP), and ventricular volumes as well as frontal and posterior-inferior cerebral regions in 18 subjects with PSP, 9 with MSA-P (parkinsonian phenotype), 9 with Parkinson's disease (PD), and 18 healthy controls. Associations between these volumes, cognitive profiles, and clinical measures of disease severity and motor disability were assessed. Mean midbrain volume was 30% smaller in PSP than in PD or controls (P < 0.001) and 15% smaller than in MSA-P (P = 0.009). The mean SCP volume in PSP was 30% smaller than in MSA-P, PD, or controls (P < 0.001). Mean cerebellar volumes in MSA-P were 20% smaller than in controls and PD and 18% smaller than in PSP (P = 0.01). Mean pontine volume in MSA-P was 30% smaller than in PD or controls (P < 0.001) and 25% smaller than in PSP (P = 0.01). Motor disability was most strongly associated with midbrain volume, and more severe executive dysfunction was associated with reduced frontal volume. These distinct patterns of cortical and subcortical atrophy, when considered together rather than independently, better differentiate PSP and MSA-P from each other and also from healthy controls.

Aged↗
PubMed2006

Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study.

BACKGROUND: Serial MRI scanning of autosomal dominant mutation carriers for Alzheimer's disease provides an opportunity to track changes that could predate symptoms or clinical diagnosis of the disease. We used hierarchical modelling to assess how hippocampal and whole-brain volumes change as familial Alzheimer's disease progresses from the presymptomatic stage through to diagnosis. METHODS: Nine mutation carriers had serial clinical assessments and volumetric MRI scans (41 scans: range 3-8 per patient) at different clinical stages (presymptomatic, mild cognitive impairment, or clinical Alzheimer's disease). 25 healthy controls had serial scanning (54 scans: range 2-4 per patient) for comparison. We measured whole brain and total hippocampal volumes using semi-automated techniques, and adjusted for total intracranial volume. Hierarchical models were developed to estimate differences in volume and atrophy rate between mutation carriers and controls in relation to when the disease was clinically diagnosed. FINDINGS: Mutation carriers had significantly increased hippocampal and whole-brain atrophy rates compared with controls and these differences increased with time. Differences in hippocampal and whole-brain atrophy rates between controls and mutation carriers were evident 5.5 and 3.5 years, respectively, before diagnosis of Alzheimer's disease. At a cross-sectional level, differences in mean hippocampal volume between mutation carriers and controls became significant 3 years before clinical diagnosis, whereas differences in mean brain volumes became significant only 1 year before diagnosis. INTERPRETATION: Structural changes can be seen on MRI scans that predate the clinical onset of familial Alzheimer's disease. Longitudinal measures of atrophy rates can identify differences between mutation carriers and controls 2-3 years earlier than cross-sectional volumetric measures.

Adult↗
PubMed2006

New developments in mild cognitive impairment and Alzheimer's disease.

PURPOSE OF REVIEW: In this paper, we review current concepts of Alzheimer's disease, recent progress in diagnosis and treatment and important developments in our understanding of its pathogenesis with a focus on beta-amyloid both as culprit and therapeutic target. RECENT FINDINGS: The amyloid cascade hypothesis of Alzheimer's disease pathogenesis continues to predominate with evidence suggesting that small oligomeric forms of Abeta-42 rather than fibrils or senile plaques are the key pathological substrates. The concept of mild cognitive impairment continues to be refined to define better those patients who will progress to Alzheimer's disease. Structural and functional imaging techniques and cerebrospinal fluid biomarkers are gaining acceptance as diagnostic markers of Alzheimer's disease, with a potentially exciting advance being the ability to image amyloid in vivo using novel positron emission tomography ligands. Whilst available treatments afford only symptomatic benefits, disease-modifying treatments may be within reach. Despite the halting of the first amyloid beta-vaccination trial due to adverse effects, amyloid immunotherapy continues to show promise, with new approaches already entering clinical trials. Other therapeutic strategies under investigation include inhibition of beta -and gamma-secretase, key enzymes implicated in Alzheimer's disease pathogenesis. SUMMARY: Current research demonstrates the potential for diagnostic strategies and disease modifying treatments to follow from an ever more detailed understanding of the molecular mechanisms underlying the pathogenesis of Alzheimer's disease.

Alzheimer Disease↗
PubMed2006

Phenomenological model of diffuse global and regional atrophy using finite-element methods.

The main goal of this work is the generation of ground-truth data for the validation of atrophy measurement techniques, commonly used in the study of neurodegenerative diseases such as dementia. Several techniques have been used to measure atrophy in cross-sectional and longitudinal studies, but it is extremely difficult to compare their performance since they have been applied to different patient populations. Furthermore, assessment of performance based on phantom measurements or simple scaled images overestimates these techniques' ability to capture the complexity of neurodegeneration of the human brain. We propose a method for atrophy simulation in structural magnetic resonance (MR) images based on finite-element methods. The method produces cohorts of brain images with known change that is physically and clinically plausible, providing data for objective evaluation of atrophy measurement techniques. Atrophy is simulated in different tissue compartments or in different neuroanatomical structures with a phenomenological model. This model of diffuse global and regional atrophy is based on volumetric measurements such as the brain or the hippocampus, from patients with known disease and guided by clinical knowledge of the relative pathological involvement of regions and tissues. The consequent biomechanical readjustment of structures is modelled using conventional physics-based techniques based on biomechanical tissue properties and simulating plausible tissue deformations with finite-element methods. A thermoelastic model of tissue deformation is employed, controlling the rate of progression of atrophy by means of a set of thermal coefficients, each one corresponding to a different type of tissue. Tissue characterization is performed by means of the meshing of a labelled brain atlas, creating a reference volumetric mesh that will be introduced to a finite-element solver to create the simulated deformations. Preliminary work on the simulation of acquisition artefacts is also presented. Cross-sectional and longitudinal sets of simulated data are shown and a visual classification protocol has been used by experts to rate real and simulated scans according to their degree of atrophy. Results confirm the potential of the proposed methodology.

Alzheimer Disease↗
PubMed2005

A volumetric magnetic resonance imaging study of the amygdala in frontotemporal lobar degeneration and Alzheimer's disease.

The amygdala is severely atrophied at post-mortem in frontotemporal lobar degeneration (FTLD), and may contribute to the prominent behavioural changes that are early features of FTLD. The aim of this study was to assess amygdala atrophy using MRI in the main syndromic variants of FTLD and Alzheimer's disease (AD). Brain and amygdala volumes, adjusted for intracranial volume, were measured on 46 clinically diagnosed FTLD patients [22 frontal variant FTD (FTD), 14 semantic dementia (SD), 10 progressive non-fluent aphasia (PNFA)], 20 AD patients, and 17 controls. While severe amygdala atrophy was present in both FTLD (41% smaller than controls on the left; 33% on the right) and in AD (22% on the left; 19% on the right), the FTLD group had significantly greater amygdala atrophy (z = 3.21, p = 0.001 left, z = 2.50, p = 0.01 right) and left/right asymmetry (z = 2.03, p = 0.04) than AD. Amygdala atrophy was greater in SD than FTD, PNFA and AD (p < 0.02 for all). Highly asymmetrical atrophy was present in SD, greater on the left (z = 3.23, p = 0.001), and to a lesser extent in PNFA. Despite an overlap between clinical and radiological features of FTLD and AD, marked amygdala atrophy points towards a diagnosis of FTLD, with left greater than right atrophy suggestive of one of the language variants.

Aged↗
PubMed2005

Does Alzheimer's disease affect hippocampal asymmetry? Evidence from a cross-sectional and longitudinal volumetric MRI study.

OBJECTIVE: To determine whether Alzheimer's disease (AD) is associated with preferential atrophy of either the left or right hippocampus. METHODS: We examined right-left asymmetry in hippocampal volume and atrophy rates in 32 subjects with probable AD and 50 age-matched controls. Hippocampi were measured on two serial volumetric MRI scans using a technique that minimizes laterality bias. RESULTS: We found a non-significant trend for right > left (R > L) asymmetry in controls at both time points (R > L: 1.7%; CI: -0.3-3.7%; p = 0.1). AD subjects showed a similar non-significant trend for R > L asymmetry at baseline (R > L: 1.8%; CI: -1.9-5.5%; p = 0.32), but not at repeat (p = 0.739). Change in R/L ratio between visits in AD patients was significant (p = 0.02). The AD group had significantly higher variance in these ratios than the controls at baseline (p = 0.02), but not repeat (p = 0.06). AD patients had higher atrophy rates than controls (p < 0.001). Mean (CI) annualized atrophy rates for left and right hippocampi were 1.2% (0.5-1.8%) and 1.1% (0.5-1.8%) for the controls, and 4.6% (3.3-6.0%) and 6.3% (4.9-7.8%) for AD subjects. There was no significant asymmetry in atrophy rates in controls (p = 0.9), but borderline significantly higher atrophy rates in the right hippocampus of the AD group (p = 0.05) compared to the left. Presence of an APOEepsilon4 allele had no significant effect on the size, asymmetry or atrophy rates in AD (p > 0.20). CONCLUSIONS: We report minor R > L asymmetry in hippocampal volumes in controls and present some evidence to suggest that there is a change in the natural R > L asymmetry during the progression of AD.

Aged↗
PubMed2005

Sporadic and familial dementia with ubiquitin-positive tau-negative inclusions: clinical features of one histopathological abnormality underlying frontotemporal lobar degeneration.

BACKGROUND: Frontotemporal lobar degeneration comprises a group of diseases with clinical presentations and underlying histopathologies that overlap. Familial disease occurs in up to 50% of frontotemporal lobar degeneration cases. One of several underlying histopathological abnormalities is of ubiquitin-positive tau-negative inclusions, similar to those in motor neuron disease. OBJECTIVE: To compare clinical features of familial and sporadic cases in this pathological subgroup. DESIGN AND PATIENTS: Case note review of dementia patients with ubiquitin-positive tau-negative inclusion pathological abnormalities proven by autopsy. SETTING: United Kingdom tertiary referral center. MAIN OUTCOME MEASURES: Analysis of clinical features. RESULTS: Eleven familial cases (autosomal dominant) and 18 sporadic cases were identified. Most familial case patients presented with behavioral disturbances similar to those seen in sporadic behavioral cases. Semantic dementia was only seen in sporadic cases. Atypical features occurred in a minority. Sporadic and familial behavioral cases showed no differences in age at onset or disease duration. Neuropsychological test results revealed frontal or temporal deficits in most, but unexpected early parietal deficits in 1. CONCLUSIONS: Behavioral features in familial and sporadic cases were similar, but semantic dementia only occurred in sporadic cases. Diagnostic confusion with Alzheimer disease and corticobasal degeneration occurred in some cases.

Age of Onset↗