Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder.
We collected blood samples from a cohort of 225 patients with a diagnosis within ...the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease.
A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1).
These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation.
Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimer's disease. Three groups of 10 ...subjects were studied: semantic dementia patients, Alzheimer's disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimer's disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left‐sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimer's disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimer's disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role. Ann Neurol 2001;49:433–442
Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and pathologically heterogeneous neurodegenerative disorder. Two subtypes commonly present with a language disorder: semantic ...dementia (SemD) and progressive nonfluent aphasia (PNFA).
Patients meeting consensus criteria for PNFA and SemD who had volumetric MRI of sufficient quality to allow cortical thickness analysis were recruited from a tertiary referral clinic: 44 (11 pathologically confirmed) patients with SemD and 32 (4 pathologically confirmed) patients with PNFA and 29 age-matched and gender-matched healthy controls were recruited. Cortical thickness analysis was performed using the Freesurfer software tools.
Patients with SemD had significant cortical thinning in the left temporal lobe, particularly temporal pole, entorhinal cortex, and parahippocampal, fusiform, and inferior temporal gyri. A similar but less extensive pattern of loss was seen in the right temporal lobe and (with increasing severity) also in left orbitofrontal, inferior frontal, insular, and cingulate cortices. Patients with PNFA had involvement particularly of the left superior temporal lobe, inferior frontal lobe, and insula, and (with increasing severity) other areas in the left frontal, lateral temporal, and anterior parietal lobes. Similar patterns were seen in the pathologically confirmed cases. Patterns of cortical thinning differed between groups: SemD had significantly more cortical thinning in the temporal lobes bilaterally while PNFA had significantly more thinning in the frontal and parietal lobes.
The language variants of frontotemporal lobar degeneration have distinctive and significantly different patterns of cortical thinning. Increasing disease severity is associated with spread of cortical thinning and the pattern of spread is consistent with progression of clinical deficits.
Objectives: To determine the prevalence of dementia in people under the age of 65 in a large catchment area, and use these figures to estimate the number of younger people affected by dementia in the ...UK. Design: Epidemiological catchment area prevalence survey. Setting: The London boroughs of Kensington and Chelsea, Westminster, and Hillingdon with a total population of 567 500 people. Participants: All residents of the catchment area with dementia, where the illness began before the age of 65 years. Participants were notified to the study by medical and care professionals. The diagnosis and age of onset was established from all available health and social care records. In total, 227 people were identified, of whom 185 fulfilled the inclusion criteria of having a dementia which started before their 65th birthday. Main outcome measures: Diagnosis of dementia and differential diagnosis of the cause of the dementia. Results: The prevalence of dementia in those aged 30–64 was 54.0 per 100 000 (95% CI 45.1 to 64.1 per 100 000). For those aged 45–64 years, the prevalence was 98.1 per 100 000 (95% CI 81.1 to 118.0 per 100 000). From the age of 35 onwards, the prevalence of dementia approximately doubled with each 5 year increase in age. Extrapolating these figures nationally suggests that there are 18 319 (15 296–21 758) people with dementia under the age of 65 in the UK. Conclusions: The study confirms previous “guestimates” of the number of younger people affected by dementia in UK. The prevalence figures generated are robust, and are supported by other smaller and targeted prevalence surveys. The prevalence figures provided by this study will allow health planners to accurately estimate need and plan services.
Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the ...heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.
Frontotemporal lobar degeneration is currently associated with three syndromic variants. Disorders of speech and language figure prominently in two of the three variants, and are associated with ...left-sided frontotemporal atrophy. The detailed characterization of these syndromes contrasts with the relative paucity of information relating to frontotemporal lobar degeneration primarily affecting the right cerebral hemisphere. The objective of this study was to identify the clinical profile associated with asymmetrical, predominantly right-sided, temporal lobe atrophy. Twenty patients with predominant right temporal lobe atrophy were identified on the basis of blinded visual assessment of the MRI scans. The severity of right temporal lobe atrophy was quantified using volumetric analysis of the whole temporal lobes, the amygdala and the hippocampus. Profiles of cognitive function, behavioural and personality changes were obtained on each patient. The pattern of atrophy and the clinical features were compared with those observed in a group of patients with semantic dementia and predominant left-sided temporal lobe atrophy. The mean right temporal lobe volume in the right temporal lobe atrophy group was reduced by 37%, with the mean left temporal lobe volume reduced by 19%. There was marked atrophy of the right hippocampus and right amygdala, with mean volumes reduced by 41 and 51%, respectively (left hippocampus and amygdala volumes were reduced by 18 and 33%, respectively). The most prominent cognitive deficits were impairment of episodic memory and getting lost. Prosopagnosia was a symptom in right temporal lobe atrophy patients. These patients also exhibited a variety of behavioural symptoms including social disinhibition, depression and aggressive behaviour. Nearly all behavioural disorders were more prevalent in the right temporal lobe atrophy patient group than the semantic dementia group. Symptoms particular to the right temporal lobe atrophy patient group included hyper-religiosity, visual hallucinations and cross-modal sensory experiences. The combination of clinical features associated with predominant right temporal lobe atrophy differs significantly from those associated with the other syndromes associated with focal degeneration of the frontal and temporal lobes and it is, therefore, proposed that this right temporal variant should be considered a separate syndromic variant of frontotemporal lobar degeneration.
Alzheimer's disease (AD) is characterized by progressive cerebral atrophy, which may be assessed by using volumetric MRI. We describe a voxel-based analysis of nonlinear-registered serial MRI to ...demonstrate the most statistically significant (P < 0.001) regions of change at different stages of the disease. We compared presymptomatic (n = 4), mild (n = 10), and moderately affected (n = 12) patients with early- and late-onset AD, with age- and sex-matched controls, and demonstrated increasing global atrophy with advancing disease. Significantly increased rates of hippocampal atrophy were seen in presymptomatic and mildly affected patients. There was a shift in the distribution of temporal lobe atrophy with advancing disease; the inferolateral regions of the temporal lobes showed the most significantly increased rates of atrophy by the time the patients were mildly or moderately affected. Significantly increased rates of medial parietal lobe atrophy were seen at all stages, with frontal lobe involvement occurring later in the disease. Our results suggest that the sites showing the most significant rates of atrophy alter as the disease advances, and that regional atrophy is already occurring before the onset of symptoms. This technique provides insights into the natural history of AD, and may be a valuable tool in assessing the efficacy of disease-modifying treatments, especially if these treatments were to have region-specific effects.
Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. ...Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.
To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD).
The authors previously described an extended tau haplotype (H1) that covers ...the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD.
The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls.
Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X(2) = 9.1, p = 0.00255 1df, OR 3.56 8.43 > CI 95% > 1.53). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X(2) = 17.42, p = 0.00016, 2df), OR 3.61 7.05 > CI 95% > 1.85).
The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.
Three causative genes have been identified for autosomal dominant AD.
To determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these ...genes.
A mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) <61 years.
The mean AAO was 46.9 years (median 45 years; range 33 to 60 years). The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APP, PSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001).
Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD; no mutations in PSEN2 were detected. There may be a further genetic factor involved in the etiology of autosomal dominant early onset AD.
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