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To examine the usefulness of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis (ALS) Screen (ECAS) as a cognitive screening tool for the detection of behavioral variant frontotemporal dementia (bvFTD). A secondary aim was to determine whether people with FTD combined with ALS (ALS-FTD) exhibit a similar ECAS profile to that of people with bvFTD alone. Methods: Patients with ALS-FTD and bvFTD and healthy controls were recruited. Participants were administered the ECAS, which comprises tests of language, verbal fluency, executive functions, memory, and visual-spatial functions. They also carried out analogous, full-length cognitive tests that examine naming, spelling, sentence completion, and social cognition skills. Results: The study cohort comprised 20 ALS-FTD patients, 23 with bvFTD, and 30 controls. Highly significant group differences were elicited for all cognitive domains, reflecting poorer performance in patients compared to controls. No significant differences in overall test scores were found between ALS-FTD and bvFTD patients, although ALS-FTD patients showed a higher frequency of impairment on verbal fluency. Correlative analyses revealed inter-relationships in patients (but not controls) between scores in different domains, most marked in bvFTD. There were strong correlations between performance on ECAS subtests and analogous cognitive tasks. Conclusion: The ECAS is a sensitive and valuable tool for the assessment of FTD. Executive, language and behavioral breakdown may, however, compromise performance in other cognitive domains, reducing the specificity of the ‘frontotemporal’ cognitive profile. Subtle differences observed between ALS-FTD and bvFTD raise questions regarding the precise relationship between bvFTD with and without ALS.

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

ObjectiveThe precise relationship between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is incompletely understood. The association has been described as a continuum, yet data suggest that this may be an oversimplification. Direct comparisons between patients who have behavioural variant FTD (bvFTD) with and without ALS are rare. This prospective comparative study aimed to determine whether there are phenotypic differences in cognition and behaviour between patients with FTD-ALS and bvFTD alone.MethodsPatients with bvFTD or FTD-ALS and healthy controls underwent neuropsychological testing, focusing on language, executive functions and social cognition. Behavioural change was measured through caregiver interview. Blood samples were screened for known FTD genes.Results23 bvFTD, 20 FTD-ALS and 30 controls participated. On cognitive tests, highly significant differences were elicited between patients and controls, confirming the tests’ sensitivities to FTD. bvFTD and FTD-ALS groups performed similarly, although with slightly greater difficulty in patients with ALS-FTD on category fluency and a sentence-ordering task that assesses grammar production. Patients with bvFTD demonstrated more widespread behavioural change, with more frequent disinhibition, impulsivity, loss of empathy and repetitive behaviours. Behaviour in FTD-ALS was dominated by apathy. The C9ORF72 repeat expansion was associated with poorer performance on language-related tasks.ConclusionsDifferences were elicited in cognition and behaviour between bvFTD and FTD-ALS, and patients carrying the C9ORF72 repeat expansion. The findings, which raise the possibility of phenotypic variation between bvFTD and FTD-ALS, have clinical implications for early detection of FTD-ALS and theoretical implications for the nature of the relationship between FTD and ALS.

A failure of protein degradation may underpin Lewy body disease (LBD) where α-synuclein is assimilated into the pathognomic Lewy bodies and Lewy neurites. We investigated histological alterations in lysosomes and autophagosomes in the substantia nigra (SN) and cingulate gyrus (CG) in 34 patients with LBD employing antibodies against phosphorylated α-synuclein and lysosomal (lysosomal associated membrane proteins 1 and 2 (LAMP-1 and LAMP-2), cathepsin D (CTSD)) and autophagosomal (microtubule-associated protein light chain 3α (LC3A)) proteins. Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining. Four LBD patients had mutations in GBA1. There was significantly less LAMP-1, LAMP-2 and CTSD immunostaining in neurons of the SN in LBD cases compared to control cases and marginally less LAMP-1 in patients with GBA1 mutations compared to those without. Loss of LAMP-1 and CTSD immunoreactivity correlated with cell loss from the SN. There were no changes in LC3A immunoreactivity in the SN, nor any major changes in the CG, or glial cell activity in the SN and CG, for any of the markers. A proportion of amyloid plaques in both the LBD and control cases was immunoreactive for LAMP-1 and LAMP-2, but not CTSD or LC3A proteins. These immunohisochemical features were seen in glial cells, which were negative for amyloid-β. Alterations in lysosomal structure or function, but not macroautophagy, may underpin the pathogenesis of LBD.

The Last Act of Love , Cathy Rentzenbrink’s account of her brother Matty’s traumatic brain injury and consequent permanent vegetative state, was the first non-fiction book read by our neurology book club. This acclaimed memoir charts the family’s 8-year journey, starting with the initial shock of Matty’s accident and hopes for recovery, through a growing acceptance of his irreversible neurological impairment, and his eventual death following withdrawal of clinically assisted nutrition and hydration. Rentzenbrink’s prose vividly portrays her grief at the loss of her brother, and the lasting impact of his injury on her life. Through her eyes we also witness reactions of family, friends and society at large, both illuminating and poignant. The prominent theme of the first part of the book is the emotional challenge faced by the family in dealing with Matty’s vegetative state, a grey area between the …

Sporadic early-onset Alzheimer’s disease (sEOAD) exhibits the symptoms of late-onset Alzheimer’s disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer’s disease (AD) identifies APOE ε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer’s Project consortium, with association data from 17,008 late-onset Alzheimer’s disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy.

Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer’s disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aβ, with higher levels of Aβ40 promoting a more ‘aggressive’ form of CAA, and higher levels of Aβ42(3) favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD. Electronic supplementary material The online version of this article (10.1007/s00401-018-1866-3) contains supplementary material, which is available to authorized users.

Background: A proportion of patients with behavioural variant frontotemporal dementia (bvFTD) develop amyotrophic lateral sclerosis (ALS). It is currently unknown whether the behavioural and cognitive syndrome in bvFTD with ALS (ALS-FTD) is indistinguishable from that of bvFTD alone. Methods: A retrospective cohort of 241 patients with clinical diagnoses of bvFTD (n=185) or ALS-FTD (n=56) was examined with respect to behavioural, cognitive and neuropsychiatric symptoms. Features were rated as present or absent based on information recorded from clinical interviews and detailed neuropsychological assessment. Results: A number of behavioural and affective changes were reported more frequently in bvFTD than ALS-FTD: social disinhibition (p

Background Clinical criteria are important for improving diagnostic accuracy and ensuring comparability of patient cohorts in research studies. Objective The aim was to assess the National Institute on Aging and Alzheimer's Association (NIA-AA) criteria for Alzheimer's disease (AD) dementia in AD and frontotemporal lobar degeneration (FTLD). Methods Two hundred twelve consecutive patients with pathologically confirmed AD or FTLD who were clinically assessed in a specialist cognitive unit were identified. Fifty-five patients were excluded predominantly because of insufficient clinical information. Anonymized clinical data were rated against the NIA-AA criteria by raters who were blinded to clinical and pathologic diagnosis. Results The NIA-AA AD dementia criteria had a sensitivity of 65.6% for probable and 79.5% for possible AD and a specificity of 95.2% and 94.0% for probable and possible, respectively. Conclusion In patients with FTLD and predominantly early-onset AD, the NIA-AA AD dementia criteria have high specificity but lower sensitivity. The high specificity is due to the broad exclusion criteria.

Guillain-Barre syndrome (GBS) comprises a group of acute onset immune mediated polyradiculoneuropathies that are the leading cause of acute onset paralysis in the developed world.1 Management incorporates supportive care of the paralysed patient and immunomodulatory treatment. Active prevention and early treatment of complications, including venous thromboembolism (VTE), may help to improve outcomes. Over 25 000 people die in the UK each year as a result of VTE complicating a hospital admission.2 As a result, national guidelines have been produced to support decision-making regarding the most appropriate strategy of VTE prophylaxis, taking into account the bleeding risk associated with the use of anticoagulation.2 Prolonged flaccid limb weakness and the use of intravenous immunoglobulin are risk factors for the development of VTE in patients with GBS.3 While consensus statements regarding VTE prophylaxis in those with GBS do exist, these are often based on evidence from studies involving postoperative patients and as such do not specifically address the risk-benefit profile of various VTE prophylaxis regimens in GBS.4 At a recent mortality review meeting at our institution, we discussed the case of a 45-year-old patient with GBS in the intensive treatment unit (ITU) who died as a result of bleeding from his tracheostomy. Given his acute severe flaccid paralysis, he was prescribed ‘high dose’ (175 units/kg of subcutaneous tinzaparin per day equivalent) low molecular weight heparin (LMWH) for VTE prophylaxis, as per local practice. Concern was raised that this anticoagulant regimen may have contributed to the occurrence of bleeding and that other patients may be similarly at risk. We, therefore, performed an audit to assess the use of VTE prophylaxis in this patient group. Consecutive patients admitted with GBS (excluding those with Miller Fisher syndrome and Miller Fisher-GBS overlap) to our institution between …

We have screened sporadic early-onset Alzheimer’s disease (sEOAD, n=408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found two sEOAD individuals harbouring a known causative variant in PARK2 known to cause early-onset Parkinson’s disease (EOPD); p.T240M (n=1) and p.Q34fs delAG (n=1). Additionally, we identified three sEOAD individuals harbouring a predicted pathogenic variant in MAPT (p.A469T) which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration.

Aims:? We aimed to investigate the role of the nuclear carrier and binding proteins, transportin-1 (TRN1) and transportin-2 (TRN2), TATA-binding protein-associated factor 15 (TAF15) and Ewing's Sarcoma protein (EWS) in inclusion body formation in cases of Frontotemporal Lobar Degeneration (FTLD) associated with Fused in Sarcoma protein (FTLD-FUS). Methods:? Eight cases of FTLD-FUS (5 cases of atypical FTLD-U (aFTLD-U), 2 of Neuronal Intermediate Filament Inclusion Body Disease (NIFID) and 1 of Basophilic Inclusion Body Disease (BIBD)) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. 10 cases of FTLD associated with TDP-43 inclusions served as reference cases. Results:? The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD. Conclusion:? Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements. � 2012 The Authors. Neuropathology and Applied Neurobiology � 2012 British Neuropathological Society.

Early-onset Alzheimer's disease (EOAD) can be familial (FAD) or sporadic EOAD (sEOAD); both have a disease onset ≤65 years of age. A total of 451 sEOAD samples were screened for known causative mutations in exons 16 and 17 of the amyloid precursor protein (APP) gene. Four samples were shown to be heterozygous for 1 of 3 known causative mutations: p.A713T, p.V717I, and p.V717G; this highlights the importance of screening EOAD patients for causative mutations. Additionally, we document an intronic 6 base pair (bp) deletion located 83 bp downstream of exon 17 (rs367709245, IVS17 83-88delAAGTAT), which has a nonsignificantly increased minor allele frequency in our sEOAD cohort (0.006) compared to LOAD (0.002) and controls (0.002). To assess the effect of the 6-bp deletion on splicing, COS-7 and BE(2)-C cells were transfected with a minigene vector encompassing exon 17. There was no change in splicing of exon 17 from constructs containing either wild type or deletion inserts. Sequencing of cDNA generated from cerebellum and temporal cortex of a patient harboring the deletion found no evidence of transcripts with exon 17 removed.

The association between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is well recognised, with the majority of reports describing the behavioural form of FTD (bvFTD).1 Semantic dementia (SD) and progressive non-fluent aphasia (PNFA) have only rarely been reported alongside ALS. Nevertheless, there have been a number of recent reports of language abnormalities in patients with ALS, with some authors arguing that they may be even more common than behavioural/executive impairments.2 ,3 Such findings raise the question of the relationship between SD and PNFA and ALS. To date, there has been no systematic study of the relative prevalence of bvFTD, PNFA and SD in patients with and without accompanying ALS. We examined relative frequencies in a large consecutive cohort of patients with clinical forms of FTD and suspected frontotemporal lobar degeneration pathology. We examined our clinical databases for all patients referred to a specialist dementia clinic within a neuroscience department between 1980 and 2016, diagnosed with one of the canonical clinical syndromes of FTD: bvFTD, SD or PNFA, or mixed variants of those syndromes. Clinical classifications were in line with diagnostic criteria for these syndromes published by Neary et al 4 in 1998. Most patients also fulfilled recent criteria, respectively, for bvFTD, semantic variant and non-fluent variants of primary progressive aphasia, although the SD classification included patients with right-predominant temporal lobe atrophy in whom face recognition impairments preceded problems in word comprehension. Patients were included only if they had undergone a full neurological examination and comprehensive neuropsychological …

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the Fused in Sarcoma gene (FUS) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22-46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the "stereotypic" form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the FUS gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in FUS in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive 'stereotypic' picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the FUS gene cause some cases of FTLD remains unresolved.

Alzheimer’s disease (AD) manifests with progressive memory loss and decline of spatial awareness and motor skills. Neurofibrillary tangles (NFTs) represent one of the pathological hallmarks of AD. Previous studies suggest that the enzyme prolyl-peptidyl cis–trans isomerase PIN1 [protein interacting with NIMA (never in mitosis A)-1] recognizes hyperphosphorylated tau (in NFTs) and facilitates its dephosphorylation, thereby recovering its function. This study aims to determine the frequency, severity and distribution of PIN1 immunoreactivity and its relationship to NFTs and other neuropathological markers of neurodegeneration such as amyloid-β (Aβ) plaques and transcription-responsive DNA-binding protein of Mr 43 kDa (TDP-43). Immunohistochemical analysis of 194 patients (46 with AD, 43 with Parkinson’s disease/dementia with Lewy bodies, 12 with progressive supranuclear palsy/corticobasal degeneration, 36 with frontotemporal lobar degeneration, 21 with motor neuron disease and 34 non-demented (ND) individuals) revealed an increased frequency and severity of PIN1 immunoreactive inclusions in AD as compared to all diagnostic groups (P < 0.001). The hippocampal and cortical distribution of PIN1 granules was distinct from that of NFTs, Aβ and TDP-43 pathologies, though the frequency of neurons with PIN1 immunoreactivity increased with increasing NFT pathology. There was a progressive increase in PIN1 changes in ND individuals as the degree of AD-type pathological changes increased. Present findings indicate that PIN1 changes are a constant feature of AD pathology and could serve as a biomarker of the onset or spread of AD neuropathology independent of tau or Aβ.

Frontotemporal lobar degeneration (FTLD) is generally recognised as a disorder with presenile onset (that is before 65 years of age) with only occasional cases presenting later than this. We set out to determine what proportion of cases of FTLD had late onset of disease and whether such cases of FTLD had distinctive clinical and neuropathological features as compared to cases with presenile onset. Within a combined Manchester and Newcastle autopsy series of 117 cases with pathologically confirmed FTLD (109/117 cases also met Lund Manchester clinical criteria for FTLD), we identified 30 cases (onset age range 65-86 years), comprising 25% of all FTLD cases ascertained in these two centres over a 25-year period. Neuropathologically, the 30 elderly cases presented features of several FTLD histological subgroups [FTLD-TDP (types 1, 2 and 3, 19 cases (63%)], FLTD-tau [MAPT, PiD and CBD, 10 cases (33%)] and FTLD-UPS (1 case), similar in range of phenotypes to that seen in the presenile group, though patients with MAPT, but not PGRN, mutation, or FUS pathology, were notably absent or fewer in the elderly group. Hippocampal sclerosis (HS) was present in 13/30 of the elderly FTLD cases (43%) compared with 14/79 (18%) (P = 0.012) in the presenile FTLD patients. Lobar atrophy present in most of the younger patients was prominent in only 25% of the elderly subjects. Prospective and retrospective psychiatric and medical case note analysis showed that the majority of the elderly FTLD patients, like their younger counterparts, had behavioural features consistent with frontotemporal dementia. FTLD is common amongst elderly persons and all or most of the major clinical and histological subtypes present in younger individuals can be seen in the older group.

Two hundred and twenty-three consecutive patients fulfilling clinical diagnostic criteria for frontotemporal lobar degeneration (FTLD), and 259 patients with motor neuron disease (MND), for whom genomic DNA was available, were investigated for the presence of mutations in tau (MAPT) and progranulin (PGRN) genes. All FTLD patients had undergone longitudinal neuropsychological and clinical assessment, and in 44 cases, the diagnosis had been pathologically confirmed at post-mortem. Six different PGRN mutations were found in 13 (6%) patients with FTLD. Four apparently unrelated patients shared exon Q415X 10 stop codon mutation. However, genotyping data revealed all four patients shared common alleles of 15 SNPs from rs708386 to rs5848, defining a 45.8-kb haplotype containing the whole PGRN gene, suggesting they are related. Three patients shared exon 11 R493X stop codon mutation. Four patients shared exon 10 V452WfsX38 frameshift mutation. Two of these patients were siblings, though not apparently related to the other patients who in turn appeared unrelated. One patient had exon 1 C31LfsX34 frameshift mutation, one had exon 4 Q130SfsX130 frameshift mutation and one had exon 10 Q468X stop codon mutation. In addition, two non-synonymous changes were detected: G168S change in exon 5 was found in a single patient, with no family history, who showed a mixed FTLD/MND picture and A324T change in exon 9 was found in two cases; one case of frontotemporal dementia (FTD) with a sister with FTD+MND and the other in a case of progressive non-fluent aphasia (PNFA) without any apparent family history. MAPT mutations were found in 17 (8%) patients. One patient bore exon 10 + 13 splice mutation, and 16 patients bore exon 10 + 16 splice mutation. When PGRN and MAPT mutation carriers were excluded, there were no significant differences in either the allele or genotype frequencies, or haplotype frequencies, between the FTLD cohort as a whole, or for any clinical diagnostic FTLD subgroup, and 286 controls or between MND cases and controls. However, possession of the A allele of SNP rs9897526, in intron 4 of PGRN, delayed mean age at onset by approximately 4 years. Patients with PGRN and MAPT mutations did not differ significantly from other FTLD cases in terms of gender distribution or total duration of illness. However, a family history of dementia in a first-degree relative was invariably present in MAPT cases, but not always so in PGRN cases. Onset of illness was earlier in MAPT cases compared to PGRN and other FTLD cases. PNFA, combined with limb apraxia was significantly more common in PGRN mutation cases than other FTLD cases. By contrast, the behavioural disorder of FTD combined with semantic impairment was a strong predictor of MAPT mutations. These findings complement recent clinico-pathological findings in suggesting identifiable associations between clinical phenotype and genotype in FTLD.

We wished to determine whether patients with amyotrophic lateral sclerosis (ALS) show behavioural changes similar to those of frontotemporal dementia (FTD). There is accumulating evidence to suggest a link between ALS and FTD, yet there has been little systematic exploration of behaviour in ALS. An informant based semi-structured behavioural interview, sensitive to the behavioural changes of FTD, was administered to carers of 16 consecutive patients attending a motor neuron disease clinic. Findings varied across the group. At one extreme informants reported no behavioural change, whereas at the other they reported a spectrum of behaviours similar to those seen in FTD. Changes in affect and social behaviour were most common, although some patients also showed altered response to sensory stimuli, gluttony and indiscriminate eating, behavioural stereotypies and compulsions. Behavioural changes were mirrored by SPECT abnormalities in the frontal and/or temporal lobes. Thus, behavioural changes of the type seen in FTD may be present even in a small consecutive cohort of ALS patients. Detection of behavioural change is crucial for optimal management.

Our objective was to compare the clinical and pathological characteristics of frontotemporal dementia patients with MAPT, GRN and C9orf72 gene mutations. We carried out a cross-sectional comparative study of 74 gene-positive patients (15 MAPT, 17 GRN and 42 C9orf72). Thirty had post mortem pathological data permitting clinico-pathological correlation. MAPT patients were younger than other groups, and showed more frequent behavioural disinhibition, repetitive and stereotyped behaviours, semantic impairment and temporal predominance of atrophy. GRN patients were older at death and more likely to present with non-fluent aphasia. C9orf72 patients alone showed a co-occurrence of ALS. They showed more psychotic symptoms and irrational behaviour, yet were more often reported clinically as socially appropriate and warm. They showed less dietary change than other groups. C9orf72 patients with and without ALS differed only in frequency of psychosis. Greater clinical overlap was observed between GRN and C9orf72 compared to MAPT cases. MAPT cases had tau and GRN and C9orf72, with one exception, TDP-43 pathology. Non-fluent aphasia was linked to TDP subtype A in both GRN and C9orf72 cases and ALS with subtype B. In conclusion, the findings reinforce clinical heterogeneity in FTD and strengthen evidence that genotype influences clinical presentation. Clinical features may inform targeted genetic testing.

Frontotemporal lobar degeneration (FTLD) refers to a focal, non-Alzheimer form of cerebral degeneration that encompasses the distinct clinical syndromes of frontotemporal dementia (FTD), progressive non-fluent aphasia (PNFA) and semantic dementia. Some patients show tau-based pathological changes and in familial cases mutations have been identified in the microtubule-associated protein tau gene (MAPT) on chromosome 17q21. However, many cases are tau-negative, showing instead ubiquitin-immunoreactive (UBQ-ir) neuronal cytoplasmic inclusions and neurites, and in some familial cases UBQ-ir neuronal intranuclear inclusions of a lentiform appearance. Very recently, mutations have been identified in familial cases in the progranulin (PGRN) gene, also on chromosome 17q21. Clinical, pathological and molecular diversity within FTLD highlights the importance of careful examination of clinical-pathological-genetic relationships. This paper reports, for the first time, a clinico-pathological investigation of two FTLD families with PGRN mutations, and compares the clinical characteristics with those of patients studied in the department with MAPT mutations. The clinical profile associated with PGRN mutations constituted, in some patients, a prototypical picture of FTD and in others one of PNFA, both profiles occurring within the same family. Patients with PGRN mutations exhibited phonological deficits, whereas in patients with MAPT mutations language abnormalities, when present in addition to the prominent behavioural disorder, take the form of semantic disturbance. The findings provide compelling evidence for the link between FTD and PNFA, while raising the possibility of identifiable clinical differences between FTLD patients with MAPT and PGRN mutations.

We have investigated the pathological correlates of dementia in the brains from a consecutive series of 70 patients dying with a clinical diagnosis of frontotemporal lobar degeneration (FTLD). Clinical misdiagnosis rate was low with only 3 patients (4%) failing to show pathological changes consistent with this diagnosis; 1 patient had Alzheimer's disease and 2 had cerebrovascular disease (CVD). In the remaining 67 patients, the most common underlying histological cause was ubiquitin pathology with 24 (36%) cases so affected. In these, ubiquitin-positive inclusions were present in the cerebral cortex as small, rounded or crescent-shaped structures within the cytoplasm of neurones of layer II, together with coiled or curvilinear bodies within neurites, and in the hippocampus as small, solid and more spherical-shaped inclusion bodies within the cytoplasm of dentate gyrus granule cells. In one patient, "cat's eye" or "lentiform" intranuclear ubiquitin inclusions were also present. The second most common histological type was dementia lacking distinctive histology (DLDH), in which neither tau nor ubiquitin inclusions were present, with 16 cases (24%) being affected. Pick-type histology was seen in 14 cases (21%) and tau histological changes associated with frontotemporal dementia (FTD) linked to chromosome 17 (FTDP-17) were present in 11 cases (16%). One case (1%) showed an unusual tau pathology that could not be allocated to any of the other tau groups. Only 1 case (1%) had neuronal intermediate filament inclusion dementia. No cases with ubiquitinated, valosin-containing protein-immunoreactive intranuclear inclusion bodies of the type seen in inclusion body myopathy with Paget's disease of bone and frontotemporal dementia were seen. Clinicopathological correlation showed that any of these histological subtypes can be associated with FTD. However, for FTD with motor neurone disease (FTD+MND), semantic dementia or primary progressive aphasia (PA), the histological profile was either ubiquitin type or DLDH type; Pick-type histology was seen in only 1 case of PA. None of these latter three clinical subtypes was associated with a mutation in tau gene and FTDP-17 type of tau pathology. All cases of progressive apraxia were associated with Pick-type histology. Present data therefore indicate that, although ubiquitin pathology is the most common histological form associated with FTLD, this pathology is not tightly linked with, nor is pathologically diagnostic for, any particular clinical form of the disease, including FTD+MND.

Background The extreme delta brush (EDB) pattern is considered pathognomonic of anti-NMDAR encephalitis. Ketamine, a NMDA receptor antagonist has induced a similar pattern on EEG when used as an anaesthetic or for refractory epilepsy. We present a case of EDB without a diagnosis of anti-NMDAR encephalitis but with possible ketamine use. Case An 18 year old male who regularly uses illicit drugs including cannabis and benzodiazepines, presented to hospital after a road traffic accident with aggression and agitation. He self-discharged and was found collapsed with severe hypoxia secondary to pneumonia. On ICU he developed stereotyped movements of the limbs with oral-facial movements. An EEG demonstrated global cortical dysfunction with an EDB pattern. He had bilateral acute pallidal and corona radiata signal change on MRI, suggestive of hypoxic injury. CSF was unremarkable. He was treated for presumed seizures but was not immunosuppressed. He subsequently improved and admitted to using ketamine infrequently. CSF and serum NMDA receptor antibodies were later confirmed as negative. Conclusions This is the second reported case of EDB without a diagnosis of anti-NMDAR encephalitis. The EDB could be explained by the suspected ketamine use, which may suggest it is specific for NMDA receptor blockade rather than encephalitis.

Clinicogenetic and pathological studies have shown that mutations of the glucocerebrosidase gene (GBA) are a risk factor for Parkinson’s disease and Lewy body disorders. In the present study, we have identified GBA mutations in 6.8% (4/59) of cases with a pathological diagnosis of diffuse Lewy body disease. Taken with previous studies, it appears that GBA mutations are associated with a more diffuse pattern of Lewy body distribution involving the cerebral cortex than the brainstem/limbic distribution observed in typical Parkinson’s disease.

Cognitive impairment is common in patients with the neurodegenerative tauopathy progressive supranuclear palsy (PSP). Although a pattern of 'subcortical' cognitive impairment is considered prototypical in PSP, pathological and clinical observations suggest an overlap with frontotemporal dementia (FTD). Our objective was to evaluate behavioural and cognitive symptoms in a retrospective study of patients with PSP syndrome (PSPS) and their relationship to features seen in behavioural variant FTD. We reviewed the records of 62 patients (29 male, 33 female, median age 65.5 years) evaluated at a tertiary cognitive clinic who met NINDS-SPSP criteria for probable or possible PSP, and collected clinical details of their presenting history, cognitive and behavioural features. We also evaluated the proportion of patients fulfilling FTD Consensus criteria. Cognitive and behavioural symptoms were a predominant presenting feature in 58% of patients evaluated. Cognitive slowing, executive impairments, and inefficient memory recall, consistent with 'subcortical' impairment, were identified in the majority of patients. Twenty patients (32%) fulfilled cognitive and behavioural criteria for possible FTD at initial assessment, whereas behavioural changes not meeting formal diagnostic criteria were present in a greater proportion of the patients. Our findings support the existence of a spectrum of cognitive-behavioural features in PSPS, with significant clinical overlap with behavioural variant FTD. Cognitive and behavioural profiling should be an integral part of the assessment of patients with PSPS.

Mutations in the gene p62/SQSTM1 have been reported as a relatively rare cause of frontotemporal lobar degeneration (FTLD). To establish whether this was the case for cases of FTLD from the United Kingdom, we sequenced the sequenced the entire open reading frame of this gene in a large cohort of patients. We identified 3 novel mutations in p62/SQSTM1 in 4 patients. One of these was a premature stop codon that removed the last 101 amino acids of the protein that presumably has a negative effect on protein function. Another mutation was also found in a case with a repeat expansion mutation in C9orf72 confirmed by Southern blot. These findings confirm a role of p62/SQSTM1 as a cause of FTLD.

Important insights into the pathogenic mechanism of Alzheimer's disease (AD) have arisen from the identification of genetic risk factors. Recently, a variant in the TREM2 gene (rs75932628), causing a C-to-T base-pair change that results in the substitution of histidine for arginine at amino acid position 47 (R47H) in the TREM2 protein, has been associated with an increased risk of AD. We, therefore, genotyped samples from a cohort of 474 AD patients and 608 healthy controls, from the northwest region of the UK, using allelic discrimination assays, to replicate the results of the previous studies. We show a significant association of the T allele of the rs75932628 variant of TREM2 with AD (allelic odds ratio 11.08, 95% confidence interval 2.55-48.09, and Yates' corrected p value = 0.000146). TREM2 is an innate immune receptor that regulates microglial cytokine production and phagocytosis, implying that dysregulation of these processes may be involved in AD pathology, with implications for disease management.

We previously reported1 that expansions in the C9orf7 2 gene, identified by Southern blotting or using a repeat primed PCR assay,2 may go undetected using an alternative, standard PCR assay.3 We attributed this discrepancy to a 10 base pair deletion adjacent to the expansion which was presumed to interfere with genotyping.1 To determine the possible clinical and pathological relevance of the deletion, we compared patients in whom the C9orf72 expansion was detected using the Renton3 assay (C9 reference group) with those carrying an expansion not detected by this method (deletion group). The criteria for inclusion in the study were: (A) patients had been investigated and diagnosed with dementia within a single, specialist dementia clinic, (B) they had donated DNA as part of an ethically approved study into the molecular genetics of dementia and (C) expansions in the C9orf72 gene were identified using one or more standard procedures.1–3 An additional patient, in whom pathological examination showed p62 positive neuronal inclusions immunoreactive for the dipeptide repeat proteins, poly-GA, poly-GP and poly-GR, was also included since such histological findings are considered pathognomonic of the presence of an expansion in C9orf72 .4 …

Summary Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes— MAPT , GRN , and C9orf72 —have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p −8 ) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p −8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 −8 ; odds ratio=1·204 [95% CI 1·11–1·30]), rs9268856 (p=5·51 × 10 −9 ; 0·809 [0·76–0·86]) and rs1980493 (p value=1·57 × 10 −8 , 0·775 [0·69–0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38 / CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 −7 ; 0·814 [0·71–0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis . Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.

Objective: We aimed to determine the extent to which patients with progressive language impairment conform to 2011 primary progressive aphasia (PPA) classification and to examine clinicopathologic correlations within PPA variants. Methods: Sixty-two consecutive patients with pathologically confirmed dementia who presented clinically with aphasia were identified. Patients with insufficient clinical information were excluded. PPA classifications were applied to anonymized clinical data taken from patients9 initial assessment by raters who were blinded to clinical and pathologic diagnosis. Results: The final cohort comprised 52 patients, 30 of whom met basic PPA criteria. Twenty-five patients met one of the 3 PPA classifications (13 logopenic, 8 nonfluent/agrammatic, and 4 semantic). Five patients did not meet the criteria for any of the PPA variants. All patients who met semantic variant PPA and 75% of patients who met nonfluent/agrammatic variant PPA classifications had frontotemporal lobar degeneration spectrum pathology. Pathologies were heterogeneous in patients who met logopenic variant PPA criteria (46% Alzheimer disease [AD], 8% AD mixed with dementia with Lewy bodies, 23% frontotemporal lobar degeneration, and 23% other). Conclusion: The 2011 PPA recommendations classify a large proportion of patients who meet basic PPA criteria. However, some patients had aphasic syndromes that could not be classified, suggesting that the 2011 recommendations do not cover the full range of PPA variants. Classification of semantic variant PPA provides a good prediction of underlying pathology. Classification of logopenic variant does not successfully differentiate PPA due to AD from PPA due to other pathologies.

Objective: We aimed to assess sensitivity and specificity of the updated criteria for behavioral variant frontotemporal dementia (bvFTD) based on a large autopsy-confirmed cohort of patients with dementia. Methods: Two hundred thirty-nine consecutive pathologically confirmed dementia patients, clinically assessed in a specialist cognitive unit were identified. Patients with predominant aphasia, motor disorders, or insufficient clinical information were excluded. Frontotemporal Dementia Consensus criteria were applied to anonymized clinical data taken from patients9 initial assessment by raters who were blinded to clinical and pathologic diagnosis. Results: The final study cohort comprised 156 patients with predominantly early-onset dementia. The updated criteria for possible bvFTD had a sensitivity of 95% and specificity of 82%. Probable bvFTD criteria had a sensitivity of 85% and specificity of 95%. False positives were predominantly patients with presenile Alzheimer disease. Conclusion: Revised diagnostic criteria show encouragingly high sensitivity and specificity when applied to patients with early-onset dementia. They therefore provide a useful tool both for specialist researchers and general clinicians. There is a need for further prospective studies of sensitivity and specificity involving a broader spectrum of patients with dementia.

Repeat expansions in C9orf72 are a major cause of frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Not all FTD-ALS patients show expansions. The study examined whether there are clinical differences between FTD-ALS patients with and without expansions in C9orf72. We examined case notes from consecutive FTD-ALS patients, screened for C9orf72 expansions, and documented demographic, neurological, behavioural and cognitive characteristics. Sixty patients met the selection criteria, of whom 11 showed expanded repeats (C9-positive) and 49 did not (C9-negative). A strong male bias was present in the C9-negative group only. A family history of FTD or ALS was recorded in both groups, but was significantly more common in C9-positive cases. Psychotic and irrational behaviours, apathy, disinhibition and loss of empathy were significantly more common in C9-positive cases, with a trend towards more frequent bulbar signs. No differences were found in onset age, presentation (ALS or FTD first), or cognitive changes (language and executive impairments). In conclusion, FTD-ALS is not clinically uniform. Phenotypic differences exist between patients with and without C9orf72 expansions, suggesting that FTD-ALS may be underpinned by distinct neurobiological substrates. The presence of psychiatric symptoms in the context of FTD-ALS should alert clinicians to the possibility of C9orf72 expansions.

Frontotemporal lobar degeneration (FTLD) is a highly familial neurodegenerative disease. It has recently been shown that the most common genetic cause of FTLD and amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion in C9ORF72. To investigate whether this expansion was specific to the FTLD/ALS disease spectrum, we genotyped the hexanucleotide repeat region of C9ORF72 in a large cohort of patients with Alzheimer's disease (AD). A normal range of repeats was found in all cases. We conclude that the hexanucleotide repeat expansion is specific to the FTLD/ALS disease spectrum.

Accuracy of clinical diagnosis of dementia is increasingly important for therapeutic and scientific investigations. In this study, we examine diagnostic accuracy in a consecutive series of 228 patients referred to a specialist early-onset dementia clinic, whose brains were subsequently examined at post-mortem. Diagnosis was based on structured history, neurological examination and neuropsychological assessment, with emphasis on qualitative as well as quantitative aspects of performance. Neuroimaging provided support for but did not alter the clinical diagnosis. We set out the principles that guided diagnosis: (i) time course of illness; (ii) weighting of physical, behavioural and cognitive symptoms and signs; (iii) 'anterior' versus 'posterior' hemisphere character of cognitive change; and (iv) specificity of deficit, paying attention to the differentiation between syndromes of frontotemporal lobar degeneration and focal forms of Alzheimer's disease. Forty-two per cent of the patients had clinical diagnoses of one of the syndromes of frontotemporal lobar degeneration, the high proportion reflecting the research interests of the group. Forty-six per cent were diagnosed with Alzheimer's disease and the remaining patients, dementia with Lewy bodies, Creutzfeldt-Jakob disease, vascular or unclassified dementia. Frontotemporal lobar degeneration was identified with 100% sensitivity and 97% specificity and Alzheimer's disease with 97% sensitivity and 100% specificity. Patients with other pathologies were accurately identified on clinical grounds. Examination of subsyndromes of frontotemporal lobar degeneration showed a relatively predictable relationship between clinical diagnosis and pathological subtype. Whereas the behavioural disorder of frontotemporal dementia was associated with tau, transactive response DNA binding protein 43 and fused-in-sarcoma pathology, cases of frontotemporal dementia with motoneuron disease, semantic dementia and, with one exception, progressive non-fluent aphasia were associated with transactive response DNA binding protein 43 pathology, distinguished by ubiquitin subtyping (types B, C and A, respectively). Clinical diagnoses of progressive apraxia, corticobasal degeneration and progressive supranuclear palsy were, with one exception, associated with Pick, corticobasal and progressive supranuclear palsy subtypes of tau pathology, respectively. Unanticipated findings included Alzheimer pathology in two patients presenting with the behavioural syndrome of frontotemporal dementia and corticobasal pathology in four others with clinical frontotemporal dementia. Notwithstanding such anomalies, which serve as a reminder that there is not an absolute concordance between clinical phenotype and underlying pathology, the findings show that dementias can be distinguished in life with a high level of accuracy. Moreover, careful clinical phenotyping allows prediction of histopathological subtype of frontotemporal lobar degeneration. The principles guiding diagnosis provide the foundation for future prospective studies.

Frontotemporal lobar degeneration is a highly familial disease and the most common known genetic cause is the repeat expansion mutation in the gene C9orf72. We have identified 2 brothers with an expansion mutation in C9orf72 using Southern blotting that is undetectable using repeat-primed polymerase chain reaction. Sequencing using high concentrations of DNA denaturants of a bacterial artificial chromosome clone obtained from one of the brothers identified a 10-base pair deletion adjacent to the expansion that presumably confers strong secondary structure that interferes with the genotyping. Using an alternative method, we have identified missed expansion carriers in our cohort, and this number has increased by approximately 25%. This observation has important implications for patients undergoing genetic testing for C9orf72.

Objective: To determine whether polymorphic variations in the apolipoprotein E gene ( APOE ) are associated with increased risk of frontotemporal lobar degeneration (FTLD) when mutation in tau gene is absent. Methods: The APOE gene was genotyped by polymerase chain reaction from DNA routinely extracted from blood or brain tissues. The APOE e4 allele frequency in 198 patients with FTLD not associated with mutations in tau gene was compared with that of a control group of 756 normal individuals drawn from the same geographical region. Analyses were done according to clinical subtype or sex. Results: The APOE e4 allele frequency (19.4%) was increased (p = 0.01) in FTLD v the whole control group (14.1%), while the APOE e2 allele frequency in FTLD (6.5%) was slightly lower than in controls (8.0%) (NS). The APOE e4 allele frequency in men with FTLD (22.3%) was greater (p = 0.002) than in male controls (12.3%); the frequency in women (16.3%) was similar to that in female controls (14.8%) (NS). The APOE e2 allele frequency in men with FTLD was 4.9% while in male controls it was 9.5% (p = 0.06), but there was no difference in women (7.5% v 7.9%, NS). Neither the APOE e2 nor APOE e4 allele frequency varied significantly between any of the clinical subtypes. Conclusions: In FTLD not associated with mutations in tau gene, possession of APOE e4 allele in men roughly doubles the chances of developing disease, whereas this has no impact upon disease risk in women.

Hexanucleotide repeat expansions in the C9ORF72 gene are an important cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis.1 ,2 Whether they have a role in other conditions remains unclear.3 ,4 We previously identified in FTD a strong association between repeat expansions in C9ORF72 and the presence of psychosis.4 This raises the question whether C9ORF72 expansions might also have a role in dementia with Lewy bodies (DLB), in which hallucinations and delusions are prevalent. The study addressed this question. The cohort comprised 102 consecutive patients who fulfilled criteria for ‘probable DLB’, exhibiting at least two of the cardinal features: fluctuating …

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are considered to be part of a disease spectrum. However, with the exception of C9orf72, genes that cause ALS are rarely found to cause FTD and vice versa. To investigate this further, we have sequenced the ALS gene UBQLN2 in our FTD cohort and have found a single putative mutation. This further supports the concept that ALS genes are a rare cause of FTD.

After Alzheimer’s disease, dementia with Lewy bodies (DLB) is probably the second most common cause of dementia among the elderly, having been shown to account for around 20% of cases at necropsy.1 Pathologically, DLB is characterised by the presence of Lewy bodies within the cerebral cortex, especially the parahippocampal gyrus, cingulate gyrus and temporal neocortex, amygdala, and within brain stem nuclei, principally the substantia nigra and locus caeruleus.1 Nonetheless, histopathological changes classically associated with Alzheimer’s disease (amyloid plaques and neurofibrillary tangles) are frequently widespread within the cerebral cortex of patients with DLB.1,2 Although most cases of DLB appear to arise sporadically, cases with a previous family history of similar disorder are known, suggesting that genetic factors may …

Genetic screening of 171 patients with frontotemporal lobar degeneration disclosed 14 patients, across nine pedigrees, with mutations in the intron to exon 10 in the tau gene, a region regulating the splicing of exon 10 via a stem loop mechanism. Thirteen of these patients had the +16 splice site mutation and one had the +13 splice site mutation. Affected members of all nine families presented with changes in behaviour and social conduct that were prototypical of frontotemporal dementia (FTD). In all patients with the +16 splice site mutation, the behavioural profile was characterized by disinhibition, restless overactivity, a fatuous affect, puerile behaviour and verbal and motor stereotypies. The single patient with the +13 mutation presented a contrasting picture of apathy and inertia. In addition, all patients had evidence of semantic loss. Pathologically, five of the six patients so far autopsied shared frontotemporal atrophy with involvement of the substantia nigra. The underlying histology was that of microvacuolar-type cortical degeneration with a few swollen cells. Tau pathology was widespread throughout the brain and present in neurones and glial cells, mostly in the frontal and temporal cortical regions. This was in the form of neurofibrillary tangles and amorphous tau deposits (pre-tangles); Pick bodies were not observed. Ultrastructurally, the tau filaments had a twisted, ribbon-like morphology distinct from the paired helical filaments of Alzheimer's disease. One patient died from an unrelated illness whilst in the early clinical stages of FTD. In this patient, cortical microvacuolar and astrocytic changes were absent, though there were scattered neurones and glial cells, immunoreactive to tau, throughout the cortical and subcortical regions. The disease process underlying the neurodegeneration within these inherited forms of FTD may therefore stem directly from early, primary alterations in the function of tau. All eight families with the +16 mutation seem to be part of a common extended pedigree, possibly originating from a founder member residing within the North Wales region of Great Britain.

Background Deposits of fibrillar amyloid β (Aβ) protein are important in the pathophysiology of Alzheimer9s disease (AD), but not in frontotemporal dementia (FTD). In vivo imaging of Aβ protein deposition, therefore, is a promising tool in the differential diagnosis of dementia syndromes. Previous pathological and imaging studies suggest that a minority of FTD patients may have coexistent Aβ deposition, possibly due to possession of the apolipoprotein E ( APOE ) e4 allele. We report a PET study using the novel Aβ ligand [18F]–florbetapir in patients with AD, FTD and healthy controls. Methods Ten healthy controls (mean age 62.5±5.2, MMSE 30), 10 AD patients (mean age 62.6±4.5 years, MMSE 10–24) and eight FTD patients (mean age 62.5±9.6, MMSE 0–30) were recruited to the study. All patients underwent detailed clinical and neuropsychological assessment, and were genotyped for APOE status. All participants underwent imaging with [18F]–florbetapir using the high–resolution research tomograph, and FTD patients also underwent [18F]–fluorodeoxyglucose (FDG) PET. Motion–corrected static florbetapir PET images (50–60 minutes post–injection) were coregistered with 3T volumetric T1–weighted MR images. Grey matter uptake values, intensity–normalised to the mean grey matter cerebellar uptake, were sampled from cortical and subcortical areas using a probabilistic anatomical atlas. Group differences were analysed using non–parametric Kruskal–Wallis test. Results Total cortical grey matter florbetapir uptake values were significantly higher in AD (mean uptake ratio 1.77±0.38) compared to FTD patients (1.25±0.36, p=0.002) and controls (1.29±0.11, p=0.04). Florbetapir uptake was also higher in AD in frontal, parietal, occipital and central subcortical regions. PET images of seven of the FTD patients were visually classed as amyloid negative. One FTD patient (homozygous for APOE e4) displayed high cortical florbetapir retention, with prominent mesiofrontal hypometabolism on FDG PET consistent with the clinical diagnosis. Three AD patients were APOE e4 homozygous, while three AD and three FTD patients were e3/4 heterozygotes. APOE e4 gene dosage did not appear to be directly related to amyloid load. Discussion Imaging amyloid deposition with [18F]–florbetapir in dementia contributes to differential diagnosis between AD and non–amyloid diseases such as FTD. Our findings are in line with previous reports of coexistent amyloid deposition in a small number of FTD patients. Florbetapir imaging will be of particular interest in subjects with progressive cognitive deficits that are difficult to classify clinically.

Alzheimer's disease (AD) is generally considered to be a disorder primarily affecting memory. It is increasingly recognized that the clinical presentation or "cognitive phenotype" is variable. The apolipoprotein E ε4 (APOE ε4) allele has been associated with an amnestic presentation, but does not appear to fully explain the high prevalence of family history within this group. We examined polymorphisms in the genes ACE and IDE in relation to cognitive phenotype. In this study 276 participants with AD were categorized into 1 of 4 cognitive phenotype classifications: typical, amnestic, language, and posterior. Family history and possession of the APOE ε4 allele were most prevalent in the amnestic group. Of the 10 genetic variants of IDE, and the 3 genetic variants of ACE studied, only ACErs4291 and ACErs1800764 were nominally associated with the amnestic presentation.

Frontotemporal lobar degeneration (FTLD) can occur jointly with amyotrophic lateral sclerosis (ALS), and these 2 conditions share a genetic risk factor on chromosome 9. It has been reported that mutations in optineurin (OPTN) can cause ALS. Therefore, we sequenced OPTN in 371 FTLD cases but no mutations were detected, suggesting changes in OPTN do not cause FTLD.

Frontotemporal lobar degeneration (FTLD) is a common cause of dementia especially in patients under the age of 65. FTLD has a high incidence of heritability with as many as 40% of patients reporting a family history of disease. Recently, the first genome wide association study was performed using only FTLD patients with a pathologically confirmed TDP-43 pathology. Genome wide significance was detected for a single gene (TMEM106B) on chromosome 7, though several other loci on chromosomes 1, 8, 9, 10 and 11 reached nominal significance. Here we have undertaken an attempt to replicate the association of these loci in FTLD cohorts of British origin. We failed to detect any association of TMEM106B in the Manchester or London cohort either when analyzed individually or when combined. Genotyping of the Manchester cohort failed to replicate any of the loci on chromosome 1, 8 and 10 but did detect association of the single SNP (rs2015747) on chromosome 11. Association was also observed in the London cohort but in the opposite direction. Combining the 2 datasets yielded no association. Analysis of the chromosome 9 locus, revealed strong association in the London FTLD cohort and the Manchester FTLD+ALS cases. These data confirm that FTLD and amyotrophic lateral sclerosis (ALS) share a common genetic risk factor on chromosome 9p.

Introduction 18F-AV-45 (Florbetapir F-18) is a novel 18F-labelled positron emission tomography (PET) tracer for in vivo imaging of cerebral amyloid deposition. Here we present preliminary results for differentiation between Alzheimer9s disease (AD) and frontotemporal dementia (FTD) using this novel tracer, which is being applied in the UK for the first time. Methods A study using 18F-AV-45 PET is to be performed in 15 subjects with AD, 15 subjects with FTD and 10 healthy controls (HC). All subjects undergo physical, biochemical and cognitive screening. In recruited subjects dynamic scanning was performed for 60 min after injection on a high-resolution PET scanner, and images were coregistered with 3D T1-weighted MRI. Tracer binding to amyloid was analysed using the cerebellum as the reference region, and comparing data to pooled data from the European Network on Diagnostic Molecular Imaging (DiMI) using the tracer 11C-Pittsburgh compound-B (PIB). Regions of interest were placed in frontal, temporal and parietal neocortical areas. Results To date eight subjects have been studied. Neocortical binding of AV-45 in these subjects is in the same range as observed with PIB. Nonspecific binding to white matter was observed in all subjects. Conclusion Binding of 18F-AV-45 to amyloid in AD has been confirmed, but was absent in FTD and HC. 18F-AV-45 is a promising new PET tracer for the in vivo imaging of amyloid deposition in AD, and the distinction from other forms of dementia.