Institue of Neurology

An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43-68 years) and duration (1.7-22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features

The UCHL-1 gene is widely cited as a susceptibility factor for sporadic Parkinson's disease (PD). The strongest evidence comes from a meta-analysis of small studies that reported the S18Y polymorphism as protective against PD, after pooling studies of white and Asian subjects. Here, we present data that challenge this association. Methods: In a new large case-control study in white individuals (3,023 subjects), the S18Y variant was not protective against PD under any genetic model of inheritance. Similarly, a more powerful haplotype-tagging approach did not detect other associated variants. Results: Finally, in an updated S18Y-PD meta-analysis (6,594 subjects), no significant association was observed under additive, recessive, or dominant models (odds ratio ‫؍‬ 1.00 [95% confidence interval: 0.74-1.33]; odds ratio ‫؍‬ 1.01 [95% confidence interval: 0.76-1.35]; and odds ratio ‫؍‬ 0.96 [95% confidence interval: 0.86-1.08], respectively), and a cumulative meta-analysis showed a trend toward a null effect. Interpretation: Based on the current evidence, the UCHL-1 gene does not exhibit a protective effect in PD.

Objective-To describe the clinical, neuropsychological and radiological features of a family with a C31LfsX35 mutation in the progranulin gene (PGRN). Design-Case series Patients-A large British kindred (DRC255) with a PGRN mutation was assessed. Affected individuals presented with a mean age of 57.8 (54 to 67) and mean duration of disease of 6.1 years (2 to 11). Results-All cases exhibited a clinical and radiological phenotype compatible with FTLD based on current consensus criteria. However, unlike sporadic FTLD, parietal deficits consisting of limb

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.

Background: The pathologic substrates of frontotemporal dementia (FTD) are difficult to predict in vivo. Objective: To determine whether different pathologic substrates of FTD have distinct patterns of regional atrophy on magnetic resonance imaging (MRI).

Brain biopsy has an uncertain role in the diagnosis of dementia. Here we report a retrospective analysis of 90 consecutive cerebral biopsies undertaken for the investigation of dementia in adults at a tertiary referral centre between 1989 and 2003. In most cases (90%), biopsy consisted of a right frontal full thickness resection of cortex, white matter and overlying leptomeninges. Fifty-seven per cent of biopsies were diagnostic: the most frequent diagnoses were Alzheimer's disease (18%), Creutzfeldt-Jakob disease (12%) and inflammatory disorders (9%). Other diagnoses in individual patients included Pick's disease, corticobasal degeneration and other tauopathies, Lewy body dementia, multiple sclerosis, Whipple's disease, progressive multifocal leucoencephalopathy, cerebral autosomal dominant arteriopathy with subcortical ischaemic leucoencephalopathy, vasculopathies and paraneoplastic encephalopathy. The most frequent biopsy finding in the non-diagnostic group and for the series as a whole (37%) was non-specific gliosis variably affecting both cortex and white matter. Complications (11%) included seizures, intracranial and wound infections, and intracranial haemorrhage; there were no deaths or lasting neurological sequelae attributable to the procedure. No trends in diagnostic yield or complication rate over the course of the series were identified. Information obtained at biopsy determined treatment in 11%. A raised cerebrospinal fluid cell count was the only robust predictor of a potentially treatable (inflammatory) process at biopsy. The constellation of behavioural change, raised CSF protein and matched oligoclonal bands in CSF and serum was associated with non-specific gliosis at biopsy. This series underlines the value of cerebral biopsy in the diagnosis of dementia, and suggests that certain clinical and laboratory features may be useful in guiding the decision to proceed to brain biopsy where a treatable disease cannot be excluded by other means.

Mutations in the progranulin gene (GRN) are a major cause of frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) but the distinguishing clinical and anatomical features of this subgroup remain unclear. In a large UK cohort we found five different frameshift and premature termination mutations likely to be causative of FTLD in 25 affected family members. A previously described 4-bp insertion mutation in GRN exon 2 comprised the majority of cases in our cohort (20/25), with four novel mutations being identified in the other five affected members. Additional novel missense changes were discovered, of uncertain pathogenicity, but deletion of the entire gene was not detected. The patient collection was investigated by a single tertiary referral centre and is enriched for familial early onset FTLD with a high proportion of patients undergoing neuropsychological testing, MRI and eventual neuropathological diagnosis. Age at onset was variable, but four mutation carriers presented in their 40s and when analysed as a group, the mean age at onset of disease in GRN mutation carriers was later than tau gene (MAPT) mutation carriers and duration of disease was shorter when compared with both MAPTand FTLD-U without mutation. The most common clinical

Smear cytology in the intra-operative assessment of periodontoid pseudotumour of the craniocervical junction Objective: Periodontoid pseudotumours are lesions of presumed degenerative aetiology which typically occur in elderly patients with cervical myelopathy. The clinical and radiological differential diagnosis includes neoplastic and inflammatory lesions, and the exclusion of such lesions may be of value in the intra-operative management of the patient. This audit aimed to examine the value of intra-operative smear cytology in the management of this condition. Methods: The intra-operative smear cytological features of four cases of periodontoid pseudotumour were reviewed. Results: In each case the intra-operative cytological interpretation was in keeping with a non-neoplastic and non-inflammatory process. Conclusion: These results suggest that intra-operative smear cytology can provide information on the value in the intra-operative management of patients with this lesion.

MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association.

Contributors JDR wrote the draft of the manuscript and analysed the imaging data. JB, VP and SM performed the genetic analyses. TL and TR performed the pathological analyses. EG performed imaging analyses. JCJ, JMS, MNR, JDW and NCF performed patient evaluation. All authors reviewed and contributed to the final manuscript.

The NR4A2 gene, which may cause autosomal dominant Parkinson's disease (PD), has also been reported to be a susceptibility factor for sporadic PD. Here, we use a haplotypetagging approach in 802 PD patients and 784 controls and demonstrate that common genetic variation, including NR4A2 haplotypes, does not influence the risk of PD in the Caucasian population.

Two subjects with Parkinson's disease who had long-term survival of transplanted fetal mesencephalic dopaminergic neurons (11-16 years) developed a-synuclein-positive Lewy bodies in grafted neurons. Our observation has key implications for understanding Parkinson's pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells. However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief. Two sham surgery-controlled trials of neural transplantation in Parkinson's disease did not reach their primary endpoints 1,2. However, previous open-label trials with grafts of fetal ventral mesencephalic tissue reported long-lasting functional benefits in subjects with Parkinson's disease 3. Positron emission tomography (PET) studies showed that grafted neurons were functionally integrated and released dopamine for more than 10 years after surgery 4. In postmortem neuropathological studies performed 3-4 years after transplantation, large numbers of dopaminergic neurons were found in the grafts 1,2,5. We now report that grafted cells can survive up to at least 16 years in subjects with Parkinson's disease. Large numbers of transplanted dopaminergic neurons were found in two subjects who had undergone bilateral implantation of fetal mesencephalic tissue into the putamen (subject 3 in the Lund series; left graft 16 years before death, right graft 12 years before death) or both putamen and caudate nucleus (subject 8; left graft 13 years before death, right graft 11 years before death) 6. Graft survival was confirmed by clinical improvement at 5 months up to at least 3 years after surgery in subject 3 (ref. 6). Both subjects died from causes unrelated to grafting (Supplementary Methods online). In their substantiae nigrae, the subjects had histopathological changes characteristic of Parkinson's disease: severe

Amyloid precursor protein gene (APP) duplications have been identified in screens of selected probands with early onset familial Alzheimer's disease (FAD). A causal role for copy number variation (CNV) in the prion protein gene (PRNP) in prion dementias is not known. We aimed to determine the prevalence of copy number variation in APP and PRNP in a large referral series, test a screening method for detection of the same, and expand knowledge of clinical phenotype. We used a 3-tiered screening assay for APP and PRNP duplication (exonic real-time quantitative polymerase chain reaction [exon-qPCR], fluorescent microsatellite quantitative PCR [fm-q-PCR], and Illumina array [Illumina Inc., San Diego, CA, USA]) for analysis of a heterogeneous referral series comprising 1531 probands. Five of 1531 probands screened showed APP duplication, a similar prevalence to APP missense mutation. Real-time quantitative PCR and fluorescent microsatellite quantitative PCR were similar individually but are theoretically complementary; we used Illumina arrays as our reference assay. Two of 5 probands were from an autosomal dominant early onset Alzheimer's disease (familial Alzheimer's disease) pedigree. One extensive, noncontiguous duplication on chromosome 21 was consistent with an unbalanced translocation not including the Down's syndrome critical region. Seizures were prominent in the other typical APP duplications. A range of imaging, neuropsychological, cerebrospinal fluid, and pathological findings are reported that extend the known phenotype. APP but not PRNP duplication is a significant cause of early onset dementia in the UK. The recognized phenotype may be expanded to include the possibility of early seizures and apparently sporadic disease which, in part, may be due to different mutational mechanisms. The pros and cons of our screening method are discussed.

Background: The identification of specific, diagnostically useful predictors of protein dysfunction in the frontotemporal lobar degenerations (FTLD) is a problem of great clinical and biological interest. Correlations between regional patterns of tissue loss and specific proteinopathies have not been established. Objective: Specific brain imaging correlates of protein tau dysfunction were sought using voxel-based morphometry in FTLD subgroups with and without tau pathology. Methods: Seventeen patients with pathologically or genetically confirmed diagnoses of FTLD who had undergone volumetric brain magnetic resonance imaging (MRI) were identified retrospectively and tau-positive (n = 9) and tau-negative (n = 8) subgroups were defined. MRI data were compared with healthy age-and sex-matched controls using voxel-based morphometry implemented in a statistical parametric mapping software package. Results: Compared with controls, tau-positive and tau-negative subgroups had extensive common areas of regional brain atrophy predominantly affecting the frontal and anterior temporal lobes. No specific brain imaging features were identified for either subgroup. Conclusion: Patterns of frontotemporal atrophy do not predict the presence or absence of tau pathology; conversely, different immunohistochemical profiles are associated with similar patterns of regional vulnerability to neuronal loss in FTLD.