Device closure for patent foramen ovale following cryptogenic stroke: a survey of current practice in the UK.

Patent foramen ovale (PFO) closure for cryptogenic stroke remains controversial due to a lack of conclusive randomised controlled data. Many experts feel PFO closure is indicated in selected cases; however, national and international guideline recommendations differ. We surveyed the UK cardiologists, stroke physicians and neurologists, seeking to determine specialist interpretation of the evidence base, and to gain an insight into the current UK practice. The British Cardiac Society and British Society of Stroke physicians distributed our survey which was performed using an online platform. 120 physicians (70 stroke physicians, 23 neurologists, 27 cardiologists) completed the survey. Most (89%) felt PFO closure should be considered in selected patients. Atrial fibrillation (86.6%), significant carotid stenosis (86.6%), diabetes (38.4%) and hypertension (36.6%) were considered exclusion criteria for cryptogenic stroke diagnosis. More stroke physicians than cardiologists considered an age cut-off when considering PFO as the stroke aetiology (70.4%vs 54.5%p=0.04). Anatomical features felt to support PFO closure were aneurysmal septum (89.6%), shunt size (73.6%), prominent Eustachian valve (16%). 60% discuss patients in multidisciplinary meetings prior to PFO closure, with more cardiologists than stroke physicians/neurologists favouring this approach (76.9% vs 54.8%; p=0.05). After PFO closure, patients receive Clopidogrel (72.3%), aspirin (50%) or anticoagulants (17%). 63.2% continue therapy for a limited period after PFO closure, while 34% prefer life-long therapy (14.8% cardiologists vs 40.5% non-cardiologists; p=0.02). While experts support selective PFO closure in cryptogenic stroke, current practice remains variable with significant differences in perceptions of cardiologists and neurologists/stroke physicians.

Extended phenotypic spectrum of KIF5A mutations: From spastic paraplegia to axonal neuropathy.

OBJECTIVE: To establish the phenotypic spectrum of KIF5A mutations and to investigate whether KIF5A mutations cause axonal neuropathy associated with hereditary spastic paraplegia (HSP) or typical Charcot-Marie-Tooth disease type 2 (CMT2). METHODS: KIF5A sequencing of the motor-domain coding exons was performed in 186 patients with the clinical diagnosis of HSP and in 215 patients with typical CMT2. Another 66 patients with HSP or CMT2 with pyramidal signs were sequenced for all exons of KIF5A by targeted resequencing. One additional patient was genetically diagnosed by whole-exome sequencing. RESULTS: Five KIF5A mutations were identified in 6 unrelated patients: R204W and D232N were novel mutations; R204Q, R280C, and R280H have been previously reported. Three patients had CMT2 as the predominant and presenting phenotype; 2 of them also had pyramidal signs. The other 3 patients presented with HSP but also had significant axonal neuropathy or other additional features. CONCLUSION: This is currently the largest study investigating KIF5A mutations. By combining next-generation sequencing and conventional sequencing, we confirm that KIF5A mutations can cause variable phenotypes ranging from HSP to CMT2. The identification of mutations in CMT2 broadens the phenotypic spectrum and underlines the importance of KIF5A mutations, which involve degeneration of both the central and peripheral nervous systems and should be tested in HSP and CMT2.

CSF neurofilaments in frontotemporal dementia compared with early onset Alzheimer's disease and controls.

BACKGROUND: Frontotemporal dementia (FTD) is pathologically heterogeneous, sometimes revealing intraneuronal inclusions of neurofilaments. We therefore measured CSF neurofilament profiles in patients with FTD, patients with early onset Alzheimer's disease (EAD) and healthy control subjects to explore the discriminative potential of CSF neurofilaments compared with the existing CSF biomarkers amyloid-beta(1-42), tau and tau phosphorylated at threonine-181. METHODS: CSF levels of light chain, heavy chain and hyperphosphorylated heavy chain neurofilaments (NfL, t-NfH and P-NfH) were compared between 17 subjects with FTD, 20 with EAD and 25 cognitively healthy controls. RESULTS: A subgroup of FTD patients had remarkably high CSF levels of both NfL and NfH. The degree of NfH phosphorylation was increased in FTD compared to both other groups. The levels of CSF NfL were significantly higher in EAD compared to controls. CONCLUSION: Differences in CSF biomarker profiles might reflect differential involvement of neurofilaments and tau in FTD and EAD. The subgroup of FTD patients with high CSF neurofilament levels may have a different neuropathological substrate and future studies addressing this specific issue are needed.

The natural history of Alzheimer disease: a longitudinal presymptomatic and symptomatic study of a familial cohort.

BACKGROUND: Knowledge of the evolution of cognitive deficits in Alzheimer disease is important for our understanding of disease progression. Previous reports, however, have either lacked detail or have not covered the presymptomatic stages. OBJECTIVE: To delineate the onset and progression of clinical and neuropsychological abnormalities in familial Alzheimer disease. METHODS: Nineteen subjects with familial Alzheimer disease underwent serial clinical and neuropsychological assessments. Eight of these had undergone presymptomatic assessments. The follow-up period was 1 to 10 years (mean, 5 years). The relative timing of the occurrence of 3 markers of disease onset and progression (onset of symptoms, Mini-Mental State Examination score < or = 24, and impaired scores on a range of neuropsychological tests) were compared using the binomial exact test. RESULTS: Neurological abnormalities were not prominent, although myoclonus appeared early in some. Mini-Mental State Examination score was not sensitive to early disease. Memory and general intelligence deficits appeared at an earlier stage, in some patients when presymptomatic. Perceptual, naming, and especially spelling skills were preserved to a late stage. CONCLUSION: Familial Alzheimer disease may have a long prodromal phase of several years with subtle deficits initially of general intelligence and memory, while spelling, naming, and perception are relatively preserved until a late stage.

Evidence of a founder effect in families with frontotemporal dementia that harbor the tau +16 splice mutation.

The +16 exon 10 splice mutation of the tau gene (microtubule-associated protein tau, MAPT) has been reported in numerous families with frontotemporal dementia (FTD). To date, the majority of these families are from England and Wales in the UK, although families with this mutation have been reported from Australia and the USA. Our own analysis has identified eight families with the +16 MAPT splice mutation from around the Manchester and North Wales areas of the UK. Given the proximity of the UK families to one another it is likely that they are related and represent a single extended pedigree. In order to investigate this possibility, and the possibility that the families with this mutation from London, the USA, and Australia are related, we genotyped 11 microsatellite markers around the tau locus. In most cases (20/25, 80%), a common haplotype, approximately 3 cM in size, was identified. In the remaining cases, this haplotype appears to have been varyingly reduced in size by recombination. We demonstrate that the +16 mutation is on the H1 tau haplotype and that H1 specific polymorphisms are also shared by these families. These data provide evidence that the MAPT +16 splice mutation cases from around the world analyzed in this study are indeed related and represent a single pedigree that probably originated in the North Wales area of the UK. Furthermore, this single large pedigree may be of use in the identification of disease modifying loci in FTD.

Change in rates of cerebral atrophy over time in early-onset Alzheimer's disease: longitudinal MRI study.

The extent to which cerebral atrophy in Alzheimer's disease changes with time is unknown. We used multiple MRI scans to measure progression of cerebral atrophy in 12 patients with Alzheimer's disease who were followed up from a presymptomatic stage through to moderately severe dementia. Analysis with hierarchical regression models with quadratic terms in time provided evidence of increasing yearly percentage losses in brain volume. At the time when patients were judged to have mild dementia (mini-mental state examination score MMSE=23), mean yearly loss of brain volume was 2.8% (95% CI 2.3-3.3), which rose by 0.32% per year (0.15-0.50). Our findings reinforce the need for early diagnosis and therapeutic intervention in Alzheimer's disease.

Assessing the onset of structural change in familial Alzheimer's disease.

Regional and global cerebral atrophy are inevitable features of Alzheimer's disease (AD). We assessed volumes and atrophy rates of brain structures in patients with familial AD during the period that they developed symptoms. Five patients with presymptomatic AD and 20 controls had two or more annual volumetric MRI brain scans. Volumes of brain, ventricles, temporal lobes, hippocampi, and entorhinal cortices (ECs) were measured. Rates of volume change were calculated from serial scans. There were no significant differences in baseline measures of whole brain, temporal lobe, or ventricular volume between patients and controls; averaged volumes of medial temporal lobe structures (both hippocampi and ECs) were 16.6% (95% confidence interval [CI], 3.3-28.0%) lower in patients. Atrophy rates for brain, temporal lobe, hippocampus, and EC were significantly increased in patients compared with controls (p < 0.05). Averaged atrophy rates from both hippocampi and ECs were 5.1% (95% CI, 3.0-7.1%) greater in patients than controls. Linear extrapolation backward suggested medial temporal lobe atrophy commenced 3.5 years (95% CI, 0.7-7.5 years) before onset, when all patients were asymptomatic. We conclude that increased medial temporal lobe atrophy rates are an early and distinguishing feature of AD and that pathological atrophy probably is occurring several years before the onset of symptoms.