Protocol for the Tallaght University Hospital Institute for Memory and Cognition-Biobank for Research in Ageing and Neurodegeneration.

INTRODUCTION: Alzheimer's disease and other dementias affect >50 million individuals globally and are characterised by broad clinical and biological heterogeneity. Cohort and biobank studies have played a critical role in advancing the understanding of disease pathophysiology and in identifying novel diagnostic and treatment approaches. However, further discovery and validation cohorts are required to clarify the real-world utility of new biomarkers, facilitate research into the development of novel therapies and advance our understanding of the clinical heterogeneity and pathobiology of neurodegenerative diseases. METHODS AND ANALYSIS: The Tallaght University Hospital Institute for Memory and Cognition Biobank for Research in Ageing and Neurodegeneration (TIMC-BRAiN) will recruit 1000 individuals over 5 years. Participants, who are undergoing diagnostic workup in the TIMC Memory Assessment and Support Service (TIMC-MASS), will opt to donate clinical data and biological samples to a biobank. All participants will complete a detailed clinical, neuropsychological and dementia severity assessment (including Addenbrooke's Cognitive Assessment, Repeatable Battery for Assessment of Neuropsychological Status, Clinical Dementia Rating Scale). Participants undergoing venepuncture/lumbar puncture as part of the clinical workup will be offered the opportunity to donate additional blood (serum/plasma/whole blood) and cerebrospinal fluid samples for longitudinal storage in the TIMC-BRAiN biobank. Participants are followed at 18-month intervals for repeat clinical and cognitive assessments. Anonymised clinical data and biological samples will be stored securely in a central repository and used to facilitate future studies concerned with advancing the diagnosis and treatment of neurodegenerative diseases. ETHICS AND DISSEMINATION: Ethical approval has been granted by the St. James's Hospital/Tallaght University Hospital Joint Research Ethics Committee (Project ID: 2159), which operates in compliance with the European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations 2004 and ICH Good Clinical Practice Guidelines. Findings using TIMC-BRAiN will be published in a timely and open-access fashion.

The prevalence and incidence of progressive supranuclear palsy and corticobasal syndrome: a systematic review and meta-analysis.

INTRODUCTION: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are progressive neurodegenerative syndromes characterised by Parkinsonism with additional features including cognitive dysfunction, falls, and oculomotor abnormalities. Understanding the epidemiology of these conditions is critical to planning for future service provision. METHODS: We conducted a systematic review of studies reporting incidence and prevalence of CBS and PSP. A search of the PubMed and EMBASE data bases was conducted from their date of inception to 13th July 2021. Meta-analysis of studies sharing similar methodologies was carried out to generate estimated pooled prevalence and incidence. RESULTS: We found 32 studies meeting our criteria for inclusion. There were 20 studies with data on prevalence and 12 with incidence data of PSP. Prevalence of CBS was reported in eight studies while seven studies reported incidence. Reported estimates of prevalence for PSP ranged from 1.00 (0.9-1.1) to 18 (8-28) per 100,000 while prevalence rates for CBS ranged from 0.83 (0.1-3.0) to 25 (0-59). Incidence rates for PSP and CBS respectively ranged from 0.16 (0.07-0.39) to 2.6 per 100,000 person-years and 0.03 (0-0.18) to 0.8 (0.4-1.3) per 100,000 person-years. A random effects model meta-analysis of studies with similar methodologies yielded a pooled prevalence estimate for PSP of 6.92 (4.33-11.06, I2 = 89%, τ2 = 0.3907) and 3.91 (2.03-7.51, I2 = 72%, τ2 = 0.2573) per 100,000 for CBS. CONCLUSION: Studies of the epidemiology of PSP and CBS report highly heterogeneous findings. There is a need for further studies using rigorous phenotyping and the most recent diagnostic criteria to understand the true burden of these conditions.

Mimics or Multiplicity: 2 Cases of Rare Neurological Conditions Discovered Following Presentation with Richardson's Syndrome Phenotype.

Background: Progressive supranuclear palsy (PSP)-Richardson's syndrome (RS) presents with a distinctive clinical phenotype of supranuclear ophthalmoplegia, parkinsonism, postural instability with falls, and cognitive impairment. Several rare neurological conditions have been described that mimic PSP, and the co-occurrence of dual pathologies has also been described. Cases: In this article, we present 2 cases of patients who presented with a parkinsonian phenotype suggestive of PSP-RS. In 1 case, a family history and early levodopa-induced chorea led to testing for Huntington's disease, and a pathogenic HTT mutation was found. In the second case, magnetic resonance imaging findings led to genetic confirmation of a pathogenic FMR1 mutation. Conclusions: These observations raised the possibility that HD and fragile-X tremor-ataxia syndrome may on occasion present with PSP-RS. Alternatively, and perhaps more likely, is the co-occurrence of 2 rare neurodegenerative conditions. Neuropathological studies of cases involving complex phenotypes in rare genetic conditions are required to better understand the likely pathologies in cases such as these.

Neurological update: the palliative care landscape for atypical parkinsonian syndromes.

Atypical parkinsonian syndromes are neurodegenerative conditions, characterised by rapid disease progression and shorter life expectancy compared to idiopathic Parkinson's disease. These conditions inflict substantial physical and psychosocial burden on patients and their families; hence, there is a clear rationale for a palliative care approach from diagnosis. An interdisciplinary care model has been shown to improve symptom burden, quality of life and engagement with advance care planning, in a heterogeneous group of neurodegenerative conditions. In this update, we summarise how the landscape for treating these patients has changed and the questions that still need to be resolved.

A Case of GCH-1 Mutation Dopa-Responsive Dystonia Requiring High Doses of Levodopa for Treatment.

Background: Mutations in the GCH-1 gene are associated with Autosomal Dominant Dopamine Responsive Dystonia (DYT 5). One of the hallmarks of this condition is dramatic and sustained response to low doses of levodopa. Case Report: We present the case of a 22 year old female patient with genetically confirmed GCH-1 Dopa-Responsive Dystonia who had no response to low dose Levodopa but who achieved symptom control on a total dose of 900 mg/day. Discussion: Autosomal Dominant Dopa-Responsive Dystonia is a phenotypical heterogenous condition that, in some cases, may require high doses of levodopa for treatment response. Highlights: Mutations in the GCH-1 gene are associated with Autosomal Dominant Dopamine Responsive Dystonia which is typically defined by dramatic responses to low doses of levodopa. We report a patient with genetically confirmed Dopa-Responsive Dystonia who had no response to low dose Levodopa but who achieved symptom control with 900 mg/day.

Autoimmune encephalitis associated with Ma2 antibodies and immune checkpoint inhibitor therapy.

Immune checkpoint inhibitors have transformed the treatment of advanced malignancy, while increasing the risk of immune-related adverse events. A 56-year-old woman who had received nivolumab for stage 4 renal cell carcinoma subsequently developed altered behaviour, memory deficits and worsening of previously stable epilepsy. MR scan of the brain showed bilateral FLAIR (fluid-attenuated inversion recovery) hyperintensity of the mesial temporal lobes, and there were anti-Ma2 antibodies in both serum and cerebrospinal fluid. She was treated with corticosteroids but developed further clinical relapses requiring immunoglobulin and rituximab. The immune-related adverse events relating to immune checkpoint inhibitors are an emerging challenge for the neurologist. Some cases are refractory and require serial immunosuppression.

Essen Risk Score in Prediction of Myocardial Infarction After Transient Ischemic Attack or Ischemic Stroke Without Prior Coronary Artery Disease.

Background and Purpose- More intensive secondary prevention with newer drugs may be cost-effective in patients with coronary artery disease (CAD). Whether some subgroups of patients who had a transient ischemic attack (TIA) or ischemic stroke, but no prior CAD are at similar high risk of myocardial infarction as those with prior CAD remains unclear. We determined whether the Essen score identified a subset of TIA/stroke patients without known prior CAD who, nevertheless, had a high risk of myocardial infarction on current secondary prevention management. Methods- In a population-based cohort (Oxford Vascular Study) of consecutive TIA or ischemic stroke patients recruited from 2002 to 2014, 10-year actuarial risks of myocardial infarction and of recurrent ischemic stroke were determined by face-to-face follow-up in patients with and without prior CAD using Kaplan-Meier analyses. Predictive value of the Essen score was assessed with C statistic. Results- Of 2555 patients with TIA/stroke (13 070 patient-years of follow-up), 10-year risk of myocardial infarction in those without prior CAD (n=2017, 78.9%) ranged from 0.9% (95% CI, 0-1.9) at Essen score ≤1 to 29.8% (95% CI, 7.7-46.6) in those with a score ≥5 (C statistic =0.64 [95% CI, 0.57-0.71]; P<0.001). The score tended to be less predictive (difference: P=0.0460) for the risk of recurrent ischemic stroke (C statistic =0.57 [95% CI, 0.54-0.60]). Compared with patients with prior CAD (n=538, 21.1%), an Essen risk score of ≥4 (n=294, 11.5%) in those without prior CAD identified a subgroup at similar high 10-year risks of myocardial infarction (17.2% [95% CI, 6.9-26.3] versus 16.9% [95% CI, 11.5-22.0]) and of recurrent stroke (40.4% [95% CI, 26.7-51.6] versus 32.4% [95% CI, 25.2-38.8]). Conclusions- The Essen score is a simple clinical score to risk-stratify patients with TIA/stroke without prior CAD and to identify subsets who may be at sufficiently high risk of myocardial infarction and recurrent stroke to justify more intensive treatment or inclusion in trials.

Effect of coexisting vascular disease on long-term risk of recurrent events after TIA or stroke.

OBJECTIVE: To determine whether patients with TIA or ischemic stroke with coexisting cardiovascular disease (i.e., history of coronary or peripheral artery disease) are still at high risk of recurrent ischemic events despite current secondary prevention guidelines. METHODS: In a population-based study in Oxfordshire, UK (Oxford Vascular Study), we studied consecutive patients with TIA or ischemic stroke for 2002-2014. Patients were treated according to current secondary prevention guidelines and we determined risks of coronary events, recurrent ischemic stroke, and major bleeding stratified by the presence of coexisting cardiovascular disease. RESULTS: Among 2,555 patients (9,148 patient-years of follow-up), those (n = 640; 25.0%) with coexisting cardiovascular disease (449 coronary only; 103 peripheral only; 88 both) were at higher 10-year risk of coronary events than those without (22.8%, 95% confidence interval 17.4-27.9; vs 7.1%, 5.3-8.8; p < 0.001; age- and sex-adjusted hazard ratio [HR] 3.07, 2.24-4.21) and of recurrent ischemic stroke (31.5%, 25.1-37.4; vs 23.4%, 20.5-26.2; p = 0.0049; age- and sex-adjusted HR 1.23, 0.99-1.53), despite similar rates of use of antithrombotic and lipid-lowering medication. However, in patients with noncardioembolic TIA/stroke, risk of extracranial bleeds was also higher in those with coexisting cardiovascular disease, particularly in patients aged <75 years (8.1%, 2.8-13.0; vs 3.4%, 1.6-5.3; p = 0.0050; age- and sex-adjusted HR 2.71, 1.16-6.30), although risk of intracerebral hemorrhage was not increased (age- and sex-adjusted HR 0.36, 0.04-2.99). CONCLUSIONS: As in older studies, patients with TIA/stroke with coexisting cardiovascular disease remain at high risk of recurrent ischemic events despite current management. More intensive lipid-lowering might therefore be justified, but benefit from increased antithrombotic treatment might be offset by the higher risk of extracranial bleeding.

Long-Term Prognosis of Patients With Transient Ischemic Attack or Stroke and Symptomatic Vascular Disease in Multiple Arterial Beds.

BACKGROUND AND PURPOSE: Cerebrovascular, coronary, and peripheral vascular disease have common underlying arterial pathology and risk factors, but the clinical significance of multiple-territory disease in patients with transient ischemic attack (TIA)/ischemic stroke is unclear, particularly whether the number of clinically affected territories still predicts long-term outcome on current standard secondary prevention therapies. METHODS: In a population-based study of 92 728 individuals in Oxfordshire, United Kingdom (Oxford Vascular Study), we studied patients presenting with TIA/ischemic stroke (2002-2014) in relation to the number of other vascular beds (coronary, peripheral) affected by symptomatic (current or previous) disease. We compared the risk factor profile and long-term prognosis in patients with single- versus multiple-territory disease. RESULTS: Among 2554 patients with 10 679 patient-years of follow-up, 1842 (72.1%) had single- (TIA/stroke only), 608 (23.8%) double-, and 104 (4.1%) triple-territory symptomatic vascular disease. The number of affected vascular beds increased with the number of atherosclerotic risk factors (Ptrend<0.0001). Compared with patients with TIA/stroke only, those with multiple-territory disease had more hypertension (age/sex-adjusted odds ratio [OR], 3.43; 95% confidence interval [CI], 2.76-4.27; P<0.0001), diabetes mellitus (OR, 2.89; 95% CI, 2.27-3.66; P<0.0001), hypercholesterolemia (OR, 4.67; 95% CI, 3.85-5.66; P<0.0001), and current or previous smoking (OR, 1.52; 95% CI, 1.26-1.84; P<0.0001). Triple-territory disease was particularly strongly associated with hypercholesterolemia (OR, 6.80; 95% CI, 4.39-10.53; P<0.0001). Despite more intensive secondary prevention in patients with multiple-territory disease, the 5-year risk of vascular death increased steeply with the number of territories affected (17.2% versus 30.0% versus 42.9%; P<0.0001). Compared with patients with single-territory, patients with multiple-territory disease also had higher postacute long-term risks (90 days to 10 years) of recurrent ischemic stroke (age/sex-adjusted hazard ratio, 1.38; 95% CI, 1.04-1.81; P=0.02) and nonstroke acute vascular events (hazard ratio, 3.06; 95% CI, 2.23-4.20; P<0.0001). CONCLUSIONS: Number of affected vascular beds appeared to be a simple clinical rule in identifying TIA/ischemic stroke patients who are at high long-term risk of nonstroke vascular events and vascular death.

PCDH19-related epilepsy: a rare but recognisable clinical syndrome in females.

Protocadherin 19 (PCDH19)-related epilepsy (OMIM 300088) is a distinctive clinical syndrome limited to females. We describe a 17-year-old girl who presented to a regional epilepsy clinic with a history of recurrent febrile seizures in infancy. Genetic analysis of the PCDH19 gene revealed a novel heterozygous mutation within a highly conserved region of the gene. Patients with PCDH19 mutations present with clusters of seizures associated with fever. While fever-induced seizures are common to children with PCDH19 and SCN1A mutations, there are certain clinical features that distinguish these genetic syndromes from each other. PCDH19 mutation demonstrates an unusual form of transmission such that only heterozygous females develop the phenotype. De novo mutations account for most cases although the inheritance is sometimes familial patterns of inheritance. Hemizygous males are typically unaffected. Identification of the mutation provides patients and their families with an explanation for their clinical presentation, important prognostic information and an opportunity for genetic counselling.