Dissonance in the face of Alzheimer's disease breakthroughs: clinician and lay stakeholder acceptance, concerns and willingness to pay for emerging disease-modifying therapies.

BACKGROUND: Introducing new disease-modifying therapies (DMTs) for Alzheimer's disease demands a fundamental shift in diagnosis and care for most health systems around the world. Understanding the views of health professionals, potential patients, care partners and taxpayers is crucial for service planning and expectation management about these new therapies. AIMS: To investigate the public's and professionals' perspectives regarding (1) acceptability of new DMTs for Alzheimer's disease; (2) perceptions of risk/benefits; (3) the public's willingness to pay (WTP). METHOD: Informed by the 'theoretical framework of acceptability', we conducted two online surveys with 1000 members of the general public and 77 health professionals in Ireland. Descriptive and multivariate regression analyses examined factors associated with DMT acceptance and WTP. RESULTS: Healthcare professionals had a higher acceptance (65%) than the general public (48%). Professionals were more concerned about potential brain bleeds (70%) and efficacy (68%), while the public focused on accessibility and costs. Younger participants (18-24 years) displayed a higher WTP. Education and insurance affected WTP decisions. CONCLUSIONS: This study exposes complex attitudes toward emerging DMTs for Alzheimer's disease, challenging conventional wisdom in multiple dimensions. A surprising 25% of the public expressed aversion to these new treatments, despite society's deep-rooted fear of dementia in older age. Healthcare professionals displayed nuanced concerns, prioritising clinical effectiveness and potential brain complications. Intriguingly, younger, better-educated and privately insured individuals exhibited a greater WTP, foregrounding critical questions about healthcare equity. These multifaceted findings serve as a guidepost for healthcare strategists, policymakers and ethicists as we edge closer to integrating DMTs into Alzheimer's disease care.

The impact of headache disorders: a prospective analysis of headache referrals to outpatient and inpatient neurology and emergency services in an Irish University teaching hospital.

BACKGROUND: Headache represents a significant proportion of disability globally in general practice, neurology outpatient settings, and emergency departments. There is scant literature regarding the impact of headache on healthcare services in Ireland. AIMS: We aimed to investigate headache burden across the emergency department, inpatient stays, and neurology outpatient department referrals in an Irish University teaching hospital. METHODS: We prospectively collected data regarding emergency department presentations, inpatient neurology consultations, and neurology outpatient referrals for patients with headache between 13th January and 8th March 2020. Data were analyzed using descriptive statistics. RESULTS: There were 180 emergency department attendances, 50 inpatient consultations, and 76 outpatient referrals with headache. Neurological examinations were often incomplete; neuroimaging was commonly employed. Migraine was the most frequent headache diagnosis at discharge in the emergency department and among inpatients after neurology review. Diagnostic uncertainty was identified-33% of patients left the emergency department with no diagnosis, and "unknown/unspecified headache" was recorded on 49% of outpatient referrals and 30% of inpatient consult requests. Medication overuse headache coexisted with migraine in nine patients in the inpatient group. Prophylaxis had been trialed in 56% of patients with migraine referred to outpatients. CONCLUSIONS: Primary headache disorders have a large impact on hospital services. Diagnostic uncertainty is common; neuroimaging is relied upon. Appropriate care pathways, education, and resource allocation should be prioritized.

Late-onset Tay-Sachs disease presenting with a neuromuscular phenotype-a case series.

BACKGROUND AND PURPOSE: Tay-Sachs disease is a rare and often fatal, autosomal recessive, lysosomal storage disease. Deficiency in ß-hexosaminidase leads to accumulation of GM2 ganglioside resulting in neuronal swelling and degeneration. Typical onset is in infancy with developmental regression and early death. Late-onset Tay-Sachs disease (LOTS) is extremely rare, especially in the non-Ashkenazi Jewish population, and is characterized by a more indolent presentation typically encompassing features of cerebellar and anterior horn cell dysfunction in addition to extrapyramidal and neuropsychiatric symptoms. CASES: A case series of four unrelated patients of non-Ashkenazi Jewish origin with a predominantly, and in some cases pure, neuromuscular phenotype with evidence of a motor neuronopathy on electromyography is presented. Cerebellar atrophy, reported to be a ubiquitous feature in LOTS, was absent in all patients. CONCLUSION: This case series provides evidence to support a pure neuromuscular phenotype in LOTS, which should be considered in the differential diagnosis of anterior horn cell disorders.

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.

An Update on Apathy in Alzheimer's Disease.

Apathy is a complex multi-dimensional syndrome that affects up to 70% of individuals with Alzheimer's disease (AD). Whilst many frameworks to define apathy in AD exist, most include loss of motivation or goal-directed behaviour as the central feature. Apathy is associated with significant impact on persons living with AD and their caregivers and is also associated with accelerated cognitive decline across the AD spectrum. Neuroimaging studies have highlighted a key role of fronto-striatial circuitry including the anterior cingulate cortex (ACC), orbito-frontal cortex (OFC) and associated subcortical structures. Importantly, the presence and severity of apathy strongly correlates with AD stage and neuropathological biomarkers of amyloid and tau pathology. Following from neurochemistry studies demonstrating a central role of biogenic amine neurotransmission in apathy syndrome in AD, recent clinical trial data suggest that apathy symptoms may improve following treatment with agents such as methylphenidate-which may have an important role alongside emerging non-pharmacological treatment strategies. Here, we review the diagnostic criteria, rating scales, prevalence, and risk factors for apathy in AD. The underlying neurobiology, neuropsychology and associated neuroimaging findings are reviewed in detail. Finally, we discuss current treatment approaches and strategies aimed at targeting apathy syndrome in AD, highlighting areas for future research and clinical trials in patient cohorts.

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.

DNMT1-associated sensory neuropathy and cerebellar ataxia: A novel variant and review of genotype-phenotype correlation.

AIM: Hereditary sensory neuropathy (HSN) 1E is a neurodegenerative disorder caused by pathogenic variants in DNA methyltransferase 1 (DNMT1). It is characterised by sensorineural deafness, sensory neuropathy and cognitive decline. Variants in DNMT1 are also associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy. METHODS: A 42-year-old man presented with imbalance, lancinating pain, numerous paucisymptomatic injuries, progressive deafness since his mid-20s, mild cognitive decline and apathy. Examination revealed abnormalities of eye movements, distal sensory loss to all modalities, areflexia without weakness and lower limb ataxia. MRI brain and FDG-PET scan demonstrated biparietal and cerebellar atrophy/hypometabolism. Whole exome sequencing detected a heterozygous likely pathogenic missense variant in DNMT1, c.1289G > A, p.Cys430Tyr. Cochlear implant was performed at 44 years for the bilateral high frequency sensorineural hearing loss with improvement in hearing and day-to-day function. RESULTS AND CONCLUSION: We describe a novel variant in DNMT1 and confirm that an overlapping HSN1E-cerebellar phenotype can occur. Only one prior case of cochlear implant in HSN1E has been reported to date but this case adds to that literature, suggesting that cochlear implant can be successful in such patients. We further explore the clinical and radiological signature of the cognitive syndrome associated with this disorder.

Frequency of inter-specialty consensus decisions and adherence to advice following discussion at a weekly neurovascular multidisciplinary meeting.

BACKGROUND/AIMS: Data are limited on the frequency of 'consensus decisions' between sub-specialists attending a neurovascular multidisciplinary meeting (MDM) regarding management of patients with extracranial carotid/vertebral stenoses and post-MDM 'adherence' to such advice. METHODS: This prospective audit/quality improvement project collated prospectively-recorded data from a weekly Neurovascular/Stroke Centre MDM documenting the proportion of extracranial carotid/vertebral stenosis patients in whom 'consensus management decisions' were reached by neurologists, vascular surgeons, stroke physicians-geriatricians and neuroradiologists. Adherence to MDM advice was analysed in asymptomatic carotid stenosis (ACS), symptomatic carotid stenosis (SCS), 'indeterminate symptomatic status stenosis' (ISS) and vertebral artery stenosis (VAS) patients, including intervals between index event to MDM + / - intervention. RESULTS: One hundred fifteen patients were discussed: 108 with carotid stenosis and 7 with VAS. Consensus regarding management was noted in 96.5% (111/115): 100% with ACS and VAS, 96.2% with SCS and 92.9% with ISS. Adherence to MDM management advice was 96.4% (107/111): 100% in ACS, ISS and VAS patients; 92% (46/50) in SCS patients. The median interval from index symptoms to revascularisation in 50-99% SCS patients was 12.5 days (IQR: 9-18.3 days; N = 26), with a median interval from MDM to revascularisation of 5.5 days (IQR: 1-7 days). Thirty patients underwent revascularisation. Two out of twenty-nine patients (6.9%) with either SCS or ISS had a peri-procedural ipsilateral ischaemic stroke, with no further strokes/deaths during 3-months follow-up. CONCLUSIONS: The high frequency of inter-specialty consensus regarding management and adherence to proposed treatment supports a collaborative/multidisciplinary model of care in patients with extracranial arterial stenoses. Service development should aim to shorten times between MDM discussion-intervention and optimise prevention of stroke/death.

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.

Establishing a committee for antemortem reviews of suspect Creutzfeldt-Jakob disease cases in Ireland.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, neurodegenerative disease. In Ireland, clinical diagnostics and laboratory testing remain the responsibility of the managing clinician and the Neuropathology Department at the Beaumont Hospital, respectively. Centralized review of individual cases is not undertaken. AIMS: To determine how diagnostic processes for CJD could be improved in Ireland and to outline the structure and referral process for a new CJD review panel at the Beaumont Hospital. METHODS: We surveyed Irish neurologists' experiences on the management of CJD in Ireland. We measured turnaround times (TAT) for CSF samples referred for diagnostic CJD testing. Finally, we retrospectively reviewed imaging of autopsy-proven CJD cases to compare with initial reports. RESULTS: Ninety-three percent of neurologists supported a national central review of suspect CJD cases. A second clinical opinion was considered to be of likely benefit by 79%. Additionally, 93% reported that a centralized review of neuroradiology would be useful. All respondents felt that expediting turnaround of CSF analysis would be of benefit. The average TAT for CSF testing was 35.4 days. In retrospective review of imaging, all patients demonstrated MRI findings consistent with CJD. However, in only one of these cases were the initial pre-autopsy radiological findings reported as being consistent with CJD. CONCLUSIONS: These findings support the need for improvements to the Irish National CJD Surveillance Unit to maximize antemortem diagnostic accuracy. On foot of this, a clinical CJD Multidisciplinary Team (CJD MDT) has been established to provide a second opinion on (i) the patient's clinical history, (ii) neuroradiology and (iii) and neurophysiology reports (where available).

Seeing the Woods for the Trees? Applying Diagnostic Criteria for Dementia with Lewy Bodies to Patients Presenting with Posterior Cortical Atrophy.

Posterior cortical atrophy (PCA) is a clinico-radiological syndrome characterised by progressive decline in visual processing and other posterior cognitive functions, relatively preserved memory and language in the early stages, and atrophy of posterior brain regions. Often considered a "visual variant" of Alzheimer's disease, a number of other pathological substrates are recognised. Dementia with Lewy Bodies is the second most common neurodegenerative dementia and there is increasing recognition of presentations with little or no parkinsonism, highlighting significant under-recognition of this condition. To complicate matters, some patients with PCA exhibit additional features consistent with other neurodegenerative conditions. We present a series of three such patients presenting with features satisfying the recent consensus criteria for "PCA-Plus (DLB)". We review the current classification of PCA and highlight the importance of deep clinico-radiological phenotyping in neurodegenerative disease to guide targeted interventions and establish future trial-ready cohorts.

Clinical Reasoning: A 23-Year-Old Woman Presenting With Cognitive Impairment and Gait Disturbance.

Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal disorder. The condition progresses relentlessly, with severe disability typically established within 6-14 years of symptom onset. There is no cure, and limited treatment options are available to slow disease progression. We describe the case of a 23-year-old woman with forgetfulness, unsteady gait, and falls. Neurologic examination revealed intermittent dystonic posturing of the right upper and lower limb when walking. The Addenbrooke's Cognitive Examination (ACE) score was 70/100. MRI sequences demonstrated frontal-predominant atrophy and extensive white matter hyperintensity. Differential diagnoses such as autoimmune, inflammatory, and neoplastic diseases were excluded, and a genetic diagnosis was considered. Lysosomal enzyme testing showed low arylsulfatase with elevated urinary sulfatides, and genetic testing revealed a homozygous pathogenic mutation in the ARSA gene securing a diagnosis of adult-onset MLD. A male sibling also had early cognitive impairment and was found to have the same mutation. Hematopoietic stem cell transplantation (HSCT) was offered after discussion with experts. The male sibling died of multiple complications after HSCT. The index patient is now 24 months after HSCT, and disease progression has halted. This case highlights the challenges in the accurate diagnosis of adult-onset leukoencephalopathies and explores potential treatment strategies. A stepwise approach to the differential diagnosis of white matter diseases is demonstrated. HSCT may be an effective treatment, but the significant complication rate needs to be carefully considered.

Potential eligibility for Aducanumab therapy in an Irish specialist cognitive service-Utilising cerebrospinal fluid biomarkers and appropriate use criteria.

OBJECTIVES: Aducanumab is a monoclonal antibody which has recently been licenced for use by the food and drug administration for treatment of patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD dementia. Appropriate use criteria (AUC) for Aducanumab in clinical practice are available. We look to review patients in our specialist interdisciplinary cognitive service with positive cerebrospinal fluid (CSF) biomarkers for AD for their hypothetical eligibility for Aducanumab, or a similar anti-amyloid agent. METHODS: Retrospective analysis was undertaken of patients with positive AD-biomarker CSF analysis. Data available at time of CSF analysis was reviewed to determine hypothetical eligibility for Aducanumab. RESULTS: Seventy patients had positive AD-CSF biomarkers. Forty nine of these were seen in the Gerontology-led service, with 21 in the neurology cohort. Average patient age was 70 years old. Forty patients (57%) met eligibility criteria for Aducanumab therapy by AUC guidelines. CONCLUSION: We highlight the patients within our service who would be appropriate for Aducanumab or similar anti-amyloid agents should licencing be granted in the European Union, and the need to develop the resources and capacity to deliver this or other emerging disease modifying AD therapies. CLINICAL TRIAL REGISTRATION: All patients in the combined cognitive clinic provide consent re willingness to be contacted re research.

Pembrolizumab treatment of inflammatory progressive multifocal leukoencephalopathy: a report of two cases.

Progressive multifocal leukoencephalopathy (PML) is a rare but devastating neurological disease caused by reactivation of the JC virus in susceptible individuals. The illness has classically been associated with the human immunodeficiency virus (HIV) and multiple sclerosis (MS) patients who are treated with natalizumab. It is also associated with haematological malignancies, organ transplantation, autoimmune disease and immunodeficiency. Aside from natalizumab, a range of other immunomodulators including obinutuzumab and rituximab have been associated with PML. The nature of these associations is unclear due to the overall low incidence of PML associated with these drugs and the fact that most patients will have other confounding risk factors for developing the disease. There is no known effective treatment available for PML in the non-HIV, non-MS cohort. Recent case studies and series have proposed that pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, may be a potentially efficacious option for these patients. We present two cases of non-HIV, non-MS patients with PML who were treated with pembrolizumab with little clinical benefit. The literature surrounding pembrolizumab use in PML is discussed, with a focus on potential indicators of successful outcomes for patients who receive this therapy.

Fluctuating cognition in the Lewy body dementias.

Fluctuating cognition is a core diagnostic feature of dementia with Lewy bodies and is also a key clinical feature of Parkinson's disease dementia. These dementias share common pathological features and are referred to as Lewy body dementias. Whilst highly prevalent in Lewy body dementia, with up to 90% of patients experiencing the symptom at some point in the disease trajectory, clinical identification of fluctuating cognition is often challenging. Furthermore, its underlying pathophysiological processes remain unclear. However, neuroimaging and neurophysiological techniques have recently provided insight into potential drivers of the phenomenon. In this update, we review data pertaining to clinical features and underlying mechanisms of fluctuating cognition in Lewy body dementia. We collate evidence for different proposed aetiologies: fluctuating cognition as an attentional disorder, as a consequence of loss of cholinergic drive, as a manifestation of failure in neuronal efficiency and synchrony, and as a disorder of sleep/arousal. We also review data relating to putative mechanisms that have received less attention to date. Increased understanding of fluctuating cognition may help to illuminate pathophysiological mechanisms in cognitive processing in Lewy body dementia, guide future research, and facilitate the design of targeted therapeutic approaches.