Projected Annual Lecanemab Treatment Eligibility in an Irish Regional Specialist Memory Clinic.

OBJECTIVES: The advent of Disease Modifying Therapies (DMTs) for the treatment of Alzheimer's Disease (AD) has the potential to transform the lives of those with early AD. Timely identification of eligible patients is needed to ensure treatments are delivered during a narrow window of therapeutic opportunity. Appropriate clinical service design will hinge on improved understanding of future demands, thus there is a pressing need to investigate patient eligibility in real world clinical cohorts. The primary aim of this study is to assess the eligibility by appropriate use criteria (AUC) for lecanemab therapy in a real-world, undifferentiated clinical patient cohort attending a Regional Specialist Memory Clinic (RSMC), with the secondary aims of determining the proportion of patients with biomarker positive Alzheimer's Disease (AD) who would be eligible for lecanemab therapy by AUC. Clinical trial eligibility criteria were also applied to both groups and discrepancies that exist between eligibility rates explored. METHODS: A retrospective cohort study of all new patients attending a RSMC from 1st January 2022 to 31st December 2022 was conducted. Data collected included demographic details, outcomes of diagnostic assessments and comorbidities. MRI images, where indicated, were reviewed. Amyloid positivity was defined as either Amyloid and Tau positive (A+T+) or Amyloid positive with a positive P-Tau/Ab42 ratio on cerebrospinal fluid (CSF) testing. Appropriate use criteria (AUC) and clinical trial criteria for lecanemab were applied. Proportion of eligible patients was calculated. RESULTS: Eleven (5.9%) of 188 new patient attenders were eligible (average age 66.7 years [SD 8.9], 63.6% female) by AUC, with 26.2% of patients with biomarker positive Alzheimer's Disease eligible for lecanemab therapy. The most common reason for exclusion was a lack of biomarker confirmation of AD pathology followed by cognitive ineligibility (based on defined cognitive testing cut-offs) at the time of referral and/or initial assessment. Only 40.4% of patients had CSF testing for AD biomarkers while almost 20% of the patients with biomarker positive AD were excluded due to lack of a screening MRI in the previous 12 months. CONCLUSION: In this study, the potential eligibility rate by AUC of the entire patient cohort (5.9%) was limited by the small proportion of patients who had CSF testing for AD biomarkers. So while disease-modification with Lecanemab is a welcome therapeutic advance, although only a small proportion of people currently attending specialist services will be eligible. Successful delivery of DMTs will require significant resource allocation and optimisation of referral pathways to facilitate early identification of potentially eligible patients.

Genetic testing in dementia.

There is growing public awareness and concern regarding dementia risk. In addition, genetic testing is increasingly accessible and is at the point of being integrated into routine clinical practice. As a result, there is a pressing need for treating clinicians to have the appropriate knowledge base to request and consent for diagnostic genetic testing in cognitive clinics. We outline our approach to genetic testing in patients with Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies and vascular cognitive impairment. We discuss when to consider testing, the consenting process, and the interpretation and communication of genetic test results.

Performance of plasma p-tau217 for the detection of amyloid-ß positivity in a memory clinic cohort using an electrochemiluminescence immunoassay.

BACKGROUND: Plasma p-tau217 has emerged as the most promising blood-based marker (BBM) for the detection of Alzheimer Disease (AD) pathology, yet few studies have evaluated plasma p-tau217 performance in memory clinic settings. We examined the performance of plasma p-tau217 for the detection of AD using a high-sensitivity immunoassay in individuals undergoing diagnostic lumbar puncture (LP). METHODS: Paired plasma and cerebrospinal fluid (CSF) samples were analysed from the TIMC-BRAiN cohort. Amyloid (Aß) and Tau (T) pathology were classified based on established cut-offs for CSF Aß42 and CSF p-tau181 respectively. High-sensitivity electrochemiluminescence (ECL) immunoassays were performed on paired plasma/CSF samples for p-tau217, p-tau181, Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light (NfL) and total tau (t-tau). Biomarker performance was evaluated using Receiver-Operating Curve (ROC) and Area-Under-the-Curve (AUC) analysis. RESULTS: Of 108 participants (age: 69 ± 6.5 years; 54.6% female) with paired samples obtained at time of LP, 64.8% (n = 70/108) had Aß pathology detected (35 with Mild Cognitive Impairment and 35 with mild dementia). Plasma p-tau217 was over three-fold higher in Aß + (12.4 pg/mL; 7.3-19.2 pg/mL) vs. Aß- participants (3.7 pg/mL; 2.8-4.1 pg/mL; Mann-Whitney U = 230, p < 0.001). Plasma p-tau217 exhibited excellent performance for the detection of Aß pathology (AUC: 0.91; 95% Confidence Interval [95% CI]: 0.86-0.97)-greater than for T pathology (AUC: 0.83; 95% CI: 0.75-0.90; z = 1.75, p = 0.04). Plasma p-tau217 outperformed plasma p-tau181 for the detection of Aß pathology (z = 3.24, p < 0.001). Of the other BBMs, only plasma GFAP significantly differed by Aß status which significantly correlated with plasma p-tau217 in Aß + (but not in Aß-) individuals. Application of a two-point threshold at 95% and 97.5% sensitivities & specificities may have enabled avoidance of LP in 58-68% of cases. CONCLUSIONS: Plasma p-tau217 measured using a high-sensitivity ECL immunoassay demonstrated excellent performance for detection of Aß pathology in a real-world memory clinic cohort. Moving forward, clinical use of plasma p-tau217 to detect AD pathology may substantially reduce need for confirmatory diagnostic testing for AD pathology with diagnostic LP in specialist memory services.

Navigating the future of Alzheimer's care in Ireland - a service model for disease-modifying therapies in small and medium-sized healthcare systems.

BACKGROUND: A new class of antibody-based drug therapy with the potential for disease modification is now available for Alzheimer's disease (AD). However, the complexity of drug eligibility, administration, cost, and safety of such disease modifying therapies (DMTs) necessitates adopting new treatment and care pathways. A working group was convened in Ireland to consider the implications of, and health system readiness for, DMTs for AD, and to describe a service model for the detection, diagnosis, and management of early AD in the Irish context, providing a template for similar small-medium sized healthcare systems. METHODS: A series of facilitated workshops with a multidisciplinary working group, including Patient and Public Involvement (PPI) members, were undertaken. This informed a series of recommendations for the implementation of new DMTs using an evidence-based conceptual framework for health system readiness based on [1] material resources and structures and [2] human and institutional relationships, values, and norms. RESULTS: We describe a hub-and-spoke model, which utilises the existing dementia care ecosystem as outlined in Ireland's Model of Care for Dementia, with Regional Specialist Memory Services (RSMS) acting as central hubs and Memory Assessment and Support Services (MASS) functioning as spokes for less central areas. We provide criteria for DMT referral, eligibility, administration, and ongoing monitoring. CONCLUSIONS: Healthcare systems worldwide are acknowledging the need for advanced clinical pathways for AD, driven by better diagnostics and the emergence of DMTs. Despite facing significant challenges in integrating DMTs into existing care models, the potential for overcoming challenges exists through increased funding, resources, and the development of a structured national treatment network, as proposed in Ireland's Model of Care for Dementia. This approach offers a replicable blueprint for other healthcare systems with similar scale and complexity.

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.