Improving Early Recognition of Treatment-Responsive Causes of Rapidly Progressive Dementia: The STAM3 P Score.

OBJECTIVE: To improve the timely recognition of patients with treatment-responsive causes of rapidly progressive dementia (RPD). METHODS: A total of 226 adult patients with suspected RPD were enrolled in a prospective observational study and followed for up to 2 years. Diseases associated with RPD were characterized as potentially treatment-responsive or non-responsive, referencing clinical literature. Disease progression was measured using Clinical Dementia Rating® Sum-of-Box scores. Clinical and paraclinical features associated with treatment responsiveness were assessed using multivariable logistic regression. Findings informed the development of a clinical criterion optimized to recognize patients with potentially treatment-responsive causes of RPD early in the diagnostic evaluation. RESULTS: A total of 155 patients met defined RPD criteria, of whom 86 patients (55.5%) had potentially treatment-responsive causes. The median (range) age-at-symptom onset in patients with RPD was 68.9 years (range 22.0-90.7 years), with a similar number of men and women. Seizures, tumor (disease-associated), magnetic resonance imaging suggestive of autoimmune encephalitis, mania, movement abnormalities, and pleocytosis (≥10 cells/mm3 ) in cerebrospinal fluid at presentation were independently associated with treatment-responsive causes of RPD after controlling for age and sex. Those features at presentation, as well as age-at-symptom onset <50 years (ie, STAM3 P), captured 82 of 86 (95.3%) cases of treatment-responsive RPD. The presence of ≥3 STAM3 P features had a positive predictive value of 100%. INTERPRETATION: Selected features at presentation reliably identified patients with potentially treatment-responsive causes of RPD. Adaptation of the STAM3 P screening score in clinical practice may minimize diagnostic delays and missed opportunities for treatment in patients with suspected RPD. ANN NEUROL 2024;95:237-248.

Diagnostic Utility of Cerebrospinal Fluid Biomarkers in Patients with Rapidly Progressive Dementia.

OBJECTIVE: This study was undertaken to apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD). Overlap in clinical presentation and results of diagnostic tests confounds etiologic diagnosis in patients with RPD. Objective measures are needed to improve diagnostic accuracy and to recognize patients with potentially treatment-responsive causes of RPD. METHODS: Biomarkers of Alzheimer disease neuropathology (amyloid-ß 42/40 ratio, phosphorylated tau [p-tau181, p-tau231]), neuroaxonal/neuronal injury (neurofilament light chain [NfL], visinin-like protein-1 [VILIP-1], total tau), neuroinflammation (chitinase-3-like protein [YKL-40], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], glial fibrillary acidic protein [GFAP], monocyte chemoattractant protein-1 [MCP-1]), and synaptic dysfunction (synaptosomal-associated protein 25kDa, neurogranin) were measured in CSF obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age- and sex-matched patients with typically progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by potential treatment responsiveness, and between patients with typical and rapidly progressive presentations of neurodegenerative disease. RESULTS: Alzheimer disease biomarkers were associated with neurodegenerative causes of RPD. High NfL, sTREM2, and YKL-40 and low VILIP-1 identified patients with autoimmune/inflammatory diseases. MCP-1 levels were highest in patients with vascular causes of RPD. A multivariate model including GFAP, MCP-1, p-tau181, and sTREM2 identified the 44 patients with treatment-responsive causes of RPD with 89% accuracy. Minimal differences were observed between typical and rapidly progressive presentations of neurodegenerative disease. INTERPRETATION: Selected CSF biomarkers at presentation were associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD. The ability of cross-sectional biomarkers to inform upon mechanisms that drive rapidly progressive neurodegenerative disease is less clear. ANN NEUROL 2024;95:299-313.

Normal pressure hydrocephalus, or Hakim syndrome: review and update.

This review makes the case that idiopathic normal pressure hydrocephalus (iNPH) is an outdated term because new information indicates that the syndrome is less idiopathic and that the cerebrospinal fluid (CSF) pressure of normal individuals is affected by several factors such as body mass index, age, and sex. Our review updates the epidemiology of iNPH and provides a clinical approach to the management of these patients. All the clinical features of iNPH are common in older individuals, and each has many causes, so the diagnosis is difficult. The first step in reaching an accurate diagnosis is to address the possible contributory factors to the gait abnormality and determine what if any role iNPH may be playing. The two best diagnostic tests are neuroimaging and cerebrospinal fluid (CSF) diversion (large volume lumbar puncture or external lumbar drainage) with pre/post gait evaluation. This review provides an update on the growing evidence that vascular disease, impaired CSF absorption, congenital, and genetic factors all contribute to the pathogenesis of iNPH. We suggest replacing the term iNPH with the term Hakim syndrome (HS) in acknowledgement of the first person to describe this syndrome. Lastly, we discuss the improvements in shunt technology and surgical techniques that have decreased the risks and long-term complications of shunt surgery.

Cancer in pathologically confirmed multiple system atrophy.

PURPOSE: The aim of this study was to assess whether cancer occurs with increased frequency in multiple system atrophy (MSA). The pathological hallmark of MSA is glial cytoplasmic inclusions containing aggregated α-synuclein, and the related protein γ-synuclein correlates with invasive cancer. We investigated whether these two disorders are associated clinically. METHODS: Medical records of 320 patients with pathologically confirmed MSA seen between 1998 and 2022 were reviewed. After excluding those with insufficient medical histories, the remaining 269 and an equal number of controls matched for age and sex were queried for personal and family histories of cancer recorded on standardized questionnaires and in clinical histories. Additionally, age-adjusted rates of breast cancer were compared with US population incidence data. RESULTS: Of 269 cases in each group, 37 with MSA versus 45 of controls had a personal history of cancer. Reported cases of cancer in parents were 97 versus 104 and in siblings 31 versus 44 for MSA and controls, respectively. Of 134 female cases in each group, 14 MSA versus 10 controls had a personal history of breast cancer. The age-adjusted rate of breast cancer in MSA was 0.83%, as compared with 0.67% in controls and 2.0% in the US population. All comparisons were nonsignificant. CONCLUSION: The evidence from this retrospective cohort found no significant clinical association of MSA with breast cancer or other cancers. These results do not exclude the possibility that knowledge about synuclein pathology at the molecular level in cancer may lead to future discoveries and potential therapeutic targets for MSA.

Synthetic Inversion Image Generation using MP2RAGE T1 Mapping for Surgical Targeting in Deep Brain Stimulation and Lesioning.

BACKGROUND: Advances in MRI technology have increased interest in direct targeting for deep brain stimulation (DBS). Various imaging sequences have been shown to provide increased contrast of numerous common DBS targets, such as T1-weighted, Fast Gray Matter Acquisition T1 Inversion Recovery (FGATIR), gray matter nulled, and Edge-Enhancing Gradient Echo (EDGE); however, the continual increase in the number of necessary sequences has led to an increase in imaging time, which is undesirable. Additionally, carefully timed inversion pulses can often lead to less-than-ideal contrast in some subjects, particularly in ultra-high field MRI, where B1+ field inhomogeneity can lead to substantial contrast variation. OBJECTIVES: This study proposes using 3D MP2RAGE-based T1 maps to retrospectively synthesize images of any desired inversion time, including T1-weighted, FGATIR, and EDGE contrasts, to visualize specific DBS targets at both 3T and 7T. METHOD: First, a systematic sequence optimization framework was applied to optimize MP2RAGE T1 mapping sequence parameters for the purpose of DBS planning. Next, we show that synthetic inversion-time images can be generated through a mathematical transformation of the T1 maps. The sequence was then applied to patients undergoing preoperative planning for DBS at 3T and 7T to generate synthetic contrasts used in surgical planning. RESULTS: We show that synthetic image contrasts can be generated across a full range of inversion times at 3T and 7T, including commonly used sequences for DBS targeting, such as T1-weighted, FGATIR, and EDGE. Acquisition through a single sequence shortens scan time compared to acquiring the sequences independently without affecting image quality or contrast. CONCLUSIONS: The generation of synthetic images for DBS targeting allows faster acquisition of many key sequences, as well as the ability to optimize contrast properties post-acquisition to account for the variable B1+ effects present in ultra-high field MRI. The proposed approach has the potential to reduce imaging time and improve the accuracy of DBS targeting at 1.5T, 3T, and 7T.

Updates on pharmacological treatment for Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia, and its rising prevalence is constantly increasing the global health burden. There are currently no curative therapies for AD, and current treatment options provide only modest clinical benefit. Despite numerous clinical trials, there have been no major additions to the AD treatment armamentarium this century. The prevailing pathomechanistic hypothesis for AD begins with abnormal accumulation of amyloid ß (Aß) leading to plaque development, and disease-modifying candidate therapies have largely aimed to disrupt this process. Numerous clinical trials of monoclonal antibodies directed at various stages of Aß plaque development have yielded mostly negative results; however, recent results suggest that a breakthrough may be on the horizon. The past two years have yielded positive results for three monoclonal antibodies (aducanumab, lecanemab, and donanemab) although questions remain regarding their clinical effectiveness. Additional clarity is needed to determine whether the clinical benefits are great enough to offset the treatment risks and the resource implications for healthcare systems. This review provides a foundational context and update on recent disease-modifying therapies for AD that have reached Phase III clinical trials. Up-to-date information on these therapies will help clinicians better inform their clinical decision-making and the counselling they can offer patients and their carers.

Treatment of CSF1R-Related Leukoencephalopathy: Breaking New Ground.

BACKGROUND: Colony-stimulating factor-1 receptor (CSF1R)-related leukoencephalopathy is a rapidly progressive neurodegenerative disease for which there is currently no cure. Hematopoietic stem cell transplantation (HSCT) has been proposed as a disease-modifying treatment. OBJECTIVE: The objective of this study was to determine the effect of HSCT on disease progression. METHODS: We collected all available clinical data from a cohort of 7 patients with CSF1R-related leukoencephalopathy who underwent HSCT at our institutions. Clinical data included detailed neurological examination by a board-certified neurologist, serial cognitive screens, formal neuropsychological evaluations, and serial brain magnetic resonance imaging (MRI). RESULTS: Our patients had an average disease duration of 27.6 months at the time of transplant, and we have 87 months of total posttransplant follow-up time (median, 11; range, 2-27). One patient died in the periprocedural period. The remaining patients showed a variable response to treatment, with 6 of 7 patients trending toward stabilization on motor examination, cognitive scores, and/or MRI abnormalities, especially with white matter lesion burden. CONCLUSIONS: This is the largest series of patients with CSF1R-related leukoencephalopathy receiving HSCT. We conclude that HSCT can stabilize the disease in some patients. Variability in patient responsiveness suggests that measures of disease heterogeneity and severity need to be considered when evaluating a patient's candidacy for transplant. HSCT appears to be the first disease-modifying therapy for CSF1R-related leukoencephalopathy. This milestone may serve as a foothold toward better understanding the disease's pathomechanism, thus providing new opportunities for better disease-specific therapies. © 2021 International Parkinson and Movement Disorder Society.

A Neurologist's Practical Approach to Cognitive Impairment.

The global prevalence of dementia is expected to triple by the year 2050. This impending health care crisis has led to new heights of public awareness and general concern regarding cognitive impairment. Subsequently, clinicians are seeing more and more people presenting with cognitive concerns. It is important that clinicians meet these concerns with a strategy promoting accurate diagnoses. We have diagramed and described a practical approach to cognitive impairment. Through an algorithmic approach, we determine the presence and severity of cognitive impairment, systematically evaluate domains of function, and use this information to determine the next steps in evaluation. We also discuss how to proceed when cognitive impairment is associated with motor abnormalities or rapid progression.

Dissecting parkinsonism: cognitive and gait disturbances.

Parkinsonism is usually designated a movement disorder. However, cognitive impairment comprises a major part of many parkinsonian syndromes, and inversely correlates with quality of life. Parkinsonian features are largely attributed to subcortical dopaminergic dysfunction, although other brain regions and neurotransmitters also contribute. This is illustrated by phenotypic differences among different parkinsonian syndromes. Slowed processing speed and executive dysfunction are generally expected in parkinsonian patients, but additional cognitive features can suggest specific pathological substrates, e.g. apraxia in corticobasal degeneration. Similarly, motor symptoms generally include combinations of bradykinesia, rigidity, rest tremor, and postural instability, although nuanced differences and associated clinical features often help differentiate between parkinsonian syndromes. Human gait requires complex synchronisation at every level of the nervous system, yet occurs with minimal conscious effort on behalf of the walker. Deviations from the normal gait pattern can result from otherwise unnoticeable insults to the body, both intrinsic and extrinsic to the nervous system. Gait is almost always abnormal in parkinsonism, ranging from subtle arm swing asymmetry to discrete episodes of gait freezing. Moreover, one's cognitive state can directly affect one's quality of gait. The notion that a gait profile could in fact be a disease-specific biomarker is an area of great research interest. This review focuses on the manifestations of, and correlations between, cognitive and gait impairment in common parkinsonian conditions, and provides guidance for a clinical approach to assessing them.

Effects of sex and APOE on Parkinson's Disease-related cognitive decline.

INTRODUCTION: Cognitive impairment is common in Parkinson's Disease, but the impact of predictive factors on incidence and rate of cognitive decline is incompletely understood. We aimed to determine the effects of sex and APOE allele status on cognitive performance in patients with Parkinson's Disease (PD). MATERIAL AND METHODS: We conducted a retrospective analysis of 325 clinically diagnosed PD patients who underwent one or more cognitive screenings with a Mini-Mental Status Examination (MMSE) or Mattis Dementia Rating Scale (DRS-2). We used proportional odds regression models to estimate odds ratios for higher versus lower cognitive scores in association with age, sex, education, disease duration, and APOE allele status. RESULTS: Higher cognitive scores were independently associated with female sex on the MMSE (OR 2.43; 95% CI 1.14, 5.14) and DRS-2 total (OR 4.14; 95% CI 2.01, 8.53). APOE ε4 dose was associated with lower DRS-2 totals (OR 0.42; 95% CI 0.22, 0.81), but there was no evidence of association with MMSE. Higher education level was also associated with higher scores on the MMSE (OR 1.22; 95% CI 1.07, 1.38) and DRS-2 total (OR 1.31; 95% CI 1.15, 1.50). Disease duration was not associated with cognitive performance on any measure when adjusting for age. CONCLUSION: Male sex and APOE ε4, along with age and lower education level, were associated with poorer cognitive performance among a population of predominantly non-demented PD patients.

Incorporation of Telestroke into Neurology Residency Training: "Time Is Brain and Education".

Background: With increasing demand for neurologists, nontraditional health care delivery mechanisms have been developed to leverage this limited resource. Introduction: Telemedicine has emerged as an effective digital solution. Over the past three decades, telemedicine use has steadily grown; however, neurologists often learn on the job, rather than as part of their medical training. The current literature regarding telestroke training during neurology training is sparse, focusing on cerebrovascular fellowship curricula. We sought to enhance telestroke training in our neurology residency by incorporating real-life application. Materials and Methods: We implemented a formal educational model for neurology residents to use telemedicine for remote acquisition of the National Institutes of Health Stroke Scale (NIHSS) for patients with suspected acute ischemic stroke (AIS) before arrival at our comprehensive stroke center. This three-phase educational model involved multidisciplinary classroom didactics, simulation exercises, and real-world experience. Training and feedback were provided by neurologists experienced in telemedicine. Results: All residents completed formal training in telemedicine prehospital NIHSS acquisition and had the opportunity to participate in additional simulation exercises. Currently, residents are gaining additional experience by performing prehospital NIHSS acquisition for patients in whom AIS is suspected. Our preliminary data indicate that resident video encounters average 10.6 min in duration, thus saving time once patients arrive at our hospital. Discussion: To our knowledge, this is the first report of a telestroke-integrated neurology residency program in a comprehensive stroke center resulting in shortened time to treatment in patients with suspected AIS. Conclusions: We present a model that can be adopted by other neurology residency programs as it provides real-world telemedicine training critical to future neurologists.

Sexual dysfunction in Huntington's Disease: what do we really know?

INTRODUCTION: In this edition, Szymus et al. conducted a systematic review revealing sexual dysfunction to be more prevalent in patients with Huntington's Disease compared to controls. CLINICAL REFLECTIONS: Sexual dysfunction in HD (SDHD) is common and significantly affects patient quality of life. Commonly used HD rating scales and treatment guidelines do not explicitly address SDHD, and research studies are limited by size and methodology. CLINICAL IMPLICATIONS: It is important that validated sexual dysfunction screening tools be utilised in clinical and research settings.

A practical approach to adult-onset white matter diseases, with illustrative cases.

AIM: To evaluate five illustrative cases and perform a literature review to identify and describe a working approach to adult-onset white matter diseases (WMD). STATE OF THE ART: Inherited WMD are a group of disorders often seen in childhood. In adulthood, progressive WMDs are rare, apart from the common nonspecific causes of hypertension and other cerebrovascular diseases. The pattern of WMDs on neuroimaging can be an important clue to the final diagnosis. Due to the adoption of a combined clinical-imaging-laboratory approach, WMD is becoming better recognised, in addition to the rapidly evolving field of genomics in this area. CLINICAL IMPLICATIONS: While paediatric WMDs have a well-defined and literature-based clinical-laboratory approach to diagnosis, adult-onset WMDs remain an important, pathologically diverse, radiographic phenotype, with different and distinct neuropathologies among the various subtypes of WMD. Adult-onset WMDs comprise a wide collection of both acquired and inherited aetiologies. While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neurological complications are emerging, we are as yet unaware of it causing WMD outside of post-anoxic changes. It is important to recognise WMD as a potentially undefined acquired or genetic syndrome, even when extensive full genome testing reveals variants of unknown significance. FUTURE DIRECTIONS: We propose a combined clinical-imaging-laboratory approach to WMD and continued exploration of acquired and genetic factors. Adult-onset WMD, even given this approach, can be challenging because hypertension is often comorbid. Therefore, we propose that undiagnosed patients with WMD be entered into multicentre National Organisation for Rare Diseases registries to help researchers worldwide make new discoveries that will hopefully translate into future cures.

Searching for tics.

INTRODUCTION: In the current edition, Szejko and colleagues describe a subset of patients with Gilles de la Tourette syndrome (GTS) who had dystonic tics (DTs), which occurred more frequently in those with a greater number of tics and likely contribute to impairment. Clinical Reflections: DTs manifest as an abnormal posture that may be difficult to distinguish from other movements, such as dystonia and other tic types. Electromyography is an invaluable tool that can aid clinicians in making this important distinction. CLINICAL IMPLICATIONS: Accurately diagnosing these movements can significantly impact treatment decisions and contribute to more homogenous research populations.