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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 β (Aβ) 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 Aβ 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. [ABSTRACT FROM AUTHOR]

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‐β 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 [ABSTRACT FROM AUTHOR]

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, STAM3P), captured 82 of 86 (95.3%) cases of treatment‐responsive RPD. The presence of ≥3 STAM3P 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 STAM3P 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 [ABSTRACT FROM AUTHOR]

This article provides an overview of lesioning therapies used to treat neurological conditions, specifically focusing on thalamotomy for tremor. It compares different techniques, such as radiofrequency and gamma knife thalamotomy, to deep brain stimulation (DBS) and magnetic resonance-guided focused ultrasound (FUS). The article discusses the varying levels of evidence for the efficacy of these surgical options and their safety profiles. It concludes that while FUS and DBS have the strongest evidence for efficacy, stereotactic radiotherapy is still supported by evidence. The article also discusses different treatment options for movement disorders and emphasizes the importance of clinicians being aware of these options and referring patients to high-volume centers for better outcomes. [Extracted from the article]

Background: Patients with the precipitous onset of cognitive symptoms (i.e., suspected rapid progressive dementia [RPD]) may continue to decline (true RPD) or may stabilize or improve (non‐RPD). Recognizing patients with RPD early in the disease course is important to support clinical care and enrollment in research. Method: Patients referred for the evaluation of suspected RPD were prospectively enrolled and followed for up to 2 years at Mayo Clinic in Florida (Jacksonville, FL; Jan‐2020 – Oct‐2023) and Washington University in St. Louis (Saint Louis, MO; Jun‐2016 – Dec‐2019). Clinical data were independently reviewed by two dementia specialists who established clinical diagnoses, referencing published criteria. Patients were diagnosed with RPD if they progressed to dementia (global Clinical Dementia Rating® [CDR] ≥1) within 1 year or incapacitation (CDR ≥2) within 2 years of symptom onset. Univariate statistics compared demographics, clinical details, and test results between patients with RPD and non‐RPD. Variables with p<0.1 were entered into a multivariate logistic regression model to identify factors associated with RPD. Result: Of 248 patients referred for suspected RPD, 187 (75.4%) met stated criteria for RPD. Patients with RPD were older (62.6±14.4 years vs 55.0±18.3 years; p<0.001), and more likely to be diagnosed with Alzheimer disease or related dementias (28.3% vs 9.8%; p = 0.003) or Creutzfeldt‐Jakob (19.1% vs 4.6%; p = 0.008). Non‐RPD cases were more often attributed to autoimmune/inflammatory disease (42.6% vs 29.4%, p = 0.061) or other causes (e.g., psychiatric, neoplasms, toxic/metabolic; 34.4% vs 16.6%, p = 0.006). After controlling for age, hallucinations (OR, 2.81; 95%CI: 1.21‐6.52), elevated CSF protein (OR, 2.43; 95%CI: 1.17‐5.03), and CSF white blood cell count <5 cells/mm3 (OR, 2.77; 95%CI: 1.32‐5.85) were independently associated with RPD. Cortical visual loss (15/183, 8.2%) and substantial brain atrophy on MRI (27/184, 14.7%) were specific to patients with RPD, representing additional distinguishing features. Conclusion: Hallucinations, cortical visual loss, substantial atrophy on MRI, elevated CSF protein, and normal CSF white blood cell count were independently associated with RPD. Early detection of these features in patients with suspected RPD may inform clinical care and enrollment in research studies of RPD. [ABSTRACT FROM AUTHOR]

Introduction: The neuropsychological profile of CSF1R-related leukoencephalopathy (CRL) is undefined. This study defines the profile, contrasts it with that of other dementia syndromes, and highlights measures sensitive to cognitive impairment. Methods: We administered a standardized battery of neuropsychological tests to five consecutive CRL cases. Results: The neuropsychological profile of CRL reflects impaired general cognitive function, processing speed, executive function, speeded visual problem solving, verbal fluency, and self-reported depression and anxiety. Confrontation naming and memory are preserved. Within cognitive domains, certain measures more frequently identified impairment than others. Discussion: CRL impairs general cognitive function, processing speed, executive function. Language and visual problem solving may be impaired if processing speed is required. Confrontation naming and memory are uniquely preserved, contrasting CRL to other dementia syndromes. Cognitive screens excluding processing speed and executive function may not detect CRL cognitive manifestations. Findings sharply define cognitive impairment of CRL and inform cognitive test selection. [ABSTRACT FROM AUTHOR]