IntroductionBehavioural variant frontotemporal dementia (bvFTD) characterisation has evolved, but diagnosis remains challenging, relying on clinical diagnostic criteria that have undergone revisions ...over time. In this systematic review, our aims are to evaluate the accuracy of clinical diagnostic criteria for bvFTD by comparing them against pathological diagnoses and determine potential improvement in performance over the years.Methods and analysisThis systematic review protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 guidelines and is registered on PROSPERO. We will search four databases (MEDLINE-PubMed, Web of Science, Embase and LILACS) using tailored search terms on May 1st 2024. Inclusion criteria encompass peer-reviewed articles reporting diagnostic parameters or raw data regarding bvFTD clinical diagnosis based on well-defined criteria. Screening and selection of relevant articles will be independently performed by two reviewers using the Covidence systematic review manager. Discrepancies will be resolved by a third researcher. Pathologic and genetic diagnosis will be the main gold standard, but we will also consider refined diagnoses after a follow-up period. Data will be collected on study design, baseline demographics and sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy. Study quality will be assessed with Quality Assessment of Diagnostic Accuracy Studies-2. If possible, we will conduct a meta-analysis using bivariate random-effect models. Subgroup analyses will consider study settings, gold standards, disease stages and bias.Ethics and disseminationEthics approval will not be needed because the data used in this systematic review will be extracted from published studies. Findings will be disseminated through peer-reviewed publications and presentations at relevant scientific conferences, potentially enhancing our understanding of bvFTD clinical diagnosis reliability and guiding future criteria refinements.PROSPERO registration numberCRD42023389063.
Anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) recently emerged as a potential biomarker in patients with inflammatory demyelinating diseases of the central nervous system. We here ...compare the clinical and laboratory findings observed in a cohort of MOG-Ab seropositive and seronegative cases and describe IgG subclass analysis results. Consecutive serum samples referred to Verona University Neuropathology Laboratory for aquaporin-4 (AQP4)-Ab and/or MOG-Ab testing were analysed between March 2014 and May 2017. The presence of AQP4-Ab was determined using a cell-based assay. A live cell immunofluorescence assay was used for the detection of MOG-IgG and IgG subclass analysis. Among 454 analysed samples, 29 were excluded due to AQP4-Ab positivity or to the final demonstration of a disorder not compatible with MOG-Ab. We obtained clinical data in 154 out of 425 cases. Of these, 22 subjects resulted MOG-Ab positive. MOG-Ab positive patients were mainly characterised by the involvement of the optic nerve and/or spinal cord. Half of the cases presented relapses and the recovery was usually partial. Brain MRI was heterogeneous while short lesions were the prevalent observation on spinal cord MRI. MOG-Ab titre usually decreased in non-relapsing cases. In all MOG-IgG positive cases, we observed IgG1 antibodies, which were predominant in most subjects. IgG2 (5/22), IgG3 (9/22) and IgG4 (3/22) antibodies were also detectable. We confirm that MOG-Ab-related syndromes have distinct features in the spectrum of demyelinating conditions, and we describe the possible role of the different IgG subclasses in this condition.
Delusions are part of the neuropsychiatric symptoms that patients suffering from neurodegenerative conditions frequently develop at some point of the disease course and are associated with an ...increased risk of cognitive and functional decline. Delirium is a syndrome characterized by acute onset of deficits in attention, awareness, and cognition that fluctuate in severity over a short time period. Delusions and delirium are frequently observed in the context of neurodegeneration, and their presence can easily mislead clinicians toward a misdiagnosis of psychiatric disorder further delaying the proper treatment. Risk factors for developing delusion and delirium in neurodegenerative conditions have been investigated separately while the possible interplay between these two conditions has not been explored so far. With this study, we aim to achieve a more comprehensive picture of the relationship between delusions and delirium in neurodegeneration by analyzing prevalence and subtypes of delusions in different neurodegenerative disorders; providing an overview of clinical tools to assess delusions in neurodegenerative patients and how delusions are covered by delirium assessment tools and discussing the possible common pathophysiology mechanisms between delusion and delirium in neurodegenerative patients. A more extensive characterization of the relationship between delusions and delirium may help to understand whether delusions may constitute a risk factor for delirium and may ameliorate the management of both conditions in patients with neurodegenerative disorders.
The identification of biomarkers that reflect worse progression of nonmotor symptoms (NMS) in Parkinson's disease (PD) is currently an unmet need. The main aim of this study was to investigate ...whether cerebrospinal fluid (CSF) and serum neurofilament light (NfL), measured at baseline or longitudinally, can be used to predict the progression of NMS in patients with PD.
Baseline and longitudinal NfL levels were measured in the CSF and serum in 392 PD patients and 185 healthy controls from the Parkinson's Progression Marker Initiative. NMS were assessed using several scales, including, but not restricted to, the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part I, the Geriatric Depression Scale (GDS) and the State-Trait Anxiety Inventory (STAI). The relationship between baseline and longitudinal NfL levels with changes in NMS was assessed using linear mixed effects models (LME) in PD patients. In addition, we compared CSF and serum NfL levels between groups and assessed the relationship between NfL biomarkers with baseline NMS. Finally, to assess the specificity of our findings we ran the previous LME models using other biomarkers such as CSF amyloid-β1–42, total tau, phosphorylated tau181 and total α-synuclein and we also ran the models in healthy controls.
Baseline levels and longitudinal changes in serum and CSF NfL predicted worse longitudinal MDS-UPDRS-I and depression scores over time in PD (p < 0.01). This relationship remained significant only for CSF NfL when controlling for motor and cognitive status. Furthermore, longitudinal changes in serum and CSF NfL were associated with worse anxiety over time in PD patients (p < 0.05). In contrast to CSF NfL, serum NfL levels were slightly higher at baseline (p = 0.043) and showed significant longitudinal increases (p < 0.001) in PD patients compared to controls. There were no significant correlations between NfL levels (CSF or serum) with other NMS scales, baseline NMS variables, other biomarkers or in healthy controls.
Our findings indicate that both serum and CSF NfL are associated with worse longitudinal NMS burden, particularly in relation to the progression of depression and anxiety. Serum NfL showed stronger associations with NMS suggesting it could potentially be used as a non-invasive marker of NMS progression for PD.
•There is an urgent need to identify biomarkers that reflect worse nonmotor symptoms (NMS) in Parkinson's disease (PD).•Neurofilament light chain (NfL) has recently gained attention as a promising biomarker for PD.•Our study demonstrates that NfL both in CSF and serum may predict NMS burden.•Our results suggest that NMS in PD may mechanistically result from progressive neuronal/axonal degeneration.•These findings support the hypothesis that neuro-axonal loss may be an important factor underlying neurocognitive and psychiatric symptoms in PD.
It has been recently suggested that LRRK2 mutations are associated with a more benign clinical phenotype and a potentially more preserved cholinergic function in Parkinson's disease (PD). However, to ...our knowledge, no studies have tested whether the better clinical progression observed in LRRK2-PD patients is associated with more preserved volumes of a cholinergic brain area, the basal forebrain (BF). To address this hypothesis, here we compared BF volumes in LRRK2 carriers with and without PD with respect to idiopathic PD (iPD) patients and controls, and assessed whether they are associated with better clinical progression observed in LRRK2-PD compared to iPD.
Thirty-one symptomatic LRRK2-PD patients and 13 asymptomatic LRRK2 individuals were included from the Parkinson's Progression Markers Initiative. In addition, 31 patients with iPD and 13 healthy controls matched to the previous groups were also included. BF volumes were automatically extracted from baseline T1-weighted MRI scans using a stereotactic atlas of cholinergic nuclei. These volumes were then compared between groups and their relationship with longitudinal cognitive changes was evaluated using linear mixed effects models. Mediation analyses assessed whether BF volumes mediated differences in cognitive trajectories between groups.
LRRK2-PD patients showed significantly higher BF volumes compared to iPD (P = 0.019) as did asymptomatic LRRK2 subjects compared to controls (P = 0.008). There were no other significant differences in cortical regions or subcortical volumes between these groups. BF volumes predicted longitudinal decline in several cognitive functions in iPD patients but not in LRRK2-PD, who did not show cognitive changes over a 4-year follow-up period. BF volumes were a significant mediator of the different cognitive trajectories between iPD and LRRK2-PD patients (95% CI 0.056–2.955).
Our findings suggest that mutations in LRRK2 are associated with increased BF volumes, potentially reflecting a compensatory hypercholinergic state that could prevent cognitive decline in LRRK2-PD patients.
•LRRK2-positive PD patients and unaffected carriers have increased basal forebrain (BF) volumes.•BF volumes predict cognitive decline in idiopathic PD but not in LRRK2-PD.•LRRK2-PD patients do not show significant cognitive changes over a 4-year period.•BF volumes mediate the different cognitive trajectories of idiopathic PD and LRRK2-PD.•BF volumes in LRRK2-PD may reflect a protective hypercholinergic state for cognition in PD.
Abstract
BACKGROUND
Transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) thalamotomy is a novel and effective treatment for controlling tremor in essential tremor patients.
OBJECTIVE
...To provide a comprehensive characterization of the radiological, topographical, and volumetric aspects of the tcMRgFUS thalamic lesion, and to quantify how they relate to the clinical outcomes.
METHODS
In this study, clinical and radiological data from forty patients with medically-refractory essential tremor treated with unilateral tcMRgFUS thalamotomy were retrospectively analyzed. Treatment efficacy was assessed with Clinical Rating Scale for Tremor (CRST). Lesions were manually segmented on T1, T2, and susceptibility-weighted images, and 3-dimensional topographical analysis was then carried out. Statistical comparisons were performed using nonparametric statistics.
RESULTS
The greatest clinical improvement was correlated with a more inferior and posterior lesion, a bigger lesion volume, and percentage of the ventral intermediate nucleus covered by the lesion; whereas, the largest lesions accounted for the occurrence of gait imbalance. Furthermore, the volume of the lesion was significantly predicted by the number of sonications surpassing 52°C.
CONCLUSION
Here we provide a comprehensive characterization of the thalamic tcMRgFUS lesion including radiological and topographical analysis. Our results indicate that the location and volume of the lesion were significantly associated with the clinical outcome and that mid-temperatures may be responsible for the lesion size. This could serve ultimately to improve targeting and judgment and to optimize clinical outcome of tcMRgFUS thalamotomy.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects both motor and non-motor functions, including sleep regulation. Emerging evidence suggests that the ...hypothalamus, a brain region that plays a critical role in sleep-wake regulation, may be involved in the pathogenesis of ALS-related sleep disturbances. In this review, we have summarized results of studies on sleep disorders in ALS published between 2000 and 2023. Thereafter, we examined possible mechanisms by which hypothalamic dysfunctions may contribute to ALS-related sleep disturbances. Achieving a deeper understanding of the relationship between hypothalamic dysfunction and sleep disturbances in ALS can help improve the overall management of ALS and reduce the burden on patients and their families.
To date, there are no clinically effective neuroprotective or disease-modifying treatments that can halt Parkinson's disease (PD) progression. The current clinical approach focuses on symptomatic ...management. This failure may relate to the complex neurobiology underpinning the development of PD and the absence of true translational animal models. In addition, clinical diagnosis of PD relies on presentation of motor symptoms which occur when the neuropathology is already established. These multiple factors could contribute to the unsuccessful development of neuroprotective treatments for PD. Prodromal symptoms develop years prior to formal diagnosis and may provide an excellent tool for early diagnosis and better trial design. Patients with idiopathic rapid eye movement behavior disorder (iRBD) have the highest risk of developing PD and could represent an excellent group to include in neuroprotective trials for PD. In addition, repurposing drugs with excellent safety profiles is an appealing strategy to accelerate drug discovery. The anti-diabetic drug metformin has been shown to target diverse cellular pathways implicated in PD progression. Multiple studies have, additionally, observed the benefits of metformin to counteract other age-related diseases. The purpose of this viewpoint is to discuss metformin's neuroprotective potential by outlining relevant mechanisms of action and the selection of iRBD patients for future clinical trials in PD.
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND) and has emerged, among the disorders, with the largest increase in incidence in Western countries. Although the ...typical clinical phenotype of ALS involves simultaneous upper and lower motor neurons, there is growing evidence that the neurodegeneration during the course of the disease can also involve other motor and non-motor regions. In this review, we analyzed and discussed available data from epidemiological population-based studies on extrapyramidal and non-motor features during the course of ALS.
Sarcopenia is an age-related clinical syndrome characterized by the progressive loss of muscle mass and muscle strength. It appears to be closely linked to dementia, particularly Alzheimer's disease ...(AD); however, its prevalence among AD patients remains unclear. In this study, we assessed differences in sarcopenia prevalence between non-demented individuals and AD patients. Moreover, we assessed sex-specific differences in sarcopenia prevalence and explored the diagnostic value of the Muscle Quality Index (MQI) for diagnosing sarcopenia among AD patients.
Cross-sectional study including 145 patients with probable AD and 51 older adults with normal cognition. Sarcopenia was diagnosed according to the criteria of the European Working Group on Sarcopenia in Older People (EWGSOP1 and EWGSOP2) and of the Foundation for the National Institutes of Health (FNIH). The MQI was computed as the ratio of handgrip strength to skeletal muscle mass.
No significant difference in sarcopenia prevalence was observed between AD patients and controls. Prevalence ranged from 3.4 to 23.4% in AD patients and from 2 to 11.8% in controls, depending on diagnostic criteria. Prevalence was higher using EWGSOP1 and decreased using EWGSOP2 and FNIH. Prevalence was higher in males than in females with AD. The MQI was lower in AD patients than in controls (95%CI: - 0.23, - 0.05, p < 0.001), but displayed poor diagnostic accuracy in identifying sarcopenia cases.
AD patients and controls show comparable sarcopenia prevalence. Sarcopenia prevalence is higher in males than females among AD patients and higher when using EWGSOP1 compared to FNIH and EWGSOP2 criteria.
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