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With complicated conditions and a large number of potentially causative genes, the diagnosis of a patient with complex inherited peripheral neuropathies (IPNs) is challenging. To provide an overview of the genetic and clinical features of 39 families with complex IPNs from central south China and to optimize the molecular diagnosis approach to this group of heterogeneous diseases, a total of 39 index patients from unrelated families were enrolled, and detailed clinical data were collected. TTR Sanger sequencing, hereditary spastic paraplegia (HSP) gene panel, and dynamic mutation detection in spinocerebellar ataxia (SCAs) were performed according to the respective additional clinical features. Whole-exome sequencing (WES) was used in patients with negative or unclear results. Dynamic mutation detection in NOTCH2NLC and RCF1 was applied as a supplement to WES. As a result, an overall molecular diagnosis rate of 89.7% was achieved. All 21 patients with predominant autonomic dysfunction and multiple organ system involvement carried pathogenic variants in TTR, among which nine had c.349G > T (p.A97S) hotspot variants. Five out of 7 patients (71.4%) with muscle involvement harbored biallelic pathogenic variants in GNE. Five out of 6 patients (83.3%) with spasticity reached definite genetic causes in SACS, KIF5A, BSCL2, and KIAA0196, respectively. NOTCH2NLC GGC repeat expansions were identified in all three cases accompanied by chronic coughing and in one patient accompanied by cognitive impairment. The pathogenic variants, p.F284S and p.G111R in GNE, and p.K4326E in SACS, were first reported. In conclusion, transthyretin amyloidosis with polyneuropathy (ATTR-PN), GNE myopathy, and neuronal intranuclear inclusion disease (NIID) were the most common genotypes in this cohort of complex IPNs. NOTCH2NLC dynamic mutation testing should be added to the molecular diagnostic workflow. We expanded the genetic and related clinical spectrum of GNE myopathy and ARSACS by reporting novel variants., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Purpose: The callosal angle (CA) is a useful biomarker in the diagnosis and management of idiopathic normal pressure hydrocephalus (NPH). Used incorrectly, CA measurements are variable, affecting its reliability as a clinical tool. Our objectives are to evaluate (i) reproducibility of established CA measurements between trained raters and (ii) impact of minor angular mal-rotations of the true coronal plane on CA measurements., Methods: CAs were measured by two independent raters on three-dimensional isovolumetric T1-weighted brain MRI of NPH patients and healthy controls using the established true coronal plane reformatted orthogonal to the plane containing the anterior-posterior commissural (AC-PC) line at the level of the posterior commissure. CA changes were subsequently evaluated when the coronal plane was mal-rotated by ± 5° and ± 10° in anterior-posterior and clockwise-anticlockwise directions. Inter-rater reliability of CA measurements was assessed using the intraclass correlation coefficient (ICC)., Results: On the true coronal plane, inter-rater ICC was excellent (0.973) for NPH patients and good (0.875) for controls. On mal-rotated coronal plane setups, ICC for CA was worse in controls (0.484-0.886) than NPH (0.879-0.981) groups and in clockwise-anticlockwise (0.484-0.956) than anterior-posterior (0.503-0.981) mal-rotations. CA changes secondary to mal-rotations from the true coronal plane were significant in NPH patients (P < 0.0001 to 0.0378) but not in controls (P > 0.1)., Conclusion: This is the first demonstration of how small angular mal-rotations of the coronal plane used for CA measurement affect its value and inter-rater reliability, highlighting the importance of a standardized protocol when measuring the CA in NPH workup., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder lacking reliable biomarkers. This study investigates plasma protein levels as potential biomarkers of disease severity and progression in NIID. In this study, we enrolled 30 NIID patients and 36 age- and sex-matched controls, following them for 1-2 years. Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and tau were measured using ultrasensitive single molecule array (Simoa) assays. Disease severity was evaluated with the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL), and CNS symptom counts, in addition to neuroimaging data. Our study revealed that NIID patients has significantly higher plasma NfL (median, 35.2 vs. 8.61 pg/mL, p < 0.001) and GFAP (102 vs. 79.0 pg/mL, p = 0.010) levels compared to controls, with NfL emerging as a robust diagnostic marker (AUC = 0.956). NfL levels were notably higher in acute-onset NIID (77.5 vs. 28.8 pg/mL, p = 0.001). NfL correlated strongly with disease severity, including MMSE (ρ = - 0.687, p < 0.001), MoCA (ρ = - 0.670, p < 0.001), ADL (ρ = 0.587, p = 0.001), CNS symptoms (ρ = 0.369, p = 0.045), and white matter hyperintensity volume (ρ = 0.620, p = 0.004). Higher baseline NfL (≥ 35.2 pg/mL) associated with increased ADL scores, CNS symptoms, and white matter hyperintensity at follow-up. UCH-L1 and total tau levels showed no significant differences. Our results suggested the potential of NfL as a promising biomarker of disease severity and progression in NIID., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: We aimed to examine the longitudinal change of plasma neurofilament light chain (NFL) level and explore its diagnostic and prognostic implications in Parkinson's disease (PD)., Methods: A total of 184 patients with early PD who completed 5-year annually repeated clinical assessments were included. Plasma NFL at baseline, 1 year, and 2 year were examined, which were quantified using the ultrasensitive Simoa technology. At baseline, blood from 86 sex- and age-matched healthy controls (HC) were obtained for comparison., Results: Plasma NFL in PD patients at baseline was significantly higher than those in HC (P = 0.046), and significantly increased after 2 years (P = 0.046). Receiver operating characteristic curve indicated that a plasma NFL cut-off value of 10.79 pg/mL resulted in 39.7% sensitivity and 84.0% specificity, with an area under the curve of 0.635, to distinguish PD from HC (P < 0.001). Linear mixed-effect models indicated that baseline plasma NFL (> 9.24 pg/mL) correlated with a greater increase in the Unified Parkinson's Disease Rating Scale III (estimate = 0.651, P = 0.001) and Hoehn & Yahr stage (estimate = 0.072, P < 0.001), and also correlated with a greater decrease in the Montreal Cognitive Assessment (estimate = - 0.387, P < 0.001) during follow-up visits., Conclusions: Plasma NFL exhibits a tendency to increase with disease progression, and elevated baseline plasma NFL can serve as a predictor for accelerated motor deterioration and cognitive decline in PD. However, plasma NFL does not have high accuracy to distinguish individuals with early-stage PD from HC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Although depressive symptoms are common in PD, few studies investigated sex and age differences in depressive symptoms. Our study aimed to explore the sex and age differences in the clinical correlates of depressive symptoms in patients with PD. 210 PD patients aged 50-80 were recruited. Levels of glucose and lipid profiles were measured. The Hamilton Depression Rating Scale-17 (HAMD-17), the Montreal Cognitive Assessment (MoCA) and the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) assessed depressive symptom, cognition and motor function, respectively. Male depressive PD participants had higher fasting plasma glucose (FPG) levels. Regarding the 50-59 years group, depressive patients had higher TG levels. Moreover, there were sex and age differences in the factors associated with severity of depressive symptoms. In male PD patients, FPG was an independent contributor to HAMD-17 (Beta = 0.412, t = 4.118, p < 0.001), and UPDRS-III score was still associated with HAMD-17 in female patients after controlling for confounding factors (Beta = 0.304, t = 2.961, p = 0.004). Regarding the different age groups, UPDRS-III (Beta = 0.426, t = 2.986, p = 0.005) and TG (Beta = 0.366, t = 2.561, p = 0.015) were independent contributors to HAMD-17 in PD patients aged 50-59. Furthermore, non-depressive PD patients demonstrated better performance with respect to visuospatial/executive function among the 70-80 years group. These findings suggest that sex and age are crucial non-specific factors to consider when assessing the relationship between glycolipid metabolism, PD-specific factors and depression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: The longitudinal dynamics of neurofilament light chain (NfL) in multiple system atrophy (MSA) were incompletely illuminated. This study aimed to explore whether the plasma NfL (pNfL) could serve as a potential biomarker of clinical diagnosis and disease progression for MSA., Methods: We quantified pNfL concentrations in both a large cross-sectional cohort with 214 MSA individuals, 65 PD individuals, and 211 healthy controls (HC), and a longitudinal cohort of 84 MSA patients. Propensity score matching (PSM) was used to balance the age between the three groups. The pNfL levels between groups were compared using Kruskal-Wallis test. Linear mixed models were performed to explore the disease progression-associated factors in longitudinal MSA cohort. Random forest model as a complement to linear models was employed to quantify the importance of predictors., Results: Before and after matching the age by PSM, the pNfL levels could reliably differentiate MSA from HC and PD groups, but only had mild potential to distinguish PD from HC. By combining linear and nonlinear models, we demonstrated that pNfL levels at baseline, rather than the change rate of pNfL, displayed potential prognostic value for progression of MSA. The combination of baseline pNfL levels and other modifiers, such as subtypes, Hoehn-Yahr stage at baseline, was first shown to improve the diagnosis accuracy., Conclusions: Our study contributed to a better understanding of longitudinal dynamics of pNfL in MSA, and validated the values of pNfL as a non-invasive sensitive biomarker for the diagnosis and progression. The combination of pNfL and other factors is recommended for better monitoring and prediction of MSA progression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

With increasing life expectancy, a growing number of individuals are being affected by Parkinson's Disease (PD), a Neurodegenerative Disease (ND). Approximately, 5-10% of PD is explained by genetic causes linked to known PD genes. With improvements in genetic testing and high-throughput technologies, more PD-associated susceptibility genes have been reported in recent years. However, a comprehensive review of the pathogenic mechanisms and physiological roles of these genes is still lacking. This article reviews novel genes with putative or confirmed pathogenic mutations in PD reported since 2019, summarizes the physiological functions and potential associations with PD. Newly reported PD-related genes include ANK2, DNAH1, STAB1, NOTCH2NLC, UQCRC1, ATP10B, TFG, CHMP1A, GIPC1, KIF21B, KIF24, SLC25A39, SPTBN1 and TOMM22. However, the evidence for pathogenic effects of many of these genes is inconclusive. A variety of novel PD-associated genes have been identified through clinical cases of PD patients and analysis of Genome-Wide Association Studies (GWAS). However, more evidence is needed in confirm the strong association of novel genes with disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Dementia with Lewy bodies (DLB) and Parkinson disease (PD) with and without dementia are entities of a spectrum of Lewy body diseases. About 26.3% of all PD patients develop dementia increasing up to 83%. Parkinson disease-dementia (PDD) and DLB share many clinical and morphological features that separate them from non-demented PD (PDND). Clinically distinguished by the temporal sequence of motor and cognitive symptoms, the pathology of PDD and DLB includes variable combinations of Lewy body (LB) and Alzheimer (AD) lesions, both being more severe in DLB, but much less frequent and less severe in PDND. The objective of this study was to investigate the morphological differences between these three groups. 290 patients with pathologically confirmed PD were reviewed. 190 of them had clinical dementia; 110 met the neuropathological criteria of PDD and 80 of DLB. The major demographic and clinical data were obtained from medical records. Neuropathology included semiquantitative assessment of LB and AD pathologies including cerebral amyloid angiopathy (CAA). PDD patients were significantly older than PDND and DLB ones (83.9 vs 77.9 years, p < 0.05); the age of DLB patients was between them (80.0 years), while the disease duration was shortest in DLB. Brain weight was lowest in DLB, which showed higher Braak LB scores (mean 5.2 vs 4.2) and highest Braak tau stages (mean 5.2 vs 4.4 and 2.3, respectively). Thal Aβ phases were also highest in DLB (mean 4.1 vs 3.0 and 1.8, respectively). Major findings were frequency and degree of CAA, being highest in DLB (95% vs 50% and 24%, with scores 2.9 vs 0.7 and 0.3, respectively), whereas other small vessel lesions showed no significant differences. Striatal Aβ deposits also differentiated DLB from the other groups. This and other studies of larger cohorts of PD patients indicate that the association of CAA and cortical tau-but less-LB pathologies are associated with more severe cognitive decline and worse prognosis that distinguish DLB from PDD and PDND. The particular impact of both CAA and tau pathology supports the concept of a pathogenic continuum ranging from PDND to DLB + AD within the spectrum of age-related synucleinopathies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Blood neurofilament light chain (NfL) is an easily accessible, highly sensitive and reliable biomarker for neuroaxonal damage. Currently, its role in Parkinson's disease (PD) remains unclear. Here, we demonstrate that blood NfL can distinguish idiopathic PD from atypical parkinsonian syndromes (APS) with high sensitivity and specificity. In cross-sectional studies, some found significant correlations between blood NfL with motor and cognitive function, whereas others did not. In contrast, prospective studies reported very consistent associations between baseline blood NfL with motor progression and cognitive worsening. Amongst PD subtypes, especially postural instability and gait disorder (PIGD) subtype, symptoms and scores are reliably linked with blood NfL. Different non-motor PD comorbidities have also been associated with high blood NfL levels suggesting that the neuroaxonal damage of the autonomic nervous system as well as serotonergic, cholinergic and noradrenergic neurons is quantifiable. Numerous absolute NfL cutoff levels have been suggested in different cohort studies; however, validation across cohorts remains weak. However, age-adjusted percentiles and intra-individual blood NfL changes might represent more valid and consistent parameters compared with absolute NfL concentrations. In summary, blood NfL has the potential as biomarker in PD patients to be used in clinical practice for prediction of disease severity and especially progression., (© 2023. The Author(s).)

Cognitive impairment is one of the most salient non-motor symptoms of Parkinson disease (PD) that poses a significant burden on the patients and carers as well as being a risk factor for early mortality. People with PD show a wide spectrum of cognitive dysfunctions ranging from subjective cognitive decline and mild cognitive impairment (MCI) to frank dementia. The mean frequency of PD with MCI (PD-MCI) is 25.8% and the pooled dementia frequency is 26.3% increasing up to 83% 20 years after diagnosis. A better understanding of the underlying pathological processes will aid in directing disease-specific treatment. Modern neuroimaging studies revealed considerable changes in gray and white matter in PD patients with cognitive impairment, cortical atrophy, hypometabolism, dopamine/cholinergic or other neurotransmitter dysfunction and increased amyloid burden, but multiple mechanism are likely involved. Combined analysis of imaging and fluid markers is the most promising method for identifying PD-MCI and Parkinson disease dementia (PDD). Morphological substrates are a combination of Lewy- and Alzheimer-associated and other concomitant pathologies with aggregation of α-synuclein, amyloid, tau and other pathological proteins in cortical and subcortical regions causing destruction of essential neuronal networks. Significant pathological heterogeneity within PD-MCI reflects deficits in various cognitive domains. This review highlights the essential neuroimaging data and neuropathological changes in PD with cognitive impairment, the amount and topographical distribution of pathological protein aggregates and their pathophysiological relevance. Large-scale clinicopathological correlative studies are warranted to further elucidate the exact neuropathological correlates of cognitive impairment in PD and related synucleinopathies as a basis for early diagnosis and future disease-modifying therapies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Serum neurofilament light chain (NfL) and chitinase 3-like 1 (CHI3L1, also called YKL-40) concentrations are attractive candidate biomarkers for neurodegenerative disorders, which include amyotrophic lateral sclerosis (ALS) and parkinsonian disorders. We aimed to assess the diagnostic power of serum NfL and CHI3L1 concentrations with regard to the early diagnosis of ALS and Parkinson's disease (PD). We studied 157 individuals, which included 41 healthy controls, 8 patients with ALS mimics, 18 patients initially diagnosed with ALS (ID-ALS), 32 patients late-diagnosed with ALS (LD-ALS), 29 patients with PD, 12 patients with PD mimics, and 17 patients initially diagnosed with atypical parkinsonian disorders (ID-APDs) at the initial stage of diagnosis. Electrochemiluminescence was used to measure the concentrations of serum NfL and CHI3L1, the diagnostic performance of which was assessed using the area under the receiver operating curves (AUCs). The AUCs of serum NfL were 0.90 for discriminating ALS mimics from LD-ALS at the initial stage of diagnosis and 0.89 for discriminating ALS mimics from ALS (LD/ID-ALS). The AUCs of serum NfL were 0.76 for discriminating PD from PD mimics at the initial stage of diagnosis, and 0.80 for discriminating PD from APD. No significant difference existed in serum CHI3L1 concentrations between individuals with suspected ALS or parkinsonism (p = 0.14, and p = 0.44, respectively). Serum NfL had excellent and almost good diagnostic performances for patients with ALS and PD, respectively, at the initial stage of diagnosis, whereas no significant difference existed in serum CHI3L1 between any groups., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

The PIGD (postural instability / gait difficulty) subtype of Parkinson´s disease (PD) is associated with faster cognitive and motor decline. So far, there are no quantifiable biomarkers to aid clinical subtyping. Neurofilament light chain (NfL) is a highly specific marker of neuro-axonal damage and can be assessed in blood. Here, we investigated if serum NfL concentrations are associated with PIGD subtype and PIGD scores in PD patients at advanced disease stages. Furthermore, we evaluated if serum NfL is associated with motor and cognitive function assessed with MDS-UPDRS part III and Montreal cognitive assessment (MoCA). Serum NfL levels were analyzed with Single Molecule Assays (Simoa) in blood of 223 PD patients from the bioMARKers in Parkinson's Disease (MARK-PD) study. Serum NfL concentrations were higher in PIGD patients independent of age, sex and disease duration. In linear regression analysis, serum NfL levels were associated with MoCA, MDS-UPDRS III and PIGD scores in unadjusted models, but remained significant after adjustment only with PIGD scores. In conclusion, increased serum NfL levels were associated with PIGD subtype and PIGD scores in patients with advanced PD., (© 2022. The Author(s).)

The association between dyslipidemia and cognitive performance in Parkinson's disease (PD) patients still needs to be clarified. Aim of the study was to evaluate the presence of possible associations between serum lipids fractions and executive dysfunction also exploring the sex-specific contribute of lipids level on cognition. Patients from the PACOS cohort, who underwent a complete serum lipid profile measures (total cholesterol-TC, low-density lipoprotein cholesterol-LDL, high-density lipoprotein cholesterol-HDL and triglycerides-TG) were selected. Adult Treatment Panel III guidelines of the National Cholesterol Education Program were used to classify normal/abnormal lipid fractions. Executive functioning was assessed with the Frontal Assessment Battery (FAB). Logistic regression was performed to assess associations between lipids fractions and FAB score. Correlations between lipids fractions and FAB score were explored. Sex-stratified analysis was performed. Three hundred and forty-eight PD patients (148 women; age 66.5 ± 9.5 years; disease duration 3.9 ± 4.9 years) were enrolled. Women presented significantly higher TC, LDL and HDL than men. In the whole sample, any association between lipid profile measures and FAB score was found. Among women, a positive association between hypertriglyceridemia and FAB score under cutoff was found (OR 3.4; 95%CI 1.29-9.03; p value 0.013). A statistically significant negative correlation was found between the FAB score and triglyceride serum levels (r = - 0.226; p value 0.005). Differently, among men, a statistically significant negative association between hypercholesterolemia and FAB score under cutoff (OR 0.4; 95%CI 0.17-0.84; p value 0.018) and between high LDL levels and FAB score under cutoff (OR 0.4; 95%CI 0.18-0.90; p value 0.027) were found. Our data suggest a sex-specific different role of lipids in executive functioning., (© 2022. The Author(s).)

Alzheimer's disease (AD), the most common form of dementia worldwide, is a mixed proteinopathy (β-amyloid, tau and other proteins). Classically defined as a clinicopathological entity, AD is a heterogeneous, multifactorial disorder with various pathobiological subtypes showing different forms of cognitive presentation, currently referred to as the Alzheimer spectrum or continuum. Its morphological hallmarks are extracellular β-amyloid (amyloid plaques) and intraneuronal tau aggregates forming neurofibrillary tangles and neurites, vascular amyloid deposits (cerebral amyloid angiopathy), synapse and neuronal loss as well as neuroinflammation and reactive astrogliosis, leading to cerebral atrophy and progressive mental/cognitive impairment (dementia). In addition to "classical" AD, several subtypes with characteristic regional patterns of tau pathology have been segregated that are characterized by distinct clinical features, differences in age, sex distribution, disease duration, cognitive status, APOE genotype, and biomarker levels. In addition to four major subtypes based on the distribution of tau pathology and brain atrophy (typical, limbic predominant, hippocampal sparing, and minimal atrophy), several other clinical variants (non-amnestic, corticobasal, behavioral/dysexecutive, posterior cortical variants, etc.) have been identified. These heterogeneous AD variants are characterized by different patterns of key neuronal network destructions, in particular the default-mode network that is responsible for cognitive decline. Other frequent age-related co-pathologies, e.g., cerebrovascular lesions, Lewy and TDP-43 pathologies, hippocampal sclerosis, or argyrophilic grain disease, essentially influence the clinical picture and course of AD, and can challenge our understanding of this disorder including the threshold and causal relevance of each individual pathology. Unravelling the clinico-morphological heterogeneity among the AD spectrum entities is important for better elucidation of the pathogenic mechanisms affecting the aging brain that may enable a broader diagnostic coverage of AD as a basis for implementing precision medicine approaches and for developing preventive and ultimately disease-modifying therapies for this devastating disorder., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)