Correlations between serotonin impairments and clinical indices in multiple system atrophy.

BACKGROUND AND PURPOSE: Multiple system atrophy (MSA) is a neurodegenerative disease with characteristic motor and autonomic symptoms. Impaired brain serotonergic innervation can be associated with various clinical indices of MSA; however, the relationship between clinical symptoms and cerebrospinal fluid (CSF) levels of 5-hydroxyindole acetic acid (5-HIAA), a main serotonin metabolite, has not been fully elucidated. METHODS: To compare CSF 5-HIAA levels between patients with MSA and healthy controls, we included 33 controls and 69 MSA patients with either predominant parkinsonian or cerebellar ataxia subtypes. CSF 5-HIAA levels were measured using high-performance liquid chromatography. Additionally, we investigated correlations between CSF 5-HIAA and various clinical indices in 34 MSA patients. RESULTS: CSF 5-HIAA levels were significantly lower in MSA patients than in controls (p < 0.0001). Probable MSA patients had lower CSF 5-HIAA levels than possible MSA patients (p < 0.001). In MSA patients, CSF 5-HIAA levels were inversely correlated with scores in Parts 1, 2, and 4 of the Unified Multiple System Atrophy Rating Scale, and with systolic and diastolic blood pressure in Part 3. Structural equation modeling revealed significant paths between serotonin and clinical symptoms, and significance was highest for activities of daily living, walking, and body sway. CONCLUSIONS: Serotonin dysfunction, as assessed by CSF 5-HIAA levels, may implicate greater MSA severity.

Associations of Alzheimer's-related plasma biomarkers with cognitive decline in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with cognitive decline through multiple mechanisms, including Alzheimer's disease (AD) pathology and cortical Lewy body involvement. However, its underlying mechanisms remain unclear. Recently, AD-related plasma biomarkers have emerged as potential tools for predicting abnormal pathological protein accumulation. We aimed to investigate the association between AD-related plasma biomarkers and cognitive decline in PD patients. METHODS: Plasma biomarkers were measured in 70 PD patients (49 with nondemented Parkinson's disease (PDND) and 21 with Parkinson's disease dementia (PDD)) and 38 healthy controls (HCs) using a single-molecule array. The study evaluated (1) the correlation between plasma biomarkers and clinical parameters, (2) receiver operating characteristic curves and areas under the curve to evaluate the discrimination capacity of plasma biomarkers among groups, and (3) a generalized linear model to analyze associations with Addenbrooke's Cognitive Examination-Revised and Montreal Cognitive Assessment-Japanese version scores. RESULTS: Plasma glial fibrillary acidic protein significantly correlated with cognitive function tests, including all subdomains, with a notable increase in the PDD group compared with the HC and PDND groups, while plasma neurofilament light chain captured both cognitive decline and disease severity in the PDND and PDD groups. Plasma beta-amyloid 42/40 and pholphorylated-tau181 indicated AD pathology in the PDD group, but plasma beta-amyloid 42/40 was increased in the PDND group compared with HCs and decreased in the PDD group compared with the PDND group. CONCLUSIONS: AD-related plasma biomarkers may predict cognitive decline in PD and uncover underlying mechanisms suggesting astrocytic pathologies related to cognitive decline in PD.

Enzymatic properties and clinical associations of serum alpha-galactosidase A in Parkinson's disease.

OBJECTIVE: Recent studies have revealed an association between Parkinson's disease (PD) and Fabry disease, a lysosomal storage disorder; however, the underlying mechanisms remain to be elucidated. This study aimed to investigate the enzymatic properties of serum alpha-galactosidase A (GLA) and compared them with the clinical parameters of PD. METHODS: The study participants consisted of 66 sporadic PD patients and 52 controls. We measured serum GLA activity and calculated the apparent Michaelis constant (Km ) and maximal velocity (Vmax ) by Lineweaver-Burk plot analysis. Serum GLA protein concentration was measured by enzyme-linked immunosorbent assay. We examined the potential correlations between serum GLA activity and GLA protein concentration and clinical features and the plasma neurofilament light chain (NfL) level. RESULTS: Compared to controls, PD patients showed significantly lower serum GLA activity (P < 0.0001) and apparent Vmax (P = 0.0131), but no change in the apparent Km value. Serum GLA protein concentration was lower in the PD group (P = 0.0168) and was positively associated with GLA activity. Serum GLA activity and GLA protein concentration in the PD group showed a negative correlation with age. Additionally, serum GLA activity was negatively correlated with the motor severity score and the level of plasma NfL, and was positively correlated with the score of frontal assessment battery. INTERPRETATION: This study highlights that the lower serum GLA activity in PD is the result of a quantitative decrement of GLA protein in the serum and that it may serve as a biomarker of disease severity.

Long-term response to immunotherapy in patients with hypertrophic pachymeningitis.

Objective: In this study, we aimed to clarify the relationship between initial treatment response, prednisolone (PSL) dosage, clinical type, and recurrence in patients with hypertrophic pachymeningitis (HP). Methods: The study cohort comprised eight patients with HP who had been admitted to our hospital from April 2015 to June 2020. Diagnostic criteria for HP included neurological abnormalities and dural thickening on magnetic resonance gadolinium-enhanced T1-weighted images. Results: Relevant characteristics of the eight study patients are as follows. There were two men and six women. The average age at onset was 58.3 (range: 29-79) years. Three of them had myeloperoxidase-antineutrophil cytoplasmic antibody-related vasculitis, one immunoglobulin G4-related disease, and one ulcerative colitis. The remaining three patients had idiopathic HP. The average maximum dosage of PSL was 0.79 mg/kg/day, and the average daily maintenance dosage 0.18 mg/kg/day. Three patients needed additional immunosuppressive drugs. Both idiopathic and secondary HP initially responded well to PSL, with improvement in activities of daily living. Six patients had some sequelae related to cranial nerve involvement. No relapses occurred while the patients were taking moderate doses of PSL; however, all patients with idiopathic HP had recurrences when their PSL dosage was reduced. Conclusions: Patients with idiopathic HP and HP associated with immune disorders respond to steroids and immunosuppressive drugs and recover well. However, there is a high rate of relapse after reduction of PSL dosage, mainly in those with idiopathic HP.

Multiple System Atrophy: Advances in Diagnosis and Therapy.

This review summarizes improvements in understanding the pathophysiology and early clinical symptoms of multiple system atrophy (MSA) and advancements in diagnostic methods and disease-modifying therapies for the condition. In 2022, the Movement Disorder Society proposed new diagnostic criteria to develop disease-modifying therapies and promote clinical trials of MSA since the second consensus was proposed in 2008. Regarding pathogenesis, cutting-edge findings have accumulated on the interactions of α-synuclein, neuroinflammation, and oligodendroglia with neurons. In neuroimaging, introducing artificial intelligence, machine learning, and deep learning has notably improved diagnostic accuracy and individual analyses. Advancements in treatment have also been achieved, including immunotherapy therapy against α-synuclein and serotonin-targeted and mesenchymal stem cell therapies, which are thought to affect several aspects of the disease, including neuroinflammation. The accelerated progress in clarifying the pathogenesis of MSA over the past few years and the development of diagnostic techniques for detecting early-stage MSA are expected to facilitate the development of disease-modifying therapies for one of the most intractable neurodegenerative diseases.

[Long COVID: Pathogenesis and Therapeutic Approach].

A group of patients with coronavirus disease 2019 (COVID-19) exhibited various persistent or new systemic symptoms, including psychiatric symptoms, sleep disturbances, exercise intolerance, arthralgia, headache, cognitive decline, brain fog, and autonomic symptoms, all of which persisted long after the resolution of infectious symptoms. Several imaging studies have shown that long COVID cases present with decreased glucose metabolism and progressive brain atrophy. Although no single pathological hypothesis thoroughly explains the varied clinical presentations and timings, the following have attracted attention: 1) persistent viral infection, 2) persistent inflammation, 3) involvement of the autoimmune system, and 4) mitochondrial dysfunction. In all these hypotheses, inflammatory cytokines may be involved in orthostatic dysregulation by decreasing the expression and activity of ACE2, consequently changing the blood pressure through vagus nerve hyperactivation. Myopathy and peripheral neuropathy may also be caused by direct infection of the muscles and nerves, hypoxia, mitochondrial damage, and cytokine storm. Furthermore, multiple theories regarding the mechanisms by which systemic inflammatory findings affect the central nervous system have been postulated, including neuroinflammation caused by inflammatory cells crossing the blood-brain barrier via choroid plexus cells and the involvement of various autoantibodies. Despite these findings, no definitive consensus has been reached due to the complexity and diversity of COVID-19 pathophysiology. Thus, it is essential to understand the neurological symptoms and pathophysiology involved in long COVID.

Detection of human herpesviruses in cerebrospinal fluids collected from patients suspected of neuroinfectious diseases.

The full spectrum of human herpesviruses (HHV)-associated neuroinfectious diseases in immunocompetent adults remains unclear. Hence, we sought to elucidate the epidemiology and clinical features of these diseases. The study subjects were patients over 16 years old suspected of neuroinfectious diseases who underwent spinal tap performed by neurologists in our university hospital between April 2013 and March 2018. The presence of seven HHV DNAs in cerebrospinal fluid (CSF) was determined by real-time PCR. HHV DNAs were detected in 33 (10.2%) of the 322 patients. The most frequently detected herpesvirus was varicella zoster virus (VZV) (19 patients), followed by HHV-6 (four patients), herpes simplex virus (HSV)-1 (three patients), HSV-2 (three patients), and Epstein-Barr virus (two patients). HHV DNAs were detected in CSF collected from patients with various neuroinfectious diseases, including myelitis, peripheral neuritis, encephalitis, and meningitis. All patients with HSV-1 DNA had encephalitis, whereas all patients with HSV-2 DNA had meningitis. Eleven of the 19 patients with VZV DNA had meningitis. Patients with VZV-associated encephalitis (median age, 80 years) were significantly older than non-encephalitis patients (median age, 60.5 years) (P = 0.046). Although post-herpetic neuralgia was observed in seven (54%) of the 13 patients with VZV and without encephalitis, no such neurological sequela was observed in the four encephalitis patients. In conclusion, HHVs were associated with approximately 10% of neuroinfectious diseases in this cohort. VZV was the most common pathogen, probably due to the large number of VZV meningitis patients. In addition, patients with VZV-associated meningitis were significantly younger than patients with VZV-associated encephalitis.

Nemaline Myopathy Initially Diagnosed as Right Heart Failure with Type 2 Respiratory Failure.

Nemaline myopathy (NM) is a rare muscle disease with various clinical types. In some cases, NM can lead to type 2 respiratory failure and right heart failure. We herein report a patient with congenital NM with nebulin gene mutation who presented with acute right heart failure and type 2 respiratory failure due to respiratory muscle paralysis after upper respiratory tract infection, needing a permanent ventilator for assistance. However, the limb and trunk muscle strengths were within normal limits. This case showed that NM should be considered as a cause of right heart failure and type 2 respiratory failure.

Severe dysautonomia in glycine receptor antibody-positive progressive encephalomyelitis with rigidity and myoclonus (PERM): A case report.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a severe form of stiff-person spectrum disorder. We report a 59-year-old man who presented with progressive encephalomyelitis causing diplopia, bulbar palsy, severe dysautonomia, followed by stiffness and myoclonic cluster. Laboratory tests showed mild pleocytosis, with markedly elevated plasma levels of norepinephrine, epinephrine, and arginine vasopressin. Glycine-receptor antibodies were identified in both serum and CSF. Despite a poor response to methylprednisolone, immunoglobulins, and plasma exchange, α-blocker stabilized dysautonomia. Dysautonomia is presumed to be due to antibody-mediated disinhibited sympathetic hyperactivity; however, this case suggests that concomitant use of α-blocker with immunotherapy may ameliorate dysautonomia.

Species-specific accumulation of ceramides in cerebrospinal fluid from encephalomyeloradiculoneurpathy patients associated with peripheral complement activation: A pilot study.

Glycolipids are now known to be rapidly converted to mediators for inflammatory reactions or to signaling molecules that control inflammatory events in the nervous system. The present study aimed to explore whether disturbed glycolipids metabolism in the nervous system is present in patients with a neuroinflammatory disorder, encephalo-myelo-radiculo-neuropathy (EMRN), because most EMRN patients have been reported to exhibit autoantibodies against neutral glycolipids. Although molecular pathogenesis of this disorder remains unknown, we tried to search the immunochemical abnormalities in this disorder. ELISA for activated peripheral C5 complement and mass spectrometry analysis of cerebrospinal fluid clearly disclosed a significant upregulation of active C5 complement, C5a levels in sera as well as a significant accumulation of species-specific ceramides but not sphingomyelin in cerebrospinal fluid from EMRN patients. Furthermore, we confirmed the occurrence of anti-neutral glycolipids antibodies in all EMRN patients. Thus, the present study might indicate the pathophysiology of this disorder is the dysregulation of glycolipids metabolism and abnormal production of autoantibodies against neutral glycolipids resulting in the abnormal complement activation, although molecular basis for these sphingolipids dysregulation and the occurrence of autoantibodies against glycolipids remains to be elucidated at present. The present study implicates a new therapeutic strategy employing anti-ceramide and/or anti-complement therapy for this disorder.

Characteristics of Neural Network Changes in Normal Aging and Early Dementia.

To understand the mechanisms underlying preserved and impaired cognitive function in healthy aging and dementia, respectively, the spatial relationships of brain networks and mechanisms of their resilience should be understood. The hub regions of the brain, such as the multisensory integration and default mode networks, are critical for within- and between-network communication, remain well-preserved during aging, and play an essential role in compensatory processes. On the other hand, these brain hubs are the preferred sites for lesions in neurodegenerative dementias, such as Alzheimer's disease. Disrupted primary information processing networks, such as the auditory, visual, and sensorimotor networks, may lead to overactivity of the multisensory integration networks and accumulation of pathological proteins that cause dementia. At the cellular level, the brain hub regions contain many synapses and require a large amount of energy. These regions are rich in ATP-related gene expression and had high glucose metabolism as demonstrated on positron emission tomography (PET). Importantly, the number and function of mitochondria, which are the center of ATP production, decline by about 8% every 10 years. Dementia patients often have dysfunction of the ubiquitin-proteasome and autophagy-lysosome systems, which require large amounts of ATP. If there is low energy supply but the demand is high, the risk of disease can be high. Imbalance between energy supply and demand may cause accumulation of pathological proteins and play an important role in the development of dementia. This energy imbalance may explain why brain hub regions are vulnerable to damage in different dementias. Here, we review (1) the characteristics of gray matter network, white matter network, and resting state functional network changes related to resilience in healthy aging, (2) the mode of resting state functional network disruption in neurodegenerative dementia, and (3) the cellular mechanisms associated with the disruption.

Magnetic Resonance Neurography in a Patient with Distal Neuralgic Amyotrophy.

The pathophysiology of neuralgic amyotrophy (NA) remains to be elucidated. However, high-resolution magnetic resonance imaging and ultrasound sonography have provided new insights into the mechanism underlying the development of NA and its diagnosis. We report a case of idiopathic distal NA with hyperintensity and thickening in the inferior trunk extending to the posterior and medial fasciculus of the left brachial plexus, which was detected by magnetic resonance neurography (MRN) with diffusion-weighted whole-body imaging with background body signal suppression (DWIBS). The abnormal signal intensity diminished after the improvement of symptoms following corticosteroid treatment. MRN with DWI can help diagnose distal NA and evaluate the post-therapeutic response.

[Sporadic Cerebellar Ataxia: Multiple System Atrophy and Mono System Atrophy].

Cerebellar ataxia-predominant multiple system atrophy (MSA-C) and cortical cerebellar atrophy are representative diseases of adult-onset sporadic degenerative ataxia. Both diseases are distinctly different because of α-synuclein pathology. However, it takes approximately 2 years for cerebellar ataxia to progress to concomitant severe autonomic dysfunction in patients with MSA-C. The period of only cerebellar ataxia (mono system atrophy) may extend to more than 10 years. Understanding mono system atrophy is vital for the early diagnosis and drug development for MSA. In this review, we discuss mono system atrophy focusing on the concept and natural history and the possibility of the of early diagnosis and disease-modifying therapy for MSA.

Reversible Conduction Failure in Anti-lactosylceramide-antibody-positive Combined Central and Peripheral Demyelination.

We describe a 60-year-old woman with combined central and peripheral demyelination who presented with obstinate constipation, weakness in the lower limbs, and a bilateral sensory disturbance below her chest followed by girdle sensation in the right region of the abdomen, which was responsive to steroid therapy and plasmapheresis. Serum anti-lactosylceramide antibody was positive without anti-neurofascin 155 antibody or anti-galactocerebroside antibody positivity. Two months later, the patient had a first relapse that was responsive to steroid treatment. A nerve conduction study confirmed reversible conduction failure (RCF) in both episodes. Our case is unique in that she had an RCF episode as well as some similarities to encephalomyeloradiculoneuropathy.

[Acute myelitis associated with anti-neutral glycolipid antibody].

A 48-year-old man with rapid onset of fever elevation developed acute myelitis over a period of a week. MRI of the spinal cord revealed a longitudinal T2-hyperintense intraspinal lesion extending from C6 to Th8 level. Clinical symptoms and findings resolved with immunotherapy. In serological analysis, no antibodies related to various collagen diseases, anti-aquaporin-4 (AQP4) antibody and anti-myelin oligodendrocyte glycoprotein (MOG) antibody were detected. Anti-lactosylceramide (LacCer) antibodies were detected in the acute phase of serum and cerebrospinal fluid, with titers showing decrements in the recovery phase. The present case supports the notion that acute myelitis can occur as an anti-neutral glycolipid antibody-related disorder. Anti-neutral glycolipid antibodies should be examined in future pertinent cases of myelitis.

Fatigue evaluated using the 16-item Parkinson Fatigue Scale (PFS-16) predicts Parkinson's disease prognosis.

BACKGROUND: Although fatigue is an important nonmotor symptom in Parkinson's Disease (PD) patients, little is known about the pathophysiological details of fatigue in PD, and it is still unknown whether fatigue correlates with PD prognosis. In this study, we investigated whether fatigue in PD correlates with clinical manifestations, treatment, or patient prognosis. METHODS: We recruited 75 idiopathic PD patients and used the Parkinson Fatigue Scale (PFS-16) to investigate fatigue. We compared PFS-16 scores with clinical details such as age, disease duration, daily levodopa equivalent dosage, and Hoehn & Yahr (H&Y) disease stage in the 56 patients who fully completed the questionnaire. RESULTS: In total, 62% of subjects suffered from fatigue, as defined by a mean PFS-16 score above 3.3. There was no correlation between PFS-16 scores and disease duration or levodopa equivalent daily dose. However, there was a significant correlation between mean PFS-16 scores and a worsening grade of H&Y staging. The comparison between patients who showed stable H&Y grades (n=26) and patients with severely aggravated H&Y grades (n=7) revealed that the most significant differences were in questions 14 and 16 in the PFS-16 (p<0.001). CONCLUSION: Fatigue is common in PD patients, as demonstrated in the present study. The PFS-16 questionnaire may be helpful to predict disease prognosis.

Altered regulation of serum lysosomal acid hydrolase activities in Parkinson's disease: A potential peripheral biomarker?

INTRODUCTION: Recent studies have indicated that lysosomal dysfunction contributes to the development of idiopathic Parkinson's disease (PD). It is uncertain whether dysregulation of serum lysosomal acid hydrolase activity exists in sporadic PD patients compared with normal controls (NCs) and parkinsonian syndrome (PS) patients. METHODS: Sporadic PD patients without GBA1 mutations (n = 68) were matched with normal controls (n = 45), and parkinsonian syndrome patients (n = 32) in terms of family history, age, and sex. We measured the activities of lysosomal enzymes, α-galactosidase, ß-galactosidase, and ß-hexosaminidase and examined the possible correlations between lysosomal acid hydrolase activities with age in NCs, PD, and PS patients. RESULTS: ß-Galactosidase activity was significantly higher in the PD and PS than in the NC group (P < 0.001). The ß-galactosidase to α-galactosidase and ß-hexosaminidase to ß-galactosidase activity ratios were more useful for distinguishing PD and PS patients from NCs (P < 0.0001). Furthermore, α-galactosidase activity was significantly higher in PS patients than both PD and NC groups (p = 0.04). ß-Galactosidase and α-galactosidase activities exhibited a statistically significant negative correlation with age in NCs, and ß-hexosaminidase activity showed a positive correlation with age in PS. However, PD patients did not show any of these correlations. CONCLUSION: Our results suggest the presence of an unknown regulatory mechanism(s) of serum acid hydrolase activities with aging in the normal population and abnormalities in their regulation in PD and PS patients. However, the pattern of dysregulation in these two groups is different. Thus, serum lysosomal acid hydrolase activity can be used as a peripheral biomarker for PD.

Changes in Serial D-Dimer Levels Predict the Prognoses of Trousseau's Syndrome Patients.

Background: The development of acute multiple embolic infarctions (AMEI) resulting from cancer is known as Trousseau's syndrome (TS). At present, however, there is no good marker for predicting the prognosis of TS patients. In the present study, we evaluated the use of serial D-dimer levels as a prognostic marker for TS. Methods: This retrospective cohort study included 1,409 consecutive acute ischemic stroke patients. We selected a group of patients with TS showing AMEI (n = 38; TS group) and a group of patients with atrial fibrillation (Af) and AMEI (n = 35; Af group) as controls. Serial D-dimer levels were measured between days 7 and 28 after stroke (sub-acute phase) in 21 patients of the TS group and 24 patients of the Af group. Results: D-dimer levels at onset (acute phase) were significantly higher in the TS group (8.45 ± 1.79 µg/mL, n = 38) compared with the Af group (1.14 ± 0.14 µg/mL, n = 35) (p < 0.0001). In patients for whom serial D-dimer measurements were made, D-dimer levels measured at the sub-acute phase decreased to 0.48 ± 0.12 µg/mL (n = 24) in the Af group, but remained elevated in the TS group during the sub-acute phase (11.20 ± 2.77 µg/mL, n = 21) (p < 0.0001). In all TS patients in whom serial D-dimer measurements were made, D-dimer levels in 17 patients who died within 500 days (13.31 ± 3.23 µg/mL) were significantly higher than those of the four surviving patients (2.23 ± 0.38 µg/mL) (cut-off D-dimer level = 3.0 µg/mL) during this period. Moreover, serial D-dimer levels of 10 patients who died within 90 days (17.78 ± 4.60 µg/mL) were significantly higher than those of the 11 patients who survived up to 90 days (5.21 ± 2.12 µg/mL) (p < 0.05). Conclusions: Serial D-dimer levels may be a good biomarker for TS as well as a useful predictor of the prognosis of TS patients.

Anti-neutral glycolipids antibody-positive combined central and peripheral demyelination mimicking encephalomyeloradiculoneuropathy phenotype.

We herein report the first combined central and peripheral demyelination (CCPD) case originally diagnosed as multifocal acquired demyelinating sensory and motor neuropathy followed by CNS impairments with a long lag time (160 days after first attack). The anti-neutral glycolipids antibodies, especially anti-lactosylceramide antibodies but not anti-NF155 antibodies typical for CCPD were detected in the acute phase of sera and cerebrospinal fluid (CSF) and disappeared in the recovery phase. This case strongly illustrated the significance of examining anti-neutral glycolipids antibodies in future anti-NF 155 antibodies-negative CCPD cases.

[A case of acute disseminated encephalomyelitis concomitant with polyneuropathy associated with anti-lactosylceramide antibody].

We report a case of acute disseminated encephalomyelitis (ADEM) concomitant with polyneuropathy associated with anti-lactosylceramide antibody. A 68-year-old man was admitted to our hospital with ophthalmoparesis, bulbar palsy, tetraplegia after suffering from upper respiratory infection and headache. Subsequently, he developed respiratory failure requiring mechanical ventilation. Fluid-attenuated inversion recovery (FLAIR) MRI showed high intensities in the pons and medulla, and a nerve conduction study revealed motor-dominant axonal polyneuropathy. Although the laboratory tests revealed the presence of anti-lactosylceramide antibody in his serum, he was diagnosed with acute disseminated encephalomyelitis concomitant with polyneuropathy. Whereas the intensive treatment with corticosteroids, plasmapharesis, and high-dose intravenous immunoglobulin (IVIg) brought a moderate improvement, his tetraparesis continued to exist.