A novel TBK1 loss-of-function variant associated with ALS and parkinsonism phenotypes.

Loss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases.

Higher cerebral blood flow on four-dimensional flow magnetic resonance imaging in young women.

We investigated the reduction in regional brain volume and cerebral blood flow (CBF) with aging and explored potential sex differences in healthy brains. Three-dimensional (3D) T1-weighted magnetic resonance imaging (MRI), time-of-flight magnetic resonance angiography, and four-dimensional (4D) flow MRI were performed on 129 healthy volunteers aged 22-92 years. The brains of healthy volunteers were segmented into 21 subregions using 3D T1-weighted MRI and CBFs in 16 major intracranial arteries were measured using 4D flow MRI. The cortical gray matter volume decreased linearly with aging, whereas the cerebral white matter volume increased until the 40s and then decreased, and the subcortical gray matter volume changed little with aging. The cortical gray matter volume was significantly associated with the total CBF of the major intracranial arteries distal to the circle of Willis; however, the cerebral white matter and subcortical gray matter volumes were not. Generally, women have higher total CBF than men, particularly in their 40s and younger, despite the smaller intracranial volume and smaller diameters of intracranial arteries than men. This may contribute to the higher incidence of subarachnoid hemorrhage due to cerebral aneurysms and migraine in women.

The time-course augmentation of perivascular space enlargement in the basal ganglia among a community-dwelling elder population.

PURPOSE: We examined whether time-course augmentation of perivascular space enlargement in the basal ganglia (BG-PVS) reflected cerebral small vessel disease (CSVD) severity by considering white matter hyperintensity lesion (WMHL) as an indicator for CSVD. MATERIALS AND METHODS: This study population included 416 older participants from a community-based cohort. They participated in magnetic resonance imaging (MRI) studies more than once during the study period. The grades for BG-PVS and WMHL were evaluated by visual rating scales; BG-PVS time-course augmentation in 4-9 years was also evaluated. At baseline, the participants were asked about their smoking and drinking history, and medical history. They also underwent a blood examination and their office blood pressure (BP) examination. In addition, 24-h ambulatory BP monitoring was also performed within the study period. RESULTS: Of the 416 participants, 48 participants (11.5%) had BG-PVS time-course augmentation. The participants with BG-PVS augmentation had significantly lower LDL levels, hyper-nighttime BP, and lower nighttime BP fall in univariate analysis (p = 0.03, p = 0.03, p = 0.003, respectively). In multivariate analysis, lower nighttime BP fall and male sex showed significance (p = 0.02, 0.03, respectively). Additionally, BG-PVS time-course augmentation was significantly associated with subsequent WMHL severity in univariate analysis (p < 0.001), which remained significant in multivariate analysis adjusted by imaging and demographic factors (p = 0.03). In multivariate analysis, additionally adjusted by the clinical factors, the significance disappeared (p = 0.07). CONCLUSION: This study revealed that the lower nighttime BP fall in ambulatory blood pressure monitoring was a factor significantly associated with BG-PVS augmentation. Moreover, the BG-PVS time-course augmentation would be a notable finding that was associated with the subsequent WMHL.

Augmentation of perivascular space visualization in basal ganglia and white matter hyperintensity lesion is a meaningful finding for subsequent cognitive decline.

BACKGROUND: Cerebral small vessel disease (CSVD) causes cognitive decline and perivascular space enlargement is one of the image markers for CSVD. PURPOSE: To search for clinical significance in the time-course augmentation of perivascular space in basal ganglia (BG-PVS) for cognitive decline. MATERIAL AND METHODS: This study population included 179 participants from a community-based cohort, aged 70 years at baseline. They had undergone magnetic resonance imaging (MRI) studies two or three times between 2000 and 2008. Based on the severity of BG-PVS or white matter hyperintensity lesions (WMHL) in 2000, the participants were divided into low-grade or high-grade groups, respectively. In addition, their time-course augmentation was evaluated, and we created a categorical BG-PVS WMHL change score based on their augmentation (1 = neither, 2 = BG-PVS augmentation only, 3 = WMHL augmentation only, 4 = both). Cognitive function was assessed based on the Mini-Mental State Examination (MMSE); the change was defined as the difference between scores in 2000 and 2008. We used simple or multiple regression analysis for MMSE score change according to MRI findings and clinical characteristics that were probably related to cognitive decline. RESULTS: In univariate analysis, MMSE score change was negatively associated with BG-PVS high grade at baseline and BG-PVS WMHL change score 4; this remained significant in multivariate analysis. In the final model based on the Akaike Information Criterion, BG-PVS WMHL change score 4 was associated with a 3.3-point decline in subsequent MMSE score. CONCLUSIONS: This study suggested that augmentation in both BG-PVS and WMHL was associated with subsequent cognitive decline.

Modeling cerebrospinal fluid dynamics across the entire intracranial space through integration of four-dimensional flow and intravoxel incoherent motion magnetic resonance imaging.

BACKGROUND: Bidirectional reciprocal motion of cerebrospinal fluid (CSF) was quantified using four-dimensional (4D) flow magnetic resonance imaging (MRI) and intravoxel incoherent motion (IVIM) MRI. To estimate various CSF motions in the entire intracranial region, we attempted to integrate the flow parameters calculated using the two MRI sequences. To elucidate how CSF dynamics deteriorate in Hakim's disease, an age-dependent chronic hydrocephalus, flow parameters were estimated from the two MRI sequences to assess CSF motion in the entire intracranial region. METHODS: This study included 127 healthy volunteers aged ≥ 20 years and 44 patients with Hakim's disease. On 4D flow MRI for measuring CSF motion, velocity encoding was set at 5 cm/s. For the IVIM MRI analysis, the diffusion-weighted sequence was set at six b-values (i.e., 0, 50, 100, 250, 500, and 1000 s/mm2), and the biexponential IVIM fitting method was adapted. The relationships between the fraction of incoherent perfusion (f) on IVIM MRI and 4D flow MRI parameters including velocity amplitude (VA), absolute maximum velocity, stroke volume, net flow volume, and reverse flow rate were comprehensively evaluated in seven locations in the ventricles and subarachnoid spaces. Furthermore, we developed a new parameter for fluid oscillation, the Fluid Oscillation Index (FOI), by integrating these two measurements. In addition, we investigated the relationship between the measurements and indices specific to Hakim's disease and the FOIs in the entire intracranial space. RESULTS: The VA on 4D flow MRI was significantly associated with the mean f-values on IVIM MRI. Therefore, we estimated VA that could not be directly measured on 4D flow MRI from the mean f-values on IVIM MRI in the intracranial CSF space, using the following formula; e0.2(f-85) + 0.25. To quantify fluid oscillation using one integrated parameter with weighting, FOI was calculated as VA × 10 + f × 0.02. In addition, the FOIs at the left foramen of Luschka had the strongest correlations with the Evans index (Pearson's correlation coefficient: 0.78). The other indices related with Hakim's disease were significantly associated with the FOIs at the cerebral aqueduct and bilateral foramina of Luschka. FOI at the cerebral aqueduct was also elevated in healthy controls aged ≥ 60 years. CONCLUSIONS: We estimated pulsatile CSF movements in the entire intracranial CSF space in healthy individuals and patients with Hakim's disease using FOI integrating VA from 4D flow MRI and f-values from IVIM MRI. FOI is useful for quantifying the CSF oscillation.

Automatic assessment of disproportionately enlarged subarachnoid-space hydrocephalus from 3D MRI using two deep learning models.

Background: Disproportionately enlarged subarachnoid-space hydrocephalus (DESH) is a key feature for Hakim disease (idiopathic normal pressure hydrocephalus: iNPH), but subjectively evaluated. To develop automatic quantitative assessment of DESH with automatic segmentation using combined deep learning models. Methods: This study included 180 participants (42 Hakim patients, 138 healthy volunteers; 78 males, 102 females). Overall, 159 three-dimensional (3D) T1-weighted and 180 T2-weighted MRIs were included. As a semantic segmentation, 3D MRIs were automatically segmented in the total ventricles, total subarachnoid space (SAS), high-convexity SAS, and Sylvian fissure and basal cistern on the 3D U-Net model. As an image classification, DESH, ventricular dilatation (VD), tightened sulci in the high convexities (THC), and Sylvian fissure dilatation (SFD) were automatically assessed on the multimodal convolutional neural network (CNN) model. For both deep learning models, 110 T1- and 130 T2-weighted MRIs were used for training, 30 T1- and 30 T2-weighted MRIs for internal validation, and the remaining 19 T1- and 20 T2-weighted MRIs for external validation. Dice score was calculated as (overlapping area) × 2/total area. Results: Automatic region extraction from 3D T1- and T2-weighted MRI was accurate for the total ventricles (mean Dice scores: 0.85 and 0.83), Sylvian fissure and basal cistern (0.70 and 0.69), and high-convexity SAS (0.68 and 0.60), respectively. Automatic determination of DESH, VD, THC, and SFD from the segmented regions on the multimodal CNN model was sufficiently reliable; all of the mean softmax probability scores were exceeded by 0.95. All of the areas under the receiver-operating characteristic curves of the DESH, Venthi, and Sylhi indexes calculated by the segmented regions for detecting DESH were exceeded by 0.97. Conclusion: Using 3D U-Net and a multimodal CNN, DESH was automatically detected with automatically segmented regions from 3D MRIs. Our developed diagnostic support tool can improve the precision of Hakim disease (iNPH) diagnosis.

The grasp reflex in patients with idiopathic normal pressure hydrocephalus.

OBJECTIVE: To investigate the prevalence and intensity of grasp reflexes and to examine changes in these reflexes after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: We enrolled 147 patients with probable iNPH. A standard procedure was used to determine the presence of grasp reflexes, and the intensity of these reflexes was assessed using a four-category classification. Clinical rating scales and their correlation with grasp reflexes were also evaluated. Grasp reflexes were reassessed in 72 patients 1 year after surgery. RESULTS: We found that approximately 50.3% of patients with iNPH exhibited a positive grasp reflex. Among these patients, 69% exhibited bilateral positivity, while the remaining patients showed unilateral positivity. Furthermore, the intensity of the grasp reflex was significantly correlated with the severity of gait and with cognitive, urinary, motor, and behavioural symptoms. Surgical interventions led to a reduction (41.7%) or maintenance (30.6%) of the reflex intensity in 72.3% of iNPH patients. The changes in reflex intensity showed significant positive correlations with changes in the number of steps of the Timed Up and Go test and Trail Making Test-A scores but not with changes in total scores on the iNPH Grading Scale. CONCLUSION: This retrospective study identified grasp reflexes as a highly prevalent phenomenon in patients with iNPH. These reflexes can assist in evaluating the severity of various symptoms, including cognitive, gait, urinary, motor and emotional symptoms.

[Epidemiology, Natural History, and Genetic Factors of Idiopathic Normal Pressure Hydrocephalus].

According to a cohort study in a Japanese rural area, the prevalence of idiopathic normal pressure hydrocephalus (iNPH) in the 80s was 7.7% among the older inhabitants, despite only a small percentage of the population seeking consultation. The 16-year observation of the cohort revealed that people were in the state of asymptomatic ventriculomegaly with features of iNPH on magnetic resonance imaging or asymptomatic ventricular enlargement several years before presenting symptoms and intracranial changes of iNPH. SFMBT1 was found to be a risk gene for iNPH, and investigating these risk genes will further the study of iNPH pathophysiology.

Anti-IgLON5 Disease Showing an Improvement in Dysautonomia, Including Vocal Cord Palsy, via Combined Immunotherapy.

Anti-IgLON5 disease shows various neurological manifestations, of which dysautonomia is one of the major symptoms and is rarely improved by immunotherapy. We herein report a patient with anti-IgLON5 disease who showed several autonomic failures, including vocal cord palsy for four months. The patient presented with cognitive impairments, bulbar symptoms accompanied by myorhythmia in the pharynx and tongue, cerebellar ataxia with tremor, motor neuron symptoms in the limbs, gastrointestinal dysfunction, orthostatic hypotension, non-rapid eye movement sleep disorder on polysomnography, and severe vocal cord palsy. Combined immunotherapy improved his symptoms, including vocal cord palsy, suggesting that combined immunotherapy might improve dysautonomia in anti-IgLON5 disease.