BackgroundAbnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China.MethodsPatients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy.ResultsIn the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=−0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission.ConclusionsNIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.

UL16-binding proteins [ULBPs, also termed as retinoic acid early transcripts (RAET1) molecules] are frequently expressed by malignant transformed cells and stimulate anti-tumor immune responses mediated by NKG2D-positive NK cells, CD8(+) alphabeta T cells and gammadelta T cells in vitro and in vivo. In this study, we identified four novel functional splice variants of ULBPs including ULBP4-I, ULBP4-II, ULBP4-III and RAET1G3 in HepG2 liver carcinoma cells, WISH human amnion cells, Hep-2 larynx carcinoma cells and K562 leukemia cells, respectively, by reverse transcription-PCR and T vector cloning strategy. Analysis of alignments of amino acid sequences of the splice variants illustrated that there were important modifications between splice variants and their individual parental ULBP. All ULBP4 splice variants (ULBP4-I, ULBP4-II and ULBP4-III) were type 1 membrane-spanning molecules and had the ability to bind with human NKG2D receptor in vitro. Ectopic expressions of ULBP4 and ULBP4 splice variants resulted in the enhanced cytotoxic sensitivity of target cells against NK cells, which could be blocked by anti-NKG2D mAb. Moreover, co-culture-free soluble forms of ULBP4 splice variants (their alpha1 + alpha2 ectodomains) and RAET1G3 (soluble splice variant of RAET1G2) with NK cells down-regulated the cell surface expression of NKG2D. Finally, immobilized in a plate-bound form of RAET1G3 stimulated NK cells to secrete IFN-gamma. Taken together, all the identified functional splice variants will help to advance our knowledge regarding the overall functions of ULBP gene family.

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Background: Mini-Mental State Examination (MMSE) is the most widely used tool in cognitive screening. Some individuals with normal MMSE scores have extensive cognitive impairment. Systematic neuropsychological assessment should be performed in these patients. This study aimed to optimize the systematic neuropsychological test battery (NTB) by machine learning and develop new classification models for distinguishing mild cognitive impairment (MCI) and dementia among individuals with MMSE ≥ 26. Methods: 375 participants with MMSE ≥ 26 were assigned a diagnosis of cognitively unimpaired (CU) (n = 67), MCI (n = 174), or dementia (n = 134). We compared the performance of five machine learning algorithms, including logistic regression, decision tree, SVM, XGBoost, and random forest (RF), in identifying MCI and dementia. Results: RF performed best in identifying MCI and dementia. Six neuropsychological subtests with high-importance features were selected to form a simplified NTB, and the test time was cut in half. The AUC of the RF model was 0.89 for distinguishing MCI from CU, and 0.84 for distinguishing dementia from nondementia. Conclusions: This simplified cognitive assessment model can be useful for the diagnosis of MCI and dementia in patients with normal MMSE. It not only optimizes the content of cognitive evaluation, but also improves diagnosis and reduces missed diagnosis.

Background: Cerebrospinal fluid (CSF) biomarkers are widely accepted as manifestations of Alzheimer’s disease (AD) pathogenesis and incorporated into biological definition of AD. However, the correlations between CSF and other biomarkers such as neuroimaging and neuropsychiatric evaluation are complicated and inconsistent. Objective: We aimed to better interpreting CSF biomarkers results accompanying with other indexes in improving accurate diagnosis of AD. Methods: 112 AD patients and 30 cognitive normal controls were selected. Commercial accessible ELISA kits were introduced for measurement of CSF t-tau, p-tau181, Aβ 1–42, and NfL based on standard protocol. MRI examinations were performed using a 3-T MRI scanner and visual rating scales including medial temporal atrophy score and Koedam’s scale were used to evaluate medial temporal atrophy and posterior region atrophy. Results: CSF biomarkers’ profile including decreased concentration of Aβ 1–42, increased concentration of t-tau, p-tau181, t-tau/Aβ 1–42, and NfL were diagnostic between AD and control. CSF biomarkers profile was not influenced by the APOE genotype. Increased concentration of t-tau and NfL, as well as ratio of t-tau/Aβ 1–42 were related to decrease of Mini-Mental State Examination (MMSE) score while concentration of Aβ 1–42 not. Visual assessed cortical atrophy was related to MMSE score, but most of the CSF biomarkers were not related to atrophy, except that increased concentration of p-tau181 was significantly associated with atrophy of posterior cortical region. Conclusion: Our results supported CSF biomarkers were helpful in diagnosis of AD. However, CSF biomarkers were cross-sectional reflection of pathogenesis, which did not correlate well with clinical progression. CSF biomarkers should be interpreted in combination with MRI and cognitive evaluation in clinical use.

Background: Alzheimer’s disease with a causative genetic mutation (AD-CGM) is an un- common form, characterized by a heterogeneous clinical phenotype and variations in the genotype of racial groups affected. Objective: We aimed to systemically describe the phenotype variance and mutation spectrum in the large sample size of the Peking Union Medical College Hospital (PUMCH) cohort, Beijing, China. Method: Next-generation sequencing (NGS) was carried out in 1108 patients diagnosed with dementia. A total of 40 Han Chinese patients with three AD gene mutations were enrolled. A systemic review of all the patients was performed, including clinical history, neurocognitive assessment, brain magnetic resonance imaging, and cerebrospinal fluid (CSF) biomarkers. Results: We studied the following gene mutation variants: 12 AβPP, 13 PSEN1, and 9 PSEN2, and 23 among them were novel. Most of them were early-onset, but PSEN1 mutation carriers had the youngest onset age. The commonest symptoms were similar to those of AD, including an amnestic syndrome, followed by psychiatric symptoms and movement disorder. On MRI, parietal and posterior temporal atrophy was prominent in PSEN1 and PSEN2 mutation carriers, while AβPP mutation carriers had more vascular changes. The CSF biomarkers profile was indistinguishable from sporadic AD. Conclusion: We identified a small group of AD-CGM subjects representing 3.6% among more than 1000 demented patients in the PUMCH cohort. These subjects usually presented with early-onset de- mentia and exhibited significant clinical and genetic heterogeneity. Identification required complete screening of genetic mutations using NGS. Although family history was usually present, we found non-familial cases of all three genetic mutations.

Background: The established causative mutations in the APP, PSEN1, and PSEN2 can explain less than 1%,Alzheimer’s disease (AD) patients. Of the identified variants, the PSEN2 mutations are even less common. Objective: With the genetic study from the dementia cohort of Peking Union Medical College Hospital (PUMCH), we aim to illustrate the PSEN2 mutation spectrum and novel functionally validated mutations in Chinese AD patients. Methods: 702 AD participants, aged 30–85, were identified in PUMCH dementia cohort. They all received history inquiry, physical examination, biochemical test, cognitive evaluation, brain CT/MRI, and next-generation DNA sequencing. Functional analysis was achieved by transfection of the HEK293 cells with plasmids harboring the wild-type PSEN2 or candidate mutations. Results: Nine PSEN2 rare variants were found, including two reported (M239T, R62C) and seven novel variants (N141S, I368F, L396I, G117X, I146T, S147N, H220Y). The HEK293 cells transfected with the PSEN2 N141S, M239T, I368F plasmids showed higher Aβ 42 and Aβ 42/Aβ 40 levels relative to the wild-type PSEN2. The PSEN2 L396I, G117X, S147N, H220Y, and R62C did not alter Aβ 42, Aβ 40 levels, or Aβ 42/Aβ 40 ratio. 1.9%,(13/702) subjects harbored rare PSEN2 variants. 0.4%,(3/702) subjects carried pathogenic/likely pathogenic PSEN2 mutations. The three subjects with the functionally validated PSEN2 mutations were all familial early-onset AD patients. The common symptoms included amnesia and mental symptom. Additionally, the M239T mutation carrier presented with dressing apraxia, visuospatial agraphia, dyscalculia and visual mislocalization. Conclusion: The PSEN2 N141S, M239T, and I368F are functionally validated mutations.

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