Monocytes release cystatin F dimer to associate with Aß and aggravate amyloid pathology and cognitive deficits in Alzheimer's disease.

BACKGROUND: Understanding the molecular mechanisms of Alzheimer's disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aß) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aß clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aß by monocytes in AD remains unclear. METHODS: Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aß by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aß. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology. RESULTS: Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aß deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aß by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aß to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aß. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice. CONCLUSIONS: Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aß metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention.

Three novel mutations in Chinese patients with CSF1R-related leukoencephalopathy.

BACKGROUND: CSF1R-related encephalopathy refers to adult-onset leukodystrophy with neuroaxonal spheroids and pigmented glia (ALSP) due to CSF1R mutations, which is a rare autosomal dominant white matter disease including two pathological entities, hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). The aim of this study was to identify additional causative mutations in the CSF1R gene and clarify their pathogenic effects. METHODS: Whole-exome sequencing was conducted for nine Chinese patients diagnosed with possible ALSP based on clinical and neuroimaging findings from March 2014 to June 2020 at Xuanwu Hospital (Beijing, China). Variant pathogenicity was assessed according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) Standards and Guidelines. RESULTS: Mean ± standard deviation (range) age of disease onset in the nine patients was 39.22±9.63 [25-54] years. Four of the nine patients were male, and four out of nine had a remarkable family history. Seven CSF1R mutations were identified in the nine patients; four (p.G17C, p.R579Q, p.I794T and c.2909_2910insATCA) have been previously reported, while three (p.V613L, p.W821R and c.2442+2_2442+3dupT) were novel. Of the latter, two (p.V613L and p.W821R) were likely pathogenic and 1 (c.2442+2_2442+3dupT) was of uncertain significance according to ACMG/AMP criteria. CONCLUSIONS: These findings expand the mutational spectrum of ALSP and provide a basis for future investigations on etiologic factors and potential management strategies for this disease.

Treatment of epilepsy for people with Alzheimer's disease.

BACKGROUND: Any type of seizure can be observed in Alzheimer's disease (AD). Antiepileptic drugs seem to prevent the recurrence of epileptic seizures in most people with AD. There are pharmacological and non-pharmacological treatments for epilepsy in people with AD. There are no current systematic reviews to evaluate the efficacy and tolerability of these treatments; this review aims to review those different modalities. This is an updated version of the original Cochrane Review published in Issue 11, 2016. OBJECTIVES: To assess the efficacy and tolerability of pharmacological or non-pharmacological interventions for the treatment of epilepsy in people with AD (including sporadic AD and dominantly inherited AD). SEARCH METHODS: For the latest update, on 10 July 2018 we searched the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group's Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid 1946- ), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). In an effort to identify further published, unpublished and ongoing trials, we searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted authors and pharmaceutical companies. SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials investigating treatment for epilepsy in people with AD, with the outcomes of proportion of participants with seizure freedom or proportion of participants experiencing adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to the limited available data. MAIN RESULTS: We included one randomized controlled trial on pharmacological interventions with 95 participants. No studies were found for non-pharmacological interventions. Concerning the proportion of participants with seizure freedom, no significant differences were found for the comparisons of levetiracetam (LEV) versus lamotrigine (LTG) (risk ratio (RR) 1.20, 95% confidence interval (CI) 0.53 to 2.71), LEV versus phenobarbital (PB) (RR 1.01, 95% CI 0.47 to 2.19), or LTG versus PB (RR 0.84, 95% CI 0.35 to 2.02). It seemed that LEV could improve cognition and LTG could relieve depression, while PB and LTG could worsen cognition, and LEV and PB could worsen mood. Unclear risk of bias was found in allocation, blinding and selective reporting. We judged the quality of the evidence to be very low. AUTHORS' CONCLUSIONS: This review does not provide sufficient evidence to support LEV, PB or LTG for the treatment of epilepsy in people with AD. Regarding efficacy and tolerability, no significant differences were found between LEV, PB and LTG. Large randomized controlled trials with a double-blind, parallel-group design are required to determine the efficacy and tolerability of treatment for epilepsy in people with AD.

[Posterior spinal canal decompression with screw fixation and reconstruction of three vertebral column for thoracolumbar burst fractures complicated with nerve injury].

OBJECTIVE: To explore the feasibility and clinical effect of posterior spinal canal decompression with pedicle screw fixation and reconstruction of anterior and middle vertebral column for thoracolumbar burst fractures complicated with nerve injury. METHODS: A total of 36 patients with thoracolumbar burst fractures treated from March 2011 to April 2016 were enrolled in the retrospective study. There were 20 males and 16 females, aged from 21 to 52 years old with an average of 37.6 years. All the fractures were located on a single segment, 8 cases of T1111, 10 cases of T12, 12 cases of L1, 6 cases of L2. According to thoracolumbar injury classification and severity score(TLICS) system, the score was 7 to 9 points, with an average of 7.4 points. According to the America Spine Injury Association(ASIA) grade, 4 cases were type A, 10 cases were type B, 14 cases were type C, 8 cases were type D. All the patients underwent posterior spinal canal decompression with pedicle screw fixation and reconstruction of anterior and middle vertebral column. The recovery of nerve function was evaluated by ASIA grading. The correction of kyphosis(Cobb angle), the volume change of injuried spinal canal, the change of anterior border height of injury vertebra which can be observed by X-rays;the internal fixation loosening and breakage and all the information of bone fusion were recorded. RESULTS: All the operations were successful, the mean operative time and intraoperative blood loss were(2.8±0.3) h (2.1 to 3.5 h) and (880±120) ml(550 to 1 350 ml), respectively. All the incisions got primary healing. All the patients were followed up for 12 to 28 months with an average of 18.4 months. All the patients obtained satisfactory bone fusion. No pseudoarticulation formation was found, and there was no loosening, breakage of pedicle screws or displacement of titanium mesh. Neurological function was improved in different degree, except in one patient with grade A and another one with grade B. According to the ASIA grade, there were 1 case of type A, 1 case of type B, 7 cases of type C, 10 cases of type D and 17 cases of type E, postoperatively. At 3 days after operative, the anterior border height of injury vertebra, Cobb angle and the volume changes of injury spinal canal were obviously improved(P<0.05), and there was no significant difference between postoperative at 3 days and final follow-up(P>0.05). CONCLUSIONS: Spinal canal decompression with screw fixation and reconstruction of anterior and middle vertebral column through posterior midline approach is a safe and effective method in the treatment of thoracolumbar burst fractures with nerve injury, it is worthy to be popularized. It can complete the spinal canal decompression of 360 degree, reduction of fractures and reconstruction of vertebral three-column at the same time through a single posterior approach. The advantages includes less trauma, perfect decompression, good stability and etc.

Treatment of epilepsy for people with Alzheimer's disease.

BACKGROUND: Any type of seizure can be observed in Alzheimer's disease (AD). Antiepileptic drugs seem to prevent the recurrence of epileptic seizures in most people with AD. There are pharmacological and non-pharmacological treatments for epilepsy in people with AD. There are no current systematic reviews to evaluate the efficacy and tolerability of the treatment. This review aims to review those different modalities. OBJECTIVES: To assess the efficacy and tolerability of the treatment of epilepsy for people with Alzheimer's disease (AD) (including sporadic AD and dominantly inherited AD). SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (1 February 2016), the Cochrane Central Register of Controlled Trials (1 February 2016), MEDLINE (Ovid, 1 February 2016) and ClinicalTrials.gov (1 February 2016). In an effort to identify further published, unpublished and ongoing trials, we searched ongoing trials' registers, reference lists and relevant conference proceedings, and contacted authors and pharmaceutical companies. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials investigating treatment for epilepsy in people with AD, with the outcomes of proportion of seizure freedom or experiencing adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to the limited available data. MAIN RESULTS: We included one randomised controlled trial with 95 participants. Concerning the proportion of participants with seizure freedom, no significant differences were found in levetiracetam (LEV) versus lamotrigine (LTG) (risk ratio (RR) 1.20, 95% confidence interval (CI) 0.53 to 2.71), in levetiracetam versus phenobarbital (PB) (RR 1.01, 95% CI 0.47 to 2.19), or in LTG versus PB (RR 0.84, 95% CI 0.35 to 2.02). It seemed that LEV could improve cognition and LTG could relieve depression; while PB and LTG could worsen cognition, and LEV and PB could worsen mood. We judged the quality of the evidence to be very low. AUTHORS' CONCLUSIONS: This review does not provide sufficient evidence to support LEV, PB and LTG for the treatment of epilepsy in people with AD. Regarding the efficacy and tolerability, no significant differences were found between LEV, PB and LTG. In the future, large randomised, double-blind, controlled, parallel-group clinical trials are required to determine the efficacy and tolerability of treatment for epilepsy in people with AD.

[Validity of complex figure test in differentiation of Alzheimer's disease from non-dementia].

OBJECTIVE: To assess the validity of Complex Figure Test(CFT)in differentiating Alzheimer's disease(AD)from non-dementia. METHODS: Using CFT,we tested 183 AD patients(AD group),1283 cognitively intact individuals(normal control group),and 134 individuals suffered from other diseases that could be easily confused with dementia(confused control group). RESULTS: The CFT score was 38.7±0.2 in the normal control group,35.3±0.8 in confused control group,23.7±0.8 in mild AD group,and 13.2±1.1 in moderate AD group after adjusted for educational level,age,and sex(all P<0.05).With the 5(th) percentage of the overall score as cutoff point,this tool showed a sensitivity of 73.8% and a specificity of 93.8% in differentiating AD from non-dementia. CONCLUSION: CFT is a sensitive and specific tool in the differentiation of AD from non-dementia.

Validity of auditory verbal learning test in diagnosis of Alzheimer's disease.

OBJECTIVE: To assess the validity of World Health Organization-University of California-Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) in the diagnosis of Alzheimer's disease (AD). METHODS: Using WHO-UCLA AVLT, we assessed 183 AD patients (AD group),1283 subjects with normal cognitive status (normal control group), and 134 individuals suffered from other diseases easy to be confused with AD (confused control group). RESULTS: The AVLT score was 40.9∓0.3 in normal control group, 30.7∓0.9 in confused control group, 16.6∓1.0 in mild AD group, and 10.2∓1.2 in moderate AD group after adjustment for educational level, age, sex, and rural/urban residence (all P<0.05). With the 5th percentage of the overall score as the cutoff point, this tool showed a sensitivity of 86.3% and a specificity of 93.3%. CONCLUSION: WHO-UCLA CVLT is highly sensitive and specific in the diagnosis of AD.

[Segmental root palsy (SRP) after cervical decompression surgery].

OBJECTIVE: To explore the occurrence, prevention and cure prognosis of segment root polsy (especially in C5 palsy) after cervical decompression surgery. METHODS: From February 2006 and December 2008,162 patients were operated with cervical decompression through approach for anterior or posterior in our hospital. Among them, 10 cases occurred SRP after operation included 6 males and 4 females aged from 40 to 68 with an average of 53 years old. These cases were treated with dehydration, trophic nerve, hyperbaric oxygenation. The clinical data were retrospective analzed. RESULTS: Ten patients were followed up from 8 months to 3 years with an average of 2.4 years. It was observed that all the patients recovered during a period of 4.4 months on average (ranging from 3 weeks to 8 months). CONCLUSION: SRP(especially in C5 palsy) is one of the common complications of anterior or posterior cervical decompression surgery. SRP is usually the result of various nosogenesis. As there was no effective treatment, conservative treatment is usually adopted with optimistic prognosis.

[Technology of minimally invasive percutancous plate osteosynthesis for the treatment of fractures of the distal tibia].

OBJECTIVE: To explore the technique and clinical results of minimally invasive percutancous plate osteosynthesis (MIPPO) for the treatment of fractures of the distal tibia. METHODS: A retrospective study was conducted to analyze 65 patients with the distal tibia fractures who had been treated with MIPPO. The average age of the patients was 35 years old (ranging from 13 to 75). There were 42 males and 23 females. According to AO fracture classification for the distal tibial fractures, there were 5 cases of type-A1 fracture, 22 type-A2, 32 type-A3 and 6 type-C1. RESULTS: All the patients were followed up and ranged from 6 to 18 months (averaged 11 months). All the fractures showed union. The time required for the bony union ranged from 3 to 6 months (averaged 4.5 months). The patients were evaluated with respect to functional recovery according to Mazur Grating System for the Ankle. Forty patients obtained excellent results, 19 good and 6 fair. The total satisfactory rate was 90.7%. CONCLUSION: The technology of minimally invasive percutancous plate osteosynthesis (MIPPO)is a safe and effective procedure for the distal tibial fractures with the benefits of limited invasion,less complications and high rate of bone union.

[Memory-assessing methods which help the clinical diagnosis of early Alzheimer's disease].

OBJECTIVE: To evaluate distribution and influence factors of logic memory (LM) modified in assessing and scoring method in normal population and Alzheimer's disease (AD) patients, and definite the cut-off point of the modified scale. METHODS: Totally 183 AD patients, including 118 mild and 65 moderate in degree, 1,417 controls, including 1,283 normal individuals and 134 individuals suffered from other diseases, were recruited in this study. Modified LM was conducted. RESULTS: Educational level (F=354.36, STB=0.46, P=0.0001) was the most obvious factor in demographic data to influence total score in normal control group by a fitting of multiple regression models. The total score increased with the rising of educational level in normal controls (P=0.0001) and other diseases controls (P=0.0001), but not in AD cases (P=0.1365). The total scores were significantly different among normal controls (20.2 +/- 0.2), other diseases controls (17.5 +/- 0.5), mild AD patients (9.6 +/- 0.5) and moderate AD patients (7.1 +/- 0.7) (P=0.0001, P=0.0059), after adjusted educational level, age, sex and rural/urban status by multiple analysis covariance. The sensitivity of cut-off points using modified methods to diagnose AD reasonably increased to 71.98%, while the specificity was 94.11%. According to the sum of long-delayed recall and long-delayed recognition, the sensitivity increased with the rising of educational levels. For education levels at illiteracy, elementary school, junior middle school, senior middle school and above senior middle school, the cut-off points for total score of modified method were 6.5, 9.5, 10.8, 13 and 15.8, respectively, and for sum of long-delayed recall and long-delayed recognition the cut-off points were 5, 6, 8, 9, 10. CONCLUSIONS: When modified LM used as a neuropsychological assessment, it is with high specificity, high accuracy and reasonable sensitivity. It is suitable for the diagnosis of AD in early stages, especially for individuals with high educational levels.