Background High-quality clinical practice guidelines (CPGs) are important for the effective treatment of behavioral and psychological symptoms of dementia (BPSD). However, recommendations provided by different quality guidelines may lead to varied clinical practice outcomes. Objective To assess the quality of available CPGs for the management of BPSD and summarize the best recommendations for treating BPSD. Methods This was a systematic review of CPGs for the management of BPSD with data obtained from electronic databases and evaluated using the Appraisal of Guidelines for Research and Evaluation II instrument, consisting of six domains: “Scope and purpose”, “Stakeholder involvement”, “Rigor of development”, “Clarity of presentation”, “Applicability”, and “Editorial independence”. The criteria for high-quality guidelines were set as: the score of high-quality guidelines in the “Rigor of development” domain should be ≥60% and as well as a score of >60% in at least three other domains. High-quality guidelines were selected for recommendation extraction, and the final recommendations were formed in combination with the latest meta-analysis and randomized clinical-trial results. Results In term of median scores in each domain for the six included CPGs, “Scope and purpose” (87.5%) scored better than all others, whereas “Applicability” (46.5%) was the domain with the lowest score. Four CPGs (2015 APA, 2018 NICE, 2018 CANADA, 2020 EAN) met the criteria of high-quality guidelines and were used to extract recommendations. From these four CPGs, nine specific recommendations related to the management of BPSD were summarized, of which seven were related to pharmacological treatment and two to non-pharmacological treatment. These recommendations covered the applicability of antipsychotic drugs, medication recommendations, withdrawal times, and several suitable non-pharmacological therapies. Conclusion The quality of CPGs for the management of BPSD requires improvement, especially for the “Applicability” domain. For psychotic-like symptoms in dementia, the use of antipsychotics should be based on the individual's risk-benefit ratio, and the use of atypical antipsychotics seems to be a better choice. Non-pharmacological treatments may be suitable for emotional symptoms and sleep disorders. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020209204 .
Abstract Background: Alzheimer’s disease (AD) is a leading cause of dementia in the elderly and has become a major health issue. However, a large number of genetic risk factors remain undiscovered. Methods: To identify novel risk genes and better understand the molecular pathway underlying AD, whole-exome sequencing (WES) was performed in 215 early-onset AD (EOAD) patients and 55 unrelated healthy controls of Han Chinese ethnicity. Subsequent direct sequencing was performed in 4962 individuals to validate the selected rare mutations. Computational annotation and in vitro functional studies were performed to evaluate the role of candidate mutations in EOAD and the underlying mechanisms. Results: We identified two rare missense mutations in the phosphodiesterase 11A ( PDE11A ) gene, resulting in p.Arg202His, and p.Leu756Gln, in individuals with EOAD. Both mutations are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation, and classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at T181, S404, S202, S416, S214, S396 and AT8 epitopes in vitro . PDE11A variants or PDE11A shRNA also caused increased cAMP levels, protein kinase A (PKA) activation, and cAMP response element-binding protein (CREB) phosphorylation. Additionally, pretreatment with a PKA inhibitor (H89) suppressed PDE11A mutation-induced p-Tau formation. Conclusions: Our results demonstrate that both PDE11A mutations and PDE11A knockdown increase Tau phosphorylation through the cAMP/PKA pathway, suggesting that PDE11A is a novel risk gene for AD. This study provides insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.
Abstract Introduction The PSENs/APP mutation distribution in Chinese patients with familial Alzheimer's disease (FAD) remains unclear. We aimed to analyze the genetic features of Chinese FAD pedigrees with and without PSENs/APP mutations. Methods In total, 1330 patients with Alzheimer's disease (AD) or mild cognitive impairment in 404 pedigrees were enrolled from the Chinese Familial Alzheimer's Disease Network. PSENs/APP mutations and APOE frequencies were determined. Results In total, 13.12% of pedigrees carried PSENs/APP missense mutations, 3.71% carried PSENs/APP synonymous/untranslated region variants, and 83.17% did not carry PSENs/APP mutations. Eleven missense mutations were first identified. In patients without PSENs/APP mutations, 44.31% carried one APOEε4 allele, and 14.85% two APOEε4 alleles. Discussion The new PSENs/APP mutations indicate heterogeneity in AD pathogenesis between Chinese and other ethnic groups. The low mutation rate suggests the involvement of other genes/factors in Chinese FAD. APOEε4 might be a major gene for some FAD without PSENs/APP mutations.
Studies on gender differences in the clinical manifestations of vascular dementia (VaD) are still lacking. In the present study, gender comparisons of cognitive and neuropsychiatric profiles were conducted separately for mild and moderate-to-severe VaD in a total of 467 patients with VaD. There were no significant gender differences in cognitive manifestations, except that females performed better on immediate verbal recall than males in mild stage. Women were more likely to exhibit delusions (15.5% vs 7.4%), hallucinations (9.5% vs 3.4%), and depression (43.1% vs 27.3%) in mild stage. The predominance of male patients was observed in apathy at moderate-to-severe stage (50.5% vs 34.8%). To conclude, gender differences existed in neuropsychiatric symptoms of VaD and were especially pronounced in mild stage. Delusions, hallucinations, and depression were more prevalent in females in mild VaD, with the male predominance only in apathy in the later stage.
No licensed medications are available to treat vascular dementia (VaD).Patients were randomly assigned to experimental groups (SaiLuoTong [SLT] 360 or 240 mg for groups A and B for 52 weeks, respectively) or placebo group (SLT 360 mg and 240 mg for group C only from weeks 27 to 52, respectively).Three hundred twenty-five patients were included in final analysis. At week 26, the difference in VaD Assessment Scale-cognitive subscale scores was 2.67 (95% confidence interval, 1.54 to 3.81) for groups A versus C, and 2.48 (1.34 to 3.62) for groups B versus C (both P < .0001). However, at week 52, no difference was observed among the groups on the VaD Assessment Scale-cognitive subscale (P = .062) because of the emerging efficacy of SLT in placebo beginning at week 27.This study suggests that SLT is effective for treatment of VaD, and this compound Chinese medicine may represent a better choice to treat VaD.
Vanishing white matter disease (VWMD) is one of the most prevalent inherited leukoencephalopathies, which generally presents in childhood as a progressive disorder while less beginning in adulthood. The present report describes the clinical, neuroimaging, and genetic findings of a female patient with adult-onset VWMD. In addition, to provide a clearer delineation of the clinical and genetic characteristics of female adult-onset VWMD patients, 32 genetically confirmed female adult-onset EIF2B-mutated cases are summarized. The patient described here suffered from long-term menometrorrhagia prior to manifesting progressive neurological impairments that included tremors, bilateral pyramidal tract injury, cerebellar ataxia, and dementia. To the best of our knowledge, this is the first female patient with adult-onset VWMD suffering from long-term menometrorrhagia attributed to the c.254 T > A and c.496A > G mutations in the EIF2B2 gene; the c.496A > G mutation has not been reported in previous studies. The patient also exhibited metabolic dysfunction. The present findings widen the spectrum of phenotypic heterogeneity observed in VWMD patients. The present report summarizes 33 female patients with adult-onset VWMD to provide an overview of the clinical and genetic characteristics of this disorder and ovarioleukodystrophy. The mean age of clinical onset in female patients with adult-onset VWMD was 36.8 years and the neurological symptoms primarily included motor and cognitive dysfunction such as paraparesis, cerebellar ataxia, and executive deficits. In addition, ovarian failure occurred in all of these female patients and usually preceded the neurological symptoms. Furthermore, several patients also suffered from metabolic dysfunction. All 33 patients had mutations on EIF2B1–5, and of these, the c.338 G > A mutation in the EIF2B5 gene (p.Arg113His) was the most common. These findings suggest that clinicians should be aware of adult-onset forms of VWMD as well as its typical magnetic resonance imaging (MRI) and clinical characteristics although this pathology is usually recognized as a pediatric disorder. No curative treatment is presently available, and thus early recognition is important to prevent triggering events and to allow for genetic counseling.
Abstract Introduction Vascular cognitive impairment without dementia is very common among the aged and tends to progress to dementia, but there have been no proper large‐scale intervention trials dedicated to it. Vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease (hereinafter, subcortical Vascular cognitive impairment without dementia) represents a relatively homogeneous disease process and is a suitable target for therapeutic trials investigating Vascular cognitive impairment without dementia. Preclinical trials showed that dl‐3‐n‐butylphthalide (NBP) is effective for cognitive impairment of vascular origin. Methods In this randomized, double‐blind, placebo‐controlled trial, we enrolled patients aged 50–70 years who had a diagnosis of subcortical Vascular cognitive impairment without dementia at 15 academic medical centers in China. Inclusion criteria included a clinical dementia rating ≥0.5 on at least one domain and global score ≤0.5; a mini‐mental state examination score ≥20 (primary school) or ≥24 (junior school or above); and brain magnetic resonance imaging consistent with subcortical ischemic small vessel disease. Patients were randomly assigned to NBP 200 mg three times daily or matched placebo (1:1) for 24 weeks according to a computer‐generated randomization protocol. All patients and study personnel were masked to treatment assignment. Primary outcome measures were the changes in Alzheimer's disease assessment scale‐cognitive subscale (ADAS‐cog) and clinician's interview‐based impression of change plus caregiver input (CIBIC‐plus) after 24 weeks. All patients were monitored for adverse events (AEs). Outcome measures were analyzed for both the intention‐to‐treat (ITT) population and the per protocol population. Results This study enrolled 281 patients. NBP showed greater effects than placebo on ADAS‐cog (NBP change −2.46 vs. placebo −1.39; P = .03; ITT) and CIBIC‐plus (80 [57.1%] vs. 59 [42.1%] patients improved; P = .01; ITT). NBP‐related AE were uncommon and primarily consisted of mild gastrointestinal symptoms. Discussion Over the 6‐month treatment period, NBP was effective for improving cognitive and global functioning in patients with subcortical vascular cognitive impairment without dementia and exhibited good safety.
Social cognition impairment has been recognized as an early and characteristic change in behavioral variant frontotemporal dementia (bvFTD). The Mini Social Cognition and Emotional Assessment (mini-SEA) is a clinical tool to rapidly evaluate social cognition. In this study, we explored the diagnostic value of social cognition by assessing the Chinese version of the mini-SEA and other standard neuropsychological tests in 22 patients with mild bvFTD, 26 patients with mild Alzheimer's disease (AD), including mild cognitive impairment (MCI) and mild dementia, and 30 control subjects. The discriminatory powers of these tests were evaluated and compared using the receiver operating characteristic curve (ROC). The mini-SEA scores of the bvFTD patients were significantly lower than those of the controls (Z = -6.850, adjusted P < 0.001) and AD patients (Z = -3.737, adjusted P = 0.001). ROC analysis showed that the mini-SEA had a high discriminatory power for differentiating bvFTD from the controls, with an area under the curve (AUC) value of 0.989 (95% CI = 0.905-1.000, P < 0.001). The AUC value of the mini-SEA for differentiating bvFTD from AD was 0.899 (95% CI = 0.777-0.967, P < 0.001), higher than that of the Auditory Verbal Learning Test Delayed Recall (AUC = 0.793), Boston Naming Test (AUC = 0.685) or Frontal Assessment Battery (AUC = 0.691). The Chinese version of mini-SEA is a good clinical tool for the early diagnosis of bvFTD, and has a high sensitivity and specificity to discriminate bvFTD from AD.
Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) have been recognized as the major pathogenic genes of FAD. However, the frequency and predicted risk factors of these 3 pathogenic genes of FAD in China is still unclear. 160 FAD families have been recruited from Chinese Familial Alzheimer's Disease Network (CFAN, https://www.chinacfan.org/) from Jan 2013 to Dec 2014. According to age at onset (AAO) of the proband, 93 FAD families (58.1%) were classified as early-onset (<65 years old) FAD (EOFAD) and 67 (41.9%) families were late-onset (≥65 years old) AD (LOFAD). Clinical features, neuropsychological assessments, imaging and blood and CSF samples were collected from these pedigrees following standard protocols. Mutational screening of PSEN1, PSEN2, APP genes and genotype analysis of ApoE were performed in all of the 160 FAD families. Twenty-two pedigrees (23.7% of EOFAD) were identified with mutations in PSEN1, PSEN2 or APP. Specifically, 13 (59.1%) were PSEN1 mutations (4 novel and 9 previously reported), 8 (36.4%) were APP mutations (1 novel and 7 reported), and one (4.5%) was PSEN2 novel mutations (Table 1). Compared to FAD families without known mutations, the FAD families with mutations tended to present significantly lower mean age at onset (AAO), affect more family members and more generations, and carry less ApoEε4 allele (Table 2). When the equation was applied as followed: risk score= -1×AAO+3×the number of affected individuals+10×ApoE ε4 positive, the FAD with mutations were predicted very well (area under curve 0.89) with the high sensitivity (68%) and specificity (98%) (Figure 1). For phenotype of FAD families with mutations, there were no group difference in PSEN1 and APP mutations pedigrees in terms of mean AAO (54.4 vs 50.0 years, p=0.383), the number of affected family members (6.5 vs 5.8, p=0.724) and affected generations, or ApoE ε4 status (Table 3). Six novel mutations in PSEN1, PSEN2 or APP were identified in Chinese Han FAD pedigrees. FAD with mutations was significantly predicted by the number of affected individuals, AAO and ApoEε4. No significant difference between APP and PSEN1 mutations was found in China in terms of phenotype.
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