Converging links between adult-onset neurodegenerative Alzheimer’s disease and early life neurodegenerative neuronal ceroid lipofuscinosis?

Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life.Here,we summarize emerging links between the most common late life neurodegenerative disease,Alzheimer’s disease,and the most common early life neurodegenerative diseases,neuronal ceroid lipofuscinoses.Genetic studies reported an overlap of clinically diagnosed Alzheimer’s disease and mutations in genes known to cause neuronal ceroid lipofuscinoses.Accumulating data strongly suggest dysfunction of intracellular trafficking mechanisms and the autophagy-endolysosome system in both types of neurodegenerative disorders.This suggests shared cytopathological processes underlying these different types of neurodegenerative diseases.A better understanding of the common mechanisms underlying the different diseases is important as this might lead to the identification of novel targets for therapeutic concepts,the transfer of therapeutic strategies from one disease to the other and therapeutic approaches tailored to patients with specific mutations.Here,we review dysfunctions of the endolysosomal autophagy pathway in Alzheimer’s disease and neuronal ceroid lipofuscinoses and summarize emerging etiologic and genetic overlaps.

Novel Computer-Aided Diagnosis System for the Early Detection of Alzheimer’s Disease

Aging is a natural process that leads to debility,disease,and dependency.Alzheimer’s disease(AD)causes degeneration of the brain cells leading to cognitive decline and memory loss,as well as dependence on others to fulfill basic daily needs.AD is the major cause of dementia.Computer-aided diagnosis(CADx)tools aid medical practitioners in accurately identifying diseases such as AD in patients.This study aimed to develop a CADx tool for the early detection of AD using the Intelligent Water Drop(IWD)algorithm and the Random Forest(RF)classifier.The IWD algorithm an efficient feature selection method,was used to identify the most deterministic features of AD in the dataset.RF is an ensemble method that leverages multiple weak learners to classify a patient’s disease as either demented(DN)or cognitively normal(CN).The proposed tool also classifies patients as mild cognitive impairment(MCI)or CN.The dataset on which the performance of the proposed CADx was evaluated was sourced from the Alzheimer’s Disease Neuroimaging Initiative(ADNI).The RF ensemble method achieves 100%accuracy in identifying DN patients from CN patients.The classification accuracy for classifying patients as MCI or CN is 92%.This study emphasizes the significance of pre-processing prior to classification to improve the classification results of the proposed CADx tool.

Soluble p75 neurotrophic receptor as a reliable biomarker in neurodegenerative diseases: what is the evidence?

Neurodegenerative diseases are often misdiagnosed,especially when the diagnosis is based solely on clinical symptoms.The p75 neurotrophic receptor(p75^(NTR))has been studied as an index of sensory and motor nerve development and maturation.Its cleavable extracellular domain(ECD)is readily detectable in various biological fluids including plasma,serum and urine.There is evidence for increased p75NTR ECD levels in neurodegenerative diseases such as Alzheimer’s disease,amyotrophic lateral sclerosis,age-related dementia,schizophrenia,and diabetic neuropathy.Whether p75^(NTR) ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders,and whether it could potentially lead to the development of targeted therapies,remains an open question.In this review,we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases.We also highlight areas that require further investigation to better understand the role of p75^(NTR) ECD in the clinical diagnosis and management of neurodegenerative disorders.

Dementia and Cognitive Impairment Reduction after Laser Transcatheter Treatment of Alzheimer’s Disease

Reduced cerebral perfusion and microcirculation are found among AD causes, which should be considered in the development of new treatments for the disease. 165 patients with AD were examined. The examination plan included clinical assessment of dementia severity (CDR), cognitive function assessment (MMSE), laboratory examination, cerebral scintigraphy (SG), rheoencephalography (REG), cerebral CT and MRI, morphometric AD stages assessment (TDR) and cerebral multi-gated angiography (MUGA). 89 patients aged 34 - 79 (average age 67) were selected for the treatment: 31 (34.83%) male, 58 (65.17%) female patients. According to their AD stage, the patients were divided into: TDR-0 (preclinical stage)—10 (11.24%) patients, TDR-1 (early stage with mild dementia, mild cognitive impairment)—28 (31.46%) patients, TDR-2 (medium stage with moderate dementia, cognitive impairment sufficiently persistent)—34 (38.20%) patients, TDR-3 (late stage with sufficiently severe dementia and cognitive impairment)—17 (19.10%) patients. Test Group—46 (51.68%) patients—had transcatheter treatment with low-energy lasers. Control Group—43 (48.31%)—had conservative treatment with Memantin and Rivastigmine. The Test Group had cerebral microcirculation improvement leading to permanent dementia reduction and cognitive recovery which allowed transferring the patients to a lighter TDR group or withdrawing them from the scale. Control Group patients with earlier AD stages (TDR-0, TDR-1, TDR-2) obtained stabilization for a period of 6 months-3 years, with subsequent growth of dementia and cognitive impairment;patients with late AD stage (TDR-3) showed further increase of cognitive impairment and dementia. Transcatheter treatment allows reducing the effects of dyscirculatory angiopathy of Alzheimer’s type (DAAT) improving cerebral microcirculation and metabolism, which leads to permanent dementia regression and cognitive impairment reduction. These data show that AD treatment should be comprehensive and aimed at both the recovery of cerebral microcirculation and blood supply and the normalization of amyloid beta metabolism in the cerebral tissue.

Neuroprotective Effect of Phyllanthus acidus L. on Learning and Memory Impairment in Scopolamine-Induced Animal Model of Dementia and Oxidative Stress: Natural Wonder for Regulating the Development and Progression of Alzheimer’s Disease

Nature is the best source of complementary and alternative medicine. The plant Phyllanthus acidus (PA) L. has been used traditionally in pain, inflammatory and oxidative stress related disorders. In this consequence, methanolic extract of PA (MEPA) was selected to explore the ability of this plant to enhance cognitive function, brain antioxidant enzymes and anti-acetylcholinesterase activity which can be used for the treatment of oxidative stress related disorders like Alzheimer’s disease (AD). The purpose of this study was to investigate the neuroprotective effect of MEPA on learning and memory impairment in scopolamine-induced rats of dementia and oxidative stress. Treatment with MEPA (i.e., 100 and 200 mg/kg b.w.) was investigated in scopolamine-treated Swiss albino male rats for 14 days and its neuroprotective effects were examined using Elevated Plus Maze (EPM) test, Passive Avoidance (PA) test, Novel Object Recognition (NOR) test, Morris Water Maze (MWM) test as well as level of antioxidant enzymes such as catalase (CAT), super oxide dismutase (SOD), glutathione reductase (GSR), glutathione-S-transferase (GST), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), lipid peroxidation (TBARS) contents and acetylcholinesterase (AChE) activity in rat brain tissue homogenates. Administration of MEPA significantly (P < 0.05, P < 0.01;P < 0.01) decreased RTL (retention transfer latency) in rats on 7th and 14th day compared to the disease control and control group in the EPM test. In PA test the doses of MEPA suggestively (P < 0.05, P < 0.001;P < 0.05, P < 0.01) increased STL (step-through latency) in rats on 7th and 14th day with respect to disease control and control group. For NOR test administration of MEPA considerably (P < 0.01, P < 0.001;P < 0.01) increased the DI (discrimination index) in rats with respect to that of disease control and control group. The doses of MEPA markedly (P < 0.05, P < 0.01;P < 0.01) decreased EL (escape latency) and significantly (P < 0.01, P < 0.001;P < 0.05, P < 0.01) increased TSTQ (time spent in the target quadrant) on successive days as compared to that of disease control and control group in the acquisition trial of MWM test. In case of probe trial of MWM test MEPA administration considerably (P < 0.01;P < 0.05, P < 0.01) increased TSTQ and significantly (P < 0.05, P < 0.01;P < 0.05, P < 0.01) increased TSA (time spent in the annuli) in rats on successive days as compared to that of disease control and control group. MEPA administration significantly (P < 0.05, P < 0.01, P < 0.001;P < 0.05, P < 0.01) increased the level of CAT, SOD, GSR, GST GSH, GSH-Px and markedly (P < 0.01;P < 0.01, P < 0.001) decreased TBARS level through inhibiting lipid peroxidation as well as significantly (P < 0.01, P < 0.001;P < 0.05, P < 0.01, P < 0.001) decreasing AChE activity in rats brain compared to the disease control and control group. The present study demonstrates that MEPA showed the neuroprotective effect by improving cognitive functions and reduces oxidative stress by increasing the level of brain antioxidant enzymes as well as decreasing lipid peroxidation and acetylcholinesterase activity. Therefore, this plant extract can be used for enhancing learning, memory, antioxidant potentiality and anti-acetylcholinesterase activity in neurodegenerative disorders like AD.

The Prevalence of Alzheimer’s Disease and Dementia in Alzheimer’s Disease in Patients of Long-Term Nursing Home Care in the Podlaskie Province in Poland

The prevalence of Alzheimer’s disease and dementia in Alzheimer’s disease according to the International Statistical Classification of Diseases and Related Health Problems ICD-10 in patients of long-term nursing home care in the Podlaskie province is not yet known. The aim of the study was the socio-demographic assessment of the long-term nursing home care patients with diagnosed Alzheimer’s disease and socio-demographic assessment of the long-term nursing home care patients with dementia in Alzheimer’s disease. Data concerning all 7637 patients who received long- term nursing home care benefits in the years from 2008 to 2013 in the Podlaskie province were investigated. Alzheimer’s disease was diagnosed in 2.972% of patients at the average age of 79.82 years (±8.05). The disease was diagnosed more frequently (78.4%) and earlier in women (from 44 years of age). Dementia in Alzheimer’s disease was diagnosed in 210 patients (2.749%). The mean age of patients with Alzheimer’s dementia was 81.72 years (±7.73). Stupor in patients under 65 years more frequently affected women. Research confirms the impact of Alzheimer’s disease and dementia in Alzheimer’s disease on daily activity performance. Studies suggest that the high rate of Alzheimer’s disease and dementia in Alzheimer’s disease is due to ethnic and national differences associated with learning at home and in schools in the Podlaskie province.

The Efficacy and Safety of Yokukansankachimpihange for Treating Behavioral and Psychological Symptoms of Dementia in Patients with Alzheimer’s Disease: An Open-Label Pilot Study

Previous clinical trials have demonstrated the efficacy of yokukansan, a traditional Japanese medicine, for the treatment of behavioral and psychological symptoms of dementia (BPSD). However, less evidence is available for the treatment of BPSD with yokukansankachimpihange (YKSCH), which consists of yokukansan and two additional herbal ingredients. The present study was conducted to investigate the efficacy and safety of YKSCH for treating BPSD in patients with Alzheimer’s disease (AD). We enrolled outpatients with mild-to-moderate AD who exhibited BPSD and obtained a Neuropsychiatric Inventory (NPI) score of >3 including subscale scores for “agitation”, “anxiety”, “irritability”, and “sleep and night-time behavior change”. A daily YKSCH dose of 7.5 g was administered for 12 weeks with concomitant administration of anti-dementia medication. BPSD was evaluated using the NPI at baseline and every 4 weeks during the intervention. We also examined apathy using the Japanese translation of the Apathy Scale, the short version of the Japanese version of the Zarit Caregiver Burden Interview, and the Modified Crichton Rating Scale for Predicting Activities of Daily Living. Cognitive dysfunction was evaluated using the Mini Mental State Examination and the AD Assessment Scale-Cognitive (Japanese version). Five participants were enrolled. The NPI total score tended to decrease between the baseline and 8-week evaluations during the YKSCH intervention (Wilcoxon signed rank test, P = 0.063). In terms of the NPI subscale scores, “apathy”, “agitation”, “delusions”, and “sleep and night-time behavior change” decreased after the intervention in those who exhibited each symptom at baseline. There were no significant differences in the other scores examined. No serious adverse events were observed. YKSCH could ameliorate BPSD in patients with mild-to-moderate AD with agitation, anxiety, irritability, and sleep and night-time behavior change, and it was well-tolerated.

MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes.Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia.Frontotemporal dementia is characterized by progressive impairments in behavior,executive function,and language.There are two main clinical subtypes:behavioral-variant frontotemporal dementia and primary progressive aphasia.The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients.Without validated biomarkers,the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features,but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders.In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies.Measurement of specific miRNAs singly or in combination,or as miRNA pairs(as a ratio)in blood plasma,serum,or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls,Alzheimer’s disease,and amyotrophic lateral sclerosis.Furthermore,upregulation of miR-223-3p and downregulation of miR-15a-5p,which occurred both in blood serum and cerebrospinal fluid,distinguished behavioral-variant frontotemporal dementia from healthy controls.Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia,respectively,from healthy controls.Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p,miR-15a-5p,miR-22-3p in blood serum and cerebrospinal fluid,and miR-124 in cerebrospinal fluid.No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes.Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.

Treatment Efficacy of Photobiomodulation for Moderate and Advanced Dementia or Alzheimer’s Disease: Case Studies

Extensive research is ongoing in the use of Photobiomodulation (PBM, often referred to as low-level or cold laser therapy) to treat Alzheimer’s disease as well as other debilitating diseases. The following case studies further confirm that PBM could be a breakthrough approach to limit the progression of insidious diseases. We present four cases, two with mild to moderate dementia and two with more advanced symptoms. Several publications have shown beneficial results, however, several weeks of daily treatments were necessary. The cases described here suggest that moderate and advanced dementia cases can be significantly improved with three or four eight-minute treatments over a 5 - 7-day period when using super-pulsing technology on Monday-Wednesday-Friday schedule (Figure 1). Gives a brief visual explanation of super-pulsing versus continuous wave technology.

Correlation between Alzheimer’s Disease and Dementia with Lewy Bodies Scores Using VSRAD Advance

The objective of the study was to explore the relationship between the indicators of Alzheimer’s disease and dementia with Lewy bodies using the voxel-based specific regional analysis system for Alzheimer’s Disease (VSRAD) advance. Among 36 patients with suspected dementia, patients with Alzheimer’s disease and dementia with Lewy bodies were identified using VSRAD advance from March 1 to October 30, 2019. All patients underwent brain Magnetic Resonance Imaging (MRI). We diagnosed Alzheimer’s disease using Volume of Interest (VOI) in the Medial Temporal Lobe (MTL) atrophy ratio > 2 and dementia with Lewy bodies using both VOI in the MTL atrophy ratio ≤ 2 and gray/white matter atrophy ratio ≥ 0.2. The correlation between the indicators of Alzheimer’s disease and dementia with Lewy bodies was calculated. The number of patients classified as having Alzheimer’s disease and dementia with Lewy bodies was 25 and 11, respectively. In the Alzheimer’s disease group, the correlation coefficient between the extent of gray matter atrophy and the severity of atrophy in the dorsal brainstem gray matter was r = -0.40 (p = 0.045). In dementia with Lewy bodies group, the correlation coefficient between the extent of gray matter atrophy and the severity of atrophy in the dorsal brainstem white matter was r = -0.78 (p < 0.01). Using VSRAD advance, gray matter atrophy and dorsal brainstem grey/white matter atrophy were found to be negatively correlated in Alzheimer’s disease and dementia with Lewy bodies.

Using dementia rating scales in the diagnosis of Alzheimer’s disease

Objective： To study the significance of dementia rating scales in the diagnosis of Alzheimer＇ s disease（AD）. Methods： Probable AD patients（118 cases） diagnosed according to NINCDS-ADRDA criteria and the normal controls（100 cases） were examined with a battery of neuropsychological tests and the dementia severity of AD patients was determined with clinical dementia rating （CDR）. Changed neuropsychological characteristics of different AD dementia severities were analyzed. The discriminant analysis and ROC curve analysis were perfomed to analyze the specificity, the sensitivity, and the general accuracy of various dementia rating scales in the diagnosis of AD, and the area under the ROC curve. Results： The total cognition function in mild （CDR = 1 ）, moderate（CDR = 2） and severe stages（CDR=3） of AD had an obvious trend of continuous decline, with the MMSE values 17.44±2.64, 13.90±4.32, and 5.50 ± 3.90 respectively. The trend of decline of the verbal fluency function in AD was same as that of total cognition function. The visuospatial function was reduced in early stage of AD （CDR = 1 ） and completely lost in moderate and severe AD. Delay memory function began to show decline in the early stage of AD, and the decline turned apparent in moderate and severe AD. Immediate memory function showed unchanged in early stage of AD, while showed decline in moderate AD, and the decline became very quick in severe AD. The impairment of daily living ability and social activity function developed with the severity degree of AD. But the decline of social activity function was very quick in moderate stage of AD. In general, the leading scale to diagnose AD was FOM, followed by RVR, POD, MMSE, BD,ADL and DS. When MMSE was combined with one or more of FOM, RVR, BD, DS, the general accuracy in distinguishing AD from the normal controls was improved. Conclusion： Neuropsychological test is useful in the diagnosis of AD, especially in the early stage. The validity is improved when dementia rating scales are combined correctly.

Late Life Vascular Risk Factors and Their Association with Dementia and Alzheimer’s Disease

Background:Epidemiological studies have demonstrated associations between higher levels of vascular risk factors in midlife and later development of dementia,particularly Alzheimer’s disease(AD).However,in elderly subjects with dementia,some studies have shown that these associations may decrease or even reverse.Therefore,the study aimed to find the association between late life cardiovascular risk factors and neurodegenerative dementia in general and AD in particular.Methods:It is a retrospective case control study using electronic medical records that included elderly patients that were reviewed in Ahmadi hospital geriatric clinic,Kuwait,from the period of 1/7/2019 to 1/2/2020.Two hundred and three(203)elderly patients with neurodegenerative dementia(study group)were recruited for this retrospective study and compared to two hundred and one(201)controls with normal cognition for the presence of vascular risk factors.Results:The study included 404 subjects.Age ranged from 60 to 107 years(mean age 78.79,±8.13 SD).AD was found to be the most prevalent type of dementia in the study group,as 49.3%(100/203)of the demented patients were diagnosed with AD.No significant statistical association was found between vascular risk factors and dementia(P>0.05),except for obesity which showed a negative association(P<0.001).Regarding AD,no statistical significance was found between AD and diabetes,hyperlipidemia,smoking nor atrial fibrillation.On the other hand,the authors found obesity and hypertension more prevalent in the normal cognition group(negative association with P value<0.001,0.05 respectively).Conclusions:The results of the study support an emerging concept that,while elevated levels of vascular risk factors in midlife increase the risk of development of dementia and AD later in life,once dementia begins,these associations may be diminished or reversed in the elderly.

Homocysteine and asymmetric dimethylarginine concentrations in the plasma of Alzheimer’s disease patients with varying degrees of dementia

Alzheimer’s disease (AD) is accompanied by elevated levels of homocysteine (Hcy). Homocysteine may induce elevated concentration of asymmetric dimethylarginine (ADMA). Both Hcy and ADMA are the amino acids thought to represent risk factors of vascular diseases. Studies were conducted on the plasma levels of Hcy and methionine (Met), estimated by HPLC with electrochemical detection, as well as on levels of ADMA and arginine (Arg), estimated by HPLC with fluorescent detection, in the AD patients with benign through to severe dementia estimated by MMSE scale and in a control group. The studies disclosed elevated levels of Hcy and ADMA in AD (Hcy, p < 0.001) as compared to controls, as well as in subjects older than 60 years of age (Hcy, p < 0.01). The AD patients with severe dementia have shown elevated levels of Hcy (p < 0.05) as compared to the patients with moderate dementia. The concentration of Metand Arg showed a downward trend in AD patientswith severe dementia. The highest levels of ADMA have been demonstrated in AD patients in the early stages of the disease. In parallel, in AD with varying degrees of dementia and subjects older than 60 years of age a disturbed turnover was observed of Hcy to Met and of Arg to ADMA. Similarly to Hcy, ADMA seems to be a potential risk factor of AD and important factor for progress of dementia.

Use of curcumin in diagnosis,prevention,and treatment of Alzheimer＇s disease

This review summarizes and describes the use of curcumin in diagnosis,prevention,and treatment of Alzheimer＇s disease.For diagnosis of Alzheimer＇s disease,amyloid-β and highly phosphorylated tau protein are the major biomarkers.Curcumin was developed as an early diagnostic probe based on its natural fluorescence and high binding affinity to amyloid-β.Because of its multi-target effects,curcumin has protective and preventive effects on many chronic diseases such as cerebrovascular disease,hypertension,and hyperlipidemia.For prevention and treatment of Alzheimer＇s disease,curcumin has been shown to effectively maintain the normal structure and function of cerebral vessels,mitochondria,and synapses,reduce risk factors for a variety of chronic diseases,and decrease the risk of Alzheimer＇s disease.The effect of curcumin on Alzheimer＇s disease involves multiple signaling pathways：anti-amyloid and metal iron chelating properties,antioxidation and anti-inflammatory activities.Indeed,there is a scientific basis for the rational application of curcumin in prevention and treatment of Alzheimer＇s disease.

Partial improvement in performance of patients with severe Alzheimer's disease at an early stage of fornix deep brain stimulation

Deep brain stimulation is a therapy for Alzheimer＇s disease（AD） that has previously been used for mainly mild to moderate cases. This study provides the first evidence of early alterations in performance induced by stimulation targeted at the fornix in severe AD patients. The performance of the five cases enrolled in this study was scored with specialized assessments including the Mini-Mental State Examination and Clinical Dementia Rating, both before and at an early stage after deep brain stimulation. The burden of caregivers was also evaluated using the Zarit Caregiver Burden Interview. As a whole, the cognitive performance of patients remained stable or improved to varying degrees, and caregiver burden was decreased. Individually, an improved mental state or social performance was observed in three patients, and one of these three patients showed remarkable improvement in long-term memory. The conditions of another patient deteriorated because of inappropriate antipsychotic medications that were administered by his caregivers. Taken together, deep brain stimulation was capable of improving some cognitive aspects in patients with severe AD, and of ameliorating their emotional and social performance, at least at an early stage. However, long-term effects induced by deep brain stimulation in patients with severe AD need to be further validated. More research should focus on clarifying the mechanism of deep brain stimulation. This study was registered with ClinicalTrials.gov（NCT03115814） on April 14, 2017.

Pre-moxibustion and moxibustion prevent Alzheimer's disease

The Alzheimer’s disease model in Wistar rats was established by injection of amyloid β-peptide （Aβ1-42 ） into the hippocampal CA1 region. Rats were treated with suspended moxibustion on Baihui （GV20） and Shenshu （BL23） acupoints. Prior to and post Aβ1-42 exposure. Results showed no evidence of apoptosis in hippocampal neurons, a significantly reduced apoptosis rate of neurons and improved learning and memory abilities were observed in the Alzheimer’s disease model. In particular, moxibustion prior to Aβ1-42 exposure was more effective than moxibustion after Aβ1-42 exposure in protecting the neuronal structure and lowering the apoptosis rate. Our findings indicate that a combination of preventive and therapeutic moxibustion has a beneficial effect for the tion of Alzheimer’s disease development.

Cerebrospinal fluid and blood biomarkers in Alzheimer’s disease

Due to an ever aging society and growing prevalence of Alzheimer’s disease(AD),the challenge to meet social and health care system needs will become increasingly difficult.Unfortunately,a definite ante mortem diagnosis is not possible.Thus,an early diagnosis and identification of AD patients is critical for promising,early pharmacological interventions as well as addressing health care needs.The most advanced and most reliable markers areβ-amyloid,total tau and phosphorylated tau in cerebrospinal fluid(CSF).In blood,no single biomarker has been identified despite an intense search over the last decade.The most promising approaches consist of a combination of several bloodbased markers increasing the reliability,sensitivity and specificity of the AD diagnosis.However,contradictory data make standardized testing methods in longitudinal and multi-center studies extremely difficult.In this review,we summarize a range of the most promising CSF and blood biomarkers for diagnosing AD.

APOE and APOC1 gene polymorphisms are associated with cognitive impairment progression in Chinese patients with late-onset Alzheimer's disease

Current evidence shows that apolipoprotein E （APOE）, apolipoprotein CI （APOC1） and low density lipoprotein receptor-related protein （LRP） variations are related to late-onset Alzheimer＇s disease. However, it remains unclear if genetic polymorphisms in these genes are associated with cognitive decline in late-onset Alzheimer＇s disease patients. We performed a 30-month longitudi- nal cohort study to investigate the relationship between Alzheimer＇s disease and APOE, APOC1, and LRP. In this study, 78 Chinese Han patients with late-onset Alzheimer＇s disease were recruit- ed form Guangxi Zhuang Autonomous Region in China. APOE, APOC1, and LRP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphisms. The Mini-Mental State Examination and Clinical Dementia Rating Scale were used to assess pa- tients＇ cognitive function. After a 30-month follow-up period, we found a significant reduction in Mini-Mental State Examination total score, a higher proportion of patients fulfilling cognitive impairment progression criteria, and a higher proportion of APOC1 H2 carriers in APOE 4 carriers compared with non-carriers. In addition, the APOE 4 allele frequency was significantly higher in the cognitive impairment progression group compared with the non-cognitive im- pairment progression group. In conclusion, APOE e4 plays an important role in augmenting cognitive decline, and APOC1 H2 may act synergistically with APOE ~4 in increasing the risk of cognitive decline in Chinese patients with late-onset Alzheimer＇s disease.

Systematic review of atorvastatin for the treatment of Alzheimer's disease

OBJECTIVE： To assess the clinical efficacy and safety of atorvastatin in the treatment of Alzheimer＇s disease. DATA SOURCES： Medline （1948/2011-04）, Embase （1966/2011-04）, Cochrane Library （Issue 3, 2011）, Chinese National Knowledge Infrastructure （1989/2011-04）, and the Chinese Biomedical Literature Database （1979/2011-04） were searched for randomized clinical trials regardless of language. Abstracts of conference papers were manually searched. Furthermore, Current Controlled Trials （http：//controlled-trials.com）, Clinical Trials.gov （http：//clinicaltrials.gov）, and Chinese Clinical Trial Registry （http：//www.chictr.org） were also searched. Key words included AIzheimer disease, dementia, cognition, affection, memory dysfunction, hydroxymethylglutaryI-CoA reductase inhibitors, atorvastatin and statins. DATA SELECTION： Randomized controlled trials of grade A or B according to quality evaluation criteria of the Cochrane Collaboration were selected, in which atorvastatin and placebo were used to evaluate the effects of atorvastatin in the treatment of Alzheimer＇s disease. Study methodological quality was evaluated based on criteria described in Cochrane Reviewer＇s Handbook 5.0.1. Revman 5.1 software was used for data analysis. MAIN OUTCOME MEASURES： Clinical efficacy, safety, withdrawal from the studies, and withdrawal due to adverse effects. RESULTS： Two randomized controlled trials were included, one was scale A, and the other was scale B. All patients （n = 710, age range 50-90 years） were diagnosed as probable or possible mild to moderate Alzheimer＇s disease according to standard criteria and treated with atorvastatin 80 mg/d or placebo. There was no difference between the two groups in the final follow-up for Clinical Global Impression of Change scale （WMD = 0.13, 95%CI： 0.15 to 0.40）, the Alzheimer＇s Disease Assessment Scale-cognitive subscale （WMD = 1.05, 95%C1：-3.06 to 6.05）, Mini-Mental State Examination Scale （WMD = 0.77, 95%CI： 0.57 to 2.10）, and the Neuropsychiatric Instrument （WMD = 2.07, 95%CI： 1.59 to 5.73）. The rates of abnormal liver function, withdrawal from treatment, and withdrawal due to adverse effects were higher in the treatment group （OR = 7.86, 95%CI： 2.50 24.69; OR = 4.70, 95%CI： 2.61 8.44; and OR = 5.47, 95%CI： 3.01-9.94; respectively） compared with the placebo group. CONCLUSION： There is insufficient evidence to recommend atorvastatin for the treatment of mild to moderate AIzheimer＇s disease, because there was no benefit on general function, cognitive function or mental/behavior abnormality outcome measures. Efficacy and safety need to be confirmed by larger and higher quality randomized controlled trials, especially for moderate to severe Alzheimer＇s disease, because results of this systematic review may be limited by selection bias, implementation bias, as well as measurement bias.

Inter-individual differences in the responses to aerobic exercise in Alzheimer’s disease: Findings from the FIT-AD trial

Background:Despite the strong evidence of aerobic exercise as a disease-modifying treatment for Alzheimer’s disease(AD)in animal models,its effects on cognition are inconsistent in human studies.A major contributor to these findings is inter-individual differences in the responses to aerobic exercise,which was well documented in the general population but not in those with AD.The purpose of this study was to examine inter-individual differences in aerobic fitness and cognitive responses to a 6-month aerobic exercise intervention in community-dwelling older adults with mild-to-moderate dementia due to AD.Methods:This study was a secondary analysis of the Effects of Aerobic Exercise for Treating Alzheimer’s Disease(FIT-AD)trial data.Aerobic fitness was measured by the shuttle walk test(SWT),the 6-min walk test(6MWT),and the maximal oxygen consumption(VO2max)test,and cognition by the AD Assessment Scale-Cognition(ADAS-Cog).Inter-individual differences were calculated as the differences in the standard deviation of 6-month change(SDR)in the SWT,6MWT,VO2max,and ADAS-Cog between the intervention and control groups.Results:Seventy-eight participants were included in this study(77.4±6.3 years old,mean±SD;15.7±2.8 years of education;41%were female).VO2max was available for 26 participants(77.7±7.1 years old;14.8±2.6 years of education;35%were female).The SDR was 37.0,121.1,1.7,and 2.3 for SWT,6MWT,VO2max,and ADAS-Cog,respectively.Conclusion:There are true inter-individual differences in aerobic fitness and cognitive responses to aerobic exercise in older adults with mild-tomoderate dementia due to AD.These inter-individual differences likely underline the inconsistent cognitive benefits in human studies.