Gene Expression Studies in Down Syndrome: What Do They Tell Us about Disease Phenotypes?

Down syndrome is a well-studied aneuploidy condition in humans, which is associated with various disease phenotypes including cardiovascular, neurological, haematological and immunological disease processes. This review paper aims to discuss the research conducted on gene expression studies during fetal development. A descriptive review was conducted, encompassing all papers published on the PubMed database between September 1960 and September 2022. We found that in amniotic fluid, certain genes such as COL6A1 and DSCR1 were found to be affected, resulting in phenotypical craniofacial changes. Additionally, other genes such as GSTT1, CLIC6, ITGB2, C21orf67, C21orf86 and RUNX1 were also identified to be affected in the amniotic fluid. In the placenta, dysregulation of genes like MEST, SNF1LK and LOX was observed, which in turn affected nervous system development. In the brain, dysregulation of genes DYRK1A, DNMT3L, DNMT3B, TBX1, olig2 and AQP4 has been shown to contribute to intellectual disability. In the cardiac tissues, dysregulated expression of genes GART, ETS2 and ERG was found to cause abnormalities. Furthermore, dysregulation of XIST, RUNX1, SON, ERG and STAT1 was observed, contributing to myeloproliferative disorders. Understanding the differential expression of genes provides insights into the genetic consequences of DS. A better understanding of these processes could potentially pave the way for the development of genetic and pharmacological therapies.

tVNS in Stroke: A Narrative Review on the Current State and the Future.

Ischemic stroke is a leading cause of disability and there is a paucity of therapeutic strategies that promote functional recovery after stroke. Transcutaneous vagus nerve stimulation (tVNS) has shown promising evidence as a tool to reduce infarct size in animal models of hyperacute stroke. In chronic stroke, tVNS paired with limb movements has been shown to enhance neurological recovery. In this review, we summarize the current evidence for tVNS in preclinical models and clinical trials in humans. We highlight the mechanistic pathways involved in the beneficial effects of tVNS. We critically evaluate the current gaps in knowledge and recommend the key areas of research required to translate tVNS into clinical practice in acute and chronic stroke.

Antiplatelet Use in Ischemic Stroke.

OBJECTIVE: A literature review of antiplatelet agents for primary and secondary stroke prevention, including mechanism of action, cost, and reasons for lack of benefit. DATA SOURCES: Articles were gathered from MEDLINE, Cochrane Reviews, and PubMed databases (1980-2021). Abstracts from scientific meetings were considered. Search terms included ischemic stroke, aspirin, clopidogrel, dipyridamole, ticagrelor, cilostazol, prasugrel, glycoprotein IIb/IIIa inhibitors. STUDY SELECTION AND DATA EXTRACTION: English-language original and review articles were evaluated. Guidelines from multiple countries were reviewed. Articles were evaluated independently by 2 authors. DATA SYNTHESIS: An abundance of evidence supports aspirin and clopidogrel use for secondary stroke prevention. In the acute phase (first 21 days postinitial stroke), these medications have higher efficacy for preventing further stroke when combined, but long-term combination therapy is associated with higher hemorrhage rates. Antiplatelet treatment failure is influenced by poor adherence and genetic polymorphisms. Antiplatelet agents such as cilostazol may provide extra benefit over clopidogrel and aspirin, in certain racial groups, but further research in more diverse ethnic populations is needed. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review presents the data available on the use of different antiplatelet agents poststroke. Dual therapy, recurrence after initiation of secondary preventative therapy, and areas for future research are discussed. CONCLUSIONS: Although good evidence exists for the use of certain antiplatelet agents postischemic stroke, there are considerable opportunities for future research to investigate personalized therapies. These include screening patients for platelet polymorphisms that confer antiplatelet resistance and for randomized trials including more racially diverse populations.

Mid-term outcomes of a stemless ceramic head anatomic total shoulder replacement.

BACKGROUND: In an anatomic shoulder replacement (aTSR) good results have been reported with the use of a stemless humeral prosthesis. In vitro a ceramic articulation with polyethylene has been shown to produce less polyethylene wear particles than with metal. This study aims to evaluate clinical and radiographic results of a stemless aTSR with a ceramic head articulating with a polyethylene glenoid component, with mid-term follow-up. METHODS: All patients (n = 92) in this prospective study had an aTSR utilizing a stemless humeral component with a ceramic head and a cemented double pegged cemented polyethylene glenoid component for glenohumeral osteoarthritis. Pre- and postoperative clinical evaluations at 2 years were performed using the ASES score, Constant score, SPADI score, DASH score, VAS pain score, patient satisfaction and range of motion. There was a 5-year evaluation of SPADI, ASES, pain, and satisfaction, plus radiographic assessment of glenoid component radiolucent lines and humeral osteolysis. RESULTS: Seventy-four cases (68.1 ± 7.1 years) had a five-year follow-up and demonstrated active elevation improvement from 91.3° preoperatively to 151.1° (p < 0.001). Further improvement was identified with the ASES from 41.6 to 94.3, the SPADI from 62.9 to 4.3, VAS pain from 5.6 to 0.4 (0-10), and satisfaction levels were at 96%. Sixty-two cases had no glenoid radiolucent lines with a maximum Lazarus score of 2 in one patient. Constant scores, available up to 2 years, improved significantly from 30.3 to 77.9 (p < 0.001). There was one case that required revision for glenoid loosening. CONCLUSIONS: Overall, the 5-year results of this ceramic head prosthesis demonstrated good radiographic and clinical outcomes. TRIAL REGISTRATION: ACTRN12613001183774 . Registered: 29 October 2013 - Retrospectively registered. Australian New Zealand Clinical Trials Registry (ANZCTR).

Distal Biceps Provocation Test.

PURPOSE: To describe and study a test for distal biceps tendon pathology other than complete tears. METHODS: In this prospective study, the biceps provocation test (BPT) was performed in a cohort of 30 patients with suspected distal biceps tendon pathology and 30 patients with another elbow pathology. Patients with a complete tear were excluded. Diagnosis was confirmed on magnetic resonance imaging or from surgical findings. The BPT is a 2-part test. The elbow is flexed to 70° with the forearm supinated. The examiner's hands are placed on the patient's forearm and the patient is asked to flex the elbow against resistance (BPTs). The forearm is then pronated and the test is repeated (BPTp). Pain is documented for both supination and pronation using a visual analog scale from 0 to 10. The test is positive when the patient indicates an increase in pain with BPTp compared with BPTs. RESULTS: The BPT was positive in all patients with distal biceps tendon pathology. The average visual analog scale score in this group was 1 (range, 0-7) for the supinated part of the test (BPTs) and 7 (range, 4-10) with the forearm in pronation (BPTp), with an average increase of 5 points (range, 2-8). This difference was significant. No significant difference was found in the control group. Among the controls, BPTp and BPTs were rated as equally painful by 27 patients, and BPTp was less painful than BPTs in 3. Sensitivity and specificity were both 100% in this small group of 60 patients, with a high prevalence of distal biceps tendon pathology. CONCLUSIONS: The BPT appears to be highly sensitive and specific for distal biceps partial injury or tendinitis. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II.

Proximal humeral osteolysis and glenoid radiolucent lines in an anatomic shoulder arthroplasty: a comparison of a ceramic and a metal humeral head component.

BACKGROUND: In vitro wear studies demonstrate decreased polyethylene wear with a ceramic compared with a metal humeral head. In this in vivo study, we analyzed prospectively collected 5-year data, comparing the outcomes of 2 types of humeral implants. METHODS: Sixty-two anatomic total shoulder arthroplasties (TSAs) (59 patients) were performed using the same glenoid component and 2 types of modular humeral implants (metal-head long-stem prosthesis in group A vs. ceramic-head stemless prosthesis in group B). Radiographic analysis for proximal humeral osteolysis and glenoid component radiolucent lines was performed at an average of 5.5 years. Functional outcomes were prospectively evaluated according to the visual analog scale score for pain; satisfaction level; American Shoulder and Elbow Surgeons score; active elevation; Shoulder Pain and Disability Index score; and Disabilities of the Arm, Shoulder and Hand score. RESULTS: There were 39 TSAs in group A (mean age, 68.1 years) and 23 TSAs in group B (mean age, 67 years). Clinical improvement was similar for both groups. Some proximal humeral osteolysis occurred in 56% of all TSAs. Group A showed increased osteolysis compared with group B (72% vs. 30%, P = .005). Glenoid radiolucent lines were far more frequent in group A, and group A showed a direct relationship between the extent of humeral osteolysis and the severity of glenoid radiolucent lines (P < .001). CONCLUSION: The stemless ceramic-head replacements showed fewer glenoid radiolucent lines and less humeral osteolysis than the long-stem metal-head replacements. In the group with metal-head replacements, correlation was shown between glenoid radiolucent lines and humeral osteolysis.

Peripheral Glycolysis in Neurodegenerative Diseases.

Neurodegenerative diseases are a group of nervous system conditions characterised pathologically by the abnormal deposition of protein throughout the brain and spinal cord. One common pathophysiological change seen in all neurodegenerative disease is a change to the metabolic function of nervous system and peripheral cells. Glycolysis is the conversion of glucose to pyruvate or lactate which results in the generation of ATP and has been shown to be abnormal in peripheral cells in Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Changes to the glycolytic pathway are seen early in neurodegenerative disease and highlight how in multiple neurodegenerative conditions pathology is not always confined to the nervous system. In this paper, we review the abnormalities described in glycolysis in the three most common neurodegenerative diseases. We show that in all three diseases glycolytic changes are seen in fibroblasts, and red blood cells, and that liver, kidney, muscle and white blood cells have abnormal glycolysis in certain diseases. We highlight there is potential for peripheral glycolysis to be developed into multiple types of disease biomarker, but large-scale bio sampling and deciphering how glycolysis is inherently altered in neurodegenerative disease in multiple patients' needs to be accomplished first to meet this aim.

Cerebral Venous Thrombosis at High Altitude: Analysis of 28 Cases.

OBJECTIVE: An association between cerebral venous sinus thrombosis (CVST) and high altitude has been previously proposed, but limited published data exist to support this association. We investigated 28 cases of CVST occurring at high altitude and sought to describe patient demographics, altitude and acclimatization, hematological laboratory findings, neuroimaging, treatment, and prognosis in these cases. METHODS: Twenty-eight cases of symptomatic CVST occurring at high altitude were identified between the months of August 2017 and December 2018, in collaboration with Military Hospital, Rawalpindi and Combined Military Hospital, Skardu (Pakistan). Follow-up visits were performed at 1 and 6 months. RESULTS: Twenty-seven (96%) of the patients were males, and the mean age was 33 years. In total, 32.1% were smokers. The mean NIHSS score on presentation was 5.5. 85.7% of the cases occurred at altitude higher than 8,000 feet. On average 107.8 days were spent at a high altitude prior to CVST. Totally, 71.4% had acclimatized for >2 weeks. The mean hemoglobin (Hb) value was 16.7 g/dL and 50% had d-dimer levels higher than 1,000 ng/mL. On MRI, 25% showed signs of hemorrhage and 14.3% showed infarcts. Treatments provided include low-molecular-weight heparin and Rivaroxaban and were associated with good outcomes. CONCLUSION: CVST is not uncommon at high altitude (>8,000 feet). It is predominantly a male disease. Most patients have high Hb and high D-dimer levels. The overall outcome was good.

The effect of vitamin E-enhanced cross-linked polyethylene on wear in shoulder arthroplasty-a wear simulator study.

BACKGROUND: Wear of the polyethylene glenoid component and subsequent particle-induced osteolysis remains one of the most important modes of failure of total shoulder arthroplasty. Vitamin E is added to polyethylene to act as an antioxidant to stabilize free radicals that exist as a byproduct of irradiation used to induce cross-linking. This study was performed to assess the in vitro performance of vitamin E-enhanced polyethylene compared with conventional polyethylene in a shoulder simulator model. METHODS: Vitamin E-enhanced, highly cross-linked glenoid components were compared with conventional ultrahigh-molecular-weight polyethylene glenoids, both articulating with a ceramic humeral head component using a shoulder joint simulator over 500,000 cycles. Unaged and artificially aged comparisons were performed. Volumetric wear was assessed by gravimetric measurement, and wear particle analysis was also subsequently performed. RESULTS: Vitamin E-enhanced polyethylene glenoid components were found to have significantly reduced wear rates compared with conventional polyethylene in both unaged (36% reduction) and artificially aged (49% reduction) comparisons. There were no differences detected in wear particle analysis between the 2 groups. CONCLUSION: Vitamin E-enhanced polyethylene demonstrates improved wear compared with conventional polyethylene in both unaged and artificially aged comparisons and may have clinically relevant benefits.

Treatment of the unknown patient: insights from acute stroke.

When an unidentified patient who cannot communicate presents with symptoms and signs suggesting an acute stroke, the decision to thrombolyse is a particular challenge. In a time-pressured environment, clinicians need clear thought processes for diagnosis and treatment. Ethical considerations, diagnosis, identity and previous history, contraindications, time of symptom onset (EDICT) can help decision-making in this situation.

Pain, depression and the postoperative stiff shoulder.

BACKGROUND: The surgical repair of shoulder pathologies, including rotator cuff disease and acromio-clavicular joint arthritis, have undergone many technical advances. However the debilitating postoperative stiff shoulder remains a common and significant complication of these surgeries, occurring in 4.9 to 23.2 % of patients undergoing rotator cuff repairs. The pathology of the pathological postoperative stiff shoulder and its associated condition "frozen shoulder" are poorly understood and both lack formal objective clinical diagnostic criteria. Additionally, although factors associated with the development of idiopathic frozen shoulder have been well described, multiple studies looking at predictors of postoperative stiff shoulder have produced conflicting results. It has been hypothesised that increased pain in the postoperative period, and depression may be predictors of the development of postoperative stiff shoulder. METHOD: A prospective cohort study involving 132 consecutive participants. Preoperatively, participants undergoing arthroscopic subacromial decompression and/or excision of the distal clavicle and/or rotator cuff repair will complete questionnaires about their levels of shoulder pain using a numerical rating scale from 0 to 10, and answer a Patient Health Questionnaire - 9 depression questionnaire. Postoperatively, the participants' pain levels will be self-assessed at two, five and seven days and weeks four, seven and ten. They will complete the depression questionnaire twice, at the time of their routine first and final postoperative appointments with the treating surgeon. At the final appointment, approximately three months postoperatively, the treating surgeon will clinically diagnose participants as having a postoperative stiff shoulder or not. Their shoulders' range of motion will be measured. The incidence of postoperative stiff shoulder will be determined, both pain and depression will be analysed as predictors for its development and incidences determined by different objective criteria will be compared. DISCUSSION: This trial will add to clinical understanding of the postoperative stiff shoulder by providing further insight into the incidence of this condition following shoulder surgery and assessing whether perioperative pain and depression can be used as clinical predictors of postoperative stiff shoulder or markers for possible early intervention. This study will also allow the comparison of incidences determined by different objective criteria in the same cohort. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12613001271796. 17-11-2013.

Four-dimensional computed tomography scans facilitate preoperative planning in snapping scapula syndrome.

HYPOTHESIS: Because a 4-dimensional CT scan (4D CT) is able to provide a moving 3-dimensional (3D) image in real time in patients with snapping scapula syndrome, a 4D CT scan should be able to demonstrate bony impingement of the scapula on the posterior thorax. This study was performed to determine if 4D CT scans aid the clinician in defining the size and location of the scapular bone causing impingement in patients with snapping scapula syndrome. MATERIALS AND METHODS: Between October 2009 and August 2013, 12 patients (median age, 26.5 years; range 15-55 years) with snapping scapula syndrome were investigated with 4D CT. The images formed produced a dynamic volume-rendered reconstruction of the scapulothoracic joint that displayed its movements and any dynamic area of impingement of the scapula on surrounding bony structures. Asymmetry between symptomatic and asymptomatic scapulae was used to determine the radiologic cause of the patient's symptoms. After the failure of conservative management, 8 patients underwent surgery for their condition. RESULTS: Five patients demonstrated bony contact of the scapula on the posterior thoracic ribs. Four patients demonstrated no bony contact but close apposition of the scapula to the posterior thoracic ribs. Three patients demonstrated no bony impingement but abnormal movement of the second and third rib caused by a soft-tissue tethering structure. CONCLUSION: The 4D CT scan images defined pathology well in patients with snapping scapula syndrome and improved assessment of the amount and location of the scapular bone and soft tissue causing symptoms.

The protective role of carnosine against type 2 diabetes-induced cognitive impairment.

The morbidity and mortality associated with type 2 diabetes mellitus (T2DM) have grown exponentially over the last 30 years. Together with its associated complications, the mortality rates have increased. One important complication in those living with T2DM is the acceleration of age-related cognitive decline. T2DM-induced cognitive impairment seriously affects memory, executive function, and quality of life. However, there is a lack of effective treatment for both diabetes and cognitive decline. Thus, finding novel treatments which are cheap, effective in both diabetes and cognitive impairment, are easily accessible, are needed to reduce impact on patients with diabetes and health-care systems. Carnosine, a histidine containing dipeptide, plays a protective role in cognitive diseases due to its antioxidant, anti-inflammation, and anti-glycation properties, all of which may slow the development of neurodegenerative diseases and ischemic injury. Furthermore, carnosine is also involved in regulating glucose and insulin in diabetes. Herein, we discuss the neuroprotective role of carnosine and its mechanisms in T2DM-induced cognitive impairment, which may provide a theoretical basis and evidence base to evaluate whether carnosine has therapeutic effects in alleviating cognitive dysfunction in T2DM patients.

Co-aggregation with Apolipoprotein E modulates the function of Amyloid-ß in Alzheimer's disease.

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-ß (Aß) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aß in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aß co-aggregates account for ~50% of the mass of diffusible Aß aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aß tune disease-related functions of Aß aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aß. Selectively removing non-lipidated apoE4-Aß co-aggregates enhances clearance of toxic Aß by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.

The neurology of space flight; How does space flight effect the human nervous system?

RATIONALE AND HYPOTHESIS: Advancements in technology, human adaptability, and funding have increased space exploration and in turn commercial spaceflight. Corporations such as Space X and Blue Origin are exploring methods to make space tourism possible. This could lead to an increase in the number of patients presenting with neurological diseases associated with spaceflight. Therefore, a comprehensive understanding of spaceflight stressors is required to manage neurological disease in high-risk individuals. OBJECTIVES: This review aims to describe the neurological effects of spaceflight and to assess countermeasures such as pre-flight prophylaxis, training, and possible therapeutics to reduce long-term effects. METHODOLOGY: A literature search was performed for experimental studies conducted in astronauts and in animal models that simulated the space environment. Many studies, however, only discussed these with scientific reasoning and did not include any experimental methods. Relevant studies were identified through searching research databases such as PubMed and Google Scholar. No inclusion or exclusion criteria were used. FINDINGS: Analysis of these studies provided a holistic understanding of the acute and chronic neurological changes that occur during space flight. Astronauts are exposed to hazards that include microgravity, cosmic radiation, hypercapnia, isolation, confinement and disrupted circadian rhythms. Microgravity, the absence of a gravitational force, is linked to disturbances in the vestibular system, intracranial and intraocular pressures. Furthermore, microgravity affects near field vision as part of the spaceflight-associated neuro-ocular syndrome. Exposure to cosmic radiation can increase the risk of neurodegenerative conditions and malignancies. It is estimated that cosmic radiation has significantly higher ionising capabilities than the ionising radiation used in medicine. Space travel also has potential benefits to the nervous system, including psychological development and effects on learning and memory. Future work needs to focus on how we can compare a current astronaut to a future space tourist. Potentially the physiological and psychological stresses of space flight might lead to neurological complications in future space travellers that do not have the physiological reserve of current astronauts.

The incidence and treatment of symptomatic acromioclavicular joint osteoarthritis following total shoulder arthroplasty.

Background: Acromioclavicular joint (ACJ) Osteoarthritis (OA) is very common in the general population. Despite this, there is little mention of concomitant glenohumeral and ACJ arthropathy in the literature, and no documented incidence of symptomatic ACJ OA post total shoulder arthroplasty (TSA). We present the incidence and timescale of the problem, and the response to treatments. Methods: Patients who had developed ACJ-related symptoms following a TSA were retrieved from a prospectively collected database. It was determined that these symptoms were not related to the prosthesis or other non-ACJ pathology. Results: There were 230 primary anatomic total shoulder replacements carried out over a 9-year period, with 219 with adequate follow-up for analysis. Thirty-five (16%) developed a symptomatic ACJ. The majority developed symptoms within the first two years however there was one patient who developed symptoms eight years later. Twenty six percent of patients responded to a period of rest. Seventy one percent had a cortisone injection in the ACJ and in 44% of patients this was effective. Twelve (34%) patients had an arthroscopic excision of distal clavicle with good resolution of the symptoms. Discussion: ACJ symptoms following a total shoulder replacement appears more common than thought and can be treated successfully.

Assessing the impact of blue and green spaces on mental health of disabled children: A scoping review.

During recent decades, there has been a growing consideration of the role of blue and green spaces on mental health of children, but there is insufficient attention in the literature to the mental health of children with disabilities. This paper presents an overview of the evidence on how blue and green spaces affect the mental health of children with various disabilities. A database search found twenty studies eligible for the review, after several consecutive screening stages. Most studies used a cross-sectional design and were carried out in Europe. The results consistently indicate that blue and green space can reduce emotional, behavioral, and social problems in disabled children. A protective association was found between the level of blue or greenness and depressive and anxiety symptoms. Moreover, in most of the studies there were no significant changes in the result after adjusting for socioeconomic confounders. Generally, there is an identified need for more short-term exposure studies in this area, focusing on the impact of landscape design elements on mental health of disabled children. The findings of this scoping review call on urban planners, health care workers and decision makers to consider appropriate measures and interventions providing more blue and green space exposure to disabled children.

Histidine-containing dipeptide supplementation improves delayed recall: a systematic review and meta-analysis.

CONTEXT: Histidine-containing dipeptides (carnosine, anserine, beta-alanine and others) are found in human muscle tissue and other organs like the brain. Data in rodents and humans indicate that administration of exogenous carnosine improved cognitive performance. However, RCTs results vary. OBJECTIVES: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) of histidine-containing dipeptide (HCD) supplementation on cognitive performance in humans to assess its utility as a cognitive stabiliser. DATA SOURCES: OVID Medline, Medline, EBM Reviews, Embase, and Cumulative Index to Nursing and Allied Health Literature databases from 1/1/1965 to 1/6/2022 for all RCT of HCDs were searched. DATA EXTRACTION: 2653 abstracts were screened, identifying 94 full-text articles which were assessed for eligibility. Ten articles reporting the use of HCD supplementation were meta-analysed. DATA ANALYSIS: The random effects model has been applied using the DerSimonian-Laird method. HCD treatment significantly increased performance on Wechsler Memory Scale (WMS) -2 Delayed recall (Weighted mean difference (WMD) (95% CI (CI)) = 1.5 (0.6, 2.5), P < .01). Treatment with HCDs had no effect on Alzheimer's Disease Assessment Scale-Cognitive (WMD (95% CI) = -0.2 (-1.1, 0.7), P = .65, I2 = 0%), Mini-Mental State Examination (WMD (95% CI) = 0.7 (-0.2, 1.5), P = .14, I2 = 42%), The Wechsler Adult Intelligence Scale (WAIS) Digit span Backward (WMD (95% CI) = 0.1 (-0.3, 0.5), P = .51, I2 = 0%), WAIS digit span Forward (WMD (95% CI) = 0.0 (-0.3, 0.4), P = .85, I2 = 33%) and the WMS-1 Immediate recall (WMD (95% CI) = .7 (-.2, 1.5), P = .11, I2 = 0%). The effect on delayed recall remained in subgroup meta-analysis performed on studies of patients without mild cognitive impairment (MCI), and in those without MCI where average age in the study was above 65. CONCLUSION: HCD, supplementation improved scores on the Delayed recall examination, a neuropsychological test affected early in Alzheimer's disease. Further studies are needed in people with early cognitive impairment with longer follow-up duration and standardization of carnosine doses to delineate the true effect. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42017075354.