The impact of the COVID-19 pandemic on neurosurgery in the elderly population in Sweden.

BACKGROUND: The COVID-19 pandemic prompted a refocus of health care resources to acute care which has impacted on the capacity of healthcare systems to conduct neurological surgeries. The elderly population has been shown to be particularly vulnerable to the consequences of the pandemic. Less neurosurgery can result in great impact on public health by increasing morbidity and mortality in patients with malignancies and traumatic injuries. The aim of this study was to investigate the effects of the COVID-19 pandemic on neurosurgical procedures in the elderly population in Sweden. METHODS: In this retrospective observational study, the reported incidence of all neurosurgical procedures registered in the 21 Regions of Sweden during 2015-2021 in people aged 65 year or older was collected. Surgical procedures were classified according to the NOMESCO system of classification. Neurosurgery incidence was defined as the number of NOMESCO associated interventions per 100.000 inhabitants. ICD-10 codes associated with neurosurgery-related diagnoses and deaths were also collected. Expected incidence of neurosurgery, neurosurgery-associated deaths and brain cancer diagnoses was estimated and compared to actual outcomes. Decrease in the incidence of neurosurgery was compared to regional COVID-19 incidence, other types of surgery and surgery waiting times. RESULTS: The incidence of several categories of neurosurgery decreased in Sweden during 2020 and 2021, although not as much as other surgical categories. Women were more affected than men by the decrease in neurosurgery which could be partly explained by a decrease in brain cancer diagnoses amongst women. There was an association between regional decrease in neurosurgery incidence and longer surgery waiting time. COVID-19 incidence in the region did not have an effect on regional decreases in neurosurgery incidence. CONCLUSIONS: The COVID-19 pandemic resulted in a reduction in the number of neurosurgical procedures performed in Sweden during 2020-2021, although not as much as in other European countries. There was regional difference in Sweden with respect to number of surgeries, and waiting time for elective surgeries although there was no increase in mortality.

Trend, disparities, and projection analysis of public data on foot fractures in Sweden: a retrospective analysis of 179 129 fractures.

INTRODUCTION: Orthopedic injuries to the foot constitute a significant portion of lower extremity injuries, necessitating an understanding of trends for effective preventive strategies and resource allocation. Demographic shifts, improved traffic safety, and lifelong physical activity may alter incidence rates, trauma mechanisms, and fracture distribution. This study explores the prevalence of foot fractures in Sweden using publicly available data. METHODS: Utilizing data from the Swedish National Board of Health and Welfare (SNBHW) spanning 2008-2022, retrospective study focuses on foot fractures in Sweden. Analysis includes calculating annual incidence rates per 100,000 person-years, assessing temporal trends, and exploring seasonal variations. Poisson regression analysis was used for projections into 2035. RESULTS: Between 2008-2022, the average annual foot fracture incidence was 11,942, with notable fluctuations influenced by the COVID-19 pandemic. Age and sex disparities impact rates, and seasonal variance highlights increased incidence in summer. By 2035, foot fractures will decreasae amongst several demographic groups. CONCLUSION: This study provides insights into temporal trends, sex differences, and seasonal variations foot fracture patterns in Sweden. The identified trends suggest the utilization of targeted preventive strategies, efficient resource allocation, and informed healthcare planning. Despite limitations, this research offers valuable insights into foot fractures within the Swedish population, utilizing publicly aggregated data.

Trends and projection of forearm fractures including elbow fractures of the Olecranon in Sweden: an analysis of 363 968 fractures using public aggregated data.

BACKGROUND: Forearm and olecranon fractures are a common orthopaedic injury. This study aimed to analyse whether the incidence of forearm injury is changing and identifying trends in the number of forearm and olecranon fractures using public aggregated data in Sweden. METHODS: The number of forearm and olecranon fractures as defined by the number of registered diagnoses with the ICD-10 code of S52 were collected and normalized per 100,000 inhabitants and stratified per sex, age, and month. Age-adjusted incidence for forearm and olecranon fractures were calculated using the direct method. Poisson regression was used to analyse monthly, seasonal and yearly change in forearm and olecranon fracture incidence. Logistical regression was used to predict future trends of forearm and olecranon fractures. RESULTS: The findings revealed a slight decreasing trend in forearm and olecranon fractures. The average incidence rate during the study period was 333 with women having a higher incidence rate than men. More fractures occurred in the winter months. Fluctuations in the number of forearm and olecranon fractures were observed during 2020 which may be influenced by the COVID-19 pandemic. Based on current data, forearm and olecranon fractures are expected to decrease in Sweden by 2035. CONCLUSION: This study describes the trend of forearm and olecranon fractures among individuals according to sex and age in Sweden using easily obtainable data. Trends in forearm and olecranon fractures are dependent on sex and age but generally show a decreasing trend. More precise studies are needed in order to properly quantify the specific incidence of various subtypes of forearm and olecranon fractures and associated risk factors.

Application of deep learning for automated diagnosis and classification of hip dysplasia on plain radiographs.

BACKGROUND: Hip dysplasia is a condition where the acetabulum is too shallow to support the femoral head and is commonly considered a risk factor for hip osteoarthritis. The objective of this study was to develop a deep learning model to diagnose hip dysplasia from plain radiographs and classify dysplastic hips based on their severity. METHODS: We collected pelvic radiographs of 571 patients from two single-center cohorts and one multicenter cohort. The radiographs were split in half to create hip radiographs (n = 1022). One orthopaedic surgeon and one resident assessed the radiographs for hip dysplasia on either side. We used the center edge (CE) angle as the primary diagnostic criteria. Hips with a CE angle < 20°, 20° to 25°, and > 25° were labeled as dysplastic, borderline, and normal, respectively. The dysplastic hips were also classified with both Crowe and Hartofilakidis classification of dysplasia. The dataset was divided into train, validation, and test subsets using 80:10:10 split-ratio that were used to train two deep learning models to classify images into normal, borderline and (1) Crowe grade 1-4 or (2) Hartofilakidis grade 1-3. A pre-trained on Imagenet VGG16 convolutional neural network (CNN) was utilized by performing layer-wise fine-turning. RESULTS: Both models struggled with distinguishing between normal and borderline hips. However, achieved high accuracy (Model 1: 92.2% and Model 2: 83.3%) in distinguishing between normal/borderline vs. dysplastic hips. The overall accuracy of Model 1 was 68% and for Model 2 73.5%. Most misclassifications for the Crowe and Hartofilakidis classifications were +/- 1 class from the correct class. CONCLUSIONS: This pilot study shows promising results that a deep learning model distinguish between normal and dysplastic hips with high accuracy. Future research and external validation are warranted regarding the ability of deep learning models to perform complex tasks such as identifying and classifying disorders using plain radiographs. LEVEL OF EVIDENCE: Diagnostic level IV.

Trend, disparities, and projection analysis of public data on shoulder fractures in Sweden: a retrospective analysis of two hundred and sixty two thousand, four hundred and forty four fractures.

PURPOSE: We aimed to identify temporal trends, seasonal changes and regional differences in shoulder fractures in Sweden during 2008-2022. METHODS: Data from the Swedish National Board of Health and Welfare were used to assess incidence rates per 100,000 people, categorized by sex, age, and month. RESULTS: Results showed an average of 17,496 fractures annually, with a decline in 2020 followed by a resurgence in 2021-2022. Elderly women, especially those over 65, had higher rates. Winter months exhibited increased incidence. CONCLUSIONS: Projection analysis indicated a gradual decrease in fractures over the next 15 years. Understanding these patterns can inform preventive strategies and resource allocation for shoulder fractures in Sweden.

Long-term follow-up of bone density changes in total hip arthroplasty: comparative analysis from a randomized controlled trial of a porous titanium construct shell vs. a porous coated shell.

PURPOSE: Periacetabular bone loss poses a considerable challenge in the longevity and stability of acetabular implants used in total hip arthroplasty (THA). Innovations in implant design, specifically the introduction of three-dimensional (3D) porous titanium constructs, might reduce bone resorption. The purpose of this study was to build upon our previous randomized controlled trial, which found no change in periacetabular bone loss between a 3D porous none-hydroxyapatite coated titanium cup and a standard porous hydroxyapatite coated cup over a two year follow-up period by extending the follow-up duration to ten years post-surgery. METHODS: This was a single-centre, long-term follow-up study conducted over a ten year period in patients who had previously participated in a randomized controlled trial comparing a 3D porous titanium construct shell (PTC group) with a standard porous hydroxyapatite coated titanium shell (PC-group). The primary outcome measured was the change in bone mineral density (BMD) within four specific periacetabular zones, alongside overall bone loss, which was assessed through BMD in the lumbar spine at two, six and ten years postoperatively. Secondary outcomes included clinical outcome measures. RESULTS: In total, 18 in the PTC and 20 in the PC group were analysed for the primary endpoint up to ten years. The mean bone mineral density in zones 1-4 was 3.7% higher in the PTC group than in the PC group at six years postoperatively and 12.0% higher at ten years. Clinical outcomes, and the frequency of adverse events did not differ between the groups. CONCLUSIONS: The PTC group displayed superior long-term bone preservation compared to the PC group while maintaining similar clinical outcomes up to ten years postoperatively. Although with a small sample size, our findings suggest that porous titanium cups have the potential to minimize BMD loss around the cup which could contribute to improving THA outcomes and implant durability.

DEAD Box Helicase 24 Is Increased in the Brain in Alzheimer's Disease and AppN-LF Mice and Influences Presymptomatic Pathology.

At the time of diagnosis, Alzheimer's disease (AD) patients already suffer from significant neuronal loss. The identification of proteins that influence disease progression before the onset of symptoms is thus an essential part of the development of new effective drugs and biomarkers. Here, we used an unbiased 18O labelling proteomics approach to identify proteins showing altered levels in the AD brain. We studied the relationship between the protein with the highest increase in hippocampus, DEAD box Helicase 24 (DDX24), and AD pathology. We visualised DDX24 in the human brain and in a mouse model for Aß42-induced AD pathology-AppNL-F-and studied the interaction between Aß and DDX24 in primary neurons. Immunohistochemistry in the AD brain confirmed the increased levels and indicated an altered subcellular distribution of DDX24. Immunohistochemical studies in AppNL-F mice showed that the increase of DDX24 starts before amyloid pathology or memory impairment is observed. Immunocytochemistry in AppNL-F primary hippocampal neurons showed increased DDX24 intensity in the soma, nucleus and nucleolus. Furthermore, siRNA targeting of DDX24 in neurons decreased APP and Aß42 levels, and the addition of Aß42 to the medium reduced DDX24. In conclusion, we have identified DDX24 as a protein with a potential role in Aß-induced AD pathology.

Artificial intelligence can be used in the identification and classification of shoulder osteoarthritis and avascular necrosis on plain radiographs: a training study of 7,139 radiograph sets.

BACKGROUND AND PURPOSE: Knowledge concerning the use AI models for the classification of glenohumeral osteoarthritis (GHOA) and avascular necrosis (AVN) of the humeral head is lacking. We aimed to analyze how a deep learning (DL) model trained to identify and grade GHOA on plain radiographs performs. Our secondary aim was to train a DL model to identify and grade AVN on plain radiographs. PATIENTS AND METHODS: A modified ResNet-type network was trained on a dataset of radiographic shoulder examinations from a large tertiary hospital. A total of 7,139 radiographs were included. The dataset included various projections of the shoulder, and the network was trained using stochastic gradient descent. Performance evaluation metrics, area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to assess the network's performance for each outcome. RESULTS: The network demonstrated AUC values ranging from 0.73 to 0.93 for GHOA classification and > 0.90 for all AVN classification classes. The network exhibited lower AUC for mild cases compared with definitive cases of GHOA. When none and mild grades were combined, the AUC increased, suggesting difficulties in distinguishing between these 2 grades. CONCLUSION: We found that a DL model can be trained to identify and grade GHOA on plain radiographs. Furthermore, we show that a DL model can identify and grade AVN on plain radiographs. The network performed well, particularly for definitive cases of GHOA and any level of AVN. However, challenges remain in distinguishing between none and mild GHOA grades.

Comparative outcomes of uncemented and cemented stem revision in managing periprosthetic femoral fractures: a retrospective cohort study.

INTRODUCTION: Periprosthetic femoral fractures (PFFs) following hip arthroplasty, especially Vancouver B2 and B3 fractures, present a challenge due to the association with a loose femoral stem, necessitating either open reduction and internal fixation or stem revision. This study aims to compare outcomes between uncemented and cemented stem revisions in managing Vancouver B2 and B3 fractures, considering factors such as hip-related complications, reoperations, and clinical outcome. METHODS: A retrospective cohort study was conducted at Danderyd Hospital, Sweden, from 2008 to 2022, encompassing operatively treated Vancouver B2 and B3 fractures. Patients were categorized into uncemented and cemented stem revision groups, with data collected on complications, revision surgeries, fracture healing times, and clinical outcomes. RESULTS: A total of 241 patients were identified. Significant differences were observed between the two groups in patient demographics, with the cemented group comprising older patients and more females. Follow up ranged from 1 to 15 years. Average follow up time was 3.9 years for the cemented group and 5.5 years for the uncemented group. The cemented stems demonstrated lower rates of dislocation (8.9% versus 22.5%, P = 0.004) and stem loosening (0.6% versus 9.3%, P = 0.004) than the uncemented method. Moreover, the cemented group exhibited shorter fracture healing times (11.4 weeks versus 16.7 weeks, P = 0.034). There was no difference in clinical outcome between groups. Mortality was higher in the cemented group. CONCLUSIONS: This retrospective study indicates that cemented stem revision for Vancouver B2-3 fractures is correlated with lower dislocation and stem loosening rates, necessitating fewer reoperations and shorter fracture healing times compared with the uncemented approach. The cemented group had a notably higher mortality rate, urging caution in its clinical interpretation.

The impact of the COVID-19 pandemic on mortality in people with dementia without COVID-19: a systematic review and meta-analysis.

INTRODUCTION: Significant mortality amongst vulnerable populations, such as people living with dementia, might go undetected during pandemic conditions due to refocus of care efforts. There is an urgent need to fully evaluate the pandemic impact on mortality amongst people living with dementia in order to facilitate future healthcare reforms and prevent deaths. The purpose of this study was to determine whether there was any significant difference in mortality amongst people with dementia without COVID-19 during the COVID-19 pandemic compared to previous years. METHODS: A literature search was conducted in 5 databases. The relative risk ratio and confidence interval was used to estimate the change in mortality rates amongst people with dementia during the COVID-19 pandemic. The I2 value was used to assess heterogeneity, publication bias, and sensitivity analyses were performed. RESULTS: Pooled analysis of 11 studies showed that mortality amongst people living with dementia was significantly increased during the COVID-19 pandemic for people with dementia without COVID-19. Mortality risk increased by 25% during the time period studied. Subgroup analysis was not performed due the low number of included studies. CONCLUSIONS: The results of this study suggest that people with dementia had a significant increased mortality during the pandemic even if they did not have COVID-19. People with dementia should participate in efforts that reduce general social spread and pandemic impact on healthcare system such as vaccinations, mask mandates, and testing. These results have clinical implications as preventing direct COVID-19 infection is not enough to adequately protect people living with dementia from increased mortality. Measures to limit social spread of infections and help support patients should also be a focus for clinicians. Further research should focus on the identification of mechanisms and other explanations for increased mortality as well as contributing factors such as living in care homes and differences between countries with various pandemic strategies.

Changes in dementia diagnoses in Sweden during the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic has caused large disruptions to healthcare systems. Refocus on COVID-19 related care might have contributed to indirect effects on other healthcare areas. Care focused on acute conditions have been negatively affected although research into the effects on chronic and care intensive patient groups such as patients with dementia diseases is lacking. In this study we evaluated dementia diagnosis trends in Sweden during 2015-2020 according to International Classification of Disease version 10 coding of common dementia diseases. METHODS: Regional and national statistics in the form of International Classification of Disease version 10 coding, COVID-19 incidence, mortality data, and population census data were collected from the National Institute of Health and Welfare. Logistic regression analysis was performed to identify trends of dementia diagnosis during 2015-2020. Correlation test was performed between COVID-19 incidence, mortality rates, and dementia coding. RESULTS: Dementia diagnosis incidence has been declining since 2015 and further decline was noted in many regions in Sweden during 2020. As COVID-19 incidence increased, fewer cases of dementia were diagnosed, a decrease that differentially impacted women and those who were advanced in age. CONCLUSIONS: Dementia diagnosis incidence in Sweden has been on a decline since 2015. The COVID-19 pandemic caused a further larger decline in dementia diagnosis incidence during 2020. COVID-19 incidence, but not mortality, was associated with decrease in dementia diagnosis incidence. There might be a large number of undiagnosed patients with dementia and healthcare reforms should be enacted to address this. Women and elderly are particularly vulnerable groups.

Changes in mortality trends amongst common diseases during the COVID-19 pandemic in Sweden.

OBJECTIVE: It has been found that COVID-19 increases deaths within common diseases in countries that have implemented strict lockdowns. In order to elucidate the proper national response to a pandemic, the mortality rates within COVID-19 and various diseases need to be studied in countries whose pandemic response differ. Sweden represents a country with lax pandemic restrictions, and we aimed to study the effects of COVID-19 on historical mortality rates within common diseases during 2020. METHODS: Regression models and moving averages were used to predict expected premature mortality per the ICD-10 during 2020 using historical data sets. Predicted values were then compared to recorded premature mortality to identify changes in mortality trends. RESULTS: Seasonal increased mortality was found within neurological diseases. Infectious diseases, tumours and cardiac disease mortality rates decreased compared to expected outcome. CONCLUSIONS: Changes in mortality trends were observed for several common diseases during the COVID-19 pandemic. Neurological and cardiac conditions, infections and tumours are examples of diseases that were heavily affected by the pandemic. The indirect effects of COVID-19 on certain patient populations should be considered when determining pandemic impact.

Confusion, cognitive impairment, and spinal cord compression caused by plasmacytoma: a case report.

BACKGROUND: Plasmacytomas are rare tumors comprised of neoplastic monoclonal plasma cells and can be found anywhere in the body. Plasmacytomas that involve the nervous system can give rise to diffuse symptoms depending on their location. Patients with confusion or dementia might be difficult to neurologically assess in an acute setting and the subtle symptoms of neurological pathology caused by rare malignancies might go undiagnosed. CASE PRESENTATION: The patient is an 80 year old man presenting to the ER with walking difficulties, pain, and confusion. He underwent neurological evaluation for dementia and was eventually diagnosed with possible Alzheimer's disease and a malignant plasmacytoma causing spinal cord compression. His CSF sample showed normal amyloid rate and very low Aß. Following rehabilitation and oncological treatment, his walking ability and confusion improved. CONCLUSION: This case is unique as we demonstrate that spinal cord compression by plasmacytoma can lead to abnormal CSF levels of several known pathology markers for Alzheimer's disease and neuronal damage. We suggest that highly divergent amyloid CSF levels could be indicative of spinal pathologies affecting CSF circulation. We also suggest closer assessment of elderly confusion patients in ER settings by consultants specialized in neurological disorders.

The COVID-19 pandemic caused gender-specific declines in knee surgery rates in Sweden from 2020 to 2021.

Purpose: Changes in knee surgery incidence are important factors for stakeholders and healthcare providers. The aim of this study was to examine trends and patterns in knee surgeries in Sweden from 2010 to 2022. The study focuses on gender-specific and overall rates of knee surgeries. Methods: The analysis is based on a data set sourced from national healthcare records. The data was stratified based on surgical rates and categorized by gender, year and the specific knee arthroplasty technique used. We tracked year-to-year changes in surgical rates to identify overarching patterns. We used Poisson regression to predict future trends. Comparisons were made between various surgical subcategories, such as those with and without cement in knee arthroplasty surgeries. Results: In 2010, the rate of knee surgeries per 100,000 person-years was 518.7 for males and 448.0 for females. These rates exhibited fluctuations over time, reaching their lowest point in 2020, attributed to the pandemic's disruption of elective procedures, with 386.4 surgeries per 100,000 males and 386.3 surgeries per 100,000 females. A resurgence was observed in 2022. The rates of primary knee arthroplasty increased, with a male rate of 106.2 and a female rate of 150.7 surgeries per 100,000 inhabitants in 2010, rising to 126.8 for males and 166.2 for females in 2022. Conclusion: This comprehensive nationwide open-source data analysis of knee surgeries in Sweden shows that the COVID-19 pandemic significantly impacted knee surgery rates in Sweden, causing a notable decline in 2020, followed by a resurgence in 2022. Furthermore, while men had higher surgery rates than women, they experienced a larger decline in the incidence of knee surgeries compared to women. Understanding these trends is crucial for stakeholders and healthcare providers to improve resource allocation, address gender disparities, and maintain the resilience of surgical services in the face of disruptions. Level of Evidence: Level III.

Epidemiology and regional variance of traumatic peripheral nerve injuries in Sweden: A 15-year observational study.

INTRODUCTION: Traumatic peripheral nerve injuries pose significant challenges to healthcare systems and individuals, affecting sensory function, causing neuropathic pain, and impairing quality of life. Despite their impact, comprehensive studies on the epidemiology and regional variance of these injuries are scarce. Understanding the incidence, trends, and anatomical distribution of such injuries is essential for targeted interventions and resource allocation. METHODS: This observational study utilized register-based data from the Swedish National Patient Register covering the period from 2008 to 2022. Incidence rates, trends, and anatomical distribution of traumatic peripheral nerve injuries were analyzed using descriptive statistics, Poisson regression modeling, and regional comparisons. RESULTS: Higher incidences of peripheral nerve injuries were observed among men compared to women across all age groups. The hand and wrist were the most commonly affected sites. Regional variations in incidence rates were evident, with some regions consistently exhibiting higher rates compared to others. Notably, a decreasing trend in injuries was observed over the study period. CONCLUSION: This study underscores the importance of targeted interventions and preventive strategies, considering sex, age, and regional disparities. Further research incorporating individual patient-level data is warranted to enhance our understanding and inform tailored interventions to reduce the burden of these injuries.

[Saksenaea caused invasive infection in an immunocompetent patient after trauma]. / Saksenaea-svamp gav invasiv infektion hos frisk traumapatient.

This text discusses a rare case of soft tissue infection caused by the fungus Saksenaea in a young, immunocompetent woman following an all-terrain vehicle accident abroad. Despite initial treatment, her wound worsened, necessitating multiple surgical revisions and aggressive antifungal therapy with liposomal Amphotericin B. The interdisciplinary collaboration among orthopedic surgeons, infectious disease specialists, and plastic surgeons played a vital role in her successful treatment. Prompt identification of the fungus and immediate intervention were crucial. This case emphasizes the importance of awareness among healthcare providers regarding this rare condition and underscores the significance of early diagnosis and timely surgical and medical interventions for a positive outcome.

Aß42 oligomer-specific antibody ALZ-201 reduces the neurotoxicity of Alzheimer's disease brain extracts.

BACKGROUND: In Alzheimer's disease (AD), amyloid-ß 1-42 (Aß42) neurotoxicity stems mostly from its soluble oligomeric aggregates. Studies of such aggregates have been hampered by the lack of oligomer-specific research tools and their intrinsic instability and heterogeneity. Here, we developed a monoclonal antibody with a unique oligomer-specific binding profile (ALZ-201) using oligomer-stabilising technology. Subsequently, we assessed the etiological relevance of the Aß targeted by ALZ-201 on physiologically derived, toxic Aß using extracts from post-mortem brains of AD patients and controls in primary mouse neuron cultures. METHODS: Mice were immunised with stable oligomers derived from the Aß42 peptide with A21C/A30C mutations (AßCC), and ALZ-201 was developed using hybridoma technology. Specificity for the oligomeric form of the Aß42CC antigen and Aß42 was confirmed using ELISA, and non-reactivity against plaques by immunohistochemistry (IHC). The antibody's potential for cross-protective activity against pathological Aß was evaluated in brain tissue samples from 10 individuals confirmed as AD (n=7) and non-AD (n=3) with IHC staining for Aß and phosphorylated tau (p-Tau) aggregates. Brain extracts were prepared and immunodepleted using the positive control 4G8 antibody, ALZ-201 or an isotype control to ALZ-201. Fractions were biochemically characterised, and toxicity assays were performed in primary mouse neuronal cultures using automated high-content microscopy. RESULTS: AD brain extracts proved to be more toxic than controls as demonstrated by neuronal loss and morphological determinants (e.g. synapse density and measures of neurite complexity). Immunodepletion using 4G8 reduced Aß levels in both AD and control samples compared to ALZ-201 or the isotype control, which showed no significant difference. Importantly, despite the differential effect on the total Aß content, the neuroprotective effects of 4G8 and ALZ-201 immunodepletion were similar, whereas the isotype control showed no effect. CONCLUSIONS: ALZ-201 depletes a toxic species in post-mortem AD brain extracts causing a positive physiological and protective impact on the integrity and morphology of mouse neurons. Its unique specificity indicates that a low-abundant, soluble Aß42 oligomer may account for much of the neurotoxicity in AD. This critical attribute identifies the potential of ALZ-201 as a novel drug candidate for achieving a true, clinical therapeutic effect in AD.

Microdissected Pyramidal Cell Proteomics of Alzheimer Brain Reveals Alterations in Creatine Kinase B-Type, 14-3-3-γ, and Heat Shock Cognate 71.

Novel insights on proteins involved in Alzheimer's disease (AD) are needed. Since multiple cell types and matrix components are altered in AD, bulk analysis of brain tissue maybe difficult to interpret. In the current study, we isolated pyramidal cells from the cornu ammonis 1 (CA1) region of the hippocampus from five AD and five neurologically healthy donors using laser capture microdissection (LCM). The samples were analyzed by proteomics using 18O-labeled internal standard and nano-high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for relative quantification. Fold change between AD and control was calculated for the proteins that were identified in at least two individual proteomes from each group. From the 10 cases analyzed, 62 proteins were identified in at least two AD cases and two control cases. Creatine kinase B-type (CKB), 14-3-3-γ, and heat shock cognate 71 (Hsc71), which have not been extensively studied in the context of the human AD brain previously, were selected for further studies by immunohistochemistry (IHC). In hippocampus, semi-quantitative measures of IHC staining of the three proteins confirmed the findings from our proteomic analysis. Studies of the same proteins in the frontal cortex revealed that the alterations remained for CKB and 14-3-3-γ but not for Hsc71. Protein upregulation in CA1 neurons of final stage AD is either a result of detrimental, pathological effects, or from cell-specific protective response mechanisms in surviving neurons. Based on previous findings from experimental studies, CKB and Hsc71 likely exhibit protective effects, whereas 14-3-3-γ may represent a detrimental pathway. These new players could reflect pathways of importance for the development of new therapeutic strategies.

Huntingtin Levels are Elevated in Hippocampal Post-Mortem Samples of Alzheimer's Disease Brain.

BACKGROUND: We have recently identified Huntingtin (Htt), the pathogenic protein in Huntington's disease, as a mediator of Alzheimer's disease (AD) pathology in an amyloid precursor protein (APP) knock-in mouse model of AD. That finding prompted us to examine if Htt is accumulated in the brains of AD patients and in which cell type Htt is present in the AD brain. OBJECTIVE: To investigate whether location and levels of Htt are affected in hippocampus and frontal cortex in AD. METHODS: Brains from AD patients (n=11) and controls (n=11) were stained for Htt using immunohistochemistry and signal intensity of Htt was quantified and localized in subregions and neurons. Confocal microscopy was used to characterize neuronal Htt localisation and its relationship with tau tangles and astrocytes. RESULTS: Htt levels were increased in neuronal cells in the granular layer of the dentate gyrus, in CA1 and CA3 in hippocampus and in layer III of the frontal cortex. Htt was found in the soma, perinuclear space, thin neurites and nucleus of pyramidal neurons. Htt was present in neurons containing tau tangles but did not colocalize with astrocytes. CONCLUSION: Htt accumulates in pyramidal neuron-rich areas including hippocampal subregions associated with memory and frontal cortex layer III. The accumulation of Htt in AD shows distinct cellular and morphological patterns and is not present in astrocytes. Clearly, further research is warranted to elucidate the role of Htt as a mediator of AD pathology and the potential use of Htt as a target in future therapeutic strategies.

Proteomics Time-Course Study of App Knock-In Mice Reveals Novel Presymptomatic Aß42-Induced Pathways to Alzheimer's Disease Pathology.

BACKGROUND: The 42 amino acids long amyloid-ß peptide, Aß42, may initiate a cascade of events leading to the severe neurodegeneration observed in Alzheimer's disease (AD) brain. However, the underlying molecular mechanisms remain to be established. OBJECTIVE: To find early Aß42-induced AD related mechanisms, we performed a brain proteomics time-course study on a novel App knock-in AD mouse model, AppNL-F, expressing high levels of Aß42 without AßPP overexpression artifacts. METHODS: Hippocampus and cortex were analyzed separately by using 18O-labelling mass spectrometry to reveal alterations in protein levels. Pathway analysis of proteomics data was used to identify altered biological functions. Immunohistochemistry was used to further investigate a significant key regulatory protein. RESULTS: Around 100 proteins were differently expressed in AppNL-F mice at each time point (3, 6, 9, and 18 months of age) as compared to wild type mice. Strikingly, already at 3 months of age-long before Aß plaque development and memory impairment-several pathways, including long-term potentiation and synaptic plasticity, were downregulated, and neuritogenesis was increased. Huntingtin (HTT) was identified as an upstream regulator, i.e., a key protein affecting the levels of several proteins. Increased levels of HTT in hippocampus of AppNL-F mice was supported by immunofluorescence microscopy. CONCLUSION: Notably, the proteome was significantly altered already at 3 months of age, 6 months before the development of plaques. Differentially expressed proteins varied over time, indicating that increased Aß42 levels initiate a cascade of events that eventually manifests in amyloid depositions, inflammation, and decline in memory.