Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis.

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-ß-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stßinteraction = -0.062, P = 0.032), higher education level (Stßinteraction = -0.072, P = 0.011) and higher intracranial volume (Stßinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.

Bowel function, urinary tract function, and health-related quality of life in males with anorectal malformations.

PURPOSE: There is a knowledge gap regarding long-term outcomes for males undergoing surgery for an anorectal malformation (ARM). The purpose of this study was to investigate bowel function, bladder function, and health-related quality of life (HRQoL) in male patients with an anorectal malformation. METHODS: This cross-sectional questionnaire-based study included males treated for ARM at our institution between 1994 and 2017. Bowel function was assessed with bowel function score (BFS) while urinary tract function was assessed with lower urinary tract symptoms (LUTS) questionnaires. Health-related quality of life (HRQoL) was investigated using age-relevant questionnaires (KIDSCREEN and PGWBI). Patient characteristics were retrospectively collected from the medical records and descriptive statistics were used for analysis. Functional outcomes were compared with gender and age-matched controls while HRQoL was compared to normative data. The study was approved by ethics review authorities. RESULTS: A total of 58 (44.6%) of 130 males responded to the questionnaires. Regarding bowel function, 24 (42.1%) of 57 patients and 81 (95.3%) of 85 controls, respectively, reported a well-preserved bowel function represented by a BFS ≥ 17 (p < 0.001). Soiling issues and 'feels urge' items improved significantly with age. In a linear regression model, BFS increased significantly with age. For most parameters, the proportion of ARM patients with lower urinary tract symptoms was larger, though not significantly, compared to the controls. However, straining and stress incontinence were reported significantly more often by ARM patients. In patients and controls, voiding outcomes in terms of prevalence of having symptoms and the number of cumulative symptoms drop with increasing age. Children and adults reported similar or, in some domains, better HRQoL outcomes when compared to normative European data. CONCLUSION: Bowel function is impaired in male patients with ARM but significantly improves with age. Urinary tract function was affected, but overall comparable to the controls. HRQoL was unaffected. No significant association between the studied outcomes could be shown. LEVEL OF EVIDENCE: III.

Surgical management of necrotising enterocolitis in Sweden: A national cohort study.

AIM: Necrotising enterocolitis (NEC) is the dominating surgical emergency in preterm neonates. The aims were to investigate indications, surgical management and mortality for surgically treated neonates with NEC. METHODS: Data were retrieved from the Swedish Neonatal Quality Register for Swedish neonates with surgically treated NEC from 1 January 2017 to 31 December 2021. Diagnosis was validated by surgical records and histopathology. Neonates with isolated spontaneous intestinal perforation were excluded. RESULTS: In total, 109 neonates were included. Median gestational age was 25 weeks (22-38), and median birth weight was 771 g (269-3920). Preoperative pneumoperitoneum was found in 32%, portal venous gas in 25% and clinical deterioration on conservative treatment in 26% of the neonates. Among the 97 neonates presenting with small bowel necrosis, single-focal NEC occurred in 38 (39%), multifocal NEC in 35 (36%) and panintestinal NEC in 24 (25%). A primary anastomosis was performed in 10/87 (11%) of the neonates with bowel resection at primary surgery. Clip-and-drop technique was applied in 24/87 (28%).Mortality rate was 37%. CONCLUSION: Mortality was well comparable with earlier reports considering exclusion of spontaneous intestinal perforation (SIP) and the low gestational age of the study population. Resection of necrotic bowel with stoma formation was the dominating surgical method.

Longitudinal plasma p-tau217 is increased in early stages of Alzheimer's disease.

Plasma levels of tau phosphorylated at threonine-217 (p-tau217) is a candidate tool to monitor Alzheimer's disease. We studied 150 cognitively unimpaired participants and 100 patients with mild cognitive impairment in the Swedish BioFINDER study. P-tau217 was measured repeatedly for up to 6 years (median three samples per person, median time from first to last sample, 4.3 years). Preclinical (amyloid-ß-positive cognitively unimpaired, n = 62) and prodromal (amyloid-ß-positive mild cognitive impairment, n = 49) Alzheimer's disease had accelerated p-tau217 compared to amyloid-ß-negative cognitively unimpaired (ß = 0.56, P < 0.001, using linear mixed effects models) and amyloid-ß-negative mild cognitive impairment patients (ß = 0.67, P < 0.001), respectively. Mild cognitive impairment patients who later converted to Alzheimer's disease dementia (n = 40) had accelerated p-tau217 compared to other mild cognitive impairment patients (ß = 0.79, P < 0.001). P-tau217 did not change in amyloid-ß-negative participants, or in patients with mild cognitive impairment who did not convert to Alzheimer's disease dementia. For 80% power, 109 participants per arm were required to observe a slope reduction in amyloid-ß-positive cognitively unimpaired (71 participants per arm in amyloid-ß-positive mild cognitive impairment). Longitudinal increases in p-tau217 correlated with longitudinal worsening of cognition and brain atrophy. In summary, plasma p-tau217 increases during early Alzheimer's disease and can be used to monitor disease progression.

Attention deficit hyperactivity and autism spectrum disorders in patients with anorectal malformations.

AIM: To assess the risk of neurodevelopmental disorders in patients with anorectal malformations compared to controls. METHODS: This was a population-based cohort study including all patients born in Sweden 1997-2012 with anorectal malformation in the Swedish National Patient Register and five matched controls per patient. Anorectal malformation was the exposure. All individuals were evaluated for the outcomes, attention deficit hyperactivity disorder or autism spectrum disorder in the National Patient Register. Data on drugs for attention deficit hyperactivity disorder were retrieved from the Swedish Prescribed Drug Register and used as proxy for attention deficit hyperactivity disorder. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Analyses were adjusted for confounders. RESULTS: Five hundred and fifteen patients with anorectal malformations and 2560 controls were included. Patients with anorectal malformation had a higher risk of attention deficit hyperactivity disorder (OR 3.01 (95% CI, 1.83-4.95)) and autism spectrum disorders (OR 3.07 (95% CI, 1.62-5.79)) compared to the controls. Significantly more patients with anorectal malformation had been prescribed medication for attention deficit hyperactivity disorder compared to controls (OR 2.26 (95% CI 1.33-3.85)). CONCLUSION: Patients with anorectal malformations have a higher risk of attention deficit hyperactivity disorder and autism spectrum disorders than controls.

Nonoperative Treatment Versus Appendectomy for Acute Nonperforated Appendicitis in Children: Five-year Follow Up of a Randomized Controlled Pilot Trial.

OBJECTIVE: The aim of this study was to evaluate the safety and feasibility of nonoperative treatment of acute nonperforated appendicitis in children during 5 years of follow-up. METHODS: A 4-year follow-up of a previous randomized controlled pilot trial, including 50 children with acute nonperforated appendicitis, was performed. The patients were initially randomized to nonoperative treatment with antibiotics or appendectomy with 1-year follow-up previously reported. Data were extracted from the computerized notes and telephone interviews.The primary outcome was treatment failure, defined as need for a secondary intervention under general anesthesia, related to the previous diagnosis of acute nonperforated appendicitis. RESULTS: The children were followed up for at least 5 years [median 5.3 (range 5.0-5.6)] after inclusion. There were no failures in the appendectomy group (0/26) and 11 failures in the nonoperative group (11/24). Nine failures had occurred during the first year after inclusion, 2 of whom had histologically confirmed appendicitis. There were 2 further patients with recurrent acute appendicitis 1 to 5 years after inclusion. Both these patients had uncomplicated laparoscopic appendectomies for histologically confirmed acute appendicitis. There were no losses to follow-up. CONCLUSIONS: At 5 years of follow-up 46% of children treated with antibiotics for acute nonperforated appendicitis had undergone an appendectomy, although acute appendicitis was only histologically confirmed in 4/24 (17%). Treatment with antibiotics seems to be safe in the intermediate-term; none of the children previously treated nonoperatively re-presented with complicated appendicitis.

Incidence of and risk factors for venous thrombosis in children with percutaneous non-tunnelled central venous catheters.

BACKGROUND: Venous thrombosis (VT) in children is often associated with a central venous catheter (CVC). We aimed to determine the incidence of VT associated with percutaneous non-tunnelled CVCs in a general paediatric population, and to identify risk factors for VT in this cohort. METHODS: Observational, prospective study enrolling consecutive patients at a tertiary multi-disciplinary paediatric hospital. A total of 211 percutaneous, non-tunnelled CVCs were analysed. Data regarding potential risk factors for CVC-related VT were collected. Compression ultrasonography with colour Doppler was used to diagnose VT. RESULTS: Overall, 30.3% of children developed CVC-related VT, with an incidence rate of 29.6 (confidence interval, 22.5-36.9) cases/1000 CVC days. Upper body CVC location, multiple lumen CVCs, and male gender were independent risk factors for VT in multivariate analysis. All upper body VTs were in the internal jugular vein (IJV). The occurrence of CVC-related VT did not affect length of paediatric ICU or hospital stay. In patients with VT, femoral CVCs, young age, paediatric ICU admission, and a ratio of CVC/vein diameter >0.33 were associated with VT being symptomatic, occlusive, or both. IJV VT was often asymptomatic and non-occlusive. CONCLUSIONS: Paediatric non-tunnelled CVCs are frequently complicated by VT. Avoiding IJV CVCs and multiple lumen catheters could potentially reduce the overall risk of VT. However, IJV VT was more likely to be smaller and asymptomatic compared with femoral vein VT. More data are needed on the risk of complications from smaller, asymptomatic VT compared with the group of VT with symptoms or vein occlusion. Femoral vein CVCs and CVC/vein diameter >0.33 could be modifiable risk factors for VT with larger thrombotic mass. CLINICAL TRIAL REGISTRATION: ACTRN12615000442505.

Early central line-associated blood stream infections in children with cancer pose a risk for premature catheter removal.

AIM: This study examined the clinical characteristics of central line-associated blood stream infections occurring within 30 days after insertion versus later infections in paediatric cancer patients and the subsequent risk for premature catheter removal. METHODS: This was a retrospective study of children aged 0-18 years who were diagnosed with cancer from 2013 to 2014 at the Astrid Lindgren Children Hospital, Sweden. Clinical and microbiology data for each patient were collected for 365 days after the central venous catheter (CVC) was inserted. RESULTS: During the study period, 154 children received a CVC. The overall incidence of central line associated blood stream infections was 2.0 per 1000 catheter days. A total of 108 infectious episodes were identified in 44/154 (29%) patients. Of those, 15/44 children (29%) had an early infection within 30 days and alpha-haemolytic Streptococci and coagulase-negative Staphylococci dominated. Children with early infections were more likely to have a haematological malignancy and to need premature removal of the CVC due to repeated infections. CONCLUSION: We observed a high prevalence of early CVC associated blood stream infection mainly in patients with haematological malignancies. Our study highlights the importance of preventive measures in reducing infections in paediatric cancer patients.

In-hospital Surgical Delay Does Not Increase the Risk for Perforated Appendicitis in Children: A Single-center Retrospective Cohort Study.

OBJECTIVE: To investigate the correlation between in-hospital surgical delay before appendectomy for suspected appendicitis and the finding of perforated appendicitis in children. METHODS: All children undergoing acute appendectomy for suspected acute appendicitis at Karolinska University Hospital, Stockholm, Sweden from 2006 to 2013 were reviewed for the exposure of surgical delay. Primary endpoint was the histopathologic finding of perforated appendicitis. The main explanatory variable was in-hospital surgical delay, using surgery within 12 hours as reference. Secondary endpoints were postoperative wound infection, intra-abdominal abscess, reoperation, length of hospital stay, and readmission. To adjust for selection bias, a logistic regression model was created to estimate odds ratios for the main outcome measures. Missing data were replaced using multiple imputation. RESULTS: The study comprised 2756 children operated for acute appendicitis. Six hundred sixty-one (24.0%) had a histopathologic diagnosis of perforated appendicitis. In the multivariate logistic regression analysis, increased time to surgery was not associated with increased risk of histopathologic perforation. There was no association between the timing of surgery and postoperative wound infection, intra-abdominal abscess, reoperation, or readmission. CONCLUSIONS: In-hospital delay of acute appendectomy in children was not associated with an increased rate of histopathologic perforation. Timing of surgery was not an independent risk factor for postoperative complications. The results were not dependent on the magnitude of the surgical delay. The findings are analogous with previous findings in adults and may aid the utilization of available hospital- and operative resources.

Population-based study shows that Hirschsprung disease does not have a negative impact on education and income.

AIM: Hirschsprung disease is a multifactorial disease, which is mainly treated during childhood. There is a risk of impaired bowel function for a long time after surgery, and its impact on adult life has not been well studied. This study assessed whether having Hirschsprung disease affected social parameters such as educational level and income. METHODS: This nationwide, population-based cohort study included all patients with Hirschsprung disease, registered in the Swedish National Patient Register from 1964 and 2013, who were each matched by age and sex to ten individuals randomly selected from the Swedish Population Register. The study outcomes were the highest educational level and individual disposable income in 2013 registered by Statistics Sweden. RESULTS: The study comprised 389 patients and 3847 controls, both 76% male, with a median age of 25 years. There were no statistically significant differences in highest educational level between the groups (p = 0.327). The median individual disposable income was 142 200 (0-817 200) Swedish Krona in the patient group and 159 000 (0-3 418 900) in the control group (p = 0.615). CONCLUSION: The highest educational level and the individual disposable income did not differ between patients with Hirschsprung disease and controls, indicating that the disease had a low impact on these parameters.

Outcomes in infants with prenatally diagnosed gastroschisis and planned preterm delivery.

BACKGROUND: The timing and mode of delivery of pregnancies with prenatally diagnosed gastroschisis remains controversial. AIM: To evaluate the outcome of patients with gastroschisis managed during two time periods: 2006-2009 and 2010-2014, with planned elective cesarean delivery at 37 versus 35 gestational weeks (gw). A secondary aim was to analyze the outcome in relation to the gestational age at birth. MATERIAL AND METHODS: Retrospective review of all cases with gastroschisis managed at our institution between 2006 and 2014. RESULTS: Fifty-two patients were identified, 24 during the initial period, and 28 during the second. There were a significantly higher number of emergency cesarean deliveries in the first period. There were no differences between groups with regard to the use of preformed silo, need of parenteral nutrition or length of hospital stay. When analyzing the outcome in relation to the gw the patients actually were born, we observed that patients delivered between 35 and 36.9 gw were primary closed in 88.5% of cases, with shorter time on mechanical ventilation, parenteral nutrition and hospital stay. CONCLUSION: Planned caesarian section at 35 completed gestational weeks for fetuses with prenatally diagnosed gastroschisis is safe. We observe the best outcome for patients born between 35 and 36.9 gw.

The Incidence of Necrotizing Enterocolitis and Late-Onset Sepsis during the COVID-19 Pandemic in Sweden: A Population-Based Cohort Study.

INTRODUCTION: The effect of the pandemic restrictions in the NICUs is not well studied. Necrotizing enterocolitis (NEC) is characterized by intestinal inflammation and bacterial invasion. This study aimed to investigate whether the incidence of NEC has changed during the COVID-19 pandemic in Sweden and whether it was associated with a change in the frequency of extremely preterm births. METHODS: Data were retrieved from the Swedish Neonatal Quality Register (SNQ) for infants registered between January 2017 and December 2021 born below a gestational age of 35 weeks. The registry completeness is 98-99%. The diagnosis of NEC was the primary outcome. Generalized linear model analysis was used to calculate the risk ratio for NEC. RESULTS: Totally 13,239 infants were included. 235 (1.8%) infants developed NEC, out of which 91 required surgical treatment. 8,967 infants were born before COVID-19 pandemic and 4,272 during. Median gestational age at birth was 32.8 weeks in both periods. The incidence of NEC was significantly lower during COVID-19 pandemic compared to the prior period (1.43 vs. 1.94%, p 0.037), but not the incidence of surgical NEC. The crude risk ratio of developing NEC during COVID-19 pandemic was 0.74 (95% CI: 0.55-0.98). The incidence of late-onset sepsis with positive culture was also declined during COVID-19 (3.21 vs. 4.15%, p value 0.008). CONCLUSION: While we found significant reduction in the incidence of NEC and culture-positive late-onset sepsis during the COVID-19 pandemic, the number of extremely preterm births was unchanged.

Functional and Health-Related Quality of Life Outcomes into Adulthood for Females Surgically Treated for Anorectal Malformation.

BACKGROUND: Controlled outcomes into adulthood for females with anorectal malformation (ARM) are still scantily studied. The primary aim was to investigate bowel function, bladder function and health-related quality of life (HRQoL) in females operated for ARM. METHODS: A cross-sectional questionnaire-based observational study was performed including females treated for ARM at our institution between 1994 and 2017. The bowel function was assessed with bowel function score (BFS) and urinary tract function with lower urinary tract symptoms (LUTS) questionnaires. HRQoL was investigated with validated age-dependent questionnaires. Patient characteristics were retrospectively retrieved from the medical records and descriptive statistics were used for analysis. HRQoL outcomes were compared with normative data whilst bowel and bladder function outcomes were compared to age-matched female controls. RESULTS: Forty-four (41.5 %) of 106 females responded to the questionnaires. Ten of 29 patients (34.5 %) aged 4-17 years and 4 of 14 patients (28.6%) aged ≥18 years, reported a well-preserved bowel function (BFS≥17). Constipation issues decreased with age. BFS was similar in patients with perineal and vestibular fistulas. Thirty-six (83.7%) of the patients had at least one LUTS. No adult patients had issues with involuntary urinary leakage. Adults scored significantly (p = 0.004) lower than normative data regarding HRQoL, while children and adolescents scored comparably to norm data. CONCLUSIONS: Only 28.6 % of the adult patients reported a well-preserved bowel function, similar to the proportion reported by children 4-17 years of age. Adult patients appear to have a diminished HRQoL, however the correlation with BFS was weak. LEVEL OF EVIDENCE: III.

Plasma lipids, genetic variants near APOA1, and the risk of infantile hypertrophic pyloric stenosis.

IMPORTANCE: Infantile hypertrophic pyloric stenosis (IHPS) is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. Infantile hypertrophic pyloric stenosis shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited. OBJECTIVES: To search the genome comprehensively for genetic associations with IHPS and validate findings in 3 independent sample sets. DESIGN, SETTING, AND PARTICIPANTS: During stage 1, we used reference data from the 1000 Genomes Project for imputation into a genome-wide data set of 1001 Danish surgery-confirmed samples (cases diagnosed 1987-2008) and 2371 disease-free controls. In stage 2, the 5 most significantly associated loci were tested in independent case-control sample sets from Denmark (cases diagnosed 1983-2010), Sweden (cases diagnosed 1958-2011), and the United States (cases diagnosed 1998-2005), with a total of 1663 cases and 2315 controls. MAIN OUTCOMES AND MEASURES: Association of genetic variation with the presence of infantile hypertrophic pyloric stenosis. RESULTS: We found a new genome-wide significant locus for IHPS at chromosome 11q23.3. The single-nucleotide polymorphism (SNP) with the lowest P value at the locus, rs12721025 (odds ratio [OR], 1.59; 95% CI, 1.38-1.83; P = 1.9 × 10(-10)), is located 301 bases downstream of the apolipoprotein A-I (APOA1) gene and is correlated (r2 between 0.46 and 0.80) with SNPs previously found to be associated with levels of circulating cholesterol. For these SNPs, the cholesterol-lowering allele consistently was associated with increased risk of IHPS. CONCLUSIONS AND RELEVANCE: This study identified a new genome-wide significant locus for IHPS. Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk, which warrants further investigation.

Genome-wide linkage analysis in families with infantile hypertrophic pyloric stenosis indicates novel susceptibility loci.

Infantile hypertrophic pyloric stenosis (IHPS) is a common cause of upper gastrointestinal obstruction during infancy. A multifactorial background of the disease is well established. Multiple susceptibility loci including the neuronal nitric oxide synthase (NOS1) gene have previously been linked to IHPS, but contradictory results of linkage studies in different materials indicate genetic heterogeneity. To identify IHPS susceptibility loci, we conducted a genome-wide linkage analysis in 37 Swedish families. In regions where the Swedish material showed most evidence in favor of linkage, 31 additional British IHPS families were analyzed. Evidence in favor of significant linkage was observed in the Swedish material to two loci on chromosome 2q24 (non-parametric linkage (NPL) =3.77) and 7p21 (NPL=4.55). In addition, evidence of suggestive linkage was found to two loci on chromosome 6p21 (NPL=2.97) and 12q24 (NPL=2.63). Extending the material with British samples did not enhance the level of significance. Regions with linkage harbor interesting candidate genes, such as glucagon-like peptide-2 (GLP-2 encoded by the glucagon gene GCG), NOS1, motilin (MLN) and neuropeptide Y (NPY). The coding exons for GLP-2, and NPY were screened for mutations with negative results. In conclusion, we could confirm suggestive linkage to the region harboring the NOS1 gene and detected additional novel susceptibility loci for IHPS.

Controlled long term outcome of pyloromyotomy for pyloric stenosis: No long-term adverse effect.

PURPOSE: Pyloromyotomy for pyloric stenosis is one of the more common surgical procedures performed on infants. The long-term effects of the procedure are however unclear. The purpose of this study was to study the effects into adult life, compare them with controls and to see if there is a need for structured follow up of patients. METHODS: Of the 101 patients operated for pyloric stenosis between 1972 and 1974 at our tertiary referral center 91 could be traced. They were all invited to participate in the study and were sent validated questionnaires (PAGI-SYM, GIQLI) as well as a study-specific questionnaire examining the use of antacid drugs, incidence of gastroscopy and abdominal surgery. Sixty patients responded (66%, mean age 45 years, 46 male) and were included. Thereafter, 600 age and sex-matched controls were sent the same questionnaires. 132 responded (22%, 90 male) and were includes as controls. RESULTS: No significant differences could be found in any of the examined parameters when looking at the whole material or the male patients. Female patients had higher PAGI-SYM-scores for post prandial fullness (mean 1.11 vs 0.43, P = 0.035) and heartburn (mean 0.59 vs 0.14, P = 0.043) when compared to controls. CONCLUSIONS: The present study shows that most patients operated for pyloric stenosis during infancy experience no negative effects into adulthood. The finding in the female patient group is interesting but is unlikely to have any clinical implications. The results from this study strongly implicate that there is no need for follow up of patients into adulthood. LEVEL OF EVIDENCE: Level III.

Axonal degeneration and amyloid pathology predict cognitive decline beyond cortical atrophy.

BACKGROUND: Cortical atrophy is associated with cognitive decline, but the association is not perfect. We aimed to identify factors explaining the discrepancy between the degree of cortical atrophy and cognitive decline in cognitively unimpaired elderly. METHODS: The discrepancy between atrophy and cognitive decline was measured using the residuals from a linear regression analysis between change in whole brain cortical thickness over time and change in a cognitive composite measure over time in 395 cognitively unimpaired participants from the Swedish BioFINDER study. We tested for bivariate associations of this residual measure with demographic, imaging, and fluid biomarker variables using Pearson correlations and independent-samples t-tests, and for multivariate associations using linear regression models. Mediation analyses were performed to explore possible paths between the included variables. RESULTS: In bivariate analyses, older age (r = -0.11, p = 0.029), male sex (t = -3.00, p = 0.003), larger intracranial volume (r = -0.17, p < 0.001), carrying an APOEe4 allele (t = -2.71, p = 0.007), larger white matter lesion volume (r = -0.16, p = 0.002), lower cerebrospinal fluid (CSF) ß-amyloid (Aß) 42/40 ratio (t = -4.05, p < 0.001), and higher CSF levels of phosphorylated tau (p-tau) 181 (r = -0.22, p < 0.001), glial fibrillary acidic protein (GFAP; r = -0.15, p = 0.003), and neurofilament light (NfL; r = -0.34, p < 0.001) were negatively associated with the residual measure, i.e., associated with worse than expected cognitive trajectory given the level of atrophy. In a multivariate analysis, only lower CSF Aß42/40 ratio and higher CSF NfL levels explained cognition beyond brain atrophy. Mediation analyses showed that associations between the residual measure and APOEe4 allele, CSF Aß42/40 ratio, and CSF GFAP and p-tau181 levels were mediated by levels of CSF NfL, as were the associations with the residual measure for age, sex, and WML volume. CONCLUSIONS: Our results suggest that axonal degeneration and amyloid pathology independently affect the rate of cognitive decline beyond the degree of cortical atrophy. Furthermore, axonal degeneration mediated the negative effects of old age, male sex, and white matter lesions, and in part also amyloid and tau pathology, on cognition over time when accounting for cortical atrophy.

Development of Apathy, Anxiety, and Depression in Cognitively Unimpaired Older Adults: Effects of Alzheimer's Disease Pathology and Cognitive Decline.

BACKGROUND: The impact of Alzheimer's disease (AD) pathology and cognitive deficits on longitudinal neuropsychiatric symptoms is unclear, especially in early disease stages. METHODS: Cognitively unimpaired older adults (N = 356) enrolled in the prospective Swedish BioFINDER study were examined. Neuropsychiatric assessments encompassed the Apathy Evaluation Scale and the Hospital Anxiety and Depression Scale, performed biennially (together with tests of global cognition) for up to 8 years. Biomarkers were measured in cerebrospinal fluid or plasma at baseline. Magnetic resonance imaging quantified white matter lesions. We used linear mixed-effect models to test associations between baseline AD biomarkers (for amyloid-ß [Aß], tau, and neurodegeneration) and white matter lesions with longitudinal neuropsychiatric symptoms (apathy, anxiety, and depressive symptoms). We also tested associations between changes in cognition and changes in neuropsychiatric symptoms. Finally, we tested if change in cognition mediated the effects of different brain pathologies on neuropsychiatric symptoms. RESULTS: Aß pathology at baseline was associated with increasing levels of apathy (ß = -0.284, p = .005) and anxiety (ß = -0.060, p = .011) longitudinally. More rapid decline of cognition over time was related to increasing levels of apathy. The effects of baseline Aß pathology on longitudinal apathy were partly mediated by changes in cognitive performance (proportion mediated 23%). CONCLUSIONS: Aß pathology may drive the development of both apathy and anxiety in very early stages of AD, largely independent of cognitive change. The effect of Aß on apathy is only partially conveyed by worse cognition. Together, these findings highlight certain neuropsychiatric symptoms as early manifestations of AD.