Biomarker profiling beyond amyloid and tau: cerebrospinal fluid markers, hippocampal atrophy, and memory change in cognitively unimpaired older adults

Brain changes occurring in aging can be indexed by biomarkers. We used cluster analysis to identify subgroups of cognitively unimpaired individuals (n ¼ 99, 64e93 years) with different profiles of the cerebrospinal fluid biomarkers beta amyloid 1e42 (Ab42), phosphorylated tau (P-tau), total tau, chitinase-3-like protein 1 (YKL-40), fatty acid binding protein 3 (FABP3), and neurofilament light (NFL). Hippocampal volume and memory were assessed across multiple follow-up examinations covering up to 6.8 years. Clustering revealed one group (39%) with more pathological concentrations of all biomarkers, which could further be divided into one group (20%) characterized by tauopathy and high FABP3 and one (19%) by brain b-amyloidosis, high NFL, and slightly higher YKL-40. The clustering approach clearly outperformed classification based on Ab42 and P-tau alone in prediction of memory decline, with the individuals with most tauopathy and FABP3 showing more memory decline, but not more hippocampal volume change. The results demonstrate that older adults can be classified based on biomarkers beyond amyloid and tau, with improved prediction of memory decline

Clustering of longitudinal viral loads in the Western Cape

Introduction: Routine viral load (VL) monitoring is important for assessing the effectiveness of ART in South Africa. There is little information however, on how the longitudinal VL patterns change for subgroups of persons living with HIV (PLHIV) who have experienced at least one elevated VL. We investigated the possible longitudinal VL patterns that may exist among this unique population. Methods: This mini-dissertation offers three components; a research protocol (Section A), a literature review (Section B) and a journal ready manuscript (Section C). We examined HIV VL data for the Western Cape from 2008 to 2018, taken from the National Health Laboratory Services (NHLS). Using< 1000 copies/mL as a threshold for viral suppression, we identified 109092 individuals who had at least one instance of an elevated VL. A nonparametric (KML-Shape) and a model-based (LCMM) clustering technique were used to identify latent subgroups of longitudinal VL trajectories among these individuals. Results: Both the KML-Shape and LCMM clustering techniques identified five latent viral load trajectory subgroups. KML-Shape found majority of individuals' trajectories belonged to clusters that had a decreasing longitudinal VL trend (76.6% of individuals), while LCMM found a smaller proportion of individuals' trajectories belonged to clusters that had a decreasing longitudinal trend (52.5% of individuals). Most of the trajectory subgroups identified had long periods of low-level viremia. Conclusion: Although majority of individuals belonged to clusters that had downward trends, further research is needed to better understand factors contributing to membership of clusters that did not have a downward longitudinal trend. Understanding these factors may help in the development of targeted HIV prevention programs for these individuals

Neurological soft signs in adolescents are associated with brain structure and postural control

Neurological soft signs (NSS) are minor deviations from the norm in sensory and motor performance. NSS exist in the general population but are more frequently found in cohorts with neurodevelopmental disorders. NSS are considered a diffuse and unspecific marker of altered neurodevelopment but receive increasing attention since the presence of NSS in children has been found to be predictive of psychiatric disorders in late adolescence. To date, only little is known about potential neurodevelopmental alterations that may underlay the presence of NSS. The prevalence of NSS has been shown to decrease during adolescence as part of continued neural development and brain re-wiring processes. Therefore, adolescence has been proposed as an important phase for the manifestation or outgrowing of NSS. The underlying mechanisms that may underly this process, however, are largely unknown. As NSS are subtle signs and commonly identified by subjective observer-based neurological examinations, quantitative tools may help to objectively investigate functional and structural correlates associated with NSS. For the work included in this dissertation, healthy adolescent athletes from three European countries were investigated. All participants underwent a neurological examination, resulting in a categorization of participants into groups with and without NSS (NSS+/NSS-). A total NSS score was calculated to provide a continuous measure spanning the whole spectrum of NSS. Two quantitative tools were used to investigate functional and structural correlates of NSS in healthy adolescents: Study I) Instrumented force plate measures to investigate postural control (Bonke et al., 2023), and Study II) Structural magnetic resonance imaging to investigate brain morphology and white matter microstructure (Bonke et al., 2022). Study I aimed to investigate the incremental value of instrumented force plate measures in addition to observer-based neurological examinations. Such associations have not been assessed before but are important for capturing subtle alterations in postural control. This will help to acquire a more comprehensive assessment of motor development. We found no statistically significant differences in postural control between NSS+ and NSS- group. However, participants performing non-optimal in the diadochokinesis sub-test measuring pronation/supination of forearms showed significantly reduced postural control in the medial-lateral (ML) direction. Moreover, the total NSS score correlated significantly with postural control performance in the ML direction. Findings from this study reveal that adolescents with NSS, and in particular adolescents that perform non-optimal in pronation/supination movements of the forearms also perform worse in ML postural control assessed by force plate assessments. As pronation/supination movements of forearms and ML postural control continue to mature until adolescence, it can be assumed that these functions are related and may indicate altered motor development. Study II aimed to identify and characterize NSS-related brain structure alterations using structural magnetic resonance imaging. NSS-related brain structure alterations have not yet been investigated in healthy adolescents. However, this investigation is of high relevance to better understand potential alterations in adolescent brain-rewiring processes related to NSS. Using T1-weighted imaging, we found significantly higher gyrification in the left superior frontal and parietal lobe in the group of adolescents with NSS, likely reflecting alterations in synaptic pruning. We did not find differences in cortical volume or thickness. Using diffusion tensor imaging, we found lower tissue fractional anisotropy (FAt) and higher tissue radial diffusivity (RDt) in widespread white matter clusters in the group of adolescents with NSS, likely indicating alterations in myelination. Findings from this study reveal that NSS in healthy adolescents are associated with brain structure alterations that can be objectively quantified using magnetic resonance imaging. As of now, the relevance of NSS-related brain structure alterations in otherwise healthy adolescents is not fully understood. Future studies should assess whether these alterations may explain the described association between NSS and psychiatric disorders. In summary, the work presented in this doctoral dissertation uses two different quantitative measures to objectively investigate functional and structural differences between adolescents with and without NSS. Insights derived from this work show the beneficial use of instrumented tools to complement neurological examinations for a better understanding of functional and structural correlates of NSS. This work will help to generate a more complete picture of NSS-related developmental alterations and potentially related psychiatric vulnerabilities. Future research should make use of larger and more representative datasets to replicate, as well as extend our findings. Specific attention should be drawn on the investigation of factors that contribute to the development of NSS, longitudinal studies that allow to capture NSS-related alterations in developmental trajectories, as well as on investigating the underlying neural mechanisms of NSS

Parsing heterogeneity within dementia with Lewy bodies using clustering of biological, clinical, and demographic data

Dementia with Lewy bodies (DLB) includes various core clinical features that result in different phenotypes. In addition, Alzheimer's disease (AD) and cerebrovascular pathologies are common in DLB. All this increases the heterogeneity within DLB and hampers clinical diagnosis. We addressed this heterogeneity by investigating subgroups of patients with similar biological, clinical, and demographic features. We studied 107 extensively phenotyped DLB patients from the European DLB consortium. Factorial analysis of mixed data (FAMD) was used to identify dimensions in the data, based on sex, age, years of education, disease duration, Mini-Mental State Examination (MMSE), cerebrospinal fluid (CSF) levels of AD biomarkers, core features of DLB, and regional brain atrophy. Subsequently, hierarchical clustering analysis was used to subgroup individuals based on the FAMD dimensions. We identified 3 dimensions using FAMD that explained 38% of the variance. Subsequent hierarchical clustering identified 4 clusters. Cluster 1 was characterized by amyloid-β and cerebrovascular pathologies, medial temporal atrophy, and cognitive fluctuations. Cluster 2 had posterior atrophy and showed the lowest frequency of visual hallucinations and cognitive fluctuations and the worst cognitive performance. Cluster 3 had the highest frequency of tau pathology, showed posterior atrophy, and had a low frequency of parkinsonism. Cluster 4 had virtually normal AD biomarkers, the least regional brain atrophy and cerebrovascular pathology, and the highest MMSE scores. This study demonstrates that there are subgroups of DLB patients with different biological, clinical, and demographic characteristics. These findings may have implications in the diagnosis and prognosis of DLB, as well as in the treatment response in clinical trials. The online version contains supplementary material available at 10.1186/s13195-021-00946-w

Neuropathic pain after thoracotomy: tracking signs and symptoms before and at monthly intervals following surgery

Background: Because the development of neuropathic symptoms contributes to pain severity and chronification after surgery, their early prediction is important to allow targeted treatment. Objectives: We longitudinally investigated trajectories of signs and symptoms in patients undergoing thoracotomy and assessed whether and at which time they were related to the development of neuropathic pain symptoms six months after surgery. Methods: Presurgical and six, monthly postsurgical assessments included questionnaires for mental and physical well-being (e.g. depression/anxiety, pain catastrophizing, sleep quality, neuropathic pain symptoms), and quantitative sensory testing (QST). Results: QST trajectories indicated nerve impairment of the surgery site with predominant loss of function. Signs of recovery towards the end of the assessment period were observed for some tests. Unsupervised cluster analysis with NPSI scores six months after surgery as clustering variable identified one group with no/low levels of neuropathic symptoms and one with moderate levels. The two groups differed w.r.t. several signs and symptoms already at early time points. Notably, neuropathic pain anywhere in the body differed already preoperatively and sleep impairment differentiated the two groups at all time points. Regression analysis revealed three factors that seemed particularly suited to predicted six months NPSI scores, namely preoperative neuropathic pain symptoms, with contributions from sleep impairment one month after surgery and the presence of dynamic mechanical allodynia three months after surgery. Conclusions: Clinical routine should focus on the individual’s physiological state, including pre-existing neuropathic pain and sleep quality to identify patients early who might be at risk to develop chronic post-surgical neuropathic pain