Browsing by Author "Combrinck, Marc"

Now showing 1 - 10 of 10
  • Thumbnail Image
    Item
    Open Access
    Dementia Subtypes, Cognitive Decline and Survival Among Older Adults Attending a Memory Clinic in Cape Town, South Africa: A Retrospective Study
    (2023) Ssonko, Michael; Combrinck, Marc; Kalula, Sebastiana; Naganathan, Vasi
    Background: There are no published longitudinal studies from Africa of people with dementia seen in memory clinics. The aim of this study was to determine the proportions of the different dementia subtypes, rates of cognitive decline, and predictors of survival in patients diagnosed with dementia and seen in a memory clinic. Methods: Data were collected retrospectively from clinic records of patients aged ≥60 seen in the memory clinic at Groote Schuur Hospital, Cape Town, South Africa over a 10-year period. Diagnostic and Statistical Manual of Mental Disorders (DSM–5) criteria were used to identify patients with Major Neurocognitive Disorders (dementia). Additional diagnostic criteria were used to determine the specific subtypes of dementia. Linear regression analysis was used to determine crude rates of cognitive decline, expressed as mini-mental state examination (MMSE) points lost per year. Changes in MMSE scores were derived using mixed effects modelling to curvilinear models of cognitive change, with time as the dependent variable. Multivariable cox survival analysis was used to determine factors at baseline that predicted mortality. Results: Of the 165 patients who met inclusion criteria, 117(70.9%) had Major Neurocognitive Disorder due to Alzheimer's disease (AD), 24(14.6%) Vascular Neurocognitive Disorder (VND), 6(3.6%) Dementia with Lewy Bodies (DLB), 5(3%) Parkinson disease-associated dementia (PDD), 3(1.8%) fronto-temporal dementia, 4(2.4%) mixed dementia and 6(3.6%) other types of dementia. The average annual decline in MMSE points was 2.2(DLB/PDD), 2.1(AD) and 1.3(VND). Cognitive scores at baseline were significantly lower in patients with 8 compared to 13 years of education and in those with VND compared with AD. Factors associated with shorter survival included age at onset greater than 65 (HR=1.82, 95% C.I. 1.11, 2.99, p=0.017), lower baseline MMSE (HR=1.05, 95% C.I. 1.01, 1.10, p=0.029) , Charlson's comorbidity scores of 3 to 4 (HR=1.88, 95% C.I. 1.14, 3.10, p=0.014), scores of 5 or more (HR=1.97, 95% C.I. 1.16, 3.34, p=0.012) and DLB/PDD (HR=3.07, 95% C.I. 1.50, 6.29, p=0.002). Being female (HR=0.59, 95% C.I.0.36, 0.95, p=0.029) was associated with longer survival. Conclusions: Knowledge of dementia subtypes and survival outcomes will help inform decisions about patient selection for potential future therapies and for planning dementia services in resource-poor settings.
  • Thumbnail Image
    Item
    Open Access
    Influence of Age and Cognitive Reserve on Cognitive Function in HIV-infected South African Adults
    (2021) Wagner, Marcelle; Thomas, Kevin; Combrinck, Marc; Dreyer, Anna
    Background. HIV remains a significant global public health concern. South Africa is one of the hardest-hit countries, housing more than 7 million people living with HIV (PLWH), a figure that represents more than 12% of the global infected population. Globally, HIV-associated cognitive impairment is present in almost 45% of PLWH, with 72% of that total burden found in Sub-Saharan Africa (Wang et al., 2020). The severity and trajectory of that impairment is, however, influenced by numerous risk and protective factors. This study aimed to investigate the strength of influence that two of these factors (cognitive reserve and age) have in a sample of HIV-positive South African adults. Method. Participants were 32 HIV-infected and virally suppressed adults (27 women; Mage = 41.13±9.34). They were administered the Cognitive Reserve Index Questionnaire (CRIq) and a comprehensive neuropsychological battery that assessed performance on tests of motor function, attention and working memory, information processing speed, language, memory, and executive function. They also provided 3T magnetic resonance imaging data. Bivariate correlations, independent-sample t-tests, and hierarchical regression models tested the prediction that age and cognitive reserve (as indexed by CRIq scores, fractional anisotropy, white and gray matter volume, education level, and IQ score), both independently and in interaction, will have significant effects on cognitive test performance (i.e., that increasing age and lower levels of cognitive reserve will be independently associated with poorer performance, and that older adults with lower levels of cognitive reserve will display the worst performance). Results. Regarding the association of age with global cognitive function (average performance across all tests), analyses detected a moderate negative correlation (r = -.425, p = .015.), a significant between-group difference (participants ≥ 45 years worse than those < 45 years, p = .012), and a significant proportion of variance accounted for (R 2 = .18, p = .016). There were no significant main effects of cognitive reserve, and no significant age x cognitive reserve interaction effect, on cognitive test performance. Conclusion. The current analyses confirmed the influence of age on cognition in PLWH but did not provide support for the same influence of cognitive reserve. Although neuroscience research attaches increasing importance to the construct of cognitive reserve, the lack of a universally-applied definition (and hence a standard measure) of the construct hampers investigations such as this and makes cross-study comparisons difficult. From a policy-making perspective, the contrasting findings regarding age and cognitive reserve is crucial because it is imperative that intervention efforts focus only on those modifiable factors that significantly impact cognitive function, especially in countries such as South Africa that are characterized by high HIV disease burden and limited clinical and infrastructural resources.
  • Thumbnail Image
    Item
    Open Access
    Intraindividual variability and micro-structural white matter changes in Alzheimer’s disease
    (2019) Engelbrecht, Kara; Thomas, Kevin; Combrinck, Marc
    The costs associated with diagnosis, treatment and care of Alzheimer’s disease (AD) patients places a significant financial and social strain on healthcare systems, patients and caregivers, especially in low-and middle-income countries (LAMICs). Traditional methods for diagnosing AD are time consuming and expensive, and treatments are often only effective in the early stages. These factors call for the development of alternative diagnostic methods. One such method that has gained attention due to its neural overlaps with AD is the measurement of intraindividual variability (IIV; the within-person variation in performance over multiple trials of a single task). IIV researchers have highlighted the role of white matter in increased IIV, and micro-structural white matter changes have been implicated in the early stages of AD. The current study examined the relationship between IIV on simple and choice reaction time tasks and micro-structural white matter changes, as indexed by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA) and radial diffusivity (DR) in a sample of 16 AD patients and 20 healthy older adults. Across the entire sample, increased IIV on both the simple and choice reaction time tasks was significantly correlated with lower FA in an area of the right hemisphere inferior longitudinal fasciculus (R-ILF). Increased IIV on the choice reaction time task was significantly correlated with lower DA in the same area. Finally, IIV on the choice reaction time task contributed significantly and uniquely to variance in DA in the same area. These results suggest that further longitudinal studies into the diagnostic utility of IIV for neurological disorders might be of value for clinicians, patients and caregivers.
  • Thumbnail Image
    Item
    Open Access
    Peripheral reductive capacity is associated with cognitive performance and survival in Alzheimer's disease
    (BioMed Central Ltd, 2006) Minghetti, Luisa; Greco, Anita; Puopolo, Maria; Combrinck, Marc; Warden, Donald; Smith, A David
    BACKGROUND:Oxidative stress is believed to be an early event and a key factor in Alzheimer's disease (AD) pathogenesis and progression. In spite of an intensive search for surrogate markers to monitor changes related to oxidative stress in the brain, there is as yet no consensus about which markers to use in clinical studies. The measurement of peripheral anti-oxidants is an alternative way of evaluating the involvement of oxidative stress in the course of the disease. Given the complexity of peripheral anti-oxidant defence, variations in the levels of individual anti-oxidant species may not fully reflect the overall capacity to fight oxidant conditions. We therefore chose to evaluate the total reductive capacity (herein defined as anti-oxidant capacity, AOC) in serum from control subjects and AD patients in order to study the association between peripheral anti-oxidant defence, cognitive impairment and patient survival. METHODS: We measured the levels of AOC in serum samples from 26 cognitively normal controls and 25 AD patients (12 post-mortem confirmed) who completed the Cambridge Cognitive Assessment. Cognitive decline was assessed in a subgroup of 19 patients who underwent a second cognitive assessment 2 years after the initial visit. RESULTS: Serum AOC levels were lower in AD patients than in controls and were correlated with their cognitive test scores, although AOC levels were unrelated to cognitive decline assessed two years later. On the other hand, AOC levels were predictive of the length of patients' survival, with higher levels giving longer survival. CONCLUSION: This study indicates that peripheral anti-oxidant defences are depleted in AD patients. The results suggest that serum AOC is a good index of the general health status and prognosis of patients but does not necessarily reflect the extent to which vulnerable neuronal populations are protected from oxidant processes. Further studies are required to establish whether peripheral AOC measurements may be useful in identifying asymptomatic individuals or those with early symptoms at high risk of developing significant cognitive impairment or dementia.
  • Thumbnail Image
    Item
    Open Access
    The relationship between Alzheimer's disease, inflammation, the APOE genotype and neuronal integrity
    (2013) Grace, Laurian Kerry; Combrinck, Marc; Kellaway, Lauriston
    Includes abstract. Includes bibliographical references.
  • Thumbnail Image
    Item
    Open Access
    A review of cases of motor neurone disease seen at Groote Schuur Hospital from 2005 to 2010
    (2014) Daude, Amina; Combrinck, Marc
    Motor neurone disease (MND) is a rare progressive neurodegenerative disorder in which selective degeneration of the motor neurones of the brain and spinal cord occurs. Progressive weakness of limb, bulbar and respiratory muscles eventually results in death. Most descriptive and epidemiological studies of MND have been performed in the industrialized countries of Europe and North America. We know very little about the incidence or prevalence of MND in Africa in general and South Africa in particular. However, anecdotal evidence based on observations by clinicians in the neurology and geriatric medical clinics at Groote Schuur Hospital suggest that the condition is not uncommonly seen, even in younger patients. Furthermore, many cases appear to originate from the West Coast area of the Western Cape. The proposed study aimed at describing the demographic and clinical characteristics of MND seen at Groote Schuur Hospital between 2005 and 2010. I hypothesized that disease duration, measured from age of onset of first symptoms to death, would be shorter in patients with bulbar-onset disease, in younger-onset disease, and in patients with higher CSF protein and blood creatine kinase levels at baseline. Furthermore, age of onset of the disease would be younger in familial compared with sporadic MND. I also hypothesized that smoking and certain occupational exposures might be risk factors for MND, that there would be a male preponderance of the disease, and that a disproportionate number of cases would come from the West Coast region. This was a retrospective study. I reviewed the clinical notes of cases of motor neurone disease and collected data relevant to the aims and hypotheses described above. I applied the El Escorial diagnostic criteria for MND to check the validity of the diagnoses. Mortality data were obtained through the Burden of Diseases Research Unit at the South African Medical Research Council. Forty eight patients were identified who met El Escorial criteria for the diagnosis of probable or definite MND. The median age of onset of the disease was 54 (IQR 47-63) and the mean duration of the disease from earliest symptoms to death was 2 years (IQR 1-3). These did not differ significantly between bulbar and limb-onset disease sub-types. There was a male preponderance of the disease (60%) and the majority of patients (60%) were smokers. African patients tended to have a younger age of onset. Occupations involving potential exposure to chemicals were disproportionately represented in the MND patients compared with the general population of the Western Cape. People from the West Coast region were not disproportionately represented in the patient population. Baseline CSF protein and serum creatine kinase levels were not associated with disease duration. The characteristics of MND cases seen at Groote Schuur Hospital between 2005 and 2010 are similar to those described in the world literature. Smoking and chemical exposure may be risk factors for the disease. There was no evidence of clustering of cases. This study will serve as the basis for future larger prospective studies on MND prevalence and aetiology in South Africa.
  • Thumbnail Image
    Item
    Open Access
    The role of systemic inflammation and the apolipoprotein E gene in human immunodeficiency virus-associated cognitive impairment
    (2014) van Brakel, Elana; Combrinck, Marc
    Includes abstract. Includes bibliographical references.
  • Thumbnail Image
    Item
    Open Access
    The role of von Willebrand factor and its cleaving protease, ADAMTS13, in young patients with HIV-related stroke.
    (2013) Allie, Sameera; Combrinck, Marc
    The Human Immunodeficiency Virus (HIV) is neuro-invasive and neurological complications of HIV infection occur frequently through a variety of possible mechanisms. Stroke in the setting of HIV is not uncommonly seen in young adults. High levels of von Willebrand factor (VWF), a protein with key roles in platelet adhesion and aggregation, and low levels of A Disintegrin and Metalloproteinase with a Thrombospondin type 1 motif, member 13 (ADAMTS13), the protease that cleaves ultra large VWF multimers into smaller less haemostatically active multimers, have been associated with an increased propensity for thrombosis. Stroke is a potential complication of the aberrant activity of these two proteins. HIV infection has also been associated with endothelial dysfunction, and VWF is a marker of the latter. The investigation of VWF and ADAMTS13 may therefore provide new insights into the pathogenesis of HIV-related stroke.
  • Thumbnail Image
    Item
    Open Access
    The role of the astrocytic marker S100B in HIV-associated neurocognitive disorders
    (2019) Groenewald, Engelina; Joska, John; Combrinck, Marc; Naude, Pieter
    There are as yet no ideal biomarkers of HIV-associated neurocognitive disorders. As astrocytosis is a feature of HIV encephalitis, the marker S100β may hold promise as a biomarker of HAND. We explored associations between S100β and neurocognition in individuals with HIV in Cape Town, South Africa, before and after antiretroviral therapy (ART) was initiated. The S100β levels in the cerebrospinal fluid (CSF) of forty-six participants with HIV, but not yet on antiretroviral therapy, was quantified using an enzyme-linked immunoassay (ELISA). A battery of cognitive tests was performed and the global deficit score (GDS) was calculated. In twenty of these patients, the S100β analysis and the cognitive tests were repeated approximately six months after the initiation of ART. There was no significant association between cerebrospinal fluid S100β and GDS at baseline (r= -0.070; p= 0.66) or after six months of ART (r= 0.16; p= 0.52). Cerebrospinal fluid S100β levels at baseline did not predict a change in neurocognition on ART (B(SE) = 0.001, (0.001), β=0.025, p=0.85). S100β in the cerebrospinal fluid may not adequately reflect neurocognitive impairment in individuals with HIV. Our results further demonstrate that CSF S100β levels are not affected by ART, indicating persistent neuroinflammation.
  • Thumbnail Image
    Item
    Open Access
    The role of the HIV-1 Tat protein in acute stroke: more than just a transactivator of transcription?
    (2018) McMullen, Kate Elizabeth; Bateman, Kathleen J; Combrinck, Marc; Bryer, Alan
    Background: Individuals infected with the human immunodeficiency virus (HIV) are at increased risk of developing ischaemic stroke. The reasons for this are multifactorial, but HIV-associated vasculopathy is a potentially important cause. HIVinduced chronic inflammation may initiate endothelial dysfunction or accelerate vascular injury from other disease processes. Viral proteins such as the transactivator of transcription (Tat) are emerging role-players in HIV disease pathogenesis and have a putative role in HIV-associated endothelial dysfunction. Tat has paracrine proinflammatory effects, but its role in HIV-related stroke has not yet been investigated. Aims: The primary aim of this study was to determine whether specific Tat amino acid variants are associated with ischaemic stroke and biomarkers of inflammation and endothelial dysfunction in a group of HIV-1 subtype-C-infected individuals. In order to do so, I first determined the aetiology of stroke in these participants using clinical, biochemical and neuro-imaging data. A secondary aim of the study was to identify any HIV-related and/or other traditional stroke-related risk factors that might independently or cumulatively increase stroke risk. For comparison, these putative risk factors were also determined in a group of age-matched HIV-infected non-stroke controls. Finally, I aimed to identify any HIV-related factors and/or Tat amino acid variants that might distinguish strokes due to HIV-associated vasculopathy from other mechanisms of stroke. Methods: A case-control study was performed on 58 Subtype-C HIV-infected individuals with acute ischaemic stroke and 71 HIV-1 Subtype-C-infected non-stroke controls. Clinical, demographic, laboratory and imaging data were used to determined baseline differences between groups and to distinguish different stroke aetiologies. Exon 1 of the HIV-1 Tat protein was sequenced from peripheral blood samples of stroke participants and controls and amino acid variants were identified using viral epidemiology signature pattern analysis. Regression analyses were used to examine the correlation between residues at signature positions with biomarkers of inflammation and endothelial activation. Results: Stroke and control groups were mostly young (mean age 33 years) females (62.1% & 71.8%), and of Black African ancestry. The strokes showed a higher prevalence of some traditional cardiovascular risk factors. Individuals with strokes had a higher prevalence of antiretroviral treatment interruption (25.9% vs 0.0%, p= 0.003), lower CD4 nadir (112 vs 177.5 cells/μl, p=0.008) and CD4 count (208.5 vs 322.5 cells/μl, p=0.012) than controls. Median viral loads were elevated in both strokes and controls (4.58 & 4.13 log10 copies/ml, p=0.28). The most common causes of stroke were HIV-associated vasculopathy (43.1%) and opportunistic infections (22.4%). Two amino acid variants (proline at position 21 and histidine at position 29) were associated with acute ischaemic stroke. These positions were also associated with modulation of plasma interleukin 6 and monocyte chemoattractant protein 1 levels. Threonine at position 58 distinguished strokes due to alternative mechanisms from strokes due to HIV-associated vasculopathy. Conclusions: Two Tat protein amino acid variants are associated with stroke in HIV. The precise mechanisms by which these associations occur are not known. However, they are likely to be part of a multiple-hit phenomenon in HIV stroke pathogenesis. Tatmediated inflammation with endothelial dysfunction, HIV disease severity, treatment interruption and conventional cardiovascular risk factors probably all contribute to stroke aetiology. Thus, a multi-modal approach is needed to reduce ischaemic stroke risk in HIV infection.