Russell J. Chander

Association between white matter hyperintensity and medial temporal atrophy at various stages of Alzheimer's disease

Whilst there is evidence implicating small vessel cerebrovascular disease in the pathogenesis of Alzheimers disease (AD), its specific contribution to the pathophysiology of AD remains unclear. The burden of small vessel cerebrovascular disease visualized as white matter hyperintensity (WMH) and its association with medial temporal atrophy (MTA) at different stages of AD was studied.

Influence of depression in mild Parkinson's disease on longitudinal motor and cognitive function

BACKGROUND Studies have suggested a relationship between non-motor symptoms with motor fluctuations in patients with Parkinsons disease (PD). We studied the influence of depression on longitudinal motor and cognitive function among mild PD patients. METHODS A 1.5 years longitudinal study of 102 patients with mild idiopathic PD. Patients were assessed with a standardized clinical assessment battery including motor and non-motor scales. Patients also underwent serial neurocognitive testing that assessed global cognition, memory, attention, language, visuospatial and executive function. RESULTS 81 patients with mean age of 64.9(SD = 7.9) years and mean Hoehn & Yahr of 1.9(SD = 0.4) completed baseline and follow-up visits. 22 patients had clinically significant depression at baseline with mean Geriatric Depression Scale of 6.9(SD = 2.4). These patients presented with concomitant apathy and anxiety and were more likely to be females with longer duration of PD. At baseline, patients with depression had poorer performance on global cognition and all cognitive domains although not significantly different from patients without depression. At follow-up, there was no statistically significant difference on cognitive performance between those with and without baseline depression. Patients with baseline depression demonstrated worsening of motor function after 18 months (UPDRS Motor Score Change: +5.0[7.0]vs.+0.2[7.3]; p = 0.015). On multivariate analysis Baseline Motor Score (B = -0.229,CI = -0.445 to-0.013,p = 0.038), Baseline GDS (B = 0.622,CI = 0.078 to 1.166,p = 0.026) and PD duration (B = 0.520,CI = 0.105 to 0.935,p = 0.015) independently predicted increase in UPDRS Motor Score. CONCLUSIONS The findings suggest a relationship between early depression with motor worsening and cognition decline in PD patients. Further biomarker-supported studies investigating the role of depression on motor and cognitive function are needed.

Cerebral white matter disease is independently associated with BPSD in Alzheimer's disease.

OBJECTIVES To study the association between cerebral white matter disease and burden of behavioral and psychological symptoms (BPSD) among patients with moderate to severe AD. METHODS Patients with moderate to severe AD having undergone MRI brain, cognitive and behavioral evaluations were studied. BPSD was diagnosed based on established clinical guidelines. White matter hyperintensity (WMH) and medial temporal lobe atrophy (MTA) were quantified by a blinded rater. RESULTS 122 AD patients were studied. Age [76.84 vs. 72.70, p = 0.014] and MMSE [11.69 vs. 15.16, p < 0.001] was significantly higher in patients with BPSD. BPSD patients demonstrated higher periventricular [5.44 vs. 4.21, p < 0.001], deep subcortical [5.07 vs. 3.43, p < 0.001], and total WMH [10.51 vs. 7.65, p < 0.001] compared to non-BPSD patients. Higher proportion of BPSD patients had WMH in the highest tertile of severity (82.22% vs. 45.45%, p < 0.001). After correcting for age, baseline cognition and degree of MTA, total WMH remained significantly associated with a diagnosis of BPSD [odds ratio: 1.45 (1.14-1.85; p = 0.002)]. With severe WMH, the association is significantly increased [odds ratio: 4.3 (1.3-12.5); p = 0.016]. CONCLUSION WMH is independently associated with BPSD in moderate to severe AD. Optimizing vascular risk factors may be a strategy to reduce the severity of BPSD in AD.

Associations of hippocampal subfields in the progression of cognitive decline related to Parkinson's disease

Objective Hippocampal atrophy has been associated with mild cognitive impairment (MCI) in Parkinsons disease (PD). However, literature on how hippocampal atrophy affects the pathophysiology of cognitive impairment in PD has been limited. Previous studies assessed the hippocampus as an entire entity instead of their individual subregions. We studied the progression of cognitive status in PD subjects over 18 in relation to hippocampal subfields atrophy. Methods 65 PD subjects were included. Using the MDS task force criteria, PD subjects were classified as either having no cognitive impairment (PD-NCI) or PD-MCI. We extended the study by investigating the hippocampal subfields atrophy patterns in those who converted from PD-NCI to PD-MCI (PD-converters) compared to those who remained cognitively stable (PD-stable) over 18 months. Freesurfer 6.0 was used to perform the automated segmentation of the hippocampus into thirteen subregions. Results PD-MCI showed lower baseline volumes in the left fimbria, right CA1, and right HATA; and lower global cognition scores compared to PD-NCI. Baseline right CA1 was also correlated with baseline attention. Over 18 months, decline in volumes of CA2–3 and episodic memory were also seen in PD-converters compared to PD-stable. Baseline volumes of GC-DG, right CA4, left parasubiculum, and left HATA were predictive of the conversion from PD-NCI to PD-MCI. Conclusion The findings from this study add to the anatomical knowledge of hippocampal subregions in PD, allowing us to understand the unique functional contribution of each subfield. Structural changes in the hippocampus subfields could be early biomarkers to detect cognitive impairment in PD.

Cognitive Impairment after Mild Stroke: Development and Validation of the SIGNAL2 Risk Score.

BACKGROUND Post stroke cognitive impairment (PSCI), an important complication of strokes, has numerous risk factors. A scale adequately classifying risk of cognitive impairment 3-6 months after mild stroke will be useful for clinicians. OBJECTIVE To develop a risk score based on clinical and neuroimaging variables that will be useful in identifying mild ischemic stroke patients at high risk for PSCI. METHODS The risk score development cohort comprised of a retrospective dataset of 209 mild stroke patients with MRI confirmed infarcts, without pre-stroke cognitive impairment, and evaluated within 6 months post-stroke for PSCI. Logistic regression identified factors predictive of PSCI and a risk score was developed based on regression coefficients. The risk score was checked for stability using 10-fold cross-validation and validated in an independent prospective cohort of 185 ischemic mild stroke patients. RESULTS Within 6 months post-stroke, 37.32% developed PSCI in the retrospective dataset. A 15-point risk score based on age, education, acute cortical infarcts, white matter hyperintensity, chronic lacunes, global cortical atrophy, and intracranial large vessel stenosis was highly predictive of PSCI with an AUC of 0.829. 10.11% with low scores, 52.69% with moderate scores, and 74.07% with high scores developed PSCI. In the prospective validation cohort, the model had an AUC of 0.776, and exhibited similar accuracy and stability statistics at both 6 and 12 months. CONCLUSION The seven item risk score adequately identified mild stroke patients who are at an increased risk of developing PSCI.

Higher Peripheral TREM2 mRNA Levels Relate to Cognitive Deficits and Hippocampal Atrophy in Alzheimer’s Disease and Amnestic Mild Cognitive Impairment

BACKGROUND Variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased Alzheimers disease (AD) risk. Recent studies have reported inconsistent peripheral TREM2 mRNA expression levels and relationship with cognitive scores in AD and mild cognitive impairment (MCI). Additionally, no study has examined the association of peripheral TREM2 levels with neuroimaging measures in AD and MCI. OBJECTIVE To determine peripheral TREM2 mRNA levels in AD, amnestic MCI (aMCI) and healthy controls, and the association with cognitive performance and brain structural changes. METHODS We measured peripheral TREM2 mRNA levels in 80 AD, 30 aMCI, and 86 healthy controls using real time polymerase chain reaction. TREM2 levels were correlated with various cognitive performance and brain volumes, correcting for APOE4 status. RESULTS TREM2 mRNA levels were significantly higher in AD compared to controls and aMCI. Levels did not differ between aMCI and controls. Corrected for APOE4, higher TREM2 levels correlated with lower Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA) and episodic memory scores, and lower total grey matter and right hippocampal volumes. Whole-brain voxel-based morphometry analysis found negative association between TREM2 mRNA levels and grey matter volumes in temporal, parietal and frontal regions. AD subjects with MoCA scores ≤20 had higher TREM2 levels correlating with smaller total grey matter, left hippocampal and right hippocampal volumes. CONCLUSION Peripheral TREM2 mRNA levels are higher in AD and are associated with AD-related cognitive deficits and hippocampal atrophy. Our findings suggest that TREM2 may be a potential non-invasive peripheral biomarker for AD diagnosis.

Progression of subcortical atrophy in mild Parkinson's disease and its impact on cognition

Mild cognitive impairment (MCI) is associated with pronounced grey matter atrophy in various brain regions. However, the association between atrophy patterns and progression from no cognitive impairment (NCI) to Parkinsons disease (PD)‐MCI is not clearly known. We investigated the pattern and progression of atrophy in subcortical structures and its impact on cognition in patients with mild PD.

Baseline predictors of worsening apathy in Parkinson's disease: A prospective longitudinal study

INTRODUCTION Apathy is one of the most common behavioural disorders in Parkinsons disease (PD) and contributes significantly to a reduced quality of life in PD patients. METHODS We conducted a prospective longitudinal study of 89 mild PD patients over 18 months, measuring apathy symptoms at 6-monthly intervals using the Starkstein Apathy Scale, as well as measures of motor and non-motor symptoms, cognitive function, and functional disability at baseline. Mixed-effects models were used to characterise the individual trajectories of apathy symptom severity, and linear regression with stepwise elimination procedure was used to select significant baseline predictors. RESULTS Clinically significant levels of apathy were present in 42.7% of our sample at baseline, with symptom severity remaining relatively stable on average over the course of 18 months. Male gender, lower educational attainment, higher depression symptom severity, more severe functional disability, and the presence of dyskinesias at study entry predicted increasing apathy over the subsequent 18 months. CONCLUSIONS Patients with these factors are at risk for progression of apathy, which may be prevented by treating depression and functional disability. Further studies are needed to address both the specific neurobiological pathways and psychosocial factors underpinning apathy in PD.

Influence of diabetes mellitus on longitudinal atrophy and cognition in Parkinson's disease☆

OBJECTIVE To investigate the impact of diabetes mellitus (DM) on cognitive performance and longitudinal volumetric brain changes in a cohort of cognitively normal mild PD patients. METHODS Prospective study of idiopathic PD subjects who underwent baseline and follow-up MRI imaging and neuropsychological assessments at 6month intervals for 3years. Subjects were classified based on the presence (PD-DM) or absence of DM (PD-No DM) at baseline. Volumetric analysis was performed using FreeSurfer 5.3 image analysis suite. Brain volume and cognition were compared and analyzed cross-sectionally and longitudinally. Analyses were corrected for intracranial volume. RESULTS There were 65 PD-no DM and 12 PD-DM subjects at baseline with comparable global cognition at baseline. PD-DM subjects had lower cortical grey matter (GM), amygdala, frontal white matter and temporal white matter volumes and higher total white matter hyperintensity and periventricular hyperintensities. After mean follow-up of 29.08months, there were 51 PD-no DM and 11 PD-DM subjects. PD-DM subjects demonstrated greater decline in MMSE and MOCA scores compared to PD-No DM. PD-DM subjects had a higher rate of atrophy in the cortical WM, particularly in the parietal and occipital white matter. CONCLUSION Mild PD patients with DM have lower GM and WM volumes at baseline and higher WMH volumes, despite comparable cognitive scores. Longitudinally, DM in PD results in greater rate of cognitive decline, associated with higher WM atrophy.

Depressive symptoms influence global cognitive impairment indirectly by reducing memory and executive function in patients with mild cognitive impairment

Background Depressive symptoms negatively influence global cognition in the elderly; however, the mechanism of this effect remains unclear. Objective To investigate whether depressive symptoms influence global cognitive function in patients with mild cognitive impairment (MCI) and mild Alzheimers disease (AD) by impeding specific neuropsychological abilities and under what conditions this effect might occur. Method A sample of 259 participants (104 cognitively normal elderly controls, 66 patients with MCI and 89 patients with mild AD) underwent a comprehensive neuropsychological assessment. Global cognitive impairment was indexed by the composite of Mini-Mental State Examination and Montreal Cognitive Assessment scores and severity of depressive symptoms was measured with the Geriatric Depression Scale (GDS). Results Among patients with MCI, greater severity of depressive symptoms was associated with greater global cognitive impairment, with a moderate effect size. A mediation analysis revealed that patients with MCI experiencing depressive symptoms may exhibit global cognitive impairment because their depressive symptoms were reducing their capacity for working memory, episodic memory and non-speed-based executive functions. A moderation analysis indicated that this effect was consistent across age, gender, years of education and APOE-e4 status for working memory and episodic memory, and was observed in patients with MCI older than 65 years for executive functions. In cognitively normal elderly adults and patients with AD, depressive symptoms were not associated with global cognitive impairment. Conclusions Depressive symptoms influence global cognitive function in patients with MCI indirectly by reducing mental space, mental flexibility and their capacity for consolidating and retrieving memories. These findings may guide clinicians to better diagnose and manage cognitive impairment in the context of concomitant depressive symptoms.