Distinct network topology in Alzheimer's disease and behavioral variant frontotemporal dementia.

BACKGROUND: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) cause distinct atrophy and functional disruptions within two major intrinsic brain networks, namely the default network and the salience network, respectively. It remains unclear if inter-network relationships and whole-brain network topology are also altered and underpin cognitive and social-emotional functional deficits. METHODS: In total, 111 participants (50 AD, 14 bvFTD, and 47 age- and gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Functional connectivity was derived among 144 brain regions of interest. Graph theoretical analysis was applied to characterize network integration, segregation, and module distinctiveness (degree centrality, nodal efficiency, within-module degree, and participation coefficient) in AD, bvFTD, and healthy participants. Group differences in graph theoretical measures and empirically derived network community structures, as well as the associations between these indices and cognitive performance and neuropsychiatric symptoms, were subject to general linear models, with age, gender, education, motion, and scanner type controlled. RESULTS: Our results suggested that AD had lower integration in the default and control networks, while bvFTD exhibited disrupted integration in the salience network. Interestingly, AD and bvFTD had the highest and lowest degree of integration in the thalamus, respectively. Such divergence in topological aberration was recapitulated in network segregation and module distinctiveness loss, with AD showing poorer modular structure between the default and control networks, and bvFTD having more fragmented modules in the salience network and subcortical regions. Importantly, aberrations in network topology were related to worse attention deficits and greater severity in neuropsychiatric symptoms across syndromes. CONCLUSIONS: Our findings underscore the reciprocal relationships between the default, control, and salience networks that may account for the cognitive decline and neuropsychiatric symptoms in dementia.

Age Moderates Associations of Hypertension, White Matter Hyperintensities, and Cognition.

BACKGROUND: Hypertension and white matter hyperintensities (WMH) are mutually associated risk factors for cognitive impairment. However, age may modify the associations between hypertension and WMH, and their links to cognitive impairment. OBJECTIVE: We evaluated the interaction between age and hypertension on WMH, and the age-stratified associations of hypertension and WMH with cognition. METHODS: Key measures include systolic blood pressure (SBP), WMH (modified Fazekas visual ratings of cranial MRI), and the Montreal Cognitive Assessment (MoCA). Participants (N = 488) with prodromal and mild dementia were age-stratified (≤49, 50-59, 60-69,≥70), and considered hypertensive if their SBP≥140 mmHg. The interaction between age strata and hypertension on WMH, and age-stratified associations of hypertension and WMH with cognition, were evaluated using multiple linear regression analyses. Analyses controlled for other risk factors for WMH and cognitive impairment. RESULTS: Age moderated the association between SBP and WMH. Hypertension was associated with higher WMH only in those aged 60-69, and WMH trends across age bands differed between those with and without hypertension. Finally, WMH and SBP≥140 were independently associated with lower MoCA scores within the 50-59 age band, while WMH alone was associated with poorer MoCA scores in the≥70 age band. CONCLUSION: In adults with prodromal or mild dementia, hypertension was associated with WMH specifically in the 60-69 age strata. Associations between hypertension and WMH with poorer cognition also differed across age bands. Future studies will be needed to investigate whether blood pressure management to slow cognitive decline by targeting WMH may be age dependent.

Association of Asymmetrical White Matter Hyperintensities and Apolipoprotein E4 on Cognitive Impairment.

BACKGROUND: Asymmetrical patterns of cerebral damage have been widely observed in a range of neurodegenerative diseases, including Alzheimer's disease (AD). OBJECTIVE: To elucidate the clinical associations of asymmetrical white matter hyperintensities (WMH) in mild cognitive impairment (MCI) and AD. METHODS: Regional WMH asymmetry of 340 participants (90 healthy controls, 132 MCI, 118 AD) was calculated as the difference in normalized hemispheric WMH volume (WMH/ICV) adjusted for structural brain asymmetry of respective lobar regions and total WMH. WMH asymmetry was analyzed in relation to disease classification, cognition, and APOE4 status using ANCOVA and multiple regression analysis, controlling for gender, age, ethnicity, and correcting for multiple comparisons using Bonferroni correction. Moderation analysis examined interaction effects of APOE4 on associations between cognition and WMH asymmetry. RESULTS: Greater left-dominant occipital WMH asymmetry was observed in AD, compared to healthy controls and MCI, and was associated with poorer global cognition, memory, language, and executive functions among cognitively impaired participants (MCI and AD). Cognitively impaired APOE4 carriers displayed greater left-dominant WMH asymmetry in the whole brain and frontal lobe, compared to non-carriers. Importantly, effects were independent of structural brain asymmetry, global cerebral atrophy, and overall WMH burden. Moderation analysis demonstrated associations between left-dominant WMH asymmetry and cognition in cognitively impaired APOE4 non-carriers, but not APOE4 carriers. CONCLUSION: Leftward asymmetry of WMH may be more pathological in nature, compared to symmetrical WMH. Furthermore, the detrimental effects of WMH asymmetry was more relevant in APOE4-negative cognitive impairment, compared to APOE4-positive which may be driven primarily by AD pathology.

Serial position effects differ between Alzheimer's and vascular features in mild cognitive impairment.

Individuals with mild cognitive impairment (MCI) exhibit varying serial position effect (SPE) performances. The relationship between SPE performance in word list recall and clinical, genetic, and neuroimaging features of MCI requires elucidation. 119 MCI and 68 cognitively normal (CN) participants underwent cognitive assessment, apolipoprotein E (ApoE) genotyping, and volumetric MRI brain scans processed via voxel-based morphometry. A 10-word recall task was used to assess SPE performance in relation to recency and primacy recall. MCI participants were classified as having Good SPE performance (high primacy and recency, Good SPE) or Poor SPE performance (low primacy only, LP-SPE; low recency only, LR-SPE; or both low, Low SPE). Poor SPE participants had reduced grey matter (GM) volumes and increased white matter hyperintensities (WMH) volumes. Participants with LP-SPE demonstrated reduced hippocampal GM volumes and were more likely to be ApoE ε4 carriers. LR-SPE was associated with higher WMH volumes. Presence of both greater WMH volumes and ApoE ε4 resulted in Low SPE. LP-SPE MCI participants had features typical of Alzheimer's disease. LR-SPE MCI was associated with increased WMH volumes, likely representing vascular pathology. SPE profiles are associated with distinct clinical patterns of MCI pathophysiology and could have potential as a clinical marker.

Regional White Matter Hyperintensity Influences Grey Matter Atrophy in Mild Cognitive Impairment.

The association between cerebrovascular disease pathology (measured by white matter hyperintensities, WMH) and brain atrophy in early Alzheimer's disease (AD) remain to be elucidated. Thus, we investigated how WMH influence neurodegeneration and cognition in prodromal and clinical AD. We examined 51 healthy controls, 35 subjects with mild cognitive impairment (MCI), and 30 AD patients. We tested how total and regional WMH is related to specific grey matter volume (GMV) reductions in MCI and AD compared to controls. Stepwise regression analysis was further performed to investigate the association of GMV and regional WMH volume with global cognition. We found that total WMH volume was highest in AD but showed the strongest association with lower GMV in MCI. Frontal and parietal WMH had the most extensive influence on GMV loss in MCI. Additionally, parietal lobe WMH volume (but not hippocampal atrophy) was significantly associated with global cognition in MCI while smaller hippocampal volume (but not WMH volume) was associated with lower global cognition in AD. Thus, although WMH volume was highest in AD subjects, it had a more pervasive influence on brain structure and cognitive impairment in MCI. Our study thus highlights the importance of early detection of cerebrovascular disease, as its intervention at the MCI stage might potentially slow down neurodegeneration.

Atrial Fibrillation is Independently Associated with Cognitive Impairment after Ischemic Stroke.

BACKGROUND: While atrial fibrillation (AF) is an important risk factor for ischemic strokes and mild cognitive impairment (MCI) in Alzheimer's disease, the association between AF and post-stroke cognitive impairment (PSCI), and the factors mediating this association, is unclear. OBJECTIVE: To investigate the role of AF in PSCI, especially in relation to other markers of cerebrovascular disease. METHODS: 445 subjects with mild ischemic stroke without pre-stroke cognitive decline were assessed 3-6 months post-stroke for cognitive deficits. MRIs were reviewed by trained raters for acute infarct characteristics, global cortical atrophy, white matter hyperintensities, cerebral microbleeds, and intracranial stenosis. Logistic regression analysis was used to identify factors independently associated with PSCI. Subjects were also categorized according to paroxysmal (pAF) or persistent/chronic AF (p/cAF), and presence or absence of AF or large cortical infarcts (LCI) to study cognitive trends. RESULTS: 80 (18.0%) subjects had AF. 76.3% of AF subjects and 42.7% of subjects without AF had PSCI. The odds ratio (OR) of AF in developing PSCI was 2.31 (95% CI: 1.12-4.75; p = 0.035), after correcting for other risk factors. pAF subjects and AF subjects with LCIs had higher ORs for PSCI. AF subjects performed worse in neuropsychological tasks associated with global cognition, episodic memory, and executive function. CONCLUSION: AF is a significant risk factor for PSCI, even after correcting for AF-related infarcts. Other mechanisms, such as hypoperfusion, microhemorrhages, and neuroinflammation, may be at play. All stroke patients with AF, regardless of the type of infarction, should be closely monitored for PSCI.

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.

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 Parkinson's 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.

Clinicoradiologic features distinguish tumefactive multiple sclerosis from CNS neoplasms.

BACKGROUND: There are limited data to guide clinicians in differentiating tumefactive multiple sclerosis (TMS) from CNS neoplasms. Identifying distinguishing features will inform diagnosis and management and avoid unnecessary diagnostic biopsy. Our study aimed to determine the clinical and radiologic features that differentiate TMS from glioma and CNS lymphoma (CNSL) in patients who present with tumefactive lesions. METHODS: We retrospectively reviewed all patients with tumefactive lesions and histologically proven or clinically diagnosed TMS, glioma, or CNSL at our tertiary center from 1999 to 2012. Two independent blinded neuroradiologists rated MRI brain scans at presentation. We correlated patients' demographic, clinical, laboratory, and radiologic data to final diagnosis. RESULTS: A total of 133 patients (10 TMS, 85 glioma, 38 CNSL) were analyzed. Patients with TMS were younger and a greater proportion were women. Presenting symptoms did not distinguish between diagnoses. TMS lesions were smaller compared to glioma and CNSL, had no or mild mass effect, and were always associated with contrast enhancement. Radiologic features that were more frequent in TMS lesions were incomplete rim (open-ring) enhancement, incomplete peripheral diffusion restriction, and mixed T2 signal and CT hypoattenuation of MRI-enhancing components (all p < 0.05). CONCLUSIONS: Radiologic features but not presenting symptoms are useful in distinguishing TMS from CNS neoplasms.

Progression of small vessel disease correlates with cortical thinning in Parkinson's disease.

OBJECTIVE: Cerebral small-vessel disease (SVD) is a risk factor for dementia in Parkinson's disease (PD), however the pathophysiological role of SVD in PD-dementia is unclear. We investigated the impact of baseline and progression of SVD on cortical thickness and the correlation to cognition. METHODS: Seventy-three mild PD patients with baseline and follow-up structural MRI scans, serial clinical and neuropsychological assessments were studied. SVD included the load of white matter hyperintensities (WMH), lacunes and perivascular spaces (PVS). WMH progression was assessed using the modified Rotterdam Progression scale, while for lacunes and PVS, development of new lesions was considered as lesion progression. Patients were classified as having SVD-progression and SVD-no-progression based on the longitudinal changes in their SVD measures. Freesurfer was used to measure baseline and follow-up regional cortical thickness and subcortical volumes and correlated to cognitive performance. RESULTS: Fourteen patients were classified as SVD-progression and 59 as SVD-no-progression. Over 18 months, PD SVD-progression demonstrated significant cortical thinning in the left frontal and bilateral parietal regions with associated decline in memory, executive function, and motor functions. PD SVD-progression also had reduced volumes in the nucleus accumbens and amygdala at baseline and greater atrophy in the caudate nucleus over 18 months. DISCUSSION: The extent and progression of SVD is associated with focal cerebral atrophy and domain-specific cognitive dysfunction. Measures to retard SVD may be potentially useful in preventing dementia 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.

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 Parkinson's 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.

Longitudinal brain volumetric changes and their predictive effects on cognition among cognitively asymptomatic patients with Parkinson's disease.

INTRODUCTION: Existing literature on brain volumetric alterations in patients with Parkinson's disease (PD) have mainly focused on gray matter (GM) and are largely cross-sectional. Little is known about white matter (WM) volumetric features and their impact on cognitive symptoms in PD. Therefore, the present study aims to examine both GM and WM volumes of cognitively asymptomatic PD patients with a longitudinal design. METHODS: A total of 42 cognitively asymptomatic patients with early stage PD were recruited and followed up for 1.5 years. At follow-up, 12 patients progressed to mild cognitive impairment (MCI) and were classified as "converters" while the remaining 30 patients remained cognitively asymptomatic and were classified as "non-converters". All patients underwent clinical and neuropsychological assessments as well as MRI scans at baseline and at follow-up. RESULTS: At baseline, non-converters and converters had comparable cognitive scores. At follow-up, converters showed more deficits in frontal-related cognitive function than non-converters. Volumetric analyses revealed that converters had more longitudinal reduction in WM, but not GM, volume compared to non-converters. The decreased volumes among converters were mainly localized in the frontal areas. Moreover, baseline global WM volume significantly predicted conversion to PD-MCI, while baseline GM and WM volumes of the frontal and parietal regions were associated with frontal cognitive changes across time. CONCLUSION: PD patients who develop MCI demonstrate longitudinal reduction in WM volume, especially in the frontal areas. While both regional GM and WM volumes associate with frontal cognitive decline, baseline global WM volume may be a neuroimaging marker of conversion to PD-MCI.

Hippocampal volume and white matter disease in the prediction of dementia in Parkinson's disease.

BACKGROUND: Longitudinal neuroimaging studies could provide insights into pathophysiology of cognitive impairment in PD. We examined the role of hippocampal atrophy and cerebral white matter disease as risk factors for mild cognitive impairment and dementia in PD. METHODS: Prospective longitudinal study of patients with mild PD in a tertiary neurology center. All subjects underwent baseline MRI brain and had baseline and 6 monthly cognitive evaluations. Cognitive impairment was diagnosed based on the Movement Disorder Society Criteria. The predictive role of hippocampal volume and white matter hyperintensity at baseline on progression of cognitive impairment was studied. RESULTS: 97 subjects with mean age 65.3 years, mean education of 10.3 years and mean Hoehn & Yahr of 1.9 were studied. Over 2 years, 16 subjects developed mild cognitive impairment and 8 subjects with mild cognitive impairment progressed to dementia. After adjusting for age and vascular risk factors, hippocampal volume was a significant predictor for mild cognitive impairment (OR 7.05, CI 1.5-34.1; p = 0.015) and dementia (OR 7.03, CI 2.39-25.2; p = 0.001). With Cox regression, hippocampal volume was a significant predictor for "time to cognitive impairment" (HR 7.67; CI 3.47-16.95, p < 0.001). Difference between survival curves based on volume of white matter hyperintensity in predicting "time to mild cognitive impairment" was significant (p = 0.0295). CONCLUSIONS: Hippocampal volume is a major factor predicting the development of mild cognitive impairment and dementia in PD. White matter hyperintensity also contributes to the longitudinal cognitive status in PD.