Investigating White Matter Lesion Load, Intrinsic Functional Connectivity, and Cognitive Abilities in Older Adults

Changes to the while matter of the brain disrupt neural communication between spatially distributed brain regions and are associated with cognitive changes in later life. While approximately 95% of older adults experience these brain changes, not everyone who has significant white matter damage displays cognitive impairment. Few studies have investigated the association between white matter changes and cognition in the context of functional brain network integrity. This study used a data-driven, multivariate analytical model to investigate intrinsic functional connectivity patterns associated with individual variability in white matter lesion load as related to fluid and crystallized intelligence in a sample of healthy older adults (n = 84). Several primary findings were noted. First, a reliable pattern emerged associating whole-brain resting-state functional connectivity with individual variability in measures of white matter lesion load, as indexed by total white matter lesion volume and number of lesions. Secondly, white matter lesion load was associated with increased network disintegration and dedifferentiation. Specifically, lower white matter lesion load was associated with greater within- versus between-network connectivity. Higher white matter lesion load was associated with greater between-network connectivity compared to within. These associations between intrinsic functional connectivity and white matter lesion load were not reliably associated with crystallized and fluid intelligence performance. These results suggest that changes to the white matter of the brain in typically aging older adults are characterized by increased functional brain network dedifferentiation. The findings highlight the role of white matter lesion load in altering the functional network architecture of the brain

Strategic lesions in the anterior thalamic radiation and apathy in early Alzheimer's disease

BACKGROUND Behavioural disorders and psychological symptoms of Dementia (BPSD) are commonly observed in Alzheimer's disease (AD), and strongly contribute to increasing patients' disability. Using voxel-lesion-symptom mapping (VLSM), we investigated the impact of white matter lesions (WMLs) on the severity of BPSD in patients with amnestic mild cognitive impairment (a-MCI). METHODS Thirty-one a-MCI patients (with a conversion rate to AD of 32% at 2 year follow-up) and 26 healthy controls underwent magnetic resonance imaging (MRI) examination at 3T, including T2-weighted and fluid-attenuated-inversion-recovery images, and T1-weighted volumes. In the patient group, BPSD was assessed using the Neuropsychiatric Inventory-12. After quantitative definition of WMLs, their distribution was investigated, without an a priori anatomical hypothesis, against patients' behavioural symptoms. Unbiased regional grey matter volumetrics was also used to assess the contribution of grey matter atrophy to BPSD. RESULTS Apathy, irritability, depression/dysphoria, anxiety and agitation were shown to be the most common symptoms in the patient sample. Despite a more widespread anatomical distribution, a-MCI patients did not differ from controls in WML volumes. VLSM revealed a strict association between the presence of lesions in the anterior thalamic radiations (ATRs) and the severity of apathy. Regional grey matter atrophy did not account for any BPSD. CONCLUSIONS This study indicates that damage to the ATRs is strategic for the occurrence of apathy in patients with a-MCI. Disconnection between the prefrontal cortex and the mediodorsal and anterior thalamic nuclei might represent the pathophysiological substrate for apathy, which is one of the most common psychopathological symptoms observed in dementia

The Structural Basis for Brain Health

Cardiovascular disease (CVD) remains the leading cause of mortality in the United States. Stroke and dementia are the leading causes of adult disability worldwide, and the 5th and 6th leading causes of mortality respectively in the United States. Furthermore, CVD annually accounts for approximately $330 billion in direct and indirect costs in the United States: approximately one in seven health care dollars is spent on CVD. While these diseases have different etiologies, and present with different clinical manifestations and prognosis, converging evidence increasingly supports the idea of CVD as a common pathophysiological origin of cerebrovascular disease, potentially indicating a complex interplay between brain health and cardiovascular health. In this thesis, we leverage methodological advancements in systems and computational neurosciences related to the human brain connectome to assess individual topological network organization and integrity in acute and chronic stroke cohorts, and in a non-stroke cohort with varying CV risk factor burden, using graph theory and network analysis. We propose measures that underly neuroanatomical mechanisms that constitute efficient transfer of information and brain health. We demonstrate the impact of cardiovascular risk factors on brain health, even before overt clinical manifestation, and the resulting impact on cognitive performance, and further determine the underlying pathophysiology relating white matter disease and post-stroke outcomes

Isolated Subtle Neurological Abnormalities in Mild Cognitive Impairment Types

Background: Isolated, subtle neurological abnormalities (ISNA) are commonly seen in aging and have been related to cerebral small vessel disease (SVD) and subcortical atrophy in neurologically and cognitively healthy aging subjects. Objective: To investigate the frequency of ISNA in different mild cognitive impairment (MCI) types and to evaluate for each MCI type, the crosssectional relation between ISNA and white matter hyperintensities (WMH), lacunes, caudate atrophy, and ventricular enlargement. Methods: One thousand two hundred fifty subjects with different MCI types were included in the analysis and underwent brain magnetic resonance imaging. WMHs were assessed through two visual rating scales. Lacunes were also rated. Atrophy of the caudate nuclei and ventricular enlargement were assessed through the bicaudate ratio (BCr) and the lateral ventricles to brain ratio (LVBr), respectively. Apolipoprotein E (APOE) genotypes were also assessed. The routine neurological examination was used to evaluate ISNAs that were clustered as central-based signs, cerebellar-based signs, and primitive reflexes. The items of Part-III of the Unified Parkinson’s Disease Rating Scale were used to evaluate ISNAs that were clustered as mild parkinsonian signs. Associations of ISNAs with imaging findings were determined through logistic regression analysis. Results: The ISNAs increase with the age and are present in all MCI types, particularly in those multiple domains, and carrying the APOE ϵ4 allele, and are associated with WMH, lacunes, BCr, and LVBr. Conclusion: This study demonstrates that cortical and subcortical vascular and atrophic processes contribute to ISNAs. Long prospective population-based studies are needed to disentangle the role of ISNAs in the conversion from MCI to dementia

Author response: Effects of orthostatic hypotension on cognition in Parkinson disease

OBJECTIVE: To investigate the relation between orthostatic hypotension (OH) and posture-mediated cognitive impairment in persons with Parkinson's disease (PD) without dementia. METHODS: There were 55 participants: 37 non-demented individuals with idiopathic PD, including 18 with OH (PDOH), and 19 without (PDWOH), and18 control participants (C). All participants completed neuropsychological tests in the supine and in the upright tilted position. Blood pressure was assessed in each posture using a standardized oscillometric cuff at the right brachial artery. RESULTS: The two PD groups performed similarly while supine, with a profile notable for executive dysfunction consisting of deficits in sustained attention, response inhibition, and semantic verbal fluency, as well as reduced verbal memory encoding and retention. When upright, these deficits were exacerbated and broadened to include additional cognitive functions in the PDOH group: deficits in phonemic verbal fluency, psychomotor speed, and both basic and complex aspects of auditory working memory. When group-specific supine scores were used as baseline anchors, both PD groups showed cognitive changes following tilt, though the PDOH group had a wider range of deficits in the executive functioning and memory domains and was the only group to show significant changes in visuospatial skills. CONCLUSIONS: Cognitive deficits in idiopathic PD have been widely reported, though assessments are typically performed in the supine position. While both PD groups had supine deficits that aligned with prior studies and clinical findings, we demonstrated that those with PD and orthostatic hypotension had transient, posture-mediated changes in excess of those found in PD without autonomic failure. These observed changes suggest an acute, reversible effect, and as orthostatic hypotension is a significant comorbid factor in PD, an independent target for clinical intervention. Further understanding of the effects of autonomic failure on cognition in other disorders is desirable, particularly in the context of neuroimaging studies and clinical assessments where data are collected only in the supine or seated positions. Identification of a distinct neuropsychological profile in PD with autonomic failure also has implications for functional activities of daily living and overall quality of life.Accepted manuscrip

Disconnected aging: cerebral white matter integrity and age-related differences in cognition.

Cognition arises as a result of coordinated processing among distributed brain regions and disruptions to communication within these neural networks can result in cognitive dysfunction. Cortical disconnection may thus contribute to the declines in some aspects of cognitive functioning observed in healthy aging. Diffusion tensor imaging (DTI) is ideally suited for the study of cortical disconnection as it provides indices of structural integrity within interconnected neural networks. The current review summarizes results of previous DTI aging research with the aim of identifying consistent patterns of age-related differences in white matter integrity, and of relationships between measures of white matter integrity and behavioral performance as a function of adult age. We outline a number of future directions that will broaden our current understanding of these brain-behavior relationships in aging. Specifically, future research should aim to (1) investigate multiple models of age-brain-behavior relationships; (2) determine the tract-specificity versus global effect of aging on white matter integrity; (3) assess the relative contribution of normal variation in white matter integrity versus white matter lesions to age-related differences in cognition; (4) improve the definition of specific aspects of cognitive functioning related to age-related differences in white matter integrity using information processing tasks; and (5) combine multiple imaging modalities (e.g., resting-state and task-related functional magnetic resonance imaging; fMRI) with DTI to clarify the role of cerebral white matter integrity in cognitive aging

Relationship between regional white matter hyperintensities and alpha oscillations in older adults

Aging is associated with increased white matter hyperintensities (WMHs) and with alterations of alpha oscillations (7–13 Hz). However, a crucial question remains, whether changes in alpha oscillations relate to aging per se or whether this relationship is mediated by age-related neuropathology like WMHs. Using a large cohort of cognitively healthy older adults (N=907, 60-80 years), we assessed relative alpha power, alpha peak frequency, and long-range temporal correlations (LRTC) from resting-state EEG. We further associated these parameters with voxel-wise WMHs from 3T MRI. We found that a higher prevalence of WMHs in the superior and posterior corona radiata as well as in the thalamic radiation was related to elevated alpha power, with the strongest association in the bilateral occipital cortex. In contrast, we observed no significant relation of the WMHs probability with alpha peak frequency and LRTC. Finally, higher age was associated with elevated alpha power via total WMH volume. We suggest that an elevated alpha power is a consequence of WMH affecting a spatial organization of alpha sources

Cerebral white matter status and resting state functional MRI.

White Matter (WM) is a pivotal component of the Central Nervous System (CNS), and its main role is the transmission of the neural impulses within the CNS and between CNS and Peripheral Nervous System (PNS). It is note from literature that changes in the WM affects the function of the CNS with effects on the higher neurological function, included cognition. Further, it has been theorized in the last decades that ageing-associated decline in higher neurological functions, in particular in the neurocognitive sphere, could be at least partly explained by the “disconnection” of the cortical areas of the brain due to the WM degeneration. Although standard “in-vivo” imaging biomarkers of WM integrity have not been validated yet for clinical purposes, several researches have demonstrated the correlation between different potential imaging biomarkers and WM integrity. The aim of the PhD project is to explore and better understanding the effects of WM status on the brain structure, networking and cognition. In particular, we designed three distinct explorative and cross-sectional studies; more specifically, we analyzed the effects of two Magnetic Resonance Imaging (MRI) markers of WM degeneration (the global Fractional Anisotropy (gFA) and the white matter hyperintensities burden (WMHb), respectively) on the brain activity measured with the Resting-State Functional Magnetic Resonance Imaging (rs-fMRI) technique. The project was conducted by analyzing a human population of healthy subjects extracted from the public available dataset “Leipzig Study for Mind-Body-Emotion Interactions” (LEMON). The results of these studies have been published during the PhD course on three distinct international scientific papers

Assessment Of The Interplay Between Regional β-Amyloid Burden And White Matter Hyperintensities On Cognition And Default Mode Network In Clinically Normal Older Participants

Objective: Alzheimer’s disease (AD) and subcortical vascular dementia are considered the most common pathologic contributors to dementia in the aging population. Both frequently coexist in over 80% of community dwelling adults with dementia. The neuropathological development of AD arguably begins with β-amyloid (Aβ) deposition in the brain. This series of studies aims to test the hypothesis that early focal regional amyloid deposition in the brain is associated with cognitive performance in specific cognitive domain scores in preclinical AD (pAD) (study1). Since mixed dementia is widely recognized as the norm rather than the exception, the second study aimed to explore the relation between regional and global Aβ and WMH with core cognitive function (executive function (EF) and memory) scores in cognitively normal (CN) older adults (study2). Finally, the relationship between WMH and Aβ is strongly determined by the spatial distribution of the two pathologies, so the third study aimed to quantify Aβ in Default mode network (DMN) regions to examine whether cerebral small vessels disease (SVD) disruption of connectivity affects Aβ deposition in disconnected DMN regions (study3). Method: Global and regional Standard Uptake Value ratios (SUVr) from Aβ-PET, WMH volumes from MRI FLAIR images, and cognitive test scores were analyzed across a sample of CN participants. Linear regression models adjusted for age, sex and education used to assess the relationships between regional SUVr and cognitive test scores across 99 CN from Sanders Brown Center on Aging (study1). Moderation, and mediation modeling were used to define the interplay between global, regional Aβ and WMHs measures in relation to EF and memory composite scores outcomes at baseline and after approximately 2 years across a sample of 714 CN from the Alzheimer’s Disease Neuroimaging Initiative ADNI (study2). The association of WMH volume in anatomically defined white matter tracts of atlas-based fiber tract with Aβ SUVr specifically in connected cortical regions within DMN was tested across sample of 74 CN from ADNI3. Results: EF performance was associated with increased regional SUVr in the precuneus and posterior cingulate regions only (p \u3c 0.05). The moderation regression analysis showed additive effects of Aβ and WMH over baseline memory and EF scores (p =0.401 and 0.061 respectively) and synergistic effects over follow-up EF (p \u3c 0.05). Through mediation analysis, the data from study 2 showed that WMH affects, mediated by global and regional amyloid burden, are responsible for baseline cognitive performance deficits in memory and EF. Finally, the regression analysis from study 3 demonstrated that increased WMH volumes in superior longitudinal fasciculus (SLF) was associated with increased regional SUVr in inferior parietal lobule (IPL) (p \u3c 0.05). Conclusion: While the prevailing view in the field suggests that memory performance is the earliest clinical hallmark of AD, the present data demonstrate that changes in EF, mediated by Aβ deposition in the precuneus and posterior cingulate may precede memory decline in pAD. After adding the second key driver of cognitive decline in CN, the finding suggested that WMH dependent changes in baseline cognitive performance are related to direct effect of WMH and an indirect effect through both global and regional Aβ burden. Further studies are needed to show the longitudinal influences of WMH on Aβ distributions in participants with mixed dementia

White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Background; Magnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We examined whether the distribution of axonal abnormalities is related to microvascular pathology in the underlying WM. Methods; We used post‐mortem brains from CADASIL subjects and similar age cognitively normal controls to examine WM axonal changes, microvascular pathology, and glial reaction in up to 16 different regions extending rostro‐caudally through the cerebrum. Using unbiased stereological methods, we estimated length densities of affected axons immunostained with neurofilament antibody SMI32. Standard immunohistochemistry was used to assess amyloid precursor protein immunoreactivity per WM area. To relate WM changes to microvascular pathology, we also determined the sclerotic index (SI) in WM arterioles. Results; The degree of WM pathology consistently scored higher across all brain regions in CADASIL subjects (P < 0.01) with the WM underlying the primary motor cortex exhibiting the most severe change. SMI32 immunoreactive axons in CADASIL were invariably increased compared with controls (P < 0.01), with most prominent axonal abnormalities observed in the frontal WM (P < 0.05). The SIs of arterioles in CADASIL were increased by 25–45% throughout the regions assessed, with the highest change in the mid‐frontal region (P = 0.000). Conclusions; Our results suggest disruption of either cortico‐cortical or subcortical‐cortical networks in the WM of the frontal lobe that may explain motor deficits and executive dysfunction in CADASIL. Widespread WM axonal changes arise from differential stenosis and sclerosis of arterioles in the WM of CADASIL subjects, possibly affecting some axons of projection neurones connecting to targets in the subcortical structures