Cardiovascular and metabolic health is associated with functional brain connectivity in middle-aged and older adults: Results from the Human Connectome Project-Aging study.

Several cardiovascular and metabolic indicators, such as cholesterol and blood pressure have been associated with altered neural and cognitive health as well as increased risk of dementia and Alzheimer's disease in later life. In this cross-sectional study, we examined how an aggregate index of cardiovascular and metabolic risk factor measures was associated with correlation-based estimates of resting-state functional connectivity (FC) across a broad adult age-span (36-90+ years) from 930 volunteers in the Human Connectome Project Aging (HCP-A). Increased (i.e., worse) aggregate cardiometabolic scores were associated with reduced FC globally, with especially strong effects in insular, medial frontal, medial parietal, and superior temporal regions. Additionally, at the network-level, FC between core brain networks, such as default-mode and cingulo-opercular, as well as dorsal attention networks, showed strong effects of cardiometabolic risk. These findings highlight the lifespan impact of cardiovascular and metabolic health on whole-brain functional integrity and how these conditions may disrupt higher-order network integrity.

Saving cognitive outcome data in Alzheimer's disease clinical trials during the COVID-19 pandemic: Commentary on the virtual administration of the ADAS-Cog.

Elderly participants in Alzheimer's disease (AD) clinical trials are at high risk of morbidity and mortality with interpersonal exposure to COVID-19, a situation that is likely to continue for the foreseeable future. Yet, in-person neuropsychological assessments remain the mainstay primary outcomes for clinical trials seeking prevention and cure for AD. The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) is among the most commonly used cognitive assessment in AD clinical trials, and though currently lacking specific guidelines for virtual administrations, it can be used remotely with appropriate modifications and considerations. Here we propose a novel method of virtual administration of the ADAS-Cog, which considers workarounds for technological and human limitations imposed when the participant is no longer sitting across from the test administrator.

Clinical Trials and Tribulations in the COVID-19 Era.

Advances in treating and preventing Alzheimer disease and other neurocognitive disorders of aging arise from rigorous preclinical and clinical research, with randomized controlled treatment trials as the last and definitive test. The COVID-19 pandemic has greatly disrupted ongoing interventional studies and researchers are scrambling to find ways to safely continue this critical work amidst rapidly shifting guidelines from sponsors, institutions, and state and federal guidelines. Here the authors describe novel approaches and work-flow adaptations to study visits, drug delivery and interim and endpoint safety and outcomes assessments to avoid sacrificing years of preparation and substantial financial investments, to work in the best interest of participants and their caregivers, and to continue on the path toward discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.

Structural brain correlates of fatigue in older adults with and without Parkinson's disease.

Fatigue is one of the most common and disabling nonmotor symptoms seen in Parkinson's disease (PD) and is also commonly seen in healthy older adults. Our understanding of the etiology of fatigue in older adults with or without PD is limited and it remains unclear whether fatigue in PD is specifically related to PD pathology. The objective of this study was thus to determine whether fatigue in PD was associated with structural changes in gray or white matter and explore whether these changes were similar in older adults without PD. Magnetic resonance imaging (T1 weighted) and diffusion tensor imaging were performed in 60 patients with PD (17 females; age = 67.58 ±â€¯5.51; disease duration = 5.67 ±â€¯5.83 years) and 41 age- and sex- matched healthy controls. FSL image processing was used to measure gray matter volume, fractional anisotropy, and leukoariosis differences. Voxel-based morphometry confirmed gray matter loss across the dorsal striatum and insula in the PD patient cohort. PD patients with fatigue had reduced gray matter volume in dorsal striatum relative to PD patients without fatigue (P < 0.05 False Discovery Rate corrected). No significant fatigue-related structural atrophy was found in controls. There were no areas of significant fractional anisotropy differences between high and low fatigue subjects in either the PD or non-PD groups. Control participants with high fatigue, but not PD, showed significantly greater total leukoariosis volumes (p = 0.03). Fatigue in PD is associated with unique structural changes in the caudate and putamen suggesting fatigue in PD is primarily related to PD pathology, particularly in the dorsal striatum, and not simply a consequence of aging.

Considering total intracranial volume and other nuisance variables in brain voxel based morphometry in idiopathic PD.

Voxel-based morphometry (VBM) studies of Parkinson's disease (PD), have yielded mixed results, possibly due to several studies not accounting for common nuisance variables (age, sex, and total intracranial volume [TICV]). TICV is particularly important because there is evidence for larger TICV in PD. We explored the influence of these covariates on VBM by 1) comparing PD patients and controls before adding covariates, after adding age and sex, and after adding age, sex and TICV, and 2) by comparing controls split into large and small TICV before and after controlling for TICV, with age and sex accounted for in both analyses. Experiment 1 consisted of 40 PD participants and 40 controls. Experiment 2 consisted of 88 controls median split by TICV. All participants completed an MRI on a 3 T scanner. TICV was calculated as gray + white + CSF from Freesurfer. VBM was performed on T1 images using an optimized VBM protocol. Volume differences were assessed using a voxel-wise GLM analysis. Clusters were considered significant at >10 voxels and p < .05 corrected for familywise error. Before controlling for covariates, PD showed reduced GM in temporal, occipital, and cerebellar regions. Controlling for age and sex did not affect the pattern of significance. Controlling for TICV reduced the size of the significant region although it still contained portions of bilateral temporal lobes, occipital lobes and cerebellum. The large TICV group showed reduced volume in temporal, parietal, and cerebellar areas. None of these differences survived controlling for TICV. This demonstrates that TICV influences VBM results independently from other factors. Controlling for TICV in VBM studies is recommended.

Reliability and Utility of Manual and Automated Estimates of Total Intracranial Volume.

OBJECTIVES: Total intracranial volume (TICV) is an important control variable in brain-behavior research, yet its calculation has challenges. Manual TICV (Manual) is labor intensive, and automatic methods vary in reliability. To identify an accurate automatic approach we assessed the reliability of two FreeSurfer TICV metrics (eTIV and Brainmask) relative to manual TICV. We then assessed how these metrics alter associations between left entorhinal cortex (ERC) volume and story retention. METHODS: Forty individuals with Parkinson's disease (PD) and 40 non-PD peers completed a brain MRI and memory testing. Manual metrics were compared to FreeSurfer's Brainmask (a skull strip mask with total volume of gray, white, and most cerebrospinal fluid) and eTIV (calculated using the transformation matrix into Talairach space). Volumes were compared with two-way interclass correlations and dice similarity indices. Associations between ERC volume and Wechsler Memory Scale-Third Edition Logical Memory retention were examined with and without correction using each TICV method. RESULTS: Brainmask volumes were larger and eTIV volumes smaller than Manual. Both automated metrics correlated highly with Manual. All TICV metrics explained additional variance in the ERC-Memory relationship, although none were significant. Brainmask explained slightly more variance than other methods. CONCLUSIONS: Our findings suggest Brainmask is more reliable than eTIV for TICV correction in brain-behavioral research. (JINS, 2018, 24, 206-211).

Mapping Dorsal and Ventral Caudate in Older Adults: Method and Validation.

The caudate nucleus plays important roles in cognition and affect. Depending on associated connectivity and function, the caudate can be further divided into dorsal and ventral aspects. Dorsal caudate, highly connected to dorsolateral prefrontal cortex (DLPFC), is implicated in executive function and working memory; ventral caudate, more interconnected with the limbic system, is implicated in affective functions such as pain processing. Clinically, certain brain disorders are known to differentially impact dorsal and ventral caudate. Thus, precise parcellation of caudate has both basic and clinical neuroscience significance. In young adults, past work has combined resting-state fMRI functional connectivity with clustering algorithms to define dorsal and ventral caudate. Whether the same approach is effective in older adults and how to validate the parcellation results have not been considered. We addressed these problems by obtaining resting-state fMRI data from 56 older non-demented adults (age: 69.07 ± 5.92 years and MOCA: 25.71 ± 2.46) along with a battery of cognitive and clinical assessments. Connectivity from each voxel of caudate to the rest of the brain was computed using cross correlation. Applying the K-means clustering algorithm to the connectivity patterns with K = 2 yielded two substructures within caudate, which agree well with previously reported dorsal and ventral divisions of caudate. Furthermore, dorsal-caudate-seeded functional connectivity was shown to be more strongly associated with working memory and fluid reasoning composite scores, whereas ventral-caudate-seeded functional connectivity more strongly associated with pain and fatigue severity. These results demonstrate that dorsal and ventral caudate can be reliably identified by combining resting-state fMRI and clustering algorithms in older adults.

Marked brain asymmetry with intact cognitive functioning in idiopathic Parkinson's disease: a longitudinal analysis.

OBJECTIVE: A 71-year-old (MN) with an 11-year history of left onset tremor diagnosed as Parkinson's disease (PD) completed longitudinal brain magnetic resonance imaging (MRI) and neuropsychological testing. MRI scans showed an asymmetric caudate nucleus (right < left volume). We describe this asymmetry at baseline and the progression over time relative to other subcortical gray, frontal white matter, and cortical gray matter regions of interest. Isolated structural changes are compared to MN's cognitive profiles. METHOD: MN completed yearly MRIs and neuropsychological assessments. For comparison, left onset PD (n = 15) and non-PD (n = 43) peers completed the same baseline protocol. All MRI scans were processed with FreeSurfer and the FMRIB Software Library to analyze gray matter structures and frontal fractional anisotropy (FA) metrics. Processing speed, working memory, language, verbal memory, abstract reasoning, visuospatial, and motor functions were examined using reliable change methods. RESULTS: At baseline, MN had striatal volume and frontal lobe thickness asymmetry relative to peers with mild prefrontal white matter FA asymmetry. Over time only MN's right caudate nucleus showed accelerated atrophy. Cognitively, MN had slowed psychomotor speed and visuospatial-linked deficits with mild visuospatial working memory declines longitudinally. CONCLUSIONS: This is a unique report using normative neuroimaging and neuropsychology to describe an individual diagnosed with PD who had striking striatal asymmetry followed secondarily by cortical thickness asymmetry and possible frontal white matter asymmetry. His decline and variability in visual working memory could be linked to ongoing atrophy of his right caudate nucleus.

Gray and White Matter Contributions to Cognitive Frontostriatal Deficits in Non-Demented Parkinson's Disease.

OBJECTIVE: This prospective investigation examined: 1) processing speed and working memory relative to other cognitive domains in non-demented medically managed idiopathic Parkinson's disease, and 2) the predictive role of cortical/subcortical gray thickness/volume and white matter fractional anisotropy on processing speed and working memory. METHODS: Participants completed a neuropsychological protocol, Unified Parkinson's Disease Rating Scale, brain MRI, and fasting blood draw to rule out vascular contributors. Within group a priori anatomical contributors included bilateral frontal thickness, caudate nuclei volume, and prefrontal white matter fractional anisotropy. RESULTS: Idiopathic Parkinson's disease (n = 40; Hoehn & Yahr stages 1-3) and non-Parkinson's disease 'control' peers (n = 40) matched on demographics, general cognition, comorbidity, and imaging/blood vascular metrics. Cognitively, individuals with Parkinson's disease were significantly more impaired than controls on tests of processing speed, secondary deficits on working memory, with subtle impairments in memory, abstract reasoning, and visuoperceptual/spatial abilities. Anatomically, Parkinson's disease individuals were not statistically different in cortical gray thickness or subcortical gray volumes with the exception of the putamen. Tract Based Spatial Statistics showed reduced prefrontal fractional anisotropy for Parkinson's disease relative to controls. Within Parkinson's disease, prefrontal fractional anisotropy and caudate nucleus volume partially explained processing speed. For controls, only prefrontal white matter was a significant contributor to processing speed. There were no significant anatomical predictors of working memory for either group. CONCLUSIONS: Caudate nuclei volume and prefrontal fractional anisotropy, not frontal gray matter thickness, showed unique and combined significance for processing speed in Parkinson's disease. Findings underscore the relevance for examining gray-white matter interactions and also highlight clinical processing speed metrics as potential indicators of early cognitive impairment in PD.

Impaired Switching from Self-Prepared Actions in Mild Parkinson Disease.

BACKGROUND: Planned and initiated actions frequently need to be terminated in favor of another action. It is known that many individuals with Parkinson's disease (PD) have more difficulty self-initiating movement (i.e., endogenously evoked movement)than moving in response to environmental stimuli (i.e., exogenously evoked movement). However, it is not known if individuals with PD display this same endogenous-exogenous asymmetry when needing to terminate, disengage, and reprogram movements. OBJECTIVE: This study used a novel reaction time (RT) paradigm to test whether patients with mild PD have subclinical deficits of endogenous movement initiation and endogenous movement reprogramming. METHODS: Twelve non-demented individuals with PD on medication and 15 demographically similar healthy control (HC)participants completed an experimental paradigm that examined their RTs (key press) following self-selected valid action preparation (endogenous cues) versus valid exogenously presented cues. The paradigm also assessed participants' ability to rapidly stop their endogenous or exogenous preparation following an invalid cue and execute an alternative action (key press). RESULTS: Participants with PD produced similar RTs as controls following endogenous and exogenous valid cues, and following invalid exogenous cues. However, following invalid endogenous cues, PD participants were slower than HC participants to stop an endogenous preparation and execute an alternative action. CONCLUSIONS: Despite having mild disease and being on dopaminergic medication, these individuals with PD displayed deficits in motor disengagement and reprograming of self-selected actions. Future studies should examine how this phenomenon influences every day actions, as well as possible treatments for this deficit.

Proof of principle: Transformation approach alters caudate nucleus volume and structure-function associations.

Brain magnetic resonance image (MRI) registration alters structure orientation, size, and/or shape. To determine whether linear registration methods (image transformation to 6, 9, and 12° of freedom) alter structural volume and cognitive associations, we examined transformation alterations to the caudate nucleus within individuals diagnosed with Parkinson's disease (PD) and demographically matched non-PD peers. Volumes from native and six were expected be significantly different from 9 and 12° of freedom methods. Caudate nucleus volumes were expected to be associated with measures of processing speed and mental flexibility, but the strength of the association based on transformation approach was unknown. MRI brain scans from individuals with Parkinson's disease (n = 40) and age-matched controls (n = 40) were transformed using 6, 9, and 12° of freedom to an average brain template. Correlations controlling for total intracranial volume assessed expected structural-behavioral associations. Volumetric: Raw 9 and 12° transformed volumes were significantly larger than native and 6° volumes. Only 9 and 12° volumes revealed group differences with PD less than controls. Intracranial volume considerations were essential for native and 6° between group comparisons. Structural-Behavioral: The 9 and 12° caudate nucleus volume transformations revealed the expected brain-behavioral associations. Linear registration techniques alter volumetric and cognitive-structure associations. The study highlights the need to communicate transformation approach and group intracranial volume considerations.

A case of an arachnoid cyst masquerading as corticobasal degeneration.

We present an individual, "JD", a 69-year-old Caucasian, married female with symptoms that included progressive right arm stiffness, tremor, and clumsiness; increasing gait and balance disturbance; increased fatigue and emotionality. Neuropsychological evaluation revealed compromised semantics and language-associated functions; impaired visual constructional ability; markedly reduced cognitive and visuomotor processing speed; low average to average working memory; variable praxis performance; variable abstract reasoning, problem solving, and set shifting; and lower overall intellectual functioning compared to premorbid estimates. Overall, her neuropsychological profile indicated marked compromise of the frontal and left parietal regions. The data coupled with her symptom pattern and demographics partially fit corticobasal degeneration diagnostic criteria. Neuroimaging, however, performed 2 years prior to the assessment and again during the current workup revealed an enlarging arachnoid cyst compressing the left parietal and posterior frontal lobe and a small portion of the right medial frontal-parietal region. We discuss the neuroanatomical substrates involved in her cognitive presentation and how two very distinct pathological processes (corticobasal degeneration, arachnoid cyst) can result in two similar symptom presentations. We summarize how multidisciplinary assessment assists with differential diagnosis and treatment planning.