Comparing high definition transcranial direct current stimulation to left temporoparietal junction and left inferior frontal gyrus for logopenic primary progressive aphasia: A single-case study.

Logopenic variant primary progressive aphasia (lvPPA) is characterized by word-finding deficits and phonologic errors in fluent speech. Transcranial direct current stimulation (tDCS) targeting either left temporoparietal junction (TPJ) or left inferior frontal gyrus (IFG) show evidence of improving language function in lvPPA. The present case study evaluated the effects of two separate rounds of high definition tDCS (HD-tDCS) (4 mA; 30 sessions) on language and functional neuroimaging in a 57-year-old woman with lvPPA. Stimulation was centred on two different regions across rounds: (1) left TPJ, and (2) left (IFG). Results showed an improved proportion of content to floorholder words during a naturalistic speech task through both rounds as well as change in confrontation naming after TPJ (improvement) and IFG (worsened) stimulation. fMRI connectivity during task showed left lateralized positive correlations following round 1 and anti-correlations with components of the default mode network following round 2. Resting state segregation of a language-associated functional network increased following both rounds, and task-based segregation of the same network increased following IFG stimulation. These results suggest that stimulation to both regions using HD-tDCS may improve language function in lvPPA, while simultaneously eliciting widespread changes beyond the targeted area in neuronal activity and functional connectivity.

Basal forebrain integrity, cholinergic innervation and cognition in idiopathic Parkinson's disease.

Most individuals with Parkinson's disease experience cognitive decline. Mounting evidence suggests this is partially caused by cholinergic denervation due to α-synuclein pathology in the cholinergic basal forebrain. Alpha-synuclein deposition causes inflammation, which can be measured with free water fraction, a diffusion MRI-derived metric of extracellular water. Prior studies have shown an association between basal forebrain integrity and cognition, cholinergic levels and cognition, and basal forebrain volume and acetylcholine, but no study has directly investigated whether basal forebrain physiology mediates the relationship between acetylcholine and cognition in Parkinson's disease. We investigated the relationship between these variables in a cross-sectional analysis of 101 individuals with Parkinson's disease. Cholinergic levels were measured using fluorine-18 fluoroethoxybenzovesamicol (18F-FEOBV) PET imaging. Cholinergic innervation regions of interest included the medial, lateral capsular and lateral perisylvian regions and the hippocampus. Brain volume and free water fraction were quantified using T1 and diffusion MRI, respectively. Cognitive measures included composites of attention/working memory, executive function, immediate memory and delayed memory. Data were entered into parallel mediation analyses with the cholinergic projection areas as predictors, cholinergic basal forebrain volume and free water fraction as mediators and each cognitive domain as outcomes. All mediation analyses controlled for age, years of education, levodopa equivalency dose and systolic blood pressure. The basal forebrain integrity metrics fully mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and attention/working memory, and partially mediated the relationship between medial acetylcholine and attention/working memory. Basal forebrain integrity metrics fully mediated the relationship between medial, lateral capsular and lateral perisylvian acetylcholine and free water fraction. For all mediations in attention/working memory and executive function, the free water mediation was significant, while the volume mediation was not. The basal forebrain integrity metrics fully mediated the relationship between hippocampal acetylcholine and delayed memory and partially mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and delayed memory. The volume mediation was significant for the hippocampal and lateral perisylvian models, while free water fraction was not. Free water fraction in the cholinergic basal forebrain mediated the relationship between acetylcholine and attention/working memory and executive function, while cholinergic basal forebrain volume mediated the relationship between acetylcholine in temporal regions in memory. These findings suggest that these two metrics reflect different stages of neurodegenerative processes and add additional evidence for a relationship between pathology in the basal forebrain, acetylcholine denervation and cognitive decline in Parkinson's disease.

Free Water Fraction Predicts Cognitive Decline for Individuals with Idiopathic Parkinson's disease.

INTRODUCTION: Free water fraction (FWF) is considered a metric of microstructural integrity and may be useful in predicting cognitive decline in idiopathic Parkinson's Disease (PD). We sought to determine if higher FWF within the dorsal portion of the caudate nucleus and basal nucleus of Meynert, two regions associated with cognitive decline in PD, predict change in cognition over a two-year span. Due to the existence of cognitive and neurophysiological subgroups within PD, we statistically categorized participants based on FWF in these regions. METHODS: At baseline, participants completed a research cognitive protocol followed by MRI structural and diffusion metrics. We used k-means cluster analysis with average FWF values from bilateral basal nucleus of Meynert and dorsal caudate to create data-driven FWF clusters for baseline. Two-year reliable change indices were calculated for metrics of language, visuospatial, memory, cognitive flexibility, and reasoning domains. Reliable change scores were compared between the clusters and non-PD peers. RESULTS: Baseline participants included 174 participants (112 PD, 62 non-PD). Cluster analysis yielded three clusters: low FWF in both regions of interest (ROIs), high FWF in both ROIs, and moderate FWF in both ROIs. Reliable change analyses were completed on 93 participants (67 PD, 26 non-PD). After controlling for age and education, the High FWF cluster declined more than non-PD peers in every domain except memory. CONCLUSION: Individuals with high FWF in regions associated with cognitive decline in PD show significant decline across several cognitive domains compared to non-PD peers. Future research should include FWF in additional cortical regions.

Functional connectivity of key resting state networks and objectively measured physical activity in older adults with joint pain: A pilot study.

BACKGROUND: Greater brain network integrity may associate with physically active lifestyles. Three resting state networks may provide unique insights into known physical activity-mediated brain health benefits: the default mode network (involved with self-monitoring), the salience network (involved in orienting oneself to salient external and internal stimuli), and the central executive network (responsible for higher level cognitive task). The current study explored relationships between system-wide neural network integrity measured by functional magnetic resonance imaging and objectively-measured physical activity. We hypothesize connectivity patterns as measured by fMRI networks will relate to actigraphy markers such that 1) there will be higher connectivity within the central executive network in more physically active individuals, and 2) there will be higher connectivity within the default mode network and salience network in those with higher levels of physical activity. METHODS: Eighteen non-demented older adults with orthopedic pain (age 67.11 ± 5.61, 50% female, education 15.94 ± 2.51 years) completed brain magnetic resonance imaging, and wore an actigraphy device to objectively measure types of physical and sedentary engagement. RESULTS: Results showed a negative relationship between central executive network connectivity and sedentary time (ß = -0.108, p = .039), and a positive relationship with both moderate-to-vigorous physical activity (ß = 0.629, p = .029) and total activity time (ß = 0.645, p = .039). Results also showed positive relationships for the default mode network (ß = 0.588, p = .033) and the salience network (ß = 0.608, p = .037) with mean cadence (i.e. steps per minute). CONCLUSIONS: Our work adds to the existing literature on specific types of activity measurement (i.e. sedentary time, cadence and moderate-to-vigorous physical activity) which will be useful for interventions aimed at improving the integrity of underlying neural networks.

Parkinson's Disease Cognitive Phenotypes Show Unique Clock Drawing Features when Measured with Digital Technology.

BACKGROUND: A companion paper (Crowley et al., 2020) reports on the neuroimaging and neuropsychological profiles of statistically determined idiopathic non-dementia Parkinson's disease (PD). OBJECTIVE: The current investigation sought to further examine subtle behavioral clock drawing differences within the same PD cohort by comparing 1) PD to non-PD peers on digitally acquired clock drawing latency and graphomotor metrics, and 2) PD memory, executive, and cognitively well phenotypes on the same variables. METHODS: 230 matched participants (115 PD, 115 non-PD) completed neuropsychological tests and dCDT. Statistically-derived PD cognitive phenotypes characterized PD participants as PD low executive (PDExe; n = 25), PD low memory (PDMem; n = 34), PD cognitively well (PDWell; n = 56). Using a Bayesian framework and based on apriori hypotheses, we compared groups on: total completion time (TCT), pre-first hand latency (PFHL), post-clock face latency (PCFL), total clock face area (TCFA), and total number of pen strokes. RESULTS: Fewer strokes and slower performance to command were associated with higher odds of PD diagnosis, while a larger clock face in the copy condition was associated with lower odds of PD diagnosis. Within PD cognitive phenotypes, slower performance (TCT, PCFL) and smaller clock face to command were associated with higher odds of being PDExe than PDWell, whereas larger clock faces associated with higher odds of being PDMem than PDWell. Longer disease duration, more pen strokes (command) and smaller clocks (command) associated with higher odds of being PDExe than PDWell. CONCLUSION: Digitally-acquired clock drawing profiles differ between PD and non-PD peers, and distinguish PD cognitive phenotypes.

Statistically Defined Parkinson's Disease Executive and Memory Cognitive Phenotypes: Demographic, Behavioral, and Structural Neuroimaging Comparisons.

BACKGROUND: Some individuals with Parkinson's disease (PD) experience working memory and inhibitory difficulties, others learning and memory difficulties, while some only minimal to no cognitive deficits for many years. OBJECTIVE: To statistically derive PD executive and memory phenotypes, and compare PD phenotypes on disease and demographic variables, vascular risk factors, and specific neuroimaging variables with known associations to executive and memory function relative to non-PD peers. METHODS: Non-demented individuals with PD (n = 116) and non-PD peers (n = 62) were recruited to complete neuropsychology measures, blood draw, and structural magnetic resonance imaging. Tests representing the cognitive domains of interest (4 executive function, 3 memory) were included in a k-means cluster analysis comprised of the PD participants. Resulting clusters were compared demographic and disease-related variables, vascular risk markers, gray/white regions of interest, and white matter connectivity between known regions involved in executive and memory functions (dorsolateral prefrontal cortices to caudate nuclei; entorhinal cortices to hippocampi). RESULTS: Clusters showed: 1) PD Executive, n = 25; 2) PD Memory, n = 35; 3) PD Cognitively Well; n = 56. Even after disease variable corrections, PD Executive had less subcortical gray matter, white matter, and fewer bilateral dorsolateral-prefrontal cortex to caudate nucleus connections; PD Memory showed bilaterally reduced entorhinal-hippocampal connections. PD Cognitively Well showed only reduced putamen volume and right entorhinal cortex to hippocampi connections relative to non-PD peers. Groups did not statistically differ on cortical integrity measures or cerebrovascular disease markers. CONCLUSION: PD cognitive phenotypes showed different structural gray and white matter patterns. We discuss data relative to phenotype demographics, cognitive patterns, and structural brain profiles.

Pain Severity and Interference in Different Parkinson's Disease Cognitive Phenotypes.

INTRODUCTION: Chronic pain is prevalent in idiopathic Parkinson's disease (PD) with many individuals also experiencing cognitive deficits negatively impacting everyday life. METHODS: In this study, we examine differences in pain severity and interference between 113 nondemented individuals with idiopathic PD who were statistically classified as having low executive function (n=24), low memory function (n=35), no cognitive deficits (n=54). The individuals with PD were also compared to matched non-PD controls (n=64). RESULTS: PD participants with low executive function reported significantly higher pain interference (p<0.05), despite reporting similar pain severity levels compared to other phenotypes. These differences remained statistically significant, even after accounting for important confounders such as anxiety and depression (p<0.05). DISCUSSION: Pain interference in those with lower executive function may represent a target for psychosocial interventions for individuals with pain and PD.

Regional leukoaraiosis and cognition in non-demented older adults.

Frontal lobe-executive functions are heavily dependent on distal white matter connectivity. Even with healthy aging there is an increase in leukoaraiosis that might interrupt this connectivity. The goal of this study is to learn 1) the location, depth, and percentage of leukoaraiosis in white matter among a sample of non-demented older adults and 2) associations between these leukoarioasis metrics and composites of cognitive efficiency (processing speed, working memory, and inhibitory function), and episodic memory. Participants were 154 non-demented older adults (age range 60-85) who completed a brain MRI and neuropsychological testing on the same day. Brain MRIs were segmented via Freesurfer and white matter leukoaraiosis depth segmentations was based on published criteria. On average, leukoaraiosis occupied 1 % of total white matter. There was no difference in LA distribution in the frontal (1.12%), parietal (1.10%), and occipital (0.95%) lobes; there was less LA load within the temporal lobe (0.23%). For cortical depth, leukoaraiosis was predominantly in the periventricular region (3.39%; deep 1.46%, infracortical 0.15%). Only increasing frontal lobe and periventricular leukoaraiosis were associated with a reduction in processing speed, working memory, and inhibitory function. Despite the general presence of LA throughout the brain, only frontal and periventricular LA contributed to the speeded and mental manipulation of executive functioning. This study provides a normative description of LA for non-demented adults to use as a comparison to more disease samples.

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).