The effect of white matter signal abnormalities on default mode network connectivity in mild cognitive impairment.

Regions within the default mode network (DMN) are particularly vulnerable to Alzheimer's disease pathology and mechanisms of DMN disruption in mild cognitive impairment (MCI) are still unclear. White matter lesions are presumed to be mechanistically linked to vascular dysfunction whereas cortical atrophy may be related to neurodegeneration. We examined associations between DMN seed-based connectivity, white matter lesion load, and cortical atrophy in MCI and cognitively healthy controls. MCI showed decreased functional connectivity (FC) between the precuneus-seed and bilateral lateral temporal cortex (LTC), medial prefrontal cortex (mPFC), posterior cingulate cortex, and inferior parietal lobe compared to those with controls. When controlling for white matter lesion volume, DMN connectivity differences between groups were diminished within bilateral LTC, although were significantly increased in the mPFC explained by significant regional associations between white matter lesion volume and DMN connectivity only in the MCI group. When controlling for cortical thickness, DMN FC was similarly decreased across both groups. These findings suggest that white matter lesions and cortical atrophy are differentially associated with alterations in FC patterns in MCI. Associations between white matter lesions and DMN connectivity in MCI further support at least a partial but important vascular contribution to age-associated neural and cognitive impairment.

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease.

BACKGROUND: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. METHODS: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months. RESULTS: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. CONCLUSIONS: CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.

Cortical Thickness and Local Gyrification in Children with Developmental Dyslexia.

Developmental dyslexia is frequently associated with atypical brain structure and function within regions of the left hemisphere reading network. To date, few studies have employed surface-based techniques to evaluate cortical thickness and local gyrification in dyslexia. Of the existing cortical thickness studies in children, many are limited by small sample size, variability in dyslexia identification, and the recruitment of prereaders who may or may not develop reading impairment. Further, no known study has assessed local gyrification index (LGI) in dyslexia, which may serve as a sensitive indicator of atypical neurodevelopment. In this study, children with dyslexia (n = 31) and typically decoding peers (n = 45) underwent structural magnetic resonance imaging to assess whole-brain vertex-wise cortical thickness and LGI. Children with dyslexia demonstrated reduced cortical thickness compared with controls within previously identified reading areas including bilateral occipitotemporal and occipitoparietal regions. Compared with controls, children with dyslexia also showed increased gyrification in left occipitotemporal and right superior frontal cortices. The convergence of thinner and more gyrified cortex within the left occipitotemporal region among children with dyslexia may reflect its early temporal role in processing word forms, and highlights the importance of the ventral stream for successful word reading.

Cardiorespiratory fitness is differentially associated with cortical thickness in young and older adults.

Aging is associated with reductions in gray matter volume and cortical thickness. One factor that may play a role in mitigating age-associated brain decline is cardiorespiratory fitness (CRF). Although previous work has identified a positive association between CRF and gray matter volume, the relationship between CRF and cortical thickness, which serves as a more sensitive indicator of gray matter integrity, has yet to be assessed in healthy young and older adults. To address this gap in the literature, 32 young and 29 older adults completed treadmill-based progressive maximal exercise testing to assess CRF (peak VO2), and structural magnetic resonance imaging (MRI) to determine vertex-wise surface-based cortical thickness metrics. Results indicated a significant CRF by age group interaction such that Peak VO2 was associated with thicker cortex in older adults but with thinner cortex in young adults. Notably, the majority of regions demonstrating a positive association between peak VO2 and cortical thickness in older adults overlapped with brain regions showing significant age-related cortical thinning. Further, when older adults were categorized as high or low fit based on normative data, we observed a stepwise pattern whereby cortex was thickest in young adults, intermediate in high fit older adults and thinnest in low fit older adults. Overall, these results support the notion that CRF-related neuroplasticity may reduce although not eliminate age-related cortical atrophy.

Associations between T1 white matter lesion volume and regional white matter microstructure in aging.

White matter lesions, typically manifesting as regions of signal intensity abnormality (WMSA) on MRI, increase in frequency with age. However, the role of this damage in cognitive decline and disease is still not clear, as lesion volume has only loosely been associated with clinical status. Diffusion tensor imaging (DTI) has been used to examine the quantitative microstructural integrity of white matter, and has applications in the examination of subtle changes to tissue that appear visually normal on conventional imaging. The primary goal of this study was to determine whether major macrostructural white matter damage, (total WMSA volume), is associated with microstructural integrity of normal appearing white matter, and if these macrostructural changes fully account for microstructural changes. Imaging was performed in 126 nondemented individuals, ages 43-85 years, with no history of cerebrovascular disease. Controlling for age, greater WMSA volume was associated with decreased fractional anisotropy (FA) in widespread brain regions. Patterns were similar for FA and radial diffusivity but in contrast, WMSA was associated with axial diffusivity in fewer areas. Age was associated with FA in several regions, and many of these effects remained even when controlling for WMSA volume, suggesting the etiology of WMSAs does not fully account for all age-associated white matter deterioration. These results provide evidence that WMSA volume is associated with the integrity of normal-appearing white matter. In addition, our results suggest that overt lesions may not account for the association of increasing age with decreased white matter tissue integrity.

Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease.

INTRODUCTION: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology. METHODS: The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome). RESULTS: PEGASUS enrolled 95 participants (intent-to-treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO (n = 51) versus placebo (n = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin-15 increased from baseline to Week 24 within the placebo group (n = 34). In the PB and TURSO group (n = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aß42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups. DISCUSSION: While between-group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD. Highlights: Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD).Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms.The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets.PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration.Supports further clinical development of PB and TURSO in neurodegenerative diseases.

Interindividual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults.

Prior research has demonstrated links among vascular health and the occurrence of stroke, mild cognitive decline, and dementia in older adults. However, little is known about whether normal variation in vascular indicators may be related to changes in neural tissue integrity. Even less is known about how the brain is affected by cholesterol levels in the normal to moderate risk range, leading up to overt disease pathology. This study examined associations between serum lipid levels and DTI indicators of white matter (WM) structural integrity in a sample of 125 generally healthy older adults aged 43-87 years. Whole-brain voxelwise analysis, controlling for age and gender, revealed low density lipoprotein levels (LDL) as the most robust correlate of regional WM structural integrity of the measured lipids. Higher LDL was associated with decreased WM integrity in right frontal and temporal regions, the superior longitudinal fasciculus and internal/external capsules. Increasing LDL was associated with increased radial and axial diffusivity; however, more widespread statistical effects were found for radial diffusivity. These findings suggest that normal interindividual variation in lipid levels is associated with compromised regional WM integrity, even in individuals below clinical thresholds for hyperlipidemia. Given the prevalence of cholesterol-associated sequelae in older adults, and mounting evidence suggesting a vascular role in the etiology of dementia, the current data suggest that understanding the relationship between cholesterol and brain tissue microstructure may have important clinical implications for early detection of vascular-related cognitive disorders and optimal regulation of serum lipids to maintain neural health in older adults.

Association between white matter microstructure, executive functions, and processing speed in older adults: the impact of vascular health.

Cerebral white matter damage is not only a commonly reported consequence of healthy aging, but is also associated with cognitive decline and dementia. The aetiology of this damage is unclear; however, individuals with hypertension have a greater burden of white matter signal abnormalities (WMSA) on MR imaging than those without hypertension. It is therefore possible that elevated blood pressure (BP) impacts white matter tissue structure which in turn has a negative impact on cognition. However, little information exists about whether vascular health indexed by BP mediates the relationship between cognition and white matter tissue structure. We used diffusion tensor imaging to examine the impact of vascular health on regional associations between white matter integrity and cognition in healthy older adults spanning the normotensive to moderate-severe hypertensive BP range (43-87 years; N = 128). We examined how white matter structure was associated with performance on tests of two cognitive domains, executive functioning (EF) and processing speed (PS), and how patterns of regional associations were modified by BP and WMSA. Multiple linear regression and structural equation models demonstrated associations between tissue structure, EF and PS in frontal, temporal, parietal, and occipital white matter regions. Radial diffusivity was more prominently associated with performance than axial diffusivity. BP only minimally influenced the relationship between white matter integrity, EF and PS. However, WMSA volume had a major impact on neurocognitive associations. This suggests that, although BP and WMSA are causally related, these differential metrics of vascular health may act via independent pathways to influence brain structure, EF and PS.

Associations Between Midlife Menopausal Hormone Therapy Use, Incident Diabetes, and Late Life Memory in the Wisconsin Longitudinal Study.

BACKGROUND: Prior research suggests a link between menopausal hormone therapy (MHT) use, memory function, and diabetes risk. The menopausal transition is a modifiable period to enhance long-term health and cognitive outcomes, although studies have been limited by short follow-up periods precluding a solid understanding of the lasting effects of MHT use on cognition. OBJECTIVE: We examined the effects of midlife MHT use on subsequent diabetes incidence and late life memory performance in a large, same-aged, population-based cohort. We hypothesized that the beneficial effects of MHT use on late life cognition would be partially mediated by reduced diabetes risk. METHODS: 1,792 women from the Wisconsin Longitudinal Study (WLS) were included in analysis. We employed hierarchical linear regression, Cox regression, and causal mediation models to test the associations between MHT history, diabetes incidence, and late life cognitive performance. RESULTS: 1,088/1,792 women (60.7%) reported a history of midlife MHT use and 220/1,792 (12.3%) reported a history of diabetes. MHT use history was associated with better late life immediate recall (but not delayed recall), as well as a reduced risk of diabetes with protracted time to onset. Causal mediation models suggest that the beneficial effect of midlife MHT use on late life immediate recall were at least partially mediated by diabetes risk. CONCLUSION: Our data support a beneficial effect of MHT use on late life immediate recall (learning) that was partially mediated by protection against diabetes risk, supporting MHT use in midlife as protective against late life cognitive decline and adverse health outcomes.

Inter-individual variation in blood pressure is associated with regional white matter integrity in generally healthy older adults.

Prior studies have documented a range of brain changes that occur as a result of healthy aging as well as neural alterations due to profound dysregulation in vascular health such as extreme hypertension, cerebrovascular disease and stroke. In contrast, little information exists about the more transitionary state between the normal and abnormal physiology that contributes to vascular disease and cognitive decline. Specifically, little information exists with regard to the influence of systemic vascular physiology on brain tissue structure in older individuals with low risk for cerebrovascular disease and with no evidence of cognitive impairment. We examined the association between resting blood pressure and diffusion tensor imaging (DTI) indices of white matter microstructure in 128 healthy older adults (43-87 years) spanning the normotensive to moderate-severe hypertensive range. Mean arterial blood pressure (MABP) was related to diffusion measures in several regions of the brain with greatest associations in the anterior corpus callosum and lateral frontal, precentral, superior frontal, lateral parietal and precuneus white matter. Associations between white matter integrity and blood pressure remained when controlling for age, when controlling for white matter lesions, and when limiting the analyses to only normotensive, pharmacologically controlled and pre-hypertensive individuals. Of the diffusion measures examined, associations were strongest between MABP and radial diffusivity which may indicate that blood pressure has an influence on myelin structure. Associations between MABP and white matter integrity followed spatial patterns resembling those often attributed to the effects of chronological age, suggesting that systemic cerebrovascular health may play a role in neural tissue degeneration classically ascribed to aging. These results demonstrate the importance of the consideration of vascular physiology in studies of cognitive and neural aging, and that this significance extends to even the normotensive and medically controlled population. These data additionally suggest that optimal management of blood pressure may require consideration of the more subtle influence of vascular health on neural health in addition to the primary goal of prevention of a major cerebrovascular event.

Associations of the Lifestyle for Brain Health index with longitudinal cognition and brain amyloid beta in clinically unimpaired older adults: Findings from the Wisconsin Registry for Alzheimer's Prevention.

Introduction: Modifiable health and lifestyle factors increase risk of dementia, but whether modifiable factors, when measured in late-midlife, impact the emergence or progression of Alzheimer's disease (AD) pathophysiologic or cognitive changes remains unresolved. Methods: In initially cognitively unimpaired, late middle-aged participants (N = 1215; baseline age, M [standard deviation] = 59.3 [6.7] years) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), we investigated the influence of the Lifestyle for Brain Health (LIBRA) index, a lifestyle-based dementia risk score, on AD-related cognitive trajectories and amyloid beta (Aß) plaque accumulation. Results: Overall, lower baseline LIBRA, denoting healthier lifestyle and lower dementia risk, was related to better overall cognitive performance, but did not moderate apolipoprotein E ε4 or Aß-related longitudinal cognitive trajectories. LIBRA was not significantly associated with Aß accumulation or estimated age of Aß onset. Discussion: In WRAP, late-midlife LIBRA scores were related to overall cognitive performance, but not AD-related cognitive decline or Aß accumulation in the preclinical timeframe. Highlights: The Lifestyle for Brain Health (LIBRA) index was associated with cognitive performance in late-midlife.LIBRA did not moderate apolipoprotein E ε4 or amyloid-related cognitive decline.LIBRA was not associated with the onset or accumulation of amyloid plaques.

Thickness of the human cerebral cortex is associated with metrics of cerebrovascular health in a normative sample of community dwelling older adults.

We examined how wide ranges in levels of risk factors for cerebrovascular disease are associated with thickness of the human cerebral cortex in 115 individuals ages 43-83 with no cerebrovascular or neurologic history. Cerebrovascular risk factors included blood pressure, cholesterol, body mass index, creatinine, and diabetes-related factors. Variables were submitted into a principal components analysis that confirmed four orthogonal factors (blood pressure, cholesterol, cholesterol/metabolic and glucose). T1-weighted MRI was used to create models of the cortex for calculation of regional cortical thickness. Increasing blood pressure factor scores were associated with numerous regions of reduced thickness. Increasing glucose scores were modestly associated with areas of regionally decreased thickness. Increasing cholesterol scores, in contrast, were associated with thicker cortex across the whole brain. All findings were primarily independent of age. These results provide evidence that normal and moderately abnormal levels of parameters used to assess cerebrovascular health may impact brain structure, even in the absence of cerebrovascular disease. Our data have important implications for the clinical management of vascular health, as well as for what is currently conceptualized as "normal aging" as they suggest that subclinical levels of risk may impact cortical gray matter before a disease process is evident.

Assessing Dementia Prevalence in the Wisconsin Longitudinal Study: Cohort Profile, Protocol, and Preliminary Findings.

BACKGROUND: There is growing consensus that non-genetic determinants of dementia can be linked to various risk- and resiliency-enhancing factors accumulating throughout the lifespan, including socioeconomic conditions, early life experiences, educational attainment, lifestyle behaviors, and physical/mental health. Yet, the causal impact of these diverse factors on dementia risk remain poorly understood due to few longitudinal studies prospectively characterizing these influences across the lifespan. OBJECTIVE: The Initial Lifespan's Impact on Alzheimer's Disease and Related Dementia (ILIAD) study aims to characterize dementia prevalence in the Wisconsin Longitudinal Study (WLS), a 60-year longitudinal study documenting life course trajectories of educational, family, occupational, psychological, cognitive, and health measures. METHODS: Participants are surveyed using the modified Telephone Interview for Cognitive Status (TICS-m) to identify dementia risk. Those scoring below cutoff undergo home-based neuropsychological, physical/neurological, and functional assessments. Dementia diagnosis is determined by consensus panel and merged with existing WLS data for combined analysis. RESULTS: Preliminary findings demonstrate the initial success of the ILIAD protocol in detecting dementia prevalence in the WLS. Increasing age, hearing issues, lower IQ, male sex, APOE4 positivity, and a steeper annualized rate of memory decline assessed in the prior two study waves, all increased likelihood of falling below the TICS-m cutoff for dementia risk. TICS-m scores significantly correlated with standard neuropsychological performance and functional outcomes. CONCLUSION: We provide an overview of the WLS study, describe existing key lifespan variables relevant to studies of dementia and cognitive aging, detail the current WLS-ILIAD study protocol, and provide a first glimpse of preliminary study findings.

A pilot protocol to assess the feasibility of a virtual multiple crossover, randomized controlled trial design using methylphenidate in mild cognitive impairment.

BACKGROUND: The conventional clinical trial design in Alzheimer's disease (AD) and AD-related disorders (ADRDs) is the parallel-group randomized controlled trial. However, in heterogeneous disorders like AD/ADRDs, this design requires large sample sizes to detect meaningful effects in an "average" patient. They are very costly and, despite many attempts, have not yielded new treatments for many years. An alternative, the multi-crossover, randomized control trial (MCRCT) is a design in which each patient serves as their own control across successive, randomized blocks of active treatment and placebo. This design overcomes many limitations of parallel-group trials, yielding an unbiased assessment of treatment effect at the individual level ("N-of-1") regardless of unique patient characteristics. The goal of the present study is to pilot a MCRCT of a potential symptomatic treatment, methylphenidate, for mild-stage AD/ADRDs, testing feasibility and compliance of participants in this design and efficacy of the drug using both standard and novel outcome measures suited for this design. METHODS: Ten participants with mild cognitive impairment or mild-stage dementia due to AD/ADRDs will undergo a 4-week lead-in period followed by three, month-long treatment blocks (2 weeks of treatment with methylphenidate, 2 weeks placebo in random order). This trial will be conducted entirely virtually with an optional in-person screening visit. The primary outcome of interest is feasibility as measured by compliance and retention, with secondary and exploratory outcomes including cognition as measured by neuropsychological assessment at the end of each treatment period and daily brain games played throughout the study, actigraphy, and neuropsychiatric and functional assessments. DISCUSSION: This pilot study will gauge the feasibility of conducting a virtual MCRCT for symptomatic treatment in early AD/ADRD. It will also compare home-based daily brain games with standard neuropsychological measures within a clinical trial for AD/ADRD. Particular attention will be paid to compliance, tolerability of drug and participation, learning effects, trends and stability of daily measures across blocks, medication carryover effects, and correlations between standard and brief daily assessments. These data will provide guidance for more efficient trial design and the use of potentially more robust, ecological outcome measures in AD/ADRD research. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03811847 . Registered on 21 January 2019.

Are primary and secondary types of brain anomalies exclusive factors affecting the attention networks in individuals with spina bifida?

OBJECTIVE: Individuals with spina bifida myelomeningocele (SBM) frequently exhibit cognitive impairments on tasks mediated by brain regions involved in the posterior attention network. Although such deficits have been historically assumed to result from primary and secondary brain insults, there is a dearth of literature regarding whether sequential versus simultaneous surgical closure of neural folds and surgical shunt placement affect neuropsychological function and brain structure of attention networks that have been widely studied in individuals with SBM. The current study addressed these gaps in a large cohort of children and adults with SBM. METHOD: White matter pathways and regional brain volumes of anterior and posterior attention networks were quantified through probabilistic tractography and automated segmentation, respectively. The Child Attention Network Test measured behavioral components of posterior and anterior attention networks. RESULTS: Sequential operations were associated with reduced orienting accuracy and smaller left superior parietal and dorsolateral prefrontal cortex volumes compared to simultaneous operations, controlling for a number of shunt revisions and age. Greater number of shunt revisions was associated with higher radial diffusivity values in the parietal tectocortical pathway. Older participants had greater accuracy and faster conflict resolution performance compared to younger participants, across operation type and number of shunt revisions. CONCLUSIONS: Shunt treatment and revision history related to brain structure and functions associated with the posterior attention network. Neurosurgical history also differentiated the harmful effects of early hydrocephalus on brain structure of the posterior from the anterior attention networks in SBM. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Task-related fMRI BOLD response to hyperinsulinemia in healthy older adults.

BACKGROUND: There is growing evidence to suggest that the brain is an important target for insulin action, and that states of insulin resistance may extend to the CNS with detrimental effects on cognitive functioning. Although the effect of systemic insulin resistance on peripheral organs is well-studied, the degree to which insulin impacts brain function in vivo remains unclear. METHODS: This randomized, single-blinded, 2-way-crossover, sham-controlled, pilot study determined the effects of hyperinsulinemia on fMRI brain activation during a 2-back working memory task in 9 healthy older adults (aged 57-79 years). Each participant underwent two clamp procedures (an insulin infusion and a saline placebo infusion, with normoglycemia maintained during both conditions), to examine the effects of hyperinsulinemia on task performance and associated blood-oxygen-level dependent (BOLD) signal using fMRI. RESULTS: Hyperinsulinemia (compared to saline control) was associated with an increase in both the spatial extent and relative strength of task-related BOLD signal during the 2-back task. Further, the degree of increased task-related activation in select brain regions correlated with greater systemic insulin sensitivity, as well as decreased reaction times and performance accuracy between experimental conditions. CONCLUSION: Together, these findings provide evidence of insulin action in the CNS among older adults during periods of sustained cognitive demand, with the greatest effects noted for individuals with highest systemic insulin sensitivity. FUNDING: This work was funded by the National Institutes of Health (5R21AG051958, 2016).

Biomarkers in Alzheimer's, Frontotemporal, Lewy Body, and Vascular Dementias.

This article reviews the current evidence base for biomarkers of the most common causes of dementia in later life: Alzheimer's disease (AD), frontotemporal lobar degenerations, Lewy body dementias, and vascular cognitive impairment and dementia. Biomarkers are objectively measurable indicators of normal physiology, pathological processes, or response to an intervention. Ideally, they are sensitive, specific, easy to obtain, and closely reflect the underlying biological processes of interest. While such markers are well established and in broad clinical use for common disorders in general medicine (e.g., thallium stress tests for coronary artery disease or serum blood urea nitrogen and creatinine for renal failure), analogous, validated markers for AD or other common dementias are limited, although biomarkers in research settings and specialty dementia clinics are progressing toward clinical use. By way of introducing current and future biomarkers for dementias of later life, this article will benefit the practicing clinician by increasing awareness of the availability and utility of current and emerging biomarkers in dementia diagnosis and prognosis and for monitoring new disease-modifying therapeutics that arrive in the clinic over the coming decade.

FMRI activity during associative encoding is correlated with cardiorespiratory fitness and source memory performance in older adults.

Older adults (OA), relative to young adults (YA), exhibit age-related alterations in functional Magnetic Resonance Imaging (fMRI) activity during associative encoding, which contributes to deficits in source memory. Yet, there are remarkable individual differences in brain health and memory performance among OA. Cardiorespiratory fitness (CRF) is one individual difference factor that may attenuate brain aging, and thereby contribute to enhanced source memory in OA. To examine this possibility, 26 OA and 31 YA completed a treadmill-based exercise test to evaluate CRF (peak VO2) and fMRI to examine brain activation during a face-name associative encoding task. Our results indicated that in OA, peak VO2 was positively associated with fMRI activity during associative encoding in multiple regions including bilateral prefrontal cortex, medial frontal cortex, bilateral thalamus and left hippocampus. Next, a conjunction analysis was conducted to assess whether CRF influenced age-related differences in fMRI activation. We classified OA as high or low CRF and compared their activation to YA. High fit OA (HFOA) showed fMRI activation more similar to YA than low fit OA (LFOA) (i.e., reduced age-related differences) in multiple regions including thalamus, posterior and prefrontal cortex. Conversely, in other regions, primarily in prefrontal cortex, HFOA, but not LFOA, demonstrated greater activation than YA (i.e., increased age-related differences). Further, fMRI activity in these brain regions was positively associated with source memory among OA, with a mediation model demonstrating that associative encoding activation in medial frontal cortex indirectly influenced the relationship between peak VO2 and subsequent source memory performance. These results indicate that CRF may contribute to neuroplasticity among OA, reducing age-related differences in some brain regions, consistent with the brain maintenance hypothesis, but accentuating age-differences in other regions, consistent with the brain compensation hypothesis.

White matter integrity of cerebellar-cortical tracts in reading impaired children: A probabilistic tractography study.

Little is known about the white matter integrity of cerebellar-cortical pathways in individuals with dyslexia. Building on previous findings of decreased volume in the anterior lobe of the cerebellum, we utilized novel cerebellar segmentation procedures and probabilistic tractography to examine tracts that connect the anterior lobe of the cerebellum and cortical regions typically associated with reading: the temporoparietal (TP), occipitotemporal (OT), and inferior frontal (IF) regions. The sample included 29 reading impaired children and 27 typical readers. We found greater fractional anisotropy (FA) for the poor readers in tracts connecting the cerebellum with TP and IF regions relative to typical readers. In the OT region, FA was greater for the older poor readers, but smaller for the younger ones. This study provides evidence for discrete, regionally-bound functions of the cerebellum and suggests that projections from the anterior cerebellum appear to have a regulatory effect on cortical pathways important for reading.

Gray matter integrity within regions of the dorsolateral prefrontal cortical-subcortical network predicts executive function and fine motor dexterity in spina bifida.

OBJECTIVES: This study examined microstructural properties of cortical and subcortical gray matter components of the dorsolateral prefrontal (DLPFC) cortical-subcortical circuit in relation to parent-rated executive function and fine motor dexterity performance in youth with spina bifida myelomeningocele (SBM). Aberrant gray matter integrity of the DLPFC, basal ganglia nuclei, and thalamus were hypothesized to differentially relate to neurobehavioral outcomes. METHODS: Forty-nine youth between 8 and 18 years (M = 12.34) old with SBM underwent a 3T MRI including diffusion tensor imaging. Neurobehavioral measures of parent-rated executive function and fine motor dexterity were obtained from a standardized neuropsychological evaluation. Relations among indices of gray matter microstructural integrity (mean diffusivity [MD], fractional anisotropy [FA], cortical thickness) and neurobehavior were examined using 3 correlational methods to enhance reliability of brain-behavior relations. RESULTS: In SBM, higher FA values in the caudate were associated with poorer behavioral regulation. Higher FA values in the putamen and greater DLPFC thickness were both associated with poorer fine motor dexterity. CONCLUSION: Behavioral regulation and FA in the caudate related to behavioral inhibition in SBM. Similarly, associations between fine motor dexterity and indices of gray matter integrity in the putamen and DLPFC support fronto-striatal involvement in motor control in SBM. Examination of these neurobehavioral correlates revealed a pattern of attenuated behavioral impairments when gray matter structure was more similar to that of typically developing youth. (PsycINFO Database Record