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1.  Abnormal Subcortical Brain Morphology in Patients with Knee Osteoarthritis: A Cross-sectional Study 
Despite the involvement of subcortical brain structures in the pathogenesis of chronic pain and persistent pain as the defining symptom of knee osteoarthritis (KOA), little attention has been paid to the morphometric measurements of these subcortical nuclei in patients with KOA. The purpose of this study is to explore the potential morphological abnormalities of subcortical brain structures in patients with KOA as compared to the healthy control subjects by using high-resolution MRI. Structural MR data were acquired from 26 patients with KOA and 31 demographically similar healthy individuals. The MR data were analyzed by using FMRIB’s integrated registration and segmentation tool. Both volumetric analysis and surface-based shape analysis were performed to characterize the subcortical morphology. The normalized volumes of bilateral caudate nucleus were significantly smaller in the KOA group than in the control group (P = 0.004). There was also a trend toward smaller volume of the hippocampus in KOA as compared to the control group (P = 0.027). Detailed surface analyses further localized these differences with a greater involvement of the left hemisphere (P < 0.05, corrected) for the caudate nucleus. Hemispheric asymmetry (right larger than left) of the caudate nucleus was found in both KOA and control groups. Besides, no significant correlation was found between the structural data and pain intensities. Our results indicated that patients with KOA had statistically significant smaller normalized volumes of bilateral caudate nucleus and a trend toward smaller volume of the hippocampus as compared to the control subjects. Further investigations are necessary to characterize the role of caudate nucleus in the course of chronicity of pain associated with KOA.
PMCID: PMC4717185  PMID: 26834629
knee osteoarthritis; subcortical structure; caudate nucleus; vertex analysis; FSL-FIRST
2.  Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy 
PMCID: PMC4720786  PMID: 26834630
Alzheimer's disease; Creutzfeldt-Jakob disease; prion; amyloid plaque; dementia; amyloidosis; cross-seeding; protein seed
3.  Electrophysiological Indicators of the Age-Related Deterioration in the Sensitivity to Auditory Duration Deviance 
The present study investigates age-related changes in duration discrimination in millisecond time domain. We tested young (N = 20, mean age = 24.5, SD = 2.97) and elderly (N = 20, mean age = 65.2, SD = 2.94) subjects using the mismatch negativity (MMN) paradigm. White-noise bursts of two different durations (50 and 10 ms) were presented in two oddball blocks. In one block (Increment Condition), the repetitive sequence of 10 ms standards was interspersed by occasional 50 ms deviants. In the Decrement Condition, the roles of the two stimuli were reversed. We analyzed the P1-N1 complex, MMN and P3a and found the effect of age for all these components. Moreover, the impact of stimulus presentation condition (increment/decrement) was observed for MMN and P3a. Our results confirmed the previous evidence for deteriorated duration discrimination in elderly people. Additionally, we found that this effect may be influenced by procedural factors.
PMCID: PMC4722124  PMID: 26834628
duration discrimination; mismatch negativity (MMN); P3a; aging; temporal information processing
4.  Editorial: ICT for Assessment and Rehabilitation in Alzheimer’s Disease and Related Disorders 
PMCID: PMC4718975  PMID: 26834631
information and communication technology; aging; Alzheimer’s disease; serious games; virtual reality; assessment; rehabilitation; online education
5.  Amidated and Ibuprofen-Conjugated Kyotorphins Promote Neuronal Rescue and Memory Recovery in Cerebral Hypoperfusion Dementia Model 
Chronic brain ischemia is a prominent risk factor for neurological dysfunction and progression for dementias, including Alzheimer’s disease (AD). In rats, permanent bilateral common carotid artery occlusion (2VO) causes a progressive neurodegeneration in the hippocampus, learning deficits and memory loss as it occurs in AD. Kyotorphin (KTP) is an endogenous antinociceptive dipeptide whose role as neuromodulator/neuroprotector has been suggested. Recently, we designed two analgesic KTP-derivatives, KTP-amide (KTP–NH2) and KTP–NH2 linked to ibuprofen (IbKTP–NH2) to improve KTP brain targeting. This study investigated the effects of KTP-derivatives on cognitive/behavioral functions (motor/spatial memory/nociception) and hippocampal pathology of female rats in chronic cerebral hypoperfusion (2VO-rat model). 2VO-animals were treated with KTP–NH2 or IbKTP–NH2 for 7 days at weeks 2 and 5 post-surgery. After behavioral testing (week 6), coronal sections of hippocampus were H&E-stained or immunolabeled for the cellular markers GFAP (astrocytes) and NFL (neurons). Our findings show that KTP-derivatives, mainly IbKTP–NH2, enhanced cognitive impairment of 2VO-animals and prevented neuronal damage in hippocampal CA1 subfield, suggesting their potential usefulness for the treatment of dementia.
PMCID: PMC4726799  PMID: 26858637
2VO-dementia model; chronic cerebral hypoperfusion; cognitive impairment; hippocampus; kyotorphin derivatives; neuroprotection
6.  Limited Effect of Dopaminergic Medication on Straight Walking and Turning in Early-to-Moderate Parkinson’s Disease during Single and Dual Tasking 
In Parkinson’s disease (PD), the effects of dopaminergic medication on straight walking and turning were mainly investigated under single tasking (ST) conditions. However, multitasking situations are considered more daily relevant.
Thirty-nine early-to-moderate PD patients performed the following standardized ST and dual tasks as fast as possible for 1 min during On- and Off-medication while wearing inertial sensors: straight walking and turning, checking boxes, and subtracting serial 7s. Quantitative gait parameters as well as velocity of the secondary tasks were analyzed.
The following parameters improved significantly in On-medication during ST: gait velocity during straight walking (p = 0.03); step duration (p = 0.048) and peak velocity (p = 0.04) during turning; velocity of checking boxes during ST (p = 0.04) and DT (p = 0.04). Velocity of checking boxes was the only parameter that also improved during DT.
These results suggest that dopaminergic medication does not relevantly influence straight walking and turning in early-to-moderate PD during DT.
PMCID: PMC4728201  PMID: 26858638
Parkinson’s disease; dual tasking; gait; turning; wearable sensors
7.  Thromboxane A2 Receptor Stimulation Enhances Microglial Interleukin-1β and NO Biosynthesis Mediated by the Activation of ERK Pathway 
Background and Purpose: Thromboxane A2 (TXA2) receptors (TP) interact with the ligand TXA2 to induce platelet aggregation and regulate hemostasis. Recently TP-mediated signaling has been suggested to function in multiple cell types in the brain. In this report, we aim to study the expression and physiological role of TP in microglia, in particular after brain ischemia.
Methods: Ischemic brain sections were analyzed for TP expression. Microglial cell line and primary microglia were cultured, or neuronal cell line co-culture system was used to determine the TP mediated signaling in inflammation and microglia activation.
Results: We found that the TP level was significantly increased in ipsilateral mouse brain tissue at 24 h after ischemia-reperfusion, which was also found to partly co-localize with CD11b, a marker for microglial and infiltrated monocyte/macrophage, in peri-infarct area. Immunofluorescence staining of primary microglia and microglial cell line BV2 revealed the predominant membrane distribution of TP. Conditioned culture media from TP agonist U46619-treated BV2 cells decreased neuronal SH-SY5Y cell viability and induced apoptotic morphological changes. Furthermore, U46619 enhanced IL-1β, IL-6, and iNOS mRNA expression as well as IL-1β and NO releases in BV2 cells or primary microglia. Such stimulation could be attenuated by TP antagonist SQ29548 or MEK inhibitor U0126. The dose- and time-dependent extracellular-signal-regulated kinase (ERK) phosphorylation induced by U46619 further demonstrated ERK signaling-mediated microglia activation by TP agonist.
Conclusion: This study has shown a novel role of TP in microglia activation via the ERK signaling pathway, which provides insights for the management of neuroinflammation in diseases like cerebral infarction.
PMCID: PMC4731520  PMID: 26858639
thromboxane A2 receptor; cerebral ischemia; microglia; inflammation; ERK
8.  Aberrant Functional Connectivity and Structural Atrophy in Subcortical Vascular Cognitive Impairment: Relationship with Cognitive Impairments 
Abnormal structures in the cortical and subcortical regions have been identified in subcortical vascular cognition impairment (SVCI). However, little is known about the functional alterations in SVCI, and no study refers to the functional connectivity in the prefrontal and subcortical regions in this context. The medial prefrontal cortex (MPFC) is an important region of the executive network and default mode network, and the subcortical thalamus plays vital roles in mediating or modulating these two networks. To investigate both thalamus- and MPFC-related functional connectivity as well as its relationship with cognition in SVCI, 32 SVCI patients and 23 control individuals were administered neuropsychological assessments. They also underwent structural and functional magnetic resonance imaging scans. Voxel-based morphometry and functional connectivity analysis were performed to detect gray matter (GM) atrophy and to characterize the functional alterations in the thalamus and the MPFC. For structural data, we observed that GM atrophy was distributed in both cortical regions and subcortical areas. For functional data, we observed that the thalamus functional connectivity in SVCI was significantly decreased in several cortical regions [i.e., the orbitofrontal lobe (OFL)], which are mainly involved in executive function and memory function. However, connectivity was increased in several frontal regions (i.e., the inferior frontal gyrus), which may be induced by the compensatory recruitment of the decreased functional connectivity. The MPFC functional connectivity was also decreased in executive- and memory-related regions (i.e., the anterior cingulate cortex) along with a motor region (i.e., the supplementary motor area). In addition, the cognitive performance was closely correlated with functional connectivity between the left thalamus and the left OFL in SVCI. The present study, thus, provides evidence for an association between structural and functional alterations, and sheds light on the underlying neural mechanisms of executive dysfunction in SVCI.
PMCID: PMC4736471  PMID: 26869922
resting-state fMRI; functional connectivity; gray matter atrophy; thalamus; MPFC; vascular cognition impairment
9.  Commentary: Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice 
PMCID: PMC4737912  PMID: 26869920
Alzheimer's disease (AD); Parkinson's disease; frontotemporal dementia (FTD); lysosomal storage diseases; lysosomes; neurodegenerative diseases; progranulin; glucocerebrosidase gene
10.  Motor Performance is Impaired Following Vestibular Stimulation in Ageing Mice 
Balance and maintaining postural equilibrium are important during stationary and dynamic movements to prevent falls, particularly in older adults. While our sense of balance is influenced by vestibular, proprioceptive, and visual information, this study focuses primarily on the vestibular component and its age-related effects on balance. C57Bl/6J mice of ages 1, 5–6, 8–9 and 27–28 months were tested using a combination of standard (such as grip strength and rotarod) and newly-developed behavioral tests (including balance beam and walking trajectory tests with a vestibular stimulus). In the current study, we confirm a decline in fore-limb grip strength and gross motor coordination as age increases. We also show that a vestibular stimulus of low frequency (2–3 Hz) and duration can lead to age-dependent changes in balance beam performance, which was evident by increases in latency to begin walking on the beam as well as the number of times hind-feet slip (FS) from the beam. Furthermore, aged mice (27–28 months) that received continuous access to a running wheel for 4 weeks did not improve when retested. Mice of ages 1, 10, 13 and 27–28 months were also tested for changes in walking trajectory as a result of the vestibular stimulus. While no linear relationship was observed between the changes in trajectory and age, 1-month-old mice were considerably less affected than mice of ages 10, 13 and 27–28 months. Conclusion: this study confirms there are age-related declines in grip strength and gross motor coordination. We also demonstrate age-dependent changes to finer motor abilities as a result of a low frequency and duration vestibular stimulus. These changes showed that while the ability to perform the balance beam task remained intact across all ages tested, behavioral changes in task performance were observed.
PMCID: PMC4737917  PMID: 26869921
ageing; balance; vestibular; vestibular stimulus; motor coordination; vestibular hair cell
11.  Assessing Visuospatial Abilities in Healthy Aging: A Novel Visuomotor Task 
This study examined the efficacy of a novel reaching-and-grasping task in determining visuospatial abilities across adulthood. The task required male and female young (18–25 years) and older adults (60–82 years) to replicate a series of complex models by locating and retrieving the appropriate building blocks from an array. The task allows visuospatial complexity to be manipulated independently from the visuomotor demands. Mental rotation and spatial visualization abilities were assessed. The results showed that the time taken to complete the tasks increased with increased mental rotation complexity. Patterns of hand use were also influenced by the complexity of the models being constructed with right hand use being greater for the less complex models. In addition, although older adults consistently performed the visuomotor tasks slower than the younger adults, their performance was comparable when expressed as the percent change in task demands. This is suggestive that spatial abilities are preserved in older adults. Given the ecologically validity, the described task is an excellent candidate for investigating: (1) developmental; (2) sex-based; and (3) pathology-based differences in spatial abilities in the visuomotor domain.
PMCID: PMC4740775  PMID: 26869918
spatial ability; visuomotor; visuospatial; reach-to-grasp; sex; aging
12.  Molecular Pathways Bridging Frontotemporal Lobar Degeneration and Psychiatric Disorders 
The overlap of symptoms between neurodegenerative and psychiatric diseases has been reported. Neuropsychiatric alterations are commonly observed in dementia, especially in the behavioral variant of frontotemporal dementia (bvFTD), which is the most common clinical FTD subtype. At the same time, psychiatric disorders, like schizophrenia (SCZ), can display symptoms of dementia, including features of frontal dysfunction with relative sparing of memory. In the present review, we discuss common molecular features in these pathologies with a special focus on FTD. Molecules like Brain Derived Neurotrophic Factor (BDNF) and progranulin are linked to the pathophysiology of both neurodegenerative and psychiatric diseases. In these brain-associated illnesses, the presence of disease-associated variants in BDNF and progranulin (GRN) genes cause a reduction of circulating proteins levels, through alterations in proteins expression or secretion. For these reasons, we believe that prevention and therapy of psychiatric and neurological disorders could be achieved enhancing both BDNF and progranulin levels thanks to drug discovery efforts.
PMCID: PMC4740789  PMID: 26869919
BDNF; progranulin; biomarkers; frontotemporal dementia; psychiatric disorders; neurodegenerative diseases
13.  Alzheimer’s Biomarkers are Correlated with Brain Connectivity in Older Adults Differentially during Resting and Task States 
β-amyloid (Aβ) plaques and tau-related neurodegeneration are pathologic hallmarks of Alzheimer’s disease (AD). The utility of AD biomarkers, including those measured in cerebrospinal fluid (CSF), in predicting future AD risk and cognitive decline is still being refined. Here, we explored potential relationships between functional connectivity (FC) patterns within the default-mode network (DMN), age, CSF biomarkers (Aβ42 and pTau181), and cognitive status in older adults. Multiple measures of FC were explored, including a novel time series-based measure [total interdependence (TI)]. In our sample of 27 cognitively normal older adults, no significant associations were found between levels of Aβ42 or pTau181 and cognitive scores or regional brain volumes. However, we observed several novel relationships between these biomarkers and measures of FC in DMN during both resting-state and a short-term memory task. First, increased connectivity between bilateral anterior middle temporal gyri was associated with higher levels of CSF Aβ42 and Aβ42/pTau181 ratio (reflecting lower AD risk) during both rest and task. Second, increased bilateral parietal connectivity during the short-term memory task, but not during rest, was associated with higher levels of CSF pTau181 (reflecting higher AD risk). Third, increased connectivity between left middle temporal and left parietal cortices during the active task was associated with decreased global cognitive status but not CSF biomarkers. Lastly, we found that our new TI method was more sensitive to the CSF Aβ42-connectivity relationship whereas the traditional cross-correlation method was more sensitive to levels of CSF pTau181 and cognitive status. With further refinement, resting-state connectivity and task-driven connectivity measures hold promise as non-invasive neuroimaging markers of Aβ and pTau burden in cognitively normal older adults.
PMCID: PMC4744860  PMID: 26903858
CSF biomarkers; Aβ42 peptides; pTau181; default-mode network; short-term memory task; global cognitive status; predictors of AD
14.  The Neurocognitive Basis for Impaired Dual-Task Performance in Senior Fallers 
Falls are a major health-care concern, and while dual-task performance is widely recognized as being impaired in those at-risk for falls, the underlying neurocognitive mechanisms remain unknown. A better understanding of the underlying mechanisms could lead to the refinement and development of behavioral, cognitive, or neuropharmacological interventions for falls prevention. Therefore, we conducted a cross-sectional study with community-dwelling older adults aged 70–80 years with a history of falls (i.e., two or more falls in the past 12 months) or no history of falls (i.e., zero falls in the past 12 months); n = 28 per group. We compared functional activation during cognitive-based dual-task performance between fallers and non-fallers using functional magnetic resonance imaging (fMRI). Executive cognitive functioning was assessed via Stroop, Trail Making, and Digit Span. Mobility was assessed via the Timed Up and Go test (TUG). We found that non-fallers exhibited significantly greater functional activation compared with fallers during dual-task performance in key regions responsible for resolving dual-task interference, including precentral, postcentral, and lingual gyri. Further, we report slower reaction times during dual-task performance in fallers and significant correlations between level of functional activation and independent measures of executive cognitive functioning and mobility. Our study is the first neuroimaging study to examine dual-task performance in fallers, and supports the notion that fallers have reduced functional brain activation compared with non-fallers. Given that dual-task performance—and the underlying neural concomitants—appears to be malleable with relevant training, our study serves as a launching point for promising strategies to reduce falls in the future.
PMCID: PMC4746244  PMID: 26903862
falls risk; fallers; dual-task; fMRI; aging neuroscience
15.  Diagnostic Value of microRNA for Alzheimer’s Disease: A Systematic Review and Meta-Analysis 
Sound evidence indicates that microRNAs (miRNAs) are aberrantly expressed in Alzheimer’s disease (AD) patients. We performed a systematic review and meta-analysis to investigate the role of miRNA in AD pathogenesis and their clinical diagnostic value; a systematic review of literature and meta-analysis of clinical trials were performed. In the systematic review, 236 papers were included, and we reviewed the dysregulated miRNA expression in different parts of AD patients in order to identify the relationship between aberrantly expressed miRNAs and AD pathology. In the subsequent meta-analysis, seven studies were statistically analyzed with the following results: pooled sensitivity 0.86 (95%CI 0.79–0.90), pooled specificity 0.87 (95%CI 0.72–0.95), diagnostic odds ratio (28.29), and the area under the curve (0.87). In conclusion, our review indicated that aberrant expression of various miRNAs plays an important role in the pathological process of AD, and statistical analysis of quantitative studies reveal the potential value of specific miRNAs in the diagnosis of AD.
PMCID: PMC4746262  PMID: 26903857
Alzheimer’s disease; miRNA; diagnostic value; systematic review; meta-analysis
16.  Frontotemporal Lobar Degeneration and MicroRNAs 
Frontotemporal lobar degeneration (FTLD) includes a spectrum of disorders characterized by changes of personality and social behavior and, often, a gradual and progressive language dysfunction. In the last years, several efforts have been fulfilled in identifying both genetic mutations and pathological proteins associated with FTLD. The molecular bases undergoing the onset and progression of the disease remain still unknown. Recent literature prompts an involvement of RNA metabolism in FTLD, particularly microRNAs (miRNAs). Dysregulation of miRNAs in several disorders, including neurodegenerative diseases, and increasing importance of circulating miRNAs in different pathologies has suggested to implement the study of their possible application as biological markers and new therapeutic targets; moreover, miRNA-based therapy is becoming a powerful tool to deepen the function of a gene, the mechanism of a disease, and validate therapeutic targets. Regarding FTLD, different studies showed that miRNAs are playing an important role. For example, several reports have evaluated miRNA regulation of the progranulin gene suggesting that it is under their control, as described for miR-29b, miR-107, and miR-659. More recently, it has been demonstrated that TMEM106B gene, which protein is elevated in FTLD-TDP brains, is repressed by miR-132/212 cluster; this post-transcriptional mechanism increases intracellular levels of progranulin, affecting its pathways. These findings if confirmed could suggest that these microRNAs have a role as potential targets for some related-FTLD genes. In this review, we focus on the emerging roles of the miRNAs in the pathogenesis of FTLD.
PMCID: PMC4746266  PMID: 26903860
miRNA; frontotemporal lobar degeneration; progranulin; TDP43; social behavioral deficits
17.  Neural Signaling of Food Healthiness Associated with Emotion Processing 
The ability to differentiate healthy from unhealthy foods is important in order to promote good health. Food, however, may have an emotional connotation, which could be inversely related to healthiness. The neurobiological background of differentiating healthy and unhealthy food and its relations to emotion processing are not yet well understood. We addressed the neural activations, particularly considering the single subject level, when one evaluates a food item to be of a higher, compared to a lower grade of healthiness with a particular view on emotion processing brain regions. Thirty-seven healthy subjects underwent functional magnetic resonance imaging while evaluating the healthiness of food presented as photographs with a subsequent rating on a visual analog scale. We compared individual evaluations of high and low healthiness of food items and also considered gender differences. We found increased activation when food was evaluated to be healthy in the left dorsolateral prefrontal cortex and precuneus in whole brain analyses. In ROI analyses, perceived and rated higher healthiness was associated with lower amygdala activity and higher ventral striatal and orbitofrontal cortex activity. Females exerted a higher activation in midbrain areas when rating food items as being healthy. Our results underline the close relationship between food and emotion processing, which makes sense considering evolutionary aspects. Actively evaluating and deciding whether food is healthy is accompanied by neural signaling associated with reward and self-relevance, which could promote salutary nutrition behavior. The involved brain regions may be amenable to mechanisms of emotion regulation in the context of psychotherapeutic regulation of food intake.
PMCID: PMC4748030  PMID: 26903859
functional neuroimaging; food; healthiness; amygdala; midbrain; gender
18.  A Simulation Model of Periarterial Clearance of Amyloid-β from the Brain 
The accumulation of soluble and insoluble amyloid-β (Aβ) in the brain indicates failure of elimination of Aβ from the brain with age and Alzheimer's disease (AD). There is a variety of mechanisms for elimination of Aβ from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of Aβ into the blood and periarterial lymphatic drainage of Aβ. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as Aβ, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of Aβ in the walls of human arteries with age and AD as cerebral amyloid angiopathy (CAA). Initially, Aβ diffuses through the extracellular spaces of gray matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterized, the exact mechanism whereby perivascular elimination of Aβ occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy.
PMCID: PMC4751273  PMID: 26903861
Alzheimer's disease; brain; cerebral amyloid angiopathy; dextran; diffusion; lymphatic drainage; perivascular drainage; simulation model
19.  Habituation in the Tail Withdrawal Reflex Circuit is Impaired During Aging in Aplysia californica 
The relevance of putative contributors to age-related memory loss are poorly understood. The tail withdrawal circuit of the sea hare, a straightforward neural model, was used to investigate the aging characteristics of rudimentary learning. The simplicity of this neuronal circuit permits attribution of declines in the function of specific neurons to aging declines. Memory was impaired in advanced age animals compared to their performance at the peak of sexual maturity, with habituation training failing to attenuate the tail withdrawal response or to reduce tail motoneuron excitability, as occurred in peak maturity siblings. Baseline motoneuron excitability of aged animals was significantly lower, perhaps contributing to a smaller scope for attenuation. Conduction velocity in afferent fibers to tail sensory neurons (SN) decreased during aging. The findings suggest that age-related changes in tail sensory and motor neurons result in deterioration of a simple form of learning in Aplysia.
PMCID: PMC4751345  PMID: 26903863
short term memory; long term potentiation; pleural ganglion; pedal ganglion; marine invertebrate
20.  Orthostatic Cerebral Hypoperfusion Syndrome 
Orthostatic dizziness without orthostatic hypotension is common but underlying pathophysiology is poorly understood. This study describes orthostatic cerebral hypoperfusion syndrome (OCHOs). OCHOs is defined by (1) abnormal orthostatic drop of cerebral blood flow velocity (CBFv) during the tilt test and (2) absence of orthostatic hypotension, arrhythmia, vascular abnormalities, or other causes of abnormal orthostatic CBFv.
This retrospective study included patients referred for evaluation of unexplained orthostatic dizziness. Patients underwent standardized autonomic testing, including 10 min of tilt test. The following signals were monitored: heart rate, end tidal CO2, blood pressure, and CBFv from the middle cerebral artery using transcranial Doppler. Patients were screened for OCHOs. Patients who fulfilled the OCHOs criteria were compared to age- and gender-matched controls.
From 1279 screened patients, 102 patients (60/42 women/men, age 51.1 ± 14.9, range 19–84 years) fulfilled criteria of OCHOs. There was no difference in baseline supine hemodynamic variables between OCHOs and the control group. During the tilt, mean CBFv decreased 24.1 ± 8.2% in OCHOs versus 4.2 ± 5.6% in controls (p < 0.0001) without orthostatic hypotension in both groups. Supine mean blood pressure (OCHOs/controls, 90.5 ± 10.6/91.1 ± 9.4 mmHg, p = 0.62) remained unchanged during the tilt (90.4 ± 9.7/92.1 ± 9.6 mmHg, p = 0.2). End tidal CO2 and heart rate responses to the tilt were normal and equal in both groups.
OCHOs is a novel syndrome of low orthostatic CBFv. Two main pathophysiological mechanisms are proposed, including active cerebral vasoconstriction and passive increase of peripheral venous compliance. OCHOs may be a common cause of orthostatic dizziness.
PMCID: PMC4754393  PMID: 26909037
OCHOs; POTS; OH; orthostatic; hypoperfusion; hypotension; QASAT
21.  Increased Hippocampus–Medial Prefrontal Cortex Resting-State Functional Connectivity and Memory Function after Tai Chi Chuan Practice in Elder Adults 
Previous studies provide evidence that aging is associated with the decline of memory function and alterations in the hippocampal (HPC) function, including functional connectivity to the medial prefrontal cortex (mPFC). In this study, we investigated if longitudinal (12-week) Tai Chi Chuan and Baduanjin practice can improve memory function and modulate HPC resting-state functional connectivity (rs-FC). Memory function measurements and resting-state functional magnetic resonance imaging (rs-fMRI) were applied at the beginning and the end of the experiment. The results showed that (1) the memory quotient (MQ) measured by the Wechsler Memory Scale-Chinese Revision significantly increased after Tai Chi Chuan and Baduanjin practice as compared with the control group, and no significant difference was observed in MQ between the Tai Chi Chuan and Baduanjin groups; (2) rs-FC between the bilateral hippocampus and mPFC significantly increased in the Tai Chi Chuan group compared to the control group (also in the Baduanjin group compared to the control group, albeit at a lower threshold), and no significant difference between the Tai Chi Chuan and Baduanjin groups was observed; (3) rs-FC increases between the bilateral hippocampus and mPFC were significantly associated with corresponding memory function improvement across all subjects. Similar results were observed using the left or right hippocampus as seeds. Our results suggest that both Tai Chi Chuan and Baduanjin may be effective exercises to prevent memory decline during aging.
PMCID: PMC4754402  PMID: 26909038
Tai Chi Chuan exercise; Baduanjin exercise; memory function; aging; hippocampus; medial prefrontal cortex
22.  Commentary: Age-related neurodegenerative disease research needs aging models 
PMCID: PMC4731742  PMID: 26858640
frailty; frailty index; aging; animal models of neurodegenerative disease; translational medical research
23.  Preclinical Cerebral Network Connectivity Evidence of Deficits in Mild White Matter Lesions 
White matter lesions (WMLs) are notable for their high prevalence and have been demonstrated to be a potential neuroimaging biomarker of early diagnosis of Alzheimer’s disease. This study aimed to identify the brain functional and structural mechanisms underlying cognitive decline observed in mild WMLs. Multi-domain cognitive tests, as well as resting-state, diffusion tensor and structural images were obtained on 42 mild WMLs and 42 age/sex-matched healthy controls. For each participant, we examined the functional connectivity (FC) of three resting-state networks (RSNs) related to the changed cognitive domains: the default mode network (DMN) and the bilateral fronto-parietal network (FPN). We also performed voxel-based morphometry analysis to compare whole-brain gray matter (GM) volume, atlas-based quantification of the white matter tracts interconnecting the RSNs, and the relationship between FC and structural connectivity. We observed FC alterations in the DMN and the right FPN combined with related white matter integrity disruption in mild WMLs. However, no significant GM atrophy difference was found. Furthermore, the right precuneus FC in the DMN exhibited a significantly negative correlation with the memory test scores. Our study suggests that in mild WMLs, dysfunction of RSNs might be a consequence of decreased white matter structural connectivity, which further affects cognitive performance.
PMCID: PMC4757671  PMID: 26924981
mild white matter lesions; resting-state networks; functional connectivity; white matter integrity; cognitive impairments
24.  Response: “Commentary: Duration-dependent effects of the BDNF Val66Met polymorphism on anodal tDCS induced motor cortex plasticity in older adults: a group and individual perspective” 
PMCID: PMC4759266  PMID: 26924982
BDNF; Val66Met polymorphism; transcranial magnetic stimulation (TMS); transcranial direct current stimulation (tDCS); motor cortex; older adults; corticospinal excitability; plasticity
25.  Cognitive Benefits of Social Dancing and Walking in Old Age: The Dancing Mind Randomized Controlled Trial 
A physically active lifestyle has the potential to prevent cognitive decline and dementia, yet the optimal type of physical activity/exercise remains unclear. Dance is of special interest as it complex sensorimotor rhythmic activity with additional cognitive, social, and affective dimensions.
To determine whether dance benefits executive function more than walking, an activity that is simple and functional.
Two-arm randomized controlled trial among community-dwelling older adults. The intervention group received 1 h of ballroom dancing twice weekly over 8 months (~69 sessions) in local community dance studios. The control group received a combination of a home walking program with a pedometer and optional biweekly group-based walking in local community park to facilitate socialization.
Main outcomes
Executive function tests: processing speed and task shift by the Trail Making Tests, response inhibition by the Stroop Color-Word Test, working memory by the Digit Span Backwards test, immediate and delayed verbal recall by the Rey Auditory Verbal Learning Test, and visuospatial recall by the Brief Visuospatial Memory Test (BVST).
One hundred and fifteen adults (mean 69.5 years, SD 6.4) completed baseline and delayed baseline (3 weeks apart) before being randomized to either dance (n = 60) or walking (n = 55). Of those randomized, 79 (68%) completed the follow-up measurements (32 weeks from baseline). In the dance group only, “non-completers” had significantly lower baseline scores on all executive function tests than those who completed the full program. Intention-to-treat analyses showed no group effect. In a random effects model including participants who completed all measurements, adjusted for baseline score and covariates (age, education, estimated verbal intelligence, and community), a between-group effect in favor of dance was noted only for BVST total learning (Cohen’s D Effect size 0.29, p = 0.07) and delayed recall (Cohen’s D Effect size = 0.34, p = 0.06).
The superior potential of dance over walking on executive functions of cognitively healthy and active older adults was not supported. Dance improved one of the cognitive domains (spatial memory) important for learning dance. Controlled trials targeting inactive older adults and of a higher dose may produce stronger effects, particularly for novice dancers.
Trial registration
Australian and New Zealand Clinical Trials Register (ACTRN12613000782730).
PMCID: PMC4761858  PMID: 26941640
executive functions; dance; walking; physical function; physical activity

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