Precision Medicine for Frontotemporal Dementia

Frontotemporal dementia (FTD) is a common young-onset dementia presenting with heterogeneous and distinct syndromes. It is characterized by progressive deficits in behavior, language, and executive function. The disease may exhibit similar characteristics to many psychiatric disorders owing to its prominent behavioral features. The concept of precision medicine has recently emerged, and it involves neurodegenerative disease treatment that is personalized to match an individual's specific pattern of neuroimaging, neuropathology, and genetic variability. In this paper, the pathophysiology underlying FTD, which is characterized by the selective degeneration of the frontal and temporal cortices, is reviewed. We also discuss recent advancements in FTD research from the perspectives of clinical, imaging, molecular characterizations, and treatment. This review focuses on the approach of precision medicine to manage the clinical and biological complexities of FTD

Light, photophobia and headache: an investigation of visually-induced migraine

Exacerbation of headache by light is a major symptom in migraine. A recent study unraveled the non-image forming (NIF) visual pathway to be a key component underlying photophobia in migraine. Several lines of evidence also indicate that an altered cortical excitability may render migraineurs more susceptible to attacks, although it is unclear whether the cortex is more or less excitable. Accordingly, this thesis investigated the link between migraine, visual systems and brain responsiveness using three complementary approaches. To begin with, I assessed the response of the NIF visual system to light of different wavelengths in healthy subjects. My results provided the first neuroimaging evidence that the suprachiasmatic nucleus (SCN) of the NIF system displays a sustained response to blue light but not to other wavelengths. This highlights the unique property of the SCN for mediating the circadian cycle, which some investigators have suggested drive the periodicity of migraine attacks. Next, I examined the interictal cortical sensitivity to light and visual stimuli in migraine. The fMRI results revealed a hypo-excitable response to diffuse illumination in migraineurs compared to healthy controls. The response, however, did not differ when subjects were exposed to a more aversive flickering checkerboard stimulus. Furthermore, the phenomenon appeared to be magnified in a group harboring the TRESK variant, who may be considered an extreme form of the migraine spectrum. This suggests that the initial cortical hypo- excitability may serve as a protective mechanism against further attacks. Surprisingly, I found no disturbance of glutamate, GABA and NAA in the visual cortex of interictal migraine subjects, arguing against the notion that these metabolites may mediate the protective mechanism or predispose the brain to migraine attacks. Finally, I optimized the PCR and prepared a DNA pool of 741 migraineurs and 416 controls for sequencing four candidate genes including TRESK and OPN4. Variants identified in these genes that associate with migraine may provide mechanistic insights into how genetic backgrounds alters neuronal and brain responsiveness and how this in turn increases migraine liability. Taken together, my studies reveal cortical hypo-excitability in patients with migraine between attacks and established a foundation for future studies including the NIF visual system in migraine. Longitudinal studies will also help unravel compensatory from primary changes in the migraine brain.This thesis is not currently available in ORA

Combining Transcranial Direct Current Stimulation With Tai Chi to Improve Dual-Task Gait Performance in Older Adults With Mild Cognitive Impairment: A Randomized Controlled Trial

[[abstract]]Introduction: Engaging in a secondary task while walking increases motor-cognitive interference and exacerbates fall risk in older adults with mild cognitive impairment (MCI). Previous studies have demonstrated that Tai Chi (TC) may improve cognitive function and dual-task gait performance. Intriguingly, with emerging studies also indicating the potential of transcranial direct current stimulation (tDCS) in enhancing such motor-cognitive performance, whether combining tDCS with TC might be superior to TC alone is still unclear. The purpose of this study was to investigate the effects of combining tDCS with TC on dual-task gait in patients with MCI. Materials and Methods: Twenty patients with MCI were randomly assigned to receive either anodal or sham tDCS, both combined with TC, for 36 sessions over 12 weeks. Subjects received 40 min of TC training in each session. During the first 20 min, they simultaneously received either anodal or sham tDCS over the left dorsolateral prefrontal cortex. Outcome measures included dual-task gait performance and other cognitive functions. Results: There were significant interaction effects between groups on the cognitive dual task walking. Compared to sham, the anodal tDCS group demonstrated a greater improvement on cadence and dual task cost of speed. Conclusion: Combining tDCS with TC may offer additional benefits over TC alone in enhancing dual-task gait performance in patients with MCI. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [TCTR20201201007]

Decreased Brain Structural Network Connectivity in Patients with Mild Cognitive Impairment: A Novel Fractal Dimension Analysis

Mild cognitive impairment (MCI) is widely regarded to be the intermediate stage to Alzheimer’s disease. Cerebral morphological alteration in cortical subregions can provide an accurate predictor for early recognition of MCI. Thirty patients with MCI and thirty healthy control subjects participated in this study. The Desikan–Killiany cortical atlas was applied to segment participants’ cerebral cortex into 68 subregions. A complexity measure termed fractal dimension (FD) was applied to assess morphological changes in cortical subregions of participants. The MCI group revealed significantly decreased FD values in the bilateral temporal lobes, right parietal lobe including the medial temporal, fusiform, para hippocampal, and also the orbitofrontal lobes. We further proposed a novel FD-based brain structural network to compare network parameters, including intra- and inter-lobular connectivity between groups. The control group had five modules, and the MCI group had six modules in their brain networks. The MCI group demonstrated shrinkage of modular sizes with fewer components integrated, and significantly decreased global modularity in the brain network. The MCI group had lower intra- and inter-lobular connectivity in all lobes. Between cerebral lobes, the MCI patients may maintain nodal connections between both hemispheres to reduce connectivity loss in the lateral hemispheres. The method and results presented in this study could be a suitable tool for early detection of MCI

Increased risk of essential tremor in migraine: A population-based retrospective cohort study.

PURPOSE:To examine the long-term risk of essential tremor (ET) in migraine. METHODS:Using population-based administrative data from a subset of the National Health Insurance Research Database (NHIRD) of Taiwan, we identified 22,696 newly diagnosed migraineurs (mean age 44.5 years) and a matched migraine-free cohort of 90,784 individuals in the period 2000-2008. Multivariable Cox proportional hazards regression analysis was conducted for assessing the ET risk for the migraine cohort compared to the migraine-free cohort. RESULTS:After adjusting for covariates, the migraine cohort had a 1.83-fold increased risk (95% CI 1.50-2.23) of subsequent ET in comparison to the migraine-free cohort (8.97 vs. 4.81 per 10,000 person-years). In the subgroup analysis, patients with migraine were associated with higher risks of ET, regardless of gender, age or the existence of comorbidities. CONCLUSION:Our findings demonstrated an association between migraine and ET, suggesting a possible shared pathophysiology underpinning both disorders

Using Fractal Dimension Analysis with the Desikan–Killiany Atlas to Assess the Effects of Normal Aging on Subregional Cortex Alterations in Adulthood

Normal aging is associated with functional and structural alterations in the human brain. The effects of normal aging and gender on morphological changes in specific regions of the brain are unknown. The fractal dimension (FD) can be a quantitative measure of cerebral folding. In this study, we used 3D-FD analysis with the Desikan–Killiany (DK) atlas to assess subregional morphological changes in adulthood. A total of 258 participants (112 women and 146 men) aged 30–85 years participated in this study. Participants in the middle-age group exhibited a decreased FD in the lateral frontal lobes, which then spread to the temporal and parietal lobes. Men exhibited an earlier and more significant decrease in FD values, mainly in the right frontal and left parietal lobes. Men exhibited more of a decrease in FD values in the subregions on the left than those in the right, whereas women exhibited more of a decrease in the lateral subregions. Older men were at a higher risk of developing mild cognitive impairment (MCI) and exhibited age-related memory decline earlier than women. Our FD analysis using the DK atlas-based prediagnosis may provide a suitable tool for assessing normal aging and neurodegeneration between groups or in individual patients