Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.

Globally, an aging population is increasing, and aging is a natural physiological process and a major risk factor for all age-related diseases. It seriously threatens personal health and imposes a great economic burden. Therefore, there is a growing scientific interest in strategies for well-aging with prevention and treatment of age-related diseases. The seed, root, stem or leaves of Cassia tora Linn. are useful for anti-bacteria, anti-hyperlipidemia and anti-obesity due to its pharmacological activities such as anti-inflammation and anti-oxidant both in vitro and in vivo. Nevertheless, no clinical trials have been attempted so far, therefore here we would like to understand the current preclinical activities for aging-related disease models including cataract, metabolic dysfunction and neurodegeneration, then discuss their preparation for clinical trials and perspectives.

Objectives: Alzheimer’s disease (AD) typically eludes clinical detection for years, if not decades. The identification of subtle cognitive decline associated with preclinical AD would not only advance understanding of the disease, but also provide clinical targets to assess preventative and early intervention treatments. Disrupted retrieval of detailed episodic autobiographical memories may be a sensitive indicator of subtle cognitive decline, because this type of memory taxes a core neural network affected by preclinical AD neuropathology. Methods: To begin to address this idea, we assessed the episodic specificity of autobiographical memories retrieved by cognitively normal middle-aged and older individuals who are carriers of the apolipoprotein E ε4 allele – a population at increased risk for subtle cognitive decline related to neuropathological risk factors for AD. We compared the ε4 carriers to non-carriers of ε4 similar in age, education, and gender. Results: The ε4 carriers did not perform worse than the non-carriers on a comprehensive battery of neuropsychological tests. In contrast, as a group, the ε4 carriers generated autobiographical memories that were reduced in “internal” or episodic details relative to non-carriers. Conclusions: These findings support the notion that reduced autobiographical episodic detail generation may be a marker of subtle cognitive decline associated with AD. (JINS, 2018, 24, 1073–1183)

Objectives: Evidence suggests that Alzheimer’s disease (AD) biomarkers become abnormal many years before the emergence of clinical symptoms of AD, raising the possibility that biomarker levels measured in cognitively normal individuals would be associated with cognitive performance many years later. This study examined whether performance on computerized cognitive tests is associated with levels of cerebrospinal fluid (CSF) biomarkers of amyloid, tau, and phosphorylated tau (p-tau) obtained approximately 10 years earlier, when individuals were cognitively normal and primarily middle-aged. Methods: Individuals from the BIOCARD cohort (mean age at testing=69 years) were tested on two computerized tasks hypothesized to rely on brain regions affected by the early accumulation of AD pathology: (1) a Paired Associates Learning (PAL) task (n=67) and (2) a visual search task (n=86). Results: In regression analyses, poorer performance on the PAL task was associated with higher levels of CSF p-tau obtained years earlier, whereas worse performance in the visual search task was associated with lower levels of CSF Aβ1-42. Conclusions: These findings suggest that AD biomarker levels may be differentially predictive of specific cognitive functions many years later. In line with the pattern of early accumulation of AD pathology, the PAL task, hypothesized to rely on medial temporal lobe function, was associated with CSF p-tau, whereas the visual search task, hypothesized to rely on frontoparietal function, was associated with CSF amyloid. Studies using amyloid and tau PET imaging will be useful in examining these hypothesized relationships further. (JINS, 2016, 22, 968–977)

Objectives: Mild cognitive impairments (MCI) is a transitional state in aging associated with increased risk of incident dementia. The current study investigated whether MCI status moderated the effect of time on word generation during verbal fluency tasks. Specifically, the objective was to determine whether MCI status had differential effects on initial automatic or latter more effortful retrieval processes of fluency tasks. Methods: Participants were community residing older adults enrolled in a longitudinal cohort study. Of the 408 participants, 353 were normal (age=76.06±6.61; %female=57.8) and 55 were diagnosed with MCI (age=78.62±7.00; %female=52.7). Phonemic and category fluency were each administered for 60 s, but performance was recorded at three consecutive 20-s intervals (0–20 s [T1], 21–40 s [T2], 41–60 s [T3]. Separate linear mixed effects models for each fluency task were used to determine the effects of group, time, and their interaction on word generation. Results: In both fluency tasks, word generation declined as a function of time. Individuals with MCI generated fewer words compared to controls during the first 20 s of phonemic (beta=−1.56; p<.001; d=0.28) and category fluency (beta=−1.85; p<.001; d=0.37). Group by time interactions revealed that individuals with MCI demonstrated attenuated declines in word generation from the first to the second and third time intervals of both phonemic ([T1 vs. T2] beta=2.17, p=.001; d=0.41; [T1 vs. T3]beta=2.28, p=.001; d=0.45) and category ([T1 vs. T2] beta= 2.22, p=.002; d=0.50; [T1 vs. T3]beta=3.16, p<.001; d=0.71) fluency. Conclusions: Early automatic retrieval processes in verbal fluency tasks are compromised in MCI. (JINS, 2017, 23, 44–55)

Serotonin (5-HT) plays an important role in depression and specific 5-HT reuptake blockers appear to be clinically important antidepressants. It is unclear however, which serotonergic mechanism is involved in the antidepressant effect, certainly when regarding the existence of at least seven 5-HT receptor subtypes. By testing different 5-HT ligands in two animal models of depression (forced swimming and DRL72-S test) and comparison with data from literature, evidence is provided for potential antidepressant qualities of 5-HT1A receptor-agonists and 5-HT1C receptor-antagonists. Compounds binding to 5-HT1B, 5-HT2 and 5-HT3 receptors do not have an antidepressant profile. Results of clinical research support the predicted antidepressive effects of 5-HT1A receptor-agonists.

Background: Spanish-language screening tests that are sensitive to the early cognitive changes of Alzheimer's disease (AD) are needed. Persons known to be at 50% risk for young-onset AD due to presenilin-1 (PSEN1) mutations provide the opportunity to assess which measures on the Mini-mental State Examination (MMSE) are most sensitive to these early changes.

Methods: We performed genetic and Spanish-language cognitive testing on 50 Mexican persons without dementia at risk for inheriting PSEN1 mutations. We then compared the performance on sub-items of the MMSE between PSEN1 mutation carriers (MCs) and non-carriers (NCs) using t-tests and Fisher's exact tests. Exploratory multiple logistic regression analyses were also performed.

Results: Twenty-nine persons were MCs and 21 NCs. NCs tended to achieve higher levels of education (p = 0.039) than did MCs. MCs tended to perform more poorly when spelling “MUNDO” backwards and on Orientation, particularly regarding the date. In multiple regression analyses the ability of backwards spelling to predict PSEN1 mutation status was reduced when education was included as an independent variable.

Conclusion: Subjects in the earliest stage of PSEN1-related AD showed deficits on orientation to date and in divided attention when spelling backwards. It is unclear if educational level should be considered an associated feature or a con-founding variable in this population although it should be taken into account when considering performance on the MMSE task of divided attention. The relative lack of deficits on delayed recall of three words probably represents the insensitivity of this measure in early AD. This study supports the utility of autosomal dominant AD as a model of the more common sporadic form of the disorder.

Recent studies have reported cognitive asymmetries in patients with Alzheimer's disease (AD) and in individuals with apolipoprotein E ε4 (APOE ε4) genotype who are in the preclinical phase of AD. This increased frequency of cognitive asymmetry, typically defined as a significant discrepancy (in either direction) between verbal and spatial abilities, often occurs despite an absence of differences on traditional measures of central tendency (i.e., mean test scores). We prospectively studied the relationship between APOE genotype and two modality-specific executive-function tasks: The Verbal Fluency and Design Fluency tests of the Delis-Kaplan Executive Function System (D-KEFS) in 52 normal functioning older adult participants who were grouped according to the presence (n = 24) or absence (n = 28) of the APOE ε4 allele. Nondemented older adults with the APOE ε4 allele demonstrated a greater frequency of cognitive asymmetric profile on the new switching conditions of the Verbal and Design Fluency measures than the APOE non-ε4 individuals. This study further supports the utility of assessing cognitive asymmetry for the detection of subtle cognitive differences in individuals at-risk for AD, and suggests that dual-task executive function tests (i.e., fluency plus switching) may serve as a useful preclinical marker of AD. (JINS, 2005, 11, 863–870.)

Nicotinic receptor loss has been implicated in the pathogenesis of Alzheimer's disease. The present study investigated the effects of chronic low-dose transdermal nicotine in a cohort of nondemented, healthy volunteers (mean age 63 years). The majority of subjects (85%) had a first-degree relation with dementia. Subjects were tested using a before, during, and after design on a battery of tests known to be sensitive to early cognitive decline. A mixed pattern of results was seen, with significant changes occurring with verbal learning, object learning, delayed recall, and word retrieval. Nicotine had no effect on measures of concentration or psychomotor speed. The effects were most noticeable in subjects at the lower end of baseline test performance on the tasks used. The results are discussed with reference to the relationship between strategic nicotinic receptor loss and measurable psychometric change. The potential therapeutic role of nicotinic agonists in preclinical “at risk” individuals is supported by the results of this study.

It is still a challenge to identify typical features of cognitive function in vascular dementia (VaD) in clinical as well as in preclinical stages. Selective empirical findings are described to illuminate degrees of cognitive decline. In predementia stages, speeded performance (motor and mental) and executive functions may be affected as demonstrated by CADASIL subjects and stroke survivors. In dementia stages, motor and mental speed as well as executive functions is commonly affected in addition to typical cognitive dysfunction in dementia (memory, verbal, and visuospatial). To summarize characteristics during preclinical and clinical stages, VaD appears to be associated with impairment in motor and mental speed as well as in executive function.