BACKGROUND AND PURPOSE: Subjective cognitive decline (SCD) may be the first symptomatic stage of Alzheimer's disease (AD). Hence, a screening tool to characterize the patients' complaints and assess the risk of AD is required. We investigated the SCD neuroimaging biomarker distributions and the relevance between the self-report questionnaire and Alzheimer's pathologic changes. METHODS: Individuals aged 50 and above with consistent cognitive complaints without any objective cognitive impairments were eligible for the study. The newly developed questionnaire consisted of 2 parts; 10 questions translated from the ‘SCD-plus criteria’ and a Korean version of the cognitive failure questionnaire by Broadbent. All the subjects underwent physical examinations such as blood work, detailed neuropsychological tests, the self-report questionnaire, brain magnetic resonance imagings, and florbetaben positron emission tomography (PET) scans. Amyloid PET findings were interpreted using both visual rating and quantitative analysis. Group comparisons and association analysis were performed using SPSS (version 18.0). RESULTS: A total of 31 participants with SCD completed the study and 25.8% showed positive amyloid depositions. The degree of periventricular white matter hyperintensities (WMH) and hippocampal atrophy were more severe in amyloid-positive SCDs compared to the amyloid-negative group. In the self-reported questionnaire, the ‘informant's report a decline’ and ‘symptom's onset after 65 years of age’ were associated with more Alzheimer's pathologic changes. CONCLUSIONS: Amyloid-positive SCDs differed from amyloid-negative SCDs on WMH, hippocampal atrophy, and a few self-reported clinical features, which gave clues on the prediction of AD pathology.
Alzheimer Disease ; Amyloid ; Atrophy ; Biomarkers ; Brain ; Cognition Disorders ; Mass Screening ; Neuroimaging ; Neuropsychological Tests ; Pathology ; Physical Examination ; Plaque, Amyloid ; Positron-Emission Tomography ; White Matter

Cognitive impairments and motor dysfunction are commonly observed behavioral phenotypes in genetic animal models of neurodegenerative diseases. JNPL3 transgenic mice expressing human P301L-mutant tau display motor disturbances with age- and gene dose-dependent development of neurofibrillary tangles, suggesting that tau pathology causes neurodegeneration associated with motor behavioral abnormalities. Although gait ignition failure (GIF), a syndrome marked by difficulty in initiating locomotion, has been described in patients with certain forms of tauopathies, transgenic mouse models mirroring human GIF syndrome have yet to be reported. Using the open field and balance beam tests, here we discovered that JNPL3 homozygous mice exhibit a marked delay of movement initiation. The elevated plus maze excluded the possibility that hesitation to start in JNPL3 mice was caused by enhanced levels of anxiety. Considering the normal gait ignition in rTg4510 mice expressing the same mutant tau in the forebrain, GIF in JNPL3 mice seems to arise from abnormal tau deposition in the hindbrain areas involved in locomotor initiation. Accordingly, immunohistochemistry revealed highly phosphorylated paired helical filament tau in JNPL3 brainstem areas associated with gait initiation. Together, these findings demonstrate a novel behavioral phenotype of impaired gait initiation in JNPL3 mice and underscore the value of this mouse line as a tool to study the neural mechanisms and potential treatments for human GIF syndrome.
Animals ; Anxiety ; Brain Stem ; Cognition Disorders ; Gait ; Humans ; Immunohistochemistry ; Locomotion ; Mice ; Mice, Transgenic ; Models, Animal ; Neurodegenerative Diseases ; Neurofibrillary Tangles ; Pathology ; Phenotype ; Prosencephalon ; Rhombencephalon ; Tauopathies

Neuroplastin 65 (Np65) is an immunoglobulin superfamily cell adhesion molecule involved in synaptic formation and plasticity. Our recent study showed that Np65-knockout (KO) mice exhibit abnormal cognition and emotional disorders. However, the underlying mechanisms remain unclear. In this study, we found 588 differentially-expressed genes in Np65-KO mice by microarray analysis. RT-PCR analysis also revealed the altered expression of genes associated with development and synaptic structure, such as Cdh1, Htr3a, and Kcnj9. In addition, the expression of Wnt-3, a Wnt protein involved in development, was decreased in Np65-KO mice as evidenced by western blotting. Surprisingly, MRI and DAPI staining showed a significant reduction in the lateral ventricular volume of Np65-KO mice. Together, these findings suggest that ablation of Np65 influences gene expression, which may contribute to abnormal brain development. These results provide clues to the mechanisms underlying the altered brain functions of Np65-deficient mice.
Affective Symptoms ; metabolism ; Animals ; Brain ; diagnostic imaging ; metabolism ; pathology ; Cognition Disorders ; metabolism ; Gene Expression ; Magnetic Resonance Imaging ; Membrane Glycoproteins ; deficiency ; genetics ; physiology ; Mice, Knockout ; Microarray Analysis ; Organ Size ; Real-Time Polymerase Chain Reaction ; Wnt3 Protein ; metabolism

BACKGROUND: Normal pressure hydrocephalus (NPH) is an etiology of dementia that is reversible following cerebrospinal fluid shunt placement, however, surgical intervention not always clinically effective and the respons to shunt therapy is poorly understood. Furthermore, NPH is a source of comorbidity in diseases with neurodegenerative pathology, such as Alzheimer's disease (AD). CASE REPORT: A 61-year-old woman presented to the neurology clinic with progressive gait difficulties and cognitive impairment over five years. Nine years after ventriculoperitoneal (VP) shunt treatment, the patient began to experience frequent falls. There was no improvement in clinical symptoms after the alteration of valve pressure on the VP shunt. An 18F-florbetaben amyloid positron emission tomography scan showed increased diffusion uptake over the bilateral cortices, precuneus, and posterior cingulate cortex. CONCLUSIONS: The patient of NPH was unresponsive to shunt therapy due to the development of AD.
Accidental Falls ; Alzheimer Disease* ; Amyloid ; Cerebrospinal Fluid Shunts ; Cognition Disorders ; Comorbidity ; Dementia ; Diffusion ; Female ; Gait ; Gyrus Cinguli ; Humans ; Hydrocephalus* ; Hydrocephalus, Normal Pressure ; Middle Aged ; Neurology ; Parietal Lobe ; Pathology ; Positron-Emission Tomography

The term “particulate Matter (PM)” refers to the mixture of small-sized solid particles and liquid droplets floating in the air, and is referred to as PM₁₀ ( < 10 µm), PM(2.5) ( < 2.5 µm) and PM(1.0). Much PM is an anthropogenic substance generated by transportation or industrial activities, which is transformed into a second toxic substance by chemical reactions in the atmosphere. PM reaches the brain directly through olfactory transport, or through the blood-brain barrier during systemic circulation. PM that enters the local cerebral circulation causes neuroinflammation through microglial cells and endotoxins. According to previous studies, greater PM exposure results in lower brain volume, especially white matter. Among neurodevelopmental disorders, the correlation between the occurrence of autism spectrum disorder and exposure to PM is widely known. Other studies have found that exposure to PM was associated with low cognitive function and increased rate of cognitive aging. PM can also cause pathology of early Alzheimer's disease and increases the risk of Alzheimer's dementia and mild cognitive impairment.
Air Pollution ; Alzheimer Disease ; Atmosphere ; Autism Spectrum Disorder ; Blood-Brain Barrier ; Brain ; Cerebrovascular Circulation ; Cognition ; Cognitive Aging ; Dementia ; Endotoxins ; Mild Cognitive Impairment ; Neurodevelopmental Disorders ; Particulate Matter ; Pathology ; Transportation ; White Matter

The seeds of addiction are typically sown years prior to the onset of addictive substance use or engagement in addictive behaviors, due to the priming of the reward pathway (RewP) by alterations in the mechanism of stress-signaling from the hypothalamic-pituitary-adrenal axis (HPA) and related pathways. Excessive stress from a single-event and/or cumulative life experiences during childhood, such as those documented in the Adverse Childhood Experiences Study, is translated into neurobiological toxicity that alters the set-point of the HPA axis and limbic system homeostasis [suggested new term: regulation pathway (RegP)]. The resultant alteration of the RegP not only increases the risk for psychiatric and physical illness, but also that for early onset and chronic addictions by dysregulating the RewP. This paper reviews the interface of these symbiotic pathways that result in the phenotypic pathology of emotional dysregulation, cognitive impairment, and compulsive behaviors, as well as morbidity and shorter life expectancy when dysregulated by chronic stress.
Behavior, Addictive ; Cognition Disorders ; Compulsive Behavior ; Homeostasis ; Life Change Events ; Life Expectancy ; Limbic System ; Pathology ; Reward

Psychophysiological and functional neuroimaging studies have frequently and consistently shown that emotional information can be processed outside of the conscious awareness. Non-conscious processing comprises automatic, uncontrolled, and fast processing that occurs without subjective awareness. However, how such non-conscious emotional processing occurs in patients with various psychiatric disorders requires further examination. In this article, we reviewed and discussed previous studies on the non-conscious emotional processing in patients diagnosed with anxiety disorder, schizophrenia, bipolar disorder, and depression, to further understand how non-conscious emotional processing varies across these psychiatric disorders. Although the symptom profile of each disorder does not often overlap with one another, these patients commonly show abnormal emotional processing based on the pathology of their mood and cognitive function. This indicates that the observed abnormalities of emotional processing in certain social interactions may derive from a biased mood or cognition process that precedes consciously controlled and voluntary processes. Since preconscious forms of emotional processing appear to have a major effect on behaviour and cognition in patients with these disorders, further investigation is required to understand these processes and their impact on patient pathology.
Anxiety Disorders ; Bias (Epidemiology) ; Bipolar Disorder ; Cognition ; Depression ; Functional Neuroimaging ; Humans ; Interpersonal Relations ; Pathology ; Psychopathology* ; Schizophrenia

BACKGROUNDAmyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in the AD brains, Aβ accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model.

METHODSThe 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Aβ (oAβ) (1-42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence.

RESULTSIn 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as Iba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAβ (1-42) induced the production of senescence-related protein p16, but not p53 in vitro, which was in line with the in vivo manifestation.

CONCLUSIONSoAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population.

Alzheimer Disease ; metabolism ; physiopathology ; Amyloid Precursor Protein Secretases ; genetics ; metabolism ; Amyloid beta-Peptides ; metabolism ; Amyloid beta-Protein Precursor ; metabolism ; Animals ; Aspartic Acid Endopeptidases ; genetics ; metabolism ; Brain ; metabolism ; physiopathology ; Cells, Cultured ; Cellular Senescence ; genetics ; physiology ; Cognition ; physiology ; Cognition Disorders ; metabolism ; physiopathology ; Disease Models, Animal ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurons ; metabolism ; pathology ; Real-Time Polymerase Chain Reaction

PURPOSE: This study was conducted to synthesis the results of research on relationships of cognitive impairment with multi-dimensional correlates of rheumatic disease through a systematic literature review and meta-analysis. METHODS: For the study purpose, 23 studies were selected through a systematic process of searching the literature. RESULTS: The study results showed that among general characteristics, age and education were the variables having a significant relationship with cognitive impairment. Among health risk factors, obesity appeared to have a significant positive relationship with cognitive impairment. For past history, diabetes and hypertension were shown to have a significant positive relationship with cognitive impairment. It was noted also that aPL, one of the physiological factor, had significant association with cognitive impairment. None of the medication related factors had a significant relationship with cognitive impairment. Results showed that among disease related factors, disease activity had the highest relationship with cognitive impairment. Depression, among psychological factors, was the only variable having a significant relationship with cognitive impairment. CONCLUSION: The findings indicate that the variables strongly impacting on cognitive impairment in rheumatic disease are depression and disease activity.
Anxiety ; Cognition ; Cognition Disorders/complications/*pathology ; Databases, Factual ; Depression/complications ; Humans ; Hypertension/complications ; Obesity/complications ; Rheumatic Diseases/complications/*pathology ; Risk Factors

Vascular dementia is a very frequent form of dementia. Debates over classification and diagnostic criteria, and controversy over identifiable treatment targets will continue until distinct pathophysiological mechanism of vascular dementia is found. Clinical diagnostic criteria are sufficiently strong to be useful for clinical trials, but need further refinement. Cognitive changes in vascular dementia are more variable than other disorders, and are dependent on the vascular pathology. Accurate diagnosis of vascular dementia is known to need the presence of reliable cerebrovascular disease on brain imaging. Although it seems obvious that cerebrovascular disease causes pathological damage and impaired cognition, it is very difficult to find the accurate contribution of cerebrovascular pathology to cognitive decline. Most studies have shown a small but significant benefit of cholinesterase inhibitors on cognition, the significance of this effect has been slight and benefits on global functioning, activities of daily living, and behaviour have not been consistently reported. Management of vascular dementia should focus on identifying and managing vascular risk factors.
Activities of Daily Living ; Cerebrovascular Disorders ; Cholinesterase Inhibitors ; Classification ; Cognition ; Dementia ; Dementia, Vascular* ; Diagnosis ; Neuroimaging ; Pathology ; Risk Factors