Risk of fall for individuals with intellectual disability.

Our aim was to identify risk factors for falling and establish a method to assess risk for falls in adults with intellectual disabilities. In a cross-sectional survey of 144 Japanese adults, we found that age, presence of epilepsy, and presence of paretic conditions were independent risk factors. The Tinetti balance and gait instrument was successfully administered to this population and resulted in high diagnostic accuracy (sensitivity 88.9%, specificity 91.9%) for identifying individuals at risk when the cutoff score was set at 25. Participants whose balance and gait deteriorated showed a decrease in the Tinetti score of at least 2 points per year. Thus, the Tinetti instrument may be an effective tool to detect an increased risk of fall in this population.

Psycho-educational Horseback Riding to Facilitate Communication Ability of Children with Pervasive Developmental Disorders.

In this study, we applied a novel psycho-educational horseback riding (PEHR) program to the treatment of four Japanese children with pervasive developmental disorders (PDD) in order to facilitate the acquisition of verbal and nonverbal communication skills. The behavioral changes in each child were evaluated using a psychological and behavioral scale. The scale for evaluating the effect of Human-Equips-Interaction on Mental activity (HEIM scale) was designed to assess the behavioral improvement of children based on the following 10 items: Human relationships, Imitation, Emotional expression, Sudden physical movement, Fixative behavior, Adaptation to change, Visual response, Fear or nervousness, and Verbal and nonverbal communication. After taking part in the PEHR program for several months, all subjects showed remarkably improved HEIM scores and marked improvements were observed in eye contact with others (instructors, side walkers, and leaders) in the riding area. A statistical difference was found in items 1, 2, 3, 6, 7, 8, and 9. However, no statistical difference was found in items 4, 5, and 10. As the program progressed, the children showed enhanced verbal and nonverbal communication skills, and became more expressive in their emotional and empathetic interaction with their parents. These observations suggest that the normal functioning of pleasurable emotions and empathy may facilitate further improvements in joint attention, imitation and empathy, and may result in successful verbal expression by PDD children. Therefore, horseback riding can play a very important role in the psycho-educational support required for the communication ability of PDD children.

Reduced expression of MAb6B4 epitopes on chondroitin sulfate proteoglycan aggrecan in perineuronal nets from cerebral cortices of SAMP10 mice: a model for age-dependent neurodegeneration.

The accelerated senescence-prone SAMP10 mouse strain is a model for age-dependent neurodegeneration and is characterized by brain atrophy and deficits in learning and memory. Because perineuronal nets play an important role in the synaptic plasticity of adult brains, we examined the distributions of molecules that constitute perineuronal nets in SAMP10 mouse brain samples and compared them with those in control SAMR1 mouse samples. Proteoglycan-related monoclonal antibody 6B4 (MAb6B4) clearly immunostained perineuronal nets in SAMR1 mice cortices, but the corresponding immunostaining in SAMP10 mice was very faint. MAb6B4 recognizes phosphacan/PTPzeta in immature brains. However, this antibody recognized several protein bands, including a 400-kDa core glycoprotein from chondroitin sulfate proteoglycan in homogenates of mature cortices from SAMR1 mice. The 400-kDa band was also recognized by antiaggrecan antibodies. The aggrecan core glycoprotein band was also detectable in samples from SAMP10 mice, but this glycoprotein was faintly immunostained by MAb6B4. Because MAb6B4 recognized the same set of protein bands that the monoclonal antibody Cat-315 recognized in mature cerebral cortices of SAMR1 mice, the MAb6B4 epitope appears to be closely related to that of Cat-315 and presumably represents a novel type of oligosaccharide that attaches to aggrecans. The Cat-315 epitope colocalized with aggrecan in perineuronal nets from SAMR1 mouse brain samples, whereas its expression was prominently reduced in SAMP10 mouse brain samples. The biological significance of the MAb6B4/Cat-315 epitope in brain function and its relationship to the neurodegeneration and learning disabilities observed in SAMP10 mice remain to be elucidated.

Involvement of pro-inflammatory cytokines and microglia in an age-associated neurodegeneration model, the SAMP10 mouse.

The SAMP10 mouse strain is a model of brain aging in which senescence is characterized by cerebral atrophy and neurodegeneration phenotypes. To investigate the role of neuroinflammation in the age-associated neurodegeneration of SAMP10 mice, we assessed the expression of several cytokines and chemokines in the atrophy-prone brain region of SAMP10, and control, SAMR1 mice, which show a normal aging process. We also studied morphological changes in microglia with advancing age in atrophied regions. The expression of IL-1beta and IFN-gamma mRNA was about 2-fold greater in SAMP10 mice as compared to SAMR1 mice throughout their life span. The expression of IL-6 mRNA was 2.0-fold greater in SAMP10 mice as compared to SAMR1 mice at 14 months of age, although there was no difference at 3 months of age. Fourteen-month-old mice had a 2.1-fold greater expression of TNF-alpha mRNA than 3-month-old mice in both strains. The expression of MCP-1 mRNA was greater in SAMP10 mice than SAMR1 mice, and tended to increase with advancing age. Activated microglia were rarely observed in both strains at 3 months of age. At 14 months of age, however, SAMP10 mice had a 5.6-fold greater number of activated microglia than SAMR1 mice. The aforementioned results suggest the presence of a higher pro-inflammatory status in the atrophy-prone brain region of SAMP10 mice as compared to SAMR1 mice. Neuroinflammation is a possible mechanism of age-associated neurodegeneration in SAMP10 mice.

Functional characterization of 3 thioredoxin homology domains of ERp72.

Folding of secretory proteins is associated with the formation and isomerization of disulfide bonds. ERp72, a protein disulfide isomerase (PDI) family member, possesses 3 thioredoxin homology domains, but the participation of each domain in disulfide-bond formation and isomerization remains to be determined. We analyzed the function of individual domains in the insulin reduction assay system by site-directed mutagenesis with cysteine-to-serine replacement. All domains contributed to apparent steady-state binding (Km) and catalysis at saturating substrate concentrations (kcat) but in different manners. A mutant ERp72 with mutations in domains 1 and 2 (ERp72-mut-1+2) exhibited reductions in kcat of 73.9% when compared with wild type, whereas ERp72-mut-1+3 (mutations in domains 1 and 3) and ERp72-mut-2+3 (mutations in domains 2 and 3) exhibited less substantial reductions in kcat. ERp72-mut-1+3 and ERp72-mut-2+3 showed elevations in Km of 89.9% and 96.2%, respectively, when compared with wild type, whereas ERp72-mut-1+2 exhibited smaller elevations in Km. These results suggest that domains 1 and 2 make greater contributions to catalyzing efficacy and domain 3 to binding affinity. Domain 2 is involved in binding affinity, in combination with domain 3, in addition to its own contribution to catalyzing efficacy. This assignment of functions to individual domains is similar to that observed in other PDI domains, which is consistent with the high sequence homology between ERp and PDI domains.

Expression of presenilin 1 and synapse-related proteins during postnatal development is not different between accelerated senescence-prone and -resistant mice.

SAMP1TA/Ngs is an inbred strain of senescence-accelerated mice in which there is delayed development of cognitive functions and dendritic spine formation compared with normal control SAMR1TA//Ngs mice. It is hypothesized that abnormalities might be in the postnatal expression of synapse-related proteins in SAMP1TA/Ngs mice. Quantitative western blot analyses showed that the postnatal developmental changes in the expression of synaptophysin, post-synaptic density protein 95 and presenilin 1 in the cerebrum were similar between SAMP1TA/Ngs and SAMR1TA//Ngs mice. Therefore, the expression of synapse-related proteins was not disturbed in SAMP1TA/ Ngs mice regardless of reported abnormal numbers of dendritic spines during postnatal development. Immunohistochemical studies showed that the expression of synaptophysin in the neuropil increased postnatally with development in the same way in SAMP1TA/Ngs and SAMR1TA//Ngs mice. Presenilin 1 expression was relatively high at age 5 days in the neuropil of the cerebral cortex and decreased with postnatal development in the same way in SAMP1TA/Ngs and SAMR1TA//Ngs mice. At age 5 days the distribution of presenilin 1 was similar to the distribution of synaptophysin in that there were two separate immunoreactive patterns: a subpial band and patches in the middle layers reminiscent of barrels. These findings suggest that presenilin 1 is transiently expressed in the neuropil to induce synaptogenesis, and then its expression decreases overall.

Age-related loss of synapses in the frontal cortex of SAMP10 mouse: a model of cerebral degeneration.

SAMP10 mouse is a model of brain aging in which senescence is characterized by cerebral atrophy most prominent in the frontal cortex, deterioration in performance of learning and memory tasks, and alterations of the central dopaminergic system. The present study investigates age-related changes in the expression of synapse-related proteins to determine whether the number of synapses is decreased in SAMP10 mice. We quantified expression levels of synaptophysin, a presynaptic protein, and of PSD-95, a postsynaptic protein in various brain regions by immunoblotting. Both synapse-related proteins (52% of synaptophysin and 55% of PSD-95) were lost from the anterior cerebral cortex in SAMP10 mice at age 10-12 months compared with those in mice at age 3 months. Synaptophysin was lost by 30% from the posterior cerebral cortex of SAMP10 mice at age 15-16 months. The level of synaptophysin, but not of PSD-95 decreased by about 25% in the brain stem of SAMP10 mice aged 7 and 10-12 months. A loss of synapse-related proteins was not significant in other brain regions. Age-related loss of synaptophysin or PSD-95 was not evident in normal aging control SAMR1 mice that do not develop brain atrophy. In summary, synapses were lost with aging in SAMP10 mice and the synaptic loss was most prominent in the anterior cerebral neocortex. Since a loss of neocortical synapses is the primary correlate with the intellectual decline in human neurodegenerative diseases, SAMP10 mouse is a useful model with which to study the mechanisms underlying synaptic loss in human neurodegenerative dementias.

Age-related progressive neuronal DNA damage associated with cerebral degeneration in a mouse model of accelerated senescence.

The DNA of cerebral neurons in subjects with Alzheimer's disease is extensively damaged, although the morphological features of apoptosis are absent. We investigated whether DNA is damaged in the brains of the SAMP10 strain of mouse, in which accelerated senescence is characterized by age-related cerebral atrophy and cognitive impairment. We performed quantitative terminal deoxynucleotidyl transferase-mediated digoxigenin-labeled dUTP nick end labeling (TUNEL), using paraffin sections. TUNEL positive cells increased in number in the cerebral neurons of SAMP10 mice with aging. TUNEL positive cells were widely distributed in mice at age 13-14 months, and obvious in the olfactory tubercle, anterior cingulate cortex, insular cortex, and amygdala. These TUNEL positive cells did not have the morphological features of apoptosis. Therefore, the DNA became damaged with advancing age through a mechanism other than apoptosis. SAMP10 is a useful mouse model of brain aging that mimics the progressive neuronal DNA damage associated with human neurodegenerative disorders.