Phospholipid composition and levels are not altered in fibroblasts bearing presenilin-1 mutations

Lipid alterations have been reported in brain regions affected by Alzheimer disease (AD). The mechanisms causing these changes are poorly understood because it is difficult to study dynamic, biochemical processes in post-mortem brain. Fibroblasts derived from AD patients offer an alternative model to study disease-related alterations in lipid metabolism. Therefore, we measured the phospholipid levels and composition of fibroblasts from individuals bearing two different presenilin-1 mutations and compared these values to appropriate control fibroblasts. There were no differences between groups in phospholipid composition or in individual phospholipid levels, including the plasmalogens. Cholesterol levels and the cholesterol/phospholipid ratio were not different between presenilin-1 mutation bearing and control fibroblasts. Although these presenilin-1 mutation bearing fibroblasts have a number of biochemical changes related to AD, the absence of a change in phospholipid levels suggests that under these conditions, these cells are not useful in studying the mechanisms underlying the alterations in brain phospholipid levels associated with AD. However, these results do not preclude the possible use of other fibroblasts bearing AD-related mutations, e.g., APP mutations, to examine AD-related changes in brain lipid metabolism, or of these fibroblasts under different conditions.     

Phospholipid composition and levels are altered in Down syndrome brain

Individuals chronically exposed to low levels of organophosphate insecticides may present with subtle impairments in cognition. In addition, low level diisopropylflurophosphate (DFP) exposure (0.25 mg/kg per day for 2 weeks) in rats resulted in protracted working memory impairment [29]. The current studies attempt to show a temporal relationship between the DFP-induced impairment in performance of a spatial memory task and the protracted decrease in the expression of cholinergic receptors and acetylcholinesterase in specific brain regions. Cholinergic receptors labeled with the ligands [(3)H]epibatidine and [(3)H]AFDX-384 were affected to a much greater extent and for a longer period of time than were both acetylcholinesterase activities and cholinergic receptors labeled with [(3)H]QNB. Pre-testing administration of nicotine was shown to completely reverse this DFP-induced impairment in memory-related task performance. Additionally, prophylaxis with pyridostigmine bromide (PB) caused DFP-treated animals to exhibit near normal levels of memory-related task performance. These results are consistent with the development of a protracted phase of learning impairment to sub-acute DFP exposure, which may involve the loss of hippocampal nicotinic receptors, and may be prevented or reversed by PB or nicotine, respectively.     

Phospholipid mass is increased in fibroblasts bearing the Swedish amyloid precursor mutation

Phospholipid changes occur in brain regions affected by Alzheimer disease (AD), including a marked reduction in plasmalogens, which could diminish brain function either by directly altering signaling events or by bulk membrane effects. However, model systems for studying the dynamics of lipid biosynthesis in AD are lacking. To determine if fibroblasts bearing the Swedish amyloid precursor protein (swAPP) mutation are a useful model to study the mechanism(s) associated with altered phospholipid biosynthesis in AD, we examined the steady-state phospholipid mass and composition of fibroblasts, including plasmalogens. We found a 15% increase in total phospholipid mass, accounted for by a 24% increase in the combined total of phosphatidylethanolamine and plasmanylethanolamine mass and a 19% increase in the combined total of phosphatidylcholine (PtdCho) and plasmanycholine (PakCho) mass in the swAPP mutant bearing fibroblasts. Cholesterol mass was unchanged in these cells. The changes in phospholipid mass did not alter the cellular molar composition of the phospholipids nor the cholesterol to phospholipid ratio. While plasmalogen mass was not altered, the ratio of choline plasmalogen (PlsCho) mass to PtdCho+PakCho mass was decreased 16% and there was a 14% reduction in the proportion of PlsCho as a percent of total phospholipids in the swAPP mutant bearing fibroblasts. This change in choline plasmalogen is consistent with the reported decreases in plasmalogen proportions in affected regions of AD brain, suggesting that these cells may serve as a useful model to determine the mechanism underlying changes in plasmalogen biosynthesis in AD brain.     

Gait development during lifespan in subjects with Down syndrome

In this work we studied and evaluated the effects of aging in a group of individuals with Down syndrome, using gait analysis as tool of investigation.32 individuals suffering from Down syndrome (DS) were enrolled in this study as group of pathological participants. The control group (CG) was composed by 36 healthy subjects (10 children, 15 teenagers and 16 adults) in order to evidence the differences between the normal and the pathological gait evolution in age-matched comparisons.The assessment consisted of 3D gait analysis: all pathological participants performed gait analysis in a longitudinal examination, from childhood to adulthood.Participants with DS evidenced how the delay in cognitive aspects and the typical orthopedic features of DS, as ligament laxity, led to the development of different motor strategies. During childhood, for both the considered populations, we found large variability in the gait indexes, but after this age a split in gait development was evidenced: the participants with DS developed a strategy focused on the reduction of the degrees of freedom, increasing the dispersion of generated power in the frontal plane, while in healthy participants the strategy was focused on the use of all the degrees of freedom, in order to reach the effectiveness of the gesture and finalize their movements in sagittal progression.The present study reinforces the idea that early intervention aimed to improve muscle tone, in order to supply for the excessive ligament laxity and to improve motor coordination, could represent a real goal for a more effective movement and for the prevention of compensatory strategies that increase energy cost.     

Postural control in children, teenagers and adults with Down syndrome

The goal of this work was to analyze postural control in Down syndrome (DS) participants considering three different groups composed by children, teenagers and adults with DS. An analysis of the centre of pressure (COP) displacement during standing position was therefore performed for the three groups of subjects. The obtained signal of COP was then analyzed in both time and frequency domains in order to perform a thorough analysis of the signal.Even if several parameters revealed more differences between the control and DS participants in adulthood, results indicated a divergence of these two groups starting from their early age, although the limit of this study considering a cross-sectional, and not a longitudinal comparison. In particular, COP medio-lateral range of motion pointed out a decrease for both groups considered (pathological and control) in time domain analysis that could lead to the same conclusion in developing strategies, but frequency domain analysis evidenced how this result is reached by the different population: DS people showed a larger frequency of movement in ML more evidenced in adults group (Down Syndrome Adults Group vs. Adults Control Group; 0.35 ± 0.22 Hz vs. 0.17 ± 0.15 Hz; p < 0.05). Even if less pronounced also for the other parameters computed these differences emerged. Aims for the two macro-groups, DS and CG, are different: DS people focused on overcoming the lack of equilibrium caused by hypotonia and ligament laxity, while control group attempted to improve their strategy in term of efficiency, pointing out a different strategy development.     

Effects of chronic proline administration on lipid contents of rat brain

In the present work we investigated the effects of chronic proline administration on ganglioside, cholesterol and phospholipid total contents, as well as on ganglioside profile in cerebral cortex, hippocampus, hypothalamus and cerebellum of rats. We also evaluated the ganglioside content and profile in detergent-soluble and resistant microdomains isolated from synaptic membranes obtained from cerebral cortex. Proline solution (hyperprolinemic) or saline (control) were subcutaneously administered to rats from 6th to 28th post-natal day, according to body weight. Twelve hours after the last injection, the animals were sacrificed by decapitation without anaesthesia. Brain structures were homogenized with chloroform:methanol for lipid extraction. Synaptic membranes were obtained by differential centrifugation and detergent-soluble and resistant microdomains were isolated by cold Triton X-100 treatment. Results showed that rats subjected to chronic proline treatment presented a significant increase of ganglioside content in cortex and hippocampus, while this membrane lipid content was not altered in hypothalamus and cerebellum. Besides, phospholipid and cholesterol contents were not modified in all structures studied. On the other hand, ganglioside content decreased in detergent-soluble and resistant microdomains isolated from synaptic membrane obtained from hyperprolinemic cortex. Although ganglioside profiles were apparently not modified, the individual absolute quantities were altered in cortex and hippocampus total lipid extract and membrane microdomains. Our findings suggest that chronic proline treatment affects in a distinct manner different cerebral regions concerning the lipid composition of the cell membranes, reflecting on its distribution in the cortex membrane microdomains. Among these phenomena consequences, distinct modulations in synaptic transmission may be suggested which might contribute to the impairment in cognition and/or other neurological dysfunctions found in hyperprolinemia type II patients.     

Brain stem infarction in a 6-year-old boy with Down syndrome

Infarct locations in children with arterial ischemic stroke have primarily been reported to be lobar or in the basal ganglia, and those in patients with Down syndrome (DS) and antiphospholipid syndrome (APS) are typically wide and multiple. No solitary brain stem infarctions have ever been reported in children with DS until now. Here, we report a case of brain stem infarction in a 6-year-old boy with DS who had no cardiac, renal, or intestinal complications. He exhibited ataxic gait and medial longitudinal fasciculus (MLF) symptoms at first presentation. Neuroimaging revealed a localized and isolated lesion in the midbrain. Although he did not satisfy the diagnostic criteria of APS, he showed persistently elevated levels of anticardiolipin antibody (21?U/mL; normal value <10?U/mL). Although he had the risks of a multiple vascular systems disorder, DS, and persistently elevated levels of antiphospholipid antibodies, his lesion was not similar to any of the previously reported cerebral infarctions in DS or in APS. To our knowledge, this is the first report of limited solitary brain stem infarction in a child with DS.     

Age-related changes in the density and morphology of plaques and neurofibrillary tangles in Down syndrome brain

Summary Fifteen cases of Down syndrome between age 25–59 years were examined neuropathologically. A variety of histological methods were used to identify plaques and neurofibrillary tangles (NFT). All cases had some plaques or NFT, but their density was generally not high before the age of 40 years. Plaques and NFT tended to appear at about the same time although in somewhat different cortical areas. Changes appeared first in the dentate gyrus, subiculum, entorhinal and association neocortex. The stages in the evolution of plaque morphology were quantitated in the dentate gyrus. The earliest change was the extracellular accumulation of fibrillar material with the histological characteristics of amyloid. In the second stage there was an exuberant neuritic reaction with swollen processes that contained little or no paired helical filaments (PHF). Stage 1 and 2 plaques were seen predominantly between ages 25–38 years, and were not obviously associated with blood vessels or glial cells. In the third stage of plaque formation neurites appeared to degenerate, contained more PHF, and surrounded a compact core of amyloid. Stage 3 plaques were never very numerous, and were seen only between ages 48–55 years. Stage 4 plaques consisted of a cloud of silver-positive debris. They appeared to be the final stage and were the predominant morphological type in the dentate gyrus after age 48 years. Amyloid angiopathy was present only after age 48, and was a prominent finding in only three cases.Supported in part by The Committee for the American Memorial Hospital, and by grants NS 23973, MH/NS 31862 and AGO 5134     

Onset of seizures as a poor indicator of longevity in people with down syndrome and dementia

An association between Down syndrome and dementia of Alzheimer type is well established. This study demonstrates that late onset seizures in people with Down syndrome are a strong indicator of a dementing process. Further, late onset seizures in people with Down syndrome may be used as a prognostic indicator, indicating life expectancy of less than a further 2 years, probable death within 3 years and death almost invariably within 5 years of onset.     

Visual evoked potential in the diagnosis of dementia in people with down syndrome

The diagnosis of dementia in people with Down syndrome (DS) remains controversial. In this study DS patients who had a diagnosis of clinical dementia according to modified DSM-III-R criteria were assessed using the flash (P2) and pattern-reversal (P100) visual evoked potential (VEP). Abnormal VEP recordings were apparent in both demented and non-demented subjects. None of the demented subjects had the characteristic (P2–P100 latency difference) VEP changes reported in adults in the general population suffering from dementia. The VEP is unlikely to be a useful tool in the diagnosis of dementia in people with DS.     

Germinoma in cerebral hemisphere associated with Down syndrome

A Down syndrome patient with germinoma developing in the cerebral hemisphere is reported. A review of the literature yielded only 14 cases of Down syndrome with brain tumors, including our case. This finding of brain tumors in patients with Down syndrome may reflect chance occurrence. However, it is of interest in this regard that in 6 of the 14 (43%) reported cases the lesions were intracranial germ cell tumors. Received: 15 March 1996 Revised: 20 May 1996     

Movement skills of younger versus older adults with and without Down syndrome

Adults with Down syndrome (DS) are often physically inactive, which may accelerate the onset of disease and aging symptoms. Eight older persons with DS (aged 54-61), and 10 younger persons with DS (aged 26-35) living in a residential care center were examined. Eighteen age- and gender-matched individuals without DS served as control groups. Sensory-motor tasks and Posture Scale Analyzer (PSA) were used to examine coordination and standing stability. The isokinetic muscle strength test was used for muscle strength investigation. The functional performance, coordination, and leg muscle strength of the older adults with DS were more impaired than both the younger DS and the control groups. The older DS group showed lower sway rate and more symmetrical weight-bearing distribution during quiet standing than both the younger DS and the control groups. Our observations may have significant implications for understanding movement dysfunction in older adults with DS.     

Violence: heightened brain attentional network response is selectively muted in Down syndrome

Background

The ability to recognize and respond appropriately to threat is critical to survival, and the neural substrates subserving attention to threat may be probed using depictions of media violence. Whether neural responses to potential threat differ in Down syndrome is not known.

Methods

We performed functional MRI scans of 15 adolescent and adult Down syndrome and 14 typically developing individuals, group matched by age and gender, during 50 min of passive cartoon viewing. Brain activation to auditory and visual features, violence, and presence of the protagonist and antagonist were compared across cartoon segments. fMRI signal from the brain’s dorsal attention network was compared to thematic and violent events within the cartoons between Down syndrome and control samples.

Results

We found that in typical development, the brain’s dorsal attention network was most active during violent scenes in the cartoons and that this was significantly and specifically reduced in Down syndrome. When the antagonist was on screen, there was significantly less activation in the left medial temporal lobe of individuals with Down syndrome. As scenes represented greater relative threat, the disparity between attentional brain activation in Down syndrome and control individuals increased. There was a reduction in the temporal autocorrelation of the dorsal attention network, consistent with a shortened attention span in Down syndrome. Individuals with Down syndrome exhibited significantly reduced activation in primary sensory cortices, and such perceptual impairments may constrain their ability to respond to more complex social cues such as violence.

Conclusions

These findings may indicate a relative deficit in emotive perception of violence in Down syndrome, possibly mediated by impaired sensory perception and hypoactivation of medial temporal structures in response to threats, with relative preservation of activity in pro-social brain regions. These findings indicate that specific genetic differences associated with Down syndrome can modulate the brain’s response to violence and other complex emotive ideas.

Electronic supplementary material

The online version of this article (doi:10.1186/s11689-015-9112-y) contains supplementary material, which is available to authorized users.     

Age-specific prevalence,thyroid dysfunction and depressive symptomatology in adults with down syndrome and dementia

Two hundred and one adults with Down syndrome (DS) were investigated for differing aspects of clinical dementia. Age-specific prevalence rates of 9.4% for age range 40–49 years, 36.1% for 50–59 years and 54.5% for 60–69 years were found. Findings associated with increasing severity of dementia were gait deterioration, onset of urinary incontinence, increased muscle tone and onset of seizures. No association was found between thyroid dysfunction or thyroid autoimmunity and dementia. However, depressive symptomatology of depressed mood, weight loss and reduced appetite were associated with dementia. These findings investigating Alzheimer's disease (AD) in adults with DS support findings reported for the non-learning disability population of an association between age, depressive symptomatology and AD but no association between thyroid dysfunction and AD.     

Age of onset and duration of dementia in people with down syndrome: Integration of 98 reported cases in the literature

The published case reports of 98 people with Down Syndrome were studied with respect to the age of onset and duration of clinically diagnosed dementia. The incidence of dementia was unimodal, increasing rapidly from 40 years to a peak of 30% incidence in the fifth decade of life, followed by a further rapid decline. Females with Down syndrome had an earlier onset. Duration of dementia decreased with increasing age of onset for both males and females.     

Alpha-tocopherol levels in brain are not altered in Parkinson's disease.

alpha-Tocopherol (vitamin E) levels in normal brain were lower in the cerebellum than in the cerebral cortex or basal ganglia. There was no difference in alpha-tocopherol levels in the cerebellum, basal ganglia, or cerebral cortex between control subjects and patients with Parkinson's disease.     

The role of altered sodium currents in action potential abnormalities of cultured dorsal root ganglion neurons from trisomy 21 (down syndrome) human fetuses

Trisomy 21 (Down syndrome) results in abnormalities in electrical membrane properties of cultured human fetal dorsal root ganglion (DRG) neurons. Action potentials have faster rates of depolarization and repolarization, with decreased spike duration, compared to diploid neurons. In order to analyze the faster depolarization rate observed in trisomic neurons, we examined sodium currents of cultured human fetal DRG neurons from trisomy 21 and control subjects, using the whole-cell patch-clamp technique. The neurons were replated in culture to reduce dendritic spines. Two components of the sodium current were identified: (1) a fast, tetrodotoxin (TTX)-sensitive current; and (2) a slow, TTX-resistant component. The inactivation curves of both current types in trisomic neurons showed a shift of approximately 10 mV towards more depolarized potentials compared to control neurons. Thus, whereas essetially all of the fast sodium channels were inactivated at normal resting potentials in control neurons, approximately 10% of these channels were available for activation in trisomy 21 cells. Furthermore, the fast current showed accelerated activation kinetics in trisomic neurons. The slow sodium current of trisomic neurons showed slower deactivation kinetics than control cells. No differences were observed between trisomic and control neurons in the maximal conductance or current densities of either fast or slow current components. These data indicate that the greater rate of depolarization in trisomy 21 neurons at resting potentials is primarily due to activation of residual fast sodium channels that also have a faster time course of activation.     

Differences in age-related effects on brain volume in Down syndrome as compared to Williams syndrome and typical development

Background

Individuals with Down Syndrome (DS) are reported to experience early onset of brain aging. However, it is not well understood how pre-existing neurodevelopmental effects versus neurodegenerative processes might be contributing to the observed pattern of brain atrophy in younger adults with DS. The aims of the current study were to: (1) to confirm previous findings of age-related changes in DS compared to adults with typical development (TD), (2) to test for an effect of these age-related changes in a second neurodevelopmental disorder, Williams syndrome (WS), and (3) to identify a pattern of regional age-related effects that are unique to DS.

Methods

High-resolution T1-weighted MRI of the brains of subjects with DS, WS, and TD controls were segmented, and estimates of regional brain volume were derived using FreeSurfer. A general linear model was employed to test for age-related effects on volume between groups. Secondary analyses in the DS group explored the relationship between brain volume and neuropsychological tests and APOE.

Results

Consistent with previous findings, the DS group showed significantly greater age-related effects relative to TD controls in total gray matter and in regions of the orbitofrontal cortex and the parietal cortex. Individuals with DS also showed significantly greater age-related effects on volume of the left and right inferior lateral ventricles (LILV and RILV, respectively). There were no significant differences in age-related effects on volume when comparing the WS and TD groups. In the DS group, cognitive tests scores measuring signs of dementia and APOE ϵ4 carrier status were associated with LILV and RILV volume.

Conclusions

Individuals with DS demonstrated a unique pattern of age-related effects on gray matter and ventricular volume, the latter of which was associated with dementia rating scores in the DS group. Results may indicate that early onset of brain aging in DS is primarily due to DS-specific neurodegenerative processes, as opposed to general atypical neurodevelopment.     

Serum cytokine levels are altered in patients with West syndrome.

The objective of this study is to explore the neuroimmunomodulator effect of interleukin (IL)-2, tumor necrosis factor (TNF)-alpha and interferon (IFN)-alpha in West syndrome (WS). Twenty-three cases of WS (13 males and 10 females, aged 4-14 months old) who first visited and consisted from 10 cryptogenic and 13 symptomatic, were enrolled in this study. Double-antibody sandwich enzyme-linked immunosorbent assay was used to measure serum IL-2, TNF-alpha and IFN-alpha levels in 23 patients with WS and the data were compared to those of 15 healthy infants who were matched with regard to age and sex. Levels of all three cytokines were significantly higher in both cryptogenic and symptomatic WS groups than the control group. Serum IL-2 levels in symptomatic WS were significantly higher than that in cryptogenic WS. There was a positive correlation between IL-2 and TNF-alpha in both cryptogenic and symptomatic WS groups. The immune systems of patients with WS are in an activated state. An imbalance in cytokine levels may be involved in the immunopathology of WS.