A link between sICAM-1, ACE and parietal blood flow in the aging brain.

A connection between Alzheimer's disease (AD) and endothelium pathology has been inferred from measured decreases in both blood flow and metabolism in the parietal and temporal cortex. However, it is not known whether these alterations are seen in normal aging. We performed regional cerebral blood flow (rCBF) measurements in 22 AD patients and in 44 non-demented subjects during a simple test of information processing speed. Cerebrospinal fluid (CSF) levels of angiotensin-converting enzyme (ACE) and the soluble form of intercellular adhesion molecule-1 (sICAM-1) were analyzed in non-demented subjects. We found correlations between sICAM-1 and ACE (p=0.004), and sICAM (but not ACE) and CSF/plasma albumin ratio (p<0.0001). Higher concentrations of sICAM-1 (>893ng/L) and ACE (>5.22microg/L) were exclusively associated with lower parietal blood flow (p<0.001). The rCBF patterns in the AD and non-demented subjects with biomarker levels above median showed similar reductions in the temporoparietal areas. Our findings provide evidence that elevated CSF sICAM-1 and ACE are associated with lower perfusion levels in the parietal cortex of cognitively intact elderly.

rCBF pathology in Alzheimer's disease is associated with slow processing speed.

Decreased information processing speed (mental slowing) is a known sequelae of many brain disorders, and can be assessed by continuous naming tasks. Functional imaging studies have shown that pause and articulation times in continuous speech are normally associated with different brain regions, but knowledge about such association in dementia is lacking. We therefore tested the hypothesis that perfusion deficits in Alzheimer's disease (AD) are not only associated with slower processing, but also with these speech measures. Using regional cerebral blood flow (rCBF) measurements during the performance of a continuous colour and form-naming task, we found that naming speed was substantially slower in AD patients than in controls. This slower naming was exclusively determined by an increase in mean pause time, and only to a limited extent by articulation time. The increased pause time was uniquely associated with temporo-parietal rCBF reductions of the patients, while articulation was not. By contrast, the rCBF of healthy elderly control subjects was consistently accompanied by substantially shorter articulation and pause times, although the naming measures were not statistically associated with rCBF. These findings suggest that pause time (in contrast to articulation time) may serve as a sensitive measure in the assessment of information processing speed deficits in dementia, by virtue of its close association with brain pathology.

Stability of longitudinal motor development in very low birthweight infants from 5 months to 5.5 years.

AIM: The motor performance of 165 very low birthweight (VLBW) infants was assessed prospectively at 5, 10, 18 mo and 5.5 y. The aim of the study was to evaluate longitudinal stability of motor development and its association with birthweight (BW), gestational age at birth, intraventricular haemorrhage (IVH), periventricular leucomalacia (PVL) and retinopathy of prematurity (ROP). Furthermore, at 5.5 y the motor behaviour of the VLBW population was compared with that of 124 children born at term. METHODS: The results of each examination were ranked into four levels and the stability of motor development was evaluated on the basis of this ranking. At 5.5 y, VLBW children and controls were compared according to percentiles in the Movement ABC. RESULTS: Fifty-three percent of the VLBW infants displayed a stable motor development. Only PVL and BW contributed significantly to the variability in their motor performance. Forty-seven percent of the infants exhibited an unstable motor development with no association to risk factors. In the entire group only IVH and severe ROP were related to poor motor performance. The majority of the VLBW children performed within the normal range at 5.5 y but their performances were inferior to those of control children. CONCLUSION: VLBW infants with poor early motor performance and/or severe IVH/PVL and ROP should be recruited into individualized follow-up programmes, whereas regular ongoing monitoring by follow-up may be sufficient for those with normal early motor performance and normal ultrasound findings.

[Primary pulmonary manifestation of extramedullary acute myelocytic leukemia]. / Primär pulmonale Manifestation einer extramedullären akuten myeloischen Leukämie.

We report on a 49 year old female with primary extra-medullary manifestation of a acute myeloid leukemia in the lungs without leukemic signs. The disease was diagnosed by detection of leukemic blast cells in bronchoalveolar lavage. Chemotherapy with the TAD-VP-scheme resulted in partial remission. The patient died in systemic early relapse. To our knowledge this is the first description of primary isolated extra-medullary manifestation of a acute myeloid leukemia in the lungs.

Genetic architecture of adiposity in the cross of LG/J and SM/J inbred mice.

The genetic basis of variation in obesity in human populations is thought to be owing to many genes of relatively small effect and their interactions. The LG/J by SM/J intercross of mouse inbred strains provides an excellent model system in which to investigate multigenic obesity. We previously mapped a large number of quantitative trait loci (QTLs) affecting adult body weight in this cross. We map body composition traits, adiposity, and skeletal size, in a replicate F2 intercross of the same two strains containing 510 individuals. Using interval-mapping methods, we located eight QTLs affecting adiposity (Adip1-8). Two of these adiposity loci also affected tail length (Adip4 and Adip6) along with seven additional tail length QTLs (Skl1-7). A further four QTLs (Wt1-4) affect adult weight but not body composition. These QTLs have relatively small effects, typically about 0.2-0.4 standard deviation units, and account for between 3% and 10% of the variance in individual characters. All QTLs participated in epistatic interactions with other QTLs. Most of these interactions were due to additive-by-additive epistasis, which can nullify the apparent effects of single loci in our population. Adip8 interacts with all the other adiposity QTLs and seems to play a central role in the genetic system affecting obesity in this cross. Only two adiposity QTLs, Adip4 and Adip6, also affect tail length, indicating largely separate genetic control of variation in adiposity and skeletal size. Body size and obesity QTLs in the same locations as those discovered here are commonly found in mapping experiments with other mouse strains.

Mapping quantitative trait loci for murine growth: a closer look at genetic architecture.

Over 20 years ago, D. S. Falconer and others launched an important avenue of research into the quantitative of body size growth in mice. This study continues in that tradition by locating quantitative trait loci (QTLs) responsible for murine growth, such as age-specific weights and growth periods, and examining the genetic architecture for body weight. We identified a large number of potential QTLs in an earlier F2 intercross (Intercross I) of the SM/J and LG/J inbred mouse strains. Many of these QTLs are replicated in a second F2 intercross (Intercross II) between the same two strains. These replicated regions provide candidate regions for future fine-mapping studies. We also examined body size and growth QTLs using the combined data set from these two intercrosses, resulting in 96 microsatellite markers being scored for 1045 individuals. An examination of the genetic architecture for age-specific weight and growth periods resulted in locating 20 separate QTLs, which were mainly additive in nature, although dominance was found to affect early growth and body size. QTLs affecting early and late growth were generally distinct, mapping to separate chromosome locations. This QTL pattern indicates largely separate genetic and physiological systems for early and later murine growth, as Falconer suggested. We also found sex-specific QTLs for body size with implications for the evolution of sexual dimorphism.

Cortical synaptic changes and gliosis in normal aging, Alzheimer's disease and frontal lobe degeneration.

The most important new development during recent years in the field of degenerative dementia concerns synaptic pathology. So far it has been investigated in some regions and some cortical laminae in Alzheimer's disease (AD). The present communication is a more comprehensive study of all laminae in four different regions, the prefrontal, parietal, inferior temporal and posterior cingulate cortex. Against the background of normal aging, AD was compared with another degenerative disorder, frontal lobe degeneration of non-Alzheimer type (FLD). The synapse density was measured using synaptophysin as a marker. Astrocytes were also counted in the molecular layer. In normals, the cortex showed successively lower synaptic density from layer I to layer VI and relatively lowest density in the prefrontal cortex and a general decline with increasing age. A 46-49% decrease in synaptic density was found in all laminae in all regions of AD brains, a finding different from that in FLD. The number of astrocytes increased significantly in the prefrontal cortex both in AD and FLD but parietally only in AD. These results contribute to the understanding of normal synaptic organization of cortex, demonstrate the laminar and regional distribution of synaptic loss in AD and underscore the difference between AD and FLD. The gliosis appears to be secondary to the neurodegenerative changes. Synaptic loss is likely to be a common pathogenetic feature of neurodegenerative disorders and a likely cause of clinical symptoms and regional metabolic decrements in dementia.

Synapse loss and gliosis in the molecular layer of the cerebral cortex in Alzheimer's disease and in frontal lobe degeneration.

Changes in density of synapses and astrocytes in the molecular layer of the frontal and parietal cortex were compared in Alzheimer's disease (AD) and frontal lobe degeneration of non-Alzheimer type (FLD). The investigation was limited to the molecular layer because it is possible in this part of the cortex to measure changes in synapses and astrocytes without contamination by nerve cell body changes. In the frontal pole synapse density declined by 40% in both FLD and AD whereas in the parietal area there was a 50% decrease in synapse density in AD but no significant change in FLD. Number of astrocytes showed an inverse relationship to synapse density. There was a significant increase in astrocytes in the frontal cortex in both FLD and AD but in the parietal cortex such an increase was seen only in AD. These results confirm previous reports of synapse loss in AD and demonstrate a similar loss in FLD in the frontal, but not parietal cortex. The findings underscore the regional pattern changes of FLD, previously shown for other parameters, and its difference from that of AD. We propose that these changes in molecular layer may be representative of the pathology (and the functional deficit) within the underlying cortical layers.