Interrupted vs. uninterrupted training on BMD during growth.

This study compared a resistance training program where the exercise was uninterrupted (UT, i.e., continuous repetitions) against a resistance training program where the exercise was interrupted (IT, i.e., 3 exercise sessions during a training day) for enhancing bone modeling and bone mineral density (BMD) in maturating animals. The total volume of work performed between the two resistance training programs was equivalent by design. 24 young male rats were randomly divided into Control (Con, n = 8), UT (n = 8) and IT (n = 8) resistance trained groups. The UT and IT groups were conditioned to climb a vertical ladder with weights appended to their tail 3 days/wk for 6 wks. After the 6-wk program, serum osteocalcin was not significantly different between groups, whereas the adjusted urinary deoxypyridinoline (DPD) was significantly lower for both UT (81.03 +/- 5.53) and IT (88.30 +/- 7.29) compared to Con (128.13 +/- 9.99). Tibial BMD (assessed via DXA) was significantly greater for UT (0.222 +/- 0.005 g/cm (2)) and IT (0.219 +/- 0.003 g/cm (2)) when compared to Con (0.205 +/- 0.004 g/cm (2)). There was no significant difference in DPD or BMD between UT and IT groups. The results indicate that both interrupted and continuous, uninterrupted resistance training programs were equally effective in stimulating bone modeling.

Resistance training and bone mineral density during growth.

This study examined the efficacy of two different resistance training programs in enhancing bone modeling and bone mineral density (BMD) in maturating rats. One exercise mode involved lifting a lighter weight with more repetitions (LI), while the other regimen involved lifting a heavier weight with fewer repetitions (HI) where the total volume of work between exercise programs was equivalent by design. Twenty-three male rats were randomly divided into control (Con, n = 8), LI (n = 7), and HI (n = 8) groups. The LI and HI groups were conditioned to climb a vertical ladder with weights appended to their tail 4 days/wk for 6 wks. After training, serum osteocalcin (OC) was significantly (p < 0.05) higher in both HI (45.2 +/- 1.7 ng/ml) and LI (39.1 +/- 2.2 ng/ml) when compared to Con (29.9 +/- 0.9 ng/ml). Left tibial BMD was significantly (p < 0.05) greater for HI (0.231 +/- 0.004 g/cm (2)) when compared to both LI (0.213 +/- 0.003 g/cm (2)) and Con (0.206 +/- 0.005 g/cm (2)) with no significant difference between LI and Con. The results indicate that both HI and LI are effective in elevating serum OC, implicating an osteogenic response; however, only HI resulted in a significant elevation in BMD.

Constructional apraxia in Alzheimer's disease: association with occipital lobe pathology and accelerated cognitive decline.

The functional impact and progression of occipital lobe pathology in sporadic late onset Alzheimer's disease (AD) is barely explored. It is accepted that the primary and association visual areas are affected relatively late, in the neocortical stages of AD. We analysed 60 prospectively assessed AD patients in whom global cognitive deterioration and constructional apraxia were evaluated longitudinally using the CAMDEX. Radioactive immunohistochemistry was used to assess the amount of AD-related pathology in Brodmann areas 18 and 17. Braak staging of each case was also carried out. This study showed that in AD patients constructional apraxia is associated with higher expression of hyperphosphorylated tau. Additionally our findings indicate that early constructional apraxia is a predictor of accelerated cognitive decline in AD.

Coexisting pathologies in the brain: influence of vascular disease and Parkinson's disease on Alzheimer's pathology in the hippocampus.

The finding of more than one coexisting brain pathology in dementia sufferers is not unusual. However, it is unclear how these different diseases may interact or influence the evolution of one another. In this study we analyse the hippocampal expression patterns of hyperphosphorylated tau, paired helical filament (PHF)-related protein, beta-amyloid and synaptophysin in a group of Alzheimer's disease (AD) sufferers with and without additional pathology. Compared to cases with only AD-type pathology we found that the presence of additional vascular disease augmented the accumulation of hyperphosphorylated tau in the CA1 region of the hippocampus without affecting PHF formation in cases with mild AD changes and reduced the extent of PHF formation in the CA2/3 and CA4 regions of the hippocampus in cases with severe AD pathology. We also found that synaptophysin immunoreactivity in the CA4 and dentate gyrus in pure AD was inversely related to the extent of amyloid accumulation but not to neurofibrillary pathology in the same regions. These relationships were lost when additional pathology was present. Memory scores obtained during life correlated closely with hyperphosphorylated tau and PHF-related protein expression in CA1 in pure AD but not in AD with additional pathology. Total amyloid and synaptophysin expression in the hippocampus did not correlate with memory scores in any patient group. Our findings suggest that the interactions of two pathologies in the hippocampus are complex and may differ depending on the stage reached in the evolution of a progressive disease such as AD.

Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease.

Cerebrovascular disease and Alzheimer's disease commonly occur together in the elderly and each may contribute to dementia. Here we present evidence that cerebrovascular disease significantly worsens cognitive performance in the earliest stages of Alzheimer's disease.

Cell cycle-related protein expression in vascular dementia and Alzheimer's disease.

Recent findings from our and other laboratories indicate that cell cycle-related phenomena may play a key role in the formation of Alzheimer-type pathology and neuronal cell death in both Alzheimer's and cerebro-vascular diseases. In this study we examine the expression patterns of cyclins A, B1, D1 and E in neuronal nuclei in the hippocampus in autopsied healthy elderly individuals, Alzheimer's disease patients and subjects suffering from cerebrovascular disease with and without co-existing Alzheimer's disease. Nuclear cyclin B1 and cyclin E expression was detected in hippocampal neurones in each subject category. However, cyclin B1 expression was significantly elevated in the CA1 of patients suffering from cerebro-vascular disease alone, while cyclin E expression was significantly higher in the CA4 subfield in patients suffering from mixed Alzheimer's and cerebro-vascular diseases compared to subjects in other categories. We hypothesize that cell cycle re-entry may occur in healthy elderly people leading to age-related cell death and mild Alzheimer-type pathology in the hippocampus. However, in pathological conditions, the cell cycle arrest may lead either to the development of severe Alzheimer-related pathology or to excess apoptotic cell death as in vascular dementia.

Mutation at the putative GABA(A) ion-channel gate reveals changes in allosteric modulation.

We have mutated a conserved leucine in the putative membrane-spanning domain to serine in human GABA(A) beta2 and investigated the actions of a number of GABA(A) agonists, antagonists and modulators on human alpha1beta2deltaL259Sgamma2s compared to wild type alpha1beta2gamma2s GABA(A) receptors, expressed in Xenopus oocytes. The mutation resulted in smaller maximum currents to gamma-aminobutyric acid (GABA) compared to alpha1beta2gamma2s receptors, and large leak currents resulting from spontaneous channel opening. As reported, this mutation significantly decreased the GABA EC50 (110 fold), and reduced desensitization. Muscimol and the partial agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and piperidine-4-sulphonic acid (P4S) also displayed a decrease in EC50. In addition to competitively shifting GABA concentration response curves, the antagonists bicuculline and SR95531 both inhibited the spontaneous channel activity on alpha1beta2deltaL259Sgamma2s receptors, with different degrees of maximum inhibition. The effects of a range of allosteric modulators, including benzodiazepines and anaesthetics were examined on a submaximal GABA concentration (EC20). Compared to wild type, none of these modulators potentiated the EC20 response of alpha1beta2deltaL259Sgamma2s receptors, however they all directly activated the receptor in the absence of GABA. To conclude, the above mutation resulted in receptors which exhibit a degree of spontaneous activity, and are more sensitive to agonists. Benzodiazepines and other agents modulate constitutive activity, but positive modulation of GABA is lost. The competitive antagonists bicuculline and SR95531 can also act as allosteric channel modulators through the same GABA binding site.