Neurocognitive Deficits and Effects of Cognitive Reserve in Mild Cognitive Impairment.

BACKGROUND/AIMS: Mild cognitive impairment (MCI) is a frequent syndrome in the older population, which involves an increased risk to develop Alzheimer's disease (AD). The latter can be modified by the cognitive reserve, which can be operationalized by the length of school education. MCI can be differentiated into four subtypes according to the cognitive domains involved: amnestic MCI, multiple-domain amnestic MCI, non-amnestic MCI and multiple-domain non-amnestic MCI. While neurocognitive deficits are a constituent of the diagnosis of these subtypes, the question of how they refer to the cognitive reserve still needs to be clarified. METHODS: We examined neuropsychological deficits in healthy controls, patients with MCI and patients with mild AD (n = 485) derived from a memory clinic. To reduce the number of neuropsychological variables, a factor analysis with varimax rotation was calculated. In a second step, diagnostic groups including MCI subtypes were compared with respect to their clinical and neuropsychological characteristics including cognitive reserve. RESULTS: Most MCI patients showed the amnestic multiple-domain subtype followed by the pure amnestic subtype, while the non-amnestic subtypes were rare. The amnestic subtype displayed a significantly higher level of cognitive reserve and higher MMSE scores than the amnestic multiple-domain subtype, which was in most cases characterized by additional psychomotor and executive deficits. CONCLUSIONS: These findings confirm earlier reports revealing that the amnestic multiple-domain subtype is the most frequent one and indicating that a high cognitive reserve may primarily prevent psychomotor and executive deficits in MCI.

Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism.

Skeletal muscle is composed of both slow-twitch oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function and eventually whole-body physiology. Here we show that the mesodermal transcription factor T-box 15 (Tbx15) is highly and specifically expressed in glycolytic myofibers. Ablation of Tbx15 in vivo leads to a decrease in muscle size due to a decrease in the number of glycolytic fibres, associated with a small increase in the number of oxidative fibres. This shift in fibre composition results in muscles with slower myofiber contraction and relaxation, and also decreases whole-body oxygen consumption, reduces spontaneous activity, increases adiposity and glucose intolerance. Mechanistically, ablation of Tbx15 leads to activation of AMPK signalling and a decrease in Igf2 expression. Thus, Tbx15 is one of a limited number of transcription factors to be identified with a critical role in regulating glycolytic fibre identity and muscle metabolism.

The Positivity Effect on the Intensity of Experienced Emotion and Memory Performance in Mild Cognitive Impairment and Dementia.

AIMS: We examined the 'positivity effect' on memory performance in mild cognitive impairment (MCI) and dementia patients. METHODS: In 109 subjects (28 controls, 32 with MCI, 27 with mild and 32 with moderate dementia), we investigated free recalls (immediate and delayed) and recognition of 12 pictures. Moreover, the emotional valence of the pictures perceived and the emotions evoked in the subjects were evaluated. RESULTS: Patients with mild and moderate dementia recalled fewer pictures than those with MCI or the healthy controls. Across the groups, the positive pictures were better memorized and induced a higher arousal than the negative or neutral ones. CONCLUSIONS: Our findings indicate a positivity effect on memory performance and intensity of experience not only in healthy elderly patients but also in those with MCI or mild and moderate dementia. This effect does not refer to the compliance of the patients investigated since they perceived and experienced the pictures in the expected way.

Oral health and apraxia among institutionalized elderly people--a pilot study.

OBJECTIVE: Poor oral hygiene and dental health are very common among the institutionalized elderly. The purpose of this study was to evaluate the association of apraxia with oral hygiene and/or health. MATERIALS AND METHODS: Ninety-two residents of 13 long-term care homes in southwest Germany participated in the study. For each participant, ideomotor apraxia scoring (AS) was conducted and demographic variables were collected. Participants underwent a comprehensive dental examination to assess the oral health indices gingival bleeding index (GBI), community periodontal index of treatment needs (CPITN) and denture hygiene index (DHI). Statistical comparison of dental indices among apraxic and non-apraxic individuals (cut-off < 45) was performed by use of t-tests. In addition, linear regression models were constructed with the dental indices as dependent variables. Each model was fitted with the dichotomized variable AS (pathologic or healthy) and adjusted for age and sex. RESULTS: Mean (SD) GBI of 48.5 (25.9), CPITN of 2.9 (0.7) and DHI of 82.6 (14.6) were observed among the participants. Statistical analysis revealed AS was significantly associated with all oral health indicators (p < 0.05). Linear regression models showed apraxia is a predictor of GBI (p = 0.002) and CPITN (p = 0.027), but not of denture hygiene (p = 0.916). CONCLUSIONS: Although this pilot investigation has limitations, the results suggest the presence of apraxia should be considered when planning oral healthcare strategies. Further research with larger samples is encouraged to confirm these relationships.

Prolonged thromboprophylaxis with enoxaparin in early neurological rehabilitation.

Prevention of venous thromboembolism (VTE) is essential in neurological patients. Little is known about the optimal duration, efficacy, and safety of prolonged off-label use of low-molecular-weight heparin (LMWH). We enrolled n = 1176 early neurological rehabilitation cases in a retrospective study. In most cases (n = 1151, 97.9%), 4000 anti-Xa (activated coagulation factor X [factor Xa]) units enoxaparin were administered, only 25 received 2000 units for approximately 2 months (mean of 57.5 days). In 969 cases, enoxaparin was administered for more than 2 weeks. Incidence of symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) were 0.43% (n = 5) and 1.11% (n = 13), respectively. Hemorrhages during enoxaparin therapy were more frequent. Bleeding occurred in 1.96% (n = 23) of cases, mainly gastrointestinal, urinary tract, and vitreous body bleeding. In short-term (up to 2 weeks) treatment, bleeding and VTE were more frequent than in long-term treatment. Results from this study suggest that prolonged enoxaparin thromboprophylaxis in neurological rehabilitation is safe and effective.

T tubules and surface membranes provide equally effective pathways of carbonic anhydrase-facilitated lactic acid transport in skeletal muscle.

We have studied lactic acid transport in the fast mouse extensor digitorum longus muscles (EDL) by intracellular and cell surface pH microelectrodes. The role of membrane-bound carbonic anhydrases (CA) of EDL in lactic acid transport was investigated by measuring lactate flux in muscles from wildtype, CAIV-, CAIX- and CAXIV-single ko, CAIV-CAXIV double ko and CAIV-CAIX-CAXIV-triple ko mice. This was complemented by immunocytochemical studies of the subcellular localization of CAIV, CAIX and CAXIV in mouse EDL. We find that CAXIV and CAIX single ko EDL exhibit markedly but not maximally reduced lactate fluxes, whereas triple ko and double ko EDL show maximal or near-maximal inhibition of CA-dependent lactate flux. Interpretation of the flux measurements in the light of the immunocytochemical results leads to the following conclusions. CAXIV, which is homogeneously distributed across the surface membrane of EDL fibers, facilitates lactic acid transport across this membrane. CAIX, which is associated only with T tubular membranes, facilitates lactic acid transport across the T tubule membrane. The removal of lactic acid from the lumen of T tubuli towards the interstitial space involves a CO2-HCO3- diffusional shuttle that is maintained cooperatively by CAIX within the T tubule and, besides CAXIV, by the CAIV, which is strategically located at the opening of the T tubules. The data suggest that about half the CA-dependent muscular lactate flux occurs across the surface membrane, while the other half occurs across the membranes of the T tubuli.

Carbonic anhydrases IV and IX: subcellular localization and functional role in mouse skeletal muscle.

The subcellular localization of carbonic anhydrase (CA) IV and CA IX in mouse skeletal muscle fibers has been studied immunohistochemically by confocal laser scanning microscopy. CA IV has been found to be located on the plasma membrane as well as on the sarcoplasmic reticulum (SR) membrane. CA IX is not localized in the plasma membrane but in the region of the t-tubular (TT)/terminal SR membrane. CA IV contributes 20% and CA IX 60% to the total CA activity of SR membrane vesicles isolated from mouse skeletal muscles. Our aim was to examine whether SR CA IV and TT/SR CA IX affect muscle contraction. Isolated fiber bundles of fast-twitch extensor digitorum longus and slow-twitch soleus muscle from mouse were investigated for isometric twitch and tetanic contractions and by a fatigue test. The muscle functions of CA IV knockout (KO) fibers and of CA IX KO fibers do not differ from the function of wild-type (WT) fibers. Muscle function of CA IV/XIV double KO mice unexpectedly shows a decrease in rise and relaxation time and in force of single twitches. In contrast, the CA inhibitor dorzolamide, whether applied to WT or to double KO muscle fibers, leads to a significant increase in rise time and force of twitches. It is concluded that the function of mouse skeletal muscle fibers expressing three membrane-associated CAs, IV, IX, and XIV, is not affected by the lack of one isoform but is possibly affected by the lack of all three CAs, as indicated by the inhibition studies.

Carbonic anhydrase XIV in skeletal muscle: subcellular localization and function from wild-type and knockout mice.

The expression of carbonic anhydrase (CA) XIV was investigated in mouse skeletal muscles. Sarcoplasmic reticulum (SR) and sarcolemmal (SL) membrane fractions were isolated from wild-type (WT) and CA XIV knockout (KO) mice. The CA XIV protein of 54 kDa was present in SR and SL membrane fractions as shown by Western blot analysis. CA activity measurements of WT and KO membrane fractions showed that CA XIV accounts for approximately 50% and 66% of the total CA activities determined in the SR and SL fractions, respectively. This indicates the presence of at least one other membrane-associated CA isoform in these membranes, e.g., CA IV, CA IX, or CA XII. Muscle fibers of the extensor digitorum longus (EDL) muscle were immunostained with anti-CA XIV/FITC and anti-sarco(endo)plasmic reticulum Ca(2+)-ATPase 1/TRITC, with anti-CA XIV/FITC and anti-ryanodine receptor/TRITC, or with anti-CA XIV/FITC and anti-monocarboxylate transporter-4/TRITC. CA XIV was expressed in the plasma membrane and in the longitudinal SR but not in the terminal SR. Isometric contraction measurements of single twitches and tetani and a fatigue protocol applied to fiber bundles of the fast-twitch EDL and of the slow-twitch soleus muscle from WT and KO mice showed that the lack of SR membrane-associated CA XIV did not affect maximum force, rise and relaxation times, and fatigue behavior. Thus, it is concluded that a reduction of the total SR CA activity by approximately 50% in CA XIV KO mice does not lead to an impairment of SR function.

Expression of membrane-bound carbonic anhydrases IV, IX, and XIV in the mouse heart.

Expression of membrane-bound carbonic anhydrases (CAs) of CA IV, CA IX, CA XII, and CA XIV has been investigated in the mouse heart. Western blots using microsomal membranes of wild-type hearts demonstrate a 39-, 43-, and 54-kDa band representing CA IV, CA IX, and CA XIV, respectively, but CA XII could not be detected. Expression of CA IX in the CA IV/CA XIV knockout animals was further confirmed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Cardiac cells were immunostained using anti-CA/FITC and anti-alpha-actinin/TRITC, as well as anti-CA/FITC and anti-SERCA2/TRITC. Subcellular CA localization was investigated by confocal laser scanning microscopy. CA localization in the sarcolemmal (SL) membrane was examined by double immunostaining using anti-CA/FITC and anti-MCT-1/TRITC. CAs showed a distinct distribution pattern in the sarcoplasmic reticulum (SR) membrane. CA XIV is predominantly localized in the longitudinal SR, whereas CA IX is mainly expressed in the terminal SR/t-tubular region. CA IV is present in both SR regions, whereas CA XII is not found in the SR. In the SL membrane, only CA IV and CA XIV are present. We conclude that CA IV and CA XIV are associated with the SR as well as with the SL membrane, CA IX is located in the terminal SR/t-tubular region, and CA XII is not present in the mouse heart. Therefore, the unique subcellular localization of CA IX and CA XIV in cardiac myocytes suggests different functions of both enzymes in excitation-contraction coupling.

Contractile properties of skeletal muscle fibre bundles from mice deficient in carbonic anhydrase II.

The function of cytosolic carbonic anhydrase (CA) isozyme II is largely unknown in skeletal muscle. Because of this, we compared the in vitro contractile properties of extensor digitorum longus (EDL) and soleus (SOL) fibre bundles from mice deficient in CA II (CAD) to litter mate controls (LM). Twitch rise, 1/2 relaxation time and peak twitch force at 22 degrees C of fibre bundles from CAD EDL [28.4+/-1.4 ms, 31.2+/-2.3 ms, 6.2+/-1.0 Newton/cm(2) (N/cm(2)), respectively] and CAD SOL (54.2+/-7.5 ms, 75.7+/-13.8 ms, 2.9+/-0.5 N/cm(2), respectively) were significantly higher compared to LM EDL (20.5+/-2.2 ms, 21.9+/-3.7 ms, 4.5+/-0.2 N/cm(2)) and LM SOL (42.8+/-3.5 ms, 51.4+/-2.4 ms, 2.1+/-0.4 N/cm(2)). However, in acidic Krebs-Henseleit solution, mimicking the pH, PCO(2), and HCO(3) (-) of arterial blood from CAD mice, twitch rise, 1/2 relaxation time, and peak twitch force of fibre bundles from CAD EDL (19.3+/-0.7 ms, 19.7+/-2.3 ms, 4.8+/-0.8 N/cm(2)) and CAD SOL (41.4+/-3.6 ms, 51.9+/-5.5 ms, 2.2+/-0.7 N/cm(2)) were not significantly different from LM fibre bundles in normal Krebs-Henseleit solution (EDL: 19.7+/-1.1 ms, 21.6+/-0.6 ms, 4.7+/-0.2 N/cm(2); SOL: 42.5+/-3.1 ms, 51.8+/-2.6 ms, 1.8+/-0.3 N/cm(2)). A higher pH(i) during exposure to acidic bathing solution was maintained by CAD EDL (7.37+/-0.02) and CAD SOL (7.33+/-0.05) compared to LM EDL (7.28+/-0.04) and LM SOL (7.22+/-0.02). This suggests that the skeletal muscle of CAD mice possesses an improved defense of pH(i) against elevated pCO(2). In support of this, apparent non-bicarbonate buffer capacity (in mequiv H(+) (pH unit)(-1) (kg cell H(2)O)(-1)) as determined by pH microelectrode was markedly increased in CAD EDL (75.7+/-4.1) and CAD SOL (85.9+/-3.3) compared to LM EDL (39.3+/-4.7) and LM SOL (37.5+/-3.8). Both latter phenomena may be related to the slowed rate of intracellular acidification seen in CAD SOL in comparison with LM SOL upon an increase in PCO(2) of the bath. In conclusion, skeletal muscle from mice deficient in CA II exhibits altered handling of acid-base challenges and shows normal contractile behavior at normal intracellular pH.

Carbonic anhydrase III is not required in the mouse for normal growth, development, and life span.

Carbonic anhydrase III is a cytosolic protein which is particularly abundant in skeletal muscle, adipocytes, and liver. The specific activity of this isozyme is quite low, suggesting that its physiological function is not that of hydrating carbon dioxide. To understand the cellular roles of carbonic anhydrase III, we inactivated the Car3 gene. Mice lacking carbonic anhydrase III were viable and fertile and had normal life spans. Carbonic anhydrase III has also been implicated in the response to oxidative stress. We found that mice lacking the protein had the same response to a hyperoxic challenge as did their wild-type siblings. No anatomic alterations were noted in the mice lacking carbonic anhydrase III. They had normal amounts and distribution of fat, despite the fact that carbonic anhydrase III constitutes about 30% of the soluble protein in adipocytes. We conclude that carbonic anhydrase III is dispensable for mice living under standard laboratory husbandry conditions.

Inhibition of muscle carbonic anhydrase slows the Ca(2+) transient in rat skeletal muscle fibers.

A countertransport of H(+) is coupled to Ca(2+) transport across the sarcoplasmic reticulum (SR) membrane. We propose that SR carbonic anhydrase (CA) accelerates the CO(2)-HCO reaction so that H(+) ions, which are exchanged for Ca(2+) ions, are produced or buffered in the SR at sufficient rates. Inhibition of this SR-CA is expected to reduce the rate of H(+) fluxes, which then will retard the kinetics of Ca(2+) transport. Fura 2 signals and isometric force were simultaneously recorded in fiber bundles of the soleus (SOL) and extensor digitorum longus (EDL) from rats in the absence and presence of the lipophilic CA inhibitors L-645151, chlorzolamide (CLZ), and ethoxzolamide (ETZ), as well as the hydrophilic inhibitor acetazolamide (ACTZ). Fura 2 and force signals were analyzed for time to peak (TTP), 50% decay time (t(50)), and their amplitudes. L-645151, CLZ, and ETZ significantly increased TTP of fura 2 by 10-25 ms in SOL and by 5-7 ms in EDL and TTP of force by 6-30 ms in both muscles. L-645151 and ETZ significantly prolonged t(50) of fura 2 and force by 20-55 and 40-160 ms, respectively, in SOL and EDL. L-645151, CLZ, and ETZ also increased peak force of single twitches and amplitudes of fura fluorescence ratio (R(340/380)) at an excitation wavelength of 340 to 380 nm. All effects of CA inhibitors on fura 2 and force signals could be reversed. ACTZ did not affect TTP, t(50), and amplitudes of fura 2 signals or force. L-645151, CLZ, and ETZ had no effects on myosin-, Ca(2+)-, and Na(+)-K(+)-ATPase activities, nor did they affect the amplitude and half-width of action potentials. We conclude that inhibition of SR-CA by impairing H(+) countertransport is responsible for deceleration of intracellular Ca(2+) transients and contraction times.

Inhibition of muscle carbonic anhydrase increases rise and relaxation times of twitches in rat skeletal muscle fibres.

Muscle carbonic anhydrase (CA) was inhibited in fibre bundles of the extensor digitorum longus (EDL) and soleus (SOL) muscles from rats. Isometric single twitches were recorded in the absence or presence of the CA inhibitors. The highly membrane-permeable inhibitors L-645,151, chlorzolamide (CLZ) and ethoxzolamide (ETZ) prolonged significantly the values of time-to-peak (ttp) by 5-40 ms (10-40%) in both muscles and the values of the 75% decay time (t(75%)) by 30-400 ms (13-110%) in SOL and by 9-17 ms (15-30%) in EDL and increased peak force by 20--55% in SOL and EDL. The poorly membrane-permeable inhibitors benzolamide (BZ) and acetazolamide (ACTZ) had no effects on single twitches. In CO(2)-free solution, the effects of L-645,151 on ttp, t(75%) and peak force of SOL were reduced drastically. Removal of CO(2) prolonged ttp and t(75%). In skinned fibres, ETZ and CLZ did not increase force production. Intracellular pH (pH(i)) in SOL and EDL fibres was not affected by 30-60 min exposure to CLZ, ETZ or BZ. The results of L-645,151, CLZ and ETZ on ttp, t(75%) and peak force of twitches are consistent with our hypothesis on the role of the sarcoplasmic reticulum (SR) CA. The SR-CA may mediate sufficiently fast buffering and production of H(+) in the SR that is exchanged for Ca(2+) across the SR membrane. We propose that a H(+) buffering and delivery impaired by CA inhibition slows the kinetics of Ca(2+) release and reuptake and, as a result, slows twitch ttp and t(75%). Aspects of this hypothesis await further validation.