By S. Tangach. Illinois Institute of Technology.
Prog Neuropsy- (MARCKS) in immortalized hippocampal cells: a property chopharmacol Biol Psychiatry 1995;19:1177–1187 trusted 40/60mg levitra with dapoxetine. Effects of lithium on cAMP- J Neurosci Res 1989;24:107–114 dependent protein kinase in rat brain cheap 40/60 mg levitra with dapoxetine. Abnormalities of cAMP signal- nist attenuates lithium chloride-induced c-Fos induction in rat ing in affective disorders: implications for pathophysiology and brainstem discount levitra with dapoxetine 40/60mg otc. Lithium increases transcription factor methamphetamine-induced regional Fos protein expression in binding to AP-1 and cyclic AMP-responsiveness element in cul- the rat brain purchase levitra with dapoxetine 40/60mg visa. Mol Brain Res 1999;64:52–58 brane-associated protein kinase C activity and translocation in 121. Lithium at 50: have the neuro- blood platelets from bipolar affective disorder patients. J Psychi- protective effects of this unique cation been overlooked? Lithium stimulates gene binding in postmortem brain from subjects with bipolar affec- expression through the AP-1 transcription factor pathway. Lithium attenuates nerve growth factor- protein kinase activity in postmortem brain from patients with induced activation of AP-1 DNA binding activity in PC12 cells. AP-1 and NF-kappaB stimulated by carbachol tion and goosecoid-expression identify a dorsal specification in human neuroblastoma SH-SY5Y cells are differentially sensi- pathway in the pregastrula zebrafish. Development 1993;117: tive to inhibition by lithium. A bimodal model of the mechanism of action of lith- 104. Neural and develop- activity in human neuroblastoma SH-SY5Y cells. Mol Brain Res mental actions of lithium: a unifying hypothesis. Differential effect of Chapter 79: Mechanism of Action of Antidepressants and Mood Stabilizers 1159 lithium on fos protooncogene expression mediated by receptor electrostatic interactions exert independent effects on the mem- and postreceptor activators of protein kinase C and cyclic adeno- brane association of the myristoylated alanine-rich protein ki- sine monophosphate: model for its antimanic action. J Neurosci nase C substrate protein in intact cells. Molecular genetics of circadian rhythms GAP-43 gene expression in the adult rat brain. Distribution of protein kinase C robustly protects neurons in the central nervous system against substrates MARCKS and MRP in the postnatal developing rat excitotoxicity by inhibiting N-methyl-D-aspartate receptor-me- brain. Lithium and MARCKS-related protein (MRP) in the prefrontal cortex protects cultured neurons against beta-amyloid-induced neuro- and hippocampus of suicide victims. Facial motor neuron against destabilization of Ca2 homeostasis and delayed death regeneration induces a unique spatial and temporal pattern of caused by removal of external Na. FEBS Lett 1999;448: myristoylated alanine-rich C kinase substrate (MARCKS) 173–176. Differential lithium and valproate robustly increase the levels of the neuro- changes in the phosphorylation of the protein kinase C sub- protective protein bcl-2 in the CNS. J Neurochem 1999;72: strates MARCKS and GAP 43/B-50 following Schaffer collat- 879–882. Reboxetine: a phar- stabilizing agents: therapeutic implications. J Clin Psychiatry macologically potent, selective, and specific norepinephrine 1999;60[Suppl 2]:27–39 reuptake inhibitor. Neurochemical and auto- presses p53 and Bax expression but increases Bcl-2 expression: nomic pharmacological profiles of the 6-AZA-analogue of mi- a prominent role in neuroprotection against excitotoxicity. Further studies on 2-adreno- a conserved family of signal transducers. Trends Biol Sci 1997; ceptor subtypes involved in the modulation of [3H]noradrena- 22:267–272. Tonic regulation phosphorylation by inhibition of glycogen synthase kinase-3. J of the activity of noradrenergic neurons in the locus coeruleus Biol Chem 1997;272:25326–25332. Brain GABAergic and alpha2-adrenoceptor antagonists mirtazapine, mianserin, and dopaminergic systems following lithium treatment and with- idazoxan. Inhibition of ceptor antagonist mirtazapine on the 5-hydroxytryptamine sys- GSK-3 leading to the loss of phosphorylated MAP-1B is an tem in the rat brain. Naunyn Schmiedebergs Arch Pharmacol dependent kinases and glycogen synthase kinase 3 in the phos- 1997;355:20–29. Studies on the role mice: transgenic rescue and interaction with gene background. Myristoylation-dependent and Schmiedebergs Arch Pharmacol 1992;345:137–143. Mirtazapine enhances desipramine in plasma and spinal fluid. Arch Gen Psychiatry frontocortical dopaminergic and corticolimbic adrenergic, but 1978;35:621–625. CSF and plasma levels of and serotonin2C receptors: a comparison with citalopram. The effect of paroxetine its mechanism of antidepressant activity. J Clin Psychiatry 1995; on cerebrospinal fluid concentrations of neurotransmitter me- 56:395–401. Design and optimization of Gen Psychiatry 1988;45:139–143. New York: McGraw-Hill, 1996: Psychopharmacology 1994;114:559–565. Bjerkenstedt L, Flyckt L, Fredrickson Overo K, et al. Relation- antidepressants of biogenic amine uptake into rat brain synapto- ship between clinical effects, serum drug concentration and sero- somes. Kinetics of citalopram in man: plasma Evidence for opposing roles of 5-HT2 and 5-HT1A receptors. Prog Neuropsychopharmacol Biol Psychiatry Neuropharmacology 1986;25:1307–1313. Active hydroxymetabolites of antide- for a functional interaction between central 5-HT2 and 5-HT1A pressants. Herremans AH, van der Hayden JAM, van Drimmelen M, et 191. The 5-HT1Areceptor agonist flesinoxan shares discriminative effects during treatment of depression with nortriptyline: the stimulus properties with some 5-HT2 receptor antagonists. Clin Pharmacol Ther 1987;42: Pharmacol Biochem Behav 1999;64:389–395. Hydroxylated metabo- agonist or antagonist administration on serotonin-1A receptor lites of tricyclic antidepressants: preclinical assessment of activ- sensitivity. Psychopharmacology: the fourth generation tion challenge in depressed patients treated with desipramine of progress. Pharmacologic analysis of drug–receptor interaction, third ed. Acta rat brain synaptosomes after in vivo administration of antide- Pharmacol Toxicol 1985;56[Suppl 1]:146–153. A quantitative autoradio- ceptor and transporter binding profile of antidepressants and graphic study of serotonin1A receptor regulation. Serotoninergic mediation profile of antidepressants and related compounds at human of the effects of fluoxetine, but not desipramine, in the rat forced monoamine transporters. A role for serotonin drug interactions with recombinant biogenic amine transporters and beta-endorphin in the analgesia induced by some tricyclic expressed in the same cell type. Effect of a specific 5-HT uptake inhibitor, citalopram 199. Serotoninergic and catecholaminergic (Lu 10-171), on 3H-5-HT uptake in rat brain synaptosomes in reuptake inhibitors have opposite effects on the ultrasonic isola- vitro. Clinical pharmacokinetics of selective serotonin neurons.
Table 49 shows the goodness-of-fit indices for the two longitudinal path analysis models (with energy-dense snacks and negative food markers as outcome variables) levitra with dapoxetine 40/60mg discount. Overall order levitra with dapoxetine 40/60mg, the model fits were acceptable for both outcome variables levitra with dapoxetine 40/60 mg discount, and although the CFI results were slightly below the 0 discount levitra with dapoxetine 40/60mg without a prescription. Path analysis for weekday energy-dense snacks (18 months) Figure 10 presents a diagram of the path analysis for energy-dense snacks. Not shown are the correlations of the variables at baseline, error covariances and non-significant regression weights (dashed lines). TABLE 48 Summary of Pearson correlation coefficient between the outcome variables energy-dense snacks and negative food makers with the mediating variables at 12 months Variable Energy-dense snacks Negative food markers Knowledge –0. TABLE 49 Goodness-of-fit indices for the longitudinal path analysis models with energy-dense snacks and negative food markers at 18 months as outcome variables Goodness-of-fit indices Energy-dense snacks Negative food markers Satorra–Bentler scaled χ2/df 4. B&S, behaviours and strategies; C&M, confidence and motivation; EDS, energy-dense snacks; FAB&CA, family approval/behaviours and child attitudes; NFM, negative food markers; PN, peer norms; SES, socioeconomic status. The following composite variables were significantly (p < 0. All paths shown in the diagram were significant (p < 0. The direct effect of the intervention on energy-dense snacks (18 months) was significant (p = 0. Of these three mediating variables, the effect of family approval/behaviours and child attitudes was the strongest, with a standardised regression weight of –0. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 97 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. PROCESS EVALUATION Path analysis for weekday negative food markers (18 months) Figure 11 shows the full mediation model with significant standardised regression weights of pathways for weekday negative food markers at 18 months. Not shown are the correlations of the variables at baseline, error covariances and non-significant regression weights (dashed lines). The results for negative food markers were generally similar, with the same variables correlated at baseline and at 12 months. Similar to the results for energy-dense snacks, there were no significant associations between gender and negative food markers (18 months), between school-level deprivation and negative food markers (18 months) and between peer norms and negative food markers (18 months). However, the association between behaviours and strategies and negative food markers (18 months) was significant (p < 0. Additionally, the direct effect of the intervention on negative food markers (18 months) was not significant (p = 0. Gender BMI SDS baseline Number of Year 5 classes School SES NFM baseline Intervention or control NFM 18 months 0. B&S, behaviours and strategies; C&M, confidence and motivation; EDS, energy-dense snacks; FAB&CA, Family approval/behaviours and child attitudes; NFM, negative food markers; PN, peer norms; SES, socioeconomic status. Overall, the effects of the composite mediating variables on the outcome variables were fairly small. The largest association was between family approval/behaviours and child attitudes at 12 months and the outcome variables. For both paths (between family approval/behaviours and child attitudes and energy-dense snacks and between family approval/behaviours and child attitudes and negative food markers), β was –0. Additionally, the results of the behaviours and strategies variable need to be interpreted with caution. As outlined in Appendix 18,this variable was the least psychometrically robust of MLQ variables. The path between behaviours and strategies at 12 months and energy-dense snacks was not significant, but the path between behaviours and strategies at 12 months and negative food markers resulted in a significant change in the opposite direction to those of the other mediating variables. This counterintuitive result is most likely a result of collinearity; as shown in Table 48, behaviours and strategies was negatively correlated with negative food markers. However, in the context of the other MLQ variables, this association became positive (β was 0. Such seemingly paradoxical cases have been described in the literature134 and are most likely due to collinearity with other predictor variables or the operation of suppressor variables. Table 47 shows that behaviours and strategies and confidence and motivation were correlated to an extent (r = 0. Further exploration of these composite variables could clarify which items are responsible for these effects. Summary We developed and evaluated a self-report tool, the MLQ, which aimed to capture changes in knowledge, cognitions and behaviours that could explain changes in weight gain. The MLQ contains items that are relevant, acceptable and feasible for 9- to 10-year-olds to complete in a timely manner and it has undergone psychometric testing, although future additional evaluation of the MLQ could include further tests for reliability and construct validity. Five composite variables emerged from the evaluation of the MLQ and these were used as the mediating variables in the two longitudinal path analyses. The first analysis was for the number of weekday unhealthy foods consumed per day (weekday negative food markers at 18 months) and showed statistical evidence for full mediation as the previous significant effect of the intervention on this outcome variable was no longer present (p = 0. This result suggests that the composite variables arising from the MLQ could provide a possible explanation of how the intervention generated the observed differences in dietary behaviour. However, further exploration could clarify this explanation. The analysis for the number of weekday energy dense snacks consumed per day at 18 months revealed partial mediation (p = 0. Overall, it is noted that the full and partial mediation effects were both close to the cut-off point for statistical significance (p = 0. The findings arising from our use of composite variables require cautious interpretation; we are able only to conclude that children have changed in a combination of ways for two of the secondary outcomes in the trial. Future work could include more theoretically based modelling work (which would be possible given the theoretical underpinning of many of the items in the MLQ) as well as cluster analyses135 to investigate which specific mediator and which moderator variables might predict healthy outcomes in the whole HeLP cohort. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 99 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. PROCESS EVALUATION Conclusions from the process evaluation Data from the process evaluation show that HeLP was delivered as designed in all 16 intervention schools, with high uptake and engagement from schools, children and their families across the socioeconomic spectrum. The mediation analyses show that the intervention effects on the consumption of weekday energy-dense snacks were mediated by knowledge and two composite variables, namely family approval/behaviours and child attitudes and confidence and motivation, whereas the intervention effect on weekday consumption of unhealthy foods (negative food markers) was mediated by the same variables as well as the composite variable behaviours and strategies. We found no evidence of a difference in BMI SDS at 24 months or that participating in HeLP reduced the likelihood that children would be overweight or obese compared to children not receiving the intervention. Similarly, no differences between the intervention and control groups were observed in either anthropometric measures or physical activity objectively assessed using accelerometers at 18 months post baseline. Self-reported weekly average consumption of different types of energy-dense snacks was lower in those attending intervention schools (0. These differences were largely accounted for by reported differences in weekday consumption. The cost of implementing HeLP was estimated at approximately £210 per child. Assumptions are reported regarding the proportions of children needing to move weight category for cost-effectiveness to be achieved using NICE cost-per-QALY methodology. The review identified 139 intervention studies that had weight-related outcomes, of which 115 were located in the primary school. The 37 studies that were purely school-based and did not have a family component showed a low strength of evidence for reducing BMI, BMI SDS, prevalence of obesity and overweight, percentage body fat, waist circumference and skinfold thickness. However, studies that also included a family component provided moderate evidence of effectiveness, with half reporting statistically significant beneficial intervention effects. Other systematic reviews and meta-analyses also suggest that school-based obesity prevention interventions can have a modest effect on BMI SDS and it is unclear whether such effect sizes (typically < 0. We are not aware of any recent, well-conducted, school-based obesity prevention RCTs, using objective outcome measures, for this age group, that have shown a clinically relevant effect on adiposity measures at 2-year follow-up. A very recent school-based trial (Active for Life-year 5)16 involving 60 schools and > 2000 children (aged 9–10 years), which aimed to increase physical activity, reduce sedentary behaviour and increase fruit and vegetable consumption at 2-year follow-up, found no effect of the intervention on any of these primary outcomes or on weight status. Furthermore, the exploratory trial showed changes in diet and physical activity behaviours and weight status; however, these were not replicated in the main trial. In addition, HeLP was delivered as designed in all intervention schools with very high levels of engagement, as was also seen in the exploratory trial.
A similar D1-mediated cascade postsynaptic and acts via PKC activation (105) buy levitra with dapoxetine 40/60 mg without a prescription. It is of also attenuates responses to GABA in the striatum (92 discount levitra with dapoxetine 40/60mg free shipping,93) discount levitra with dapoxetine 40/60 mg visa. Thus generic levitra with dapoxetine 40/60mg without prescription, a recent study by ate non–NMDA-mediated responses (89). There is also evi- Gines and colleagues (106) have shown that D1 and adeno-´ dence that the activation of DA neuron firing by stimulation sine A1 receptors have the capacity to form heteromeric of DA axons (70,94) occurs via a D1-mediated facilitation complexes, which appear to play a role in receptor desensiti- of glutamate transmission (94). This suggests that, within the striatal complex, with glutamate contributing to under physiologic conditions, D1-induced facilitation of DA release and DA causing a two-pronged inhibition of glutamate transmission in the striatum is mediated by burst- glutamate release, both directly via D2 presynaptic receptors firing–dependent phasic DA release (44). Finally, In addition to its ability to modulate neurotransmitter glutamate-released NO also appears to play a significant actions on postsynaptic neurons in the striatum, DA also role in modulating DA systems and striatal neuron respon- plays a significant modulatory role in the presynaptic regula- sivity. The tight interdependence and coregulation between tion of neurotransmitter release. D2 stimulation is reported DA and glutamate suggest that the system is designed to to presynaptically decrease GABA release from intrinsic maintain stable levels of transmission to the striatal neurons neurons (95) and glutamate release from corticostriatal ter- over the long term, whereas short-term changes in activity minals. Several studies report that D2 agonists cause a in either system in response to a signal are amplified by down-regulation of glutamate-mediated EPSPs on neurons their coordinated effects on each of these interdependent in the nucleus accumbens (96–99). Specifically, DA was presumed to be the glutamatergic corticostriatal afferents. In cases in which striatal excitatory acute depletion of endogenous DA, all corticoaccumbens amino acid afferents arising from the cortex are stimulated EPSPs are sensitive to DA (99). This suggests that under with high frequencies in the absence of magnesium (to en- normal circumstances, the presynaptic DA receptors may hance NMDA conductances), a long-term facilitation in already be saturated with DA, as suggested by the observa- synaptic transmission is induced, known as long-term po- tion that sulpiride increase EPSP amplitude in a majority tentiation. In contrast, if the stimulation is carried out at a of cases when administered alone (99). This unusual phar- low frequency, the opposite type of plasticity is induced; macology may reflect a contribution of presynaptic D4 re- that is, long-term depression (LTD) (107). These forms of ceptors on the corticoaccumbens terminals to this response synaptic plasticity have been proposed to play a major role (102). Although another group has reported a D1-mediated in learning and memory formation in other structures, such presynaptic action EPSPs evoked by intrastriatal stimulation as the hippocampus. Such plasticity within the striatum in slices, which was interpreted as a presynaptic effect on may be involved in such phenomena as the acquisition of corticostriatal terminals (103), this study employed exceed- complex motor skills. Repetitive stimulation of corticostria- ingly high doses of the D1 agonist to achieve these effects tal fibers to release glutamate is required for the induction (i. Moreover, anatomic studies have shown that D1 im- pretreatment prevents the induction of LTD (107), suggest- munoreactive axons are exceedingly rare in the striatum ing that a synergistic interaction between these receptor sub- (77). In contrast, recent studies suggest that DA acting on types is required for this process to occur. In contrast, corti- postsynaptic D1 receptors may actually cause a transsynap- cal stimulation-induced LTP is blocked selectively by D1 tic feed-forward inhibition of glutamate release. Both antagonists, but is actually enhanced by D2 antagonists or NMDA antagonists and adenosine antagonists can block in D2 receptor knockout mice (109). Thus, although studies done in vivo have consistently shown that direct DA application inhibits PFC neuron fir- ing, studies using in vitro slice preparations have found a DA-mediated increase (110,111) and a decrease (112,113) in neuronal excitability in this region. D1 stimulation has been shown to affect sodium conductances by increasing the sodium plateau potential and shifting the activation of sodium currents to more negative potentials (114). This increase in excitability was augmented by a D1-induced decrease in slow potassium conductances (110). D1 stimula- tion may also activate L-type calcium conductances located in proximal dendrites of pyramidal neurons to further in- crease excitability in these neurons (66). Such an interaction has been postulated to differentially modulate afferent input to these neurons (Fig. Indeed, the highly organized DAergic input onto virtually every dendrite of PFC pyrami- dal neurons in the primate provides a means for this neuro- transmitter to regulate nearly the entire complement of glu- tamatergic afferents to this cell type (115). In contrast, at least part of the inhibitory action of DA on PFC pyramidal neurons may occur by DA-induced excitation of GABAer- FIGURE 9. A simplified diagram illustrating the basic process- ing units within the prefrontal cortex. Each unit consists of a deep gic interneurons (116), which also receive a direct DA inner- layer pyramidal neuron that projects to the nucleus accumbens vation (115,117). The apical and basal dendrites of the pyramidal neu- ron receive functionally segregated inputs from various cortical membrane potentials, which alternate between a hyperpo- and subcortical regions, whereas the GABAergic interneuron, larized, nonfiring condition and a depolarized plateau state which is also modulated by DA, exerts inhibitory influences over where they fire action potentials. Moreover, studies have both the apical dendrite and soma of the pyramidal neuron. By acting on both the interneuron and pyramidal neuron dendrites, shown that the effects of DA vary depending on the state the DA input has the capacity to modulate the integration of the of the membrane potential at which it is administered. In functionally diverse array of inputs to this neuron. DA activation of the GABAergic interneuron can also serve bining in vivo microdialysis administration of drugs with to suppress information input from the apical dendrites. In con- trast, DA modulation of conductances at the somatodendritic re- intracellular recording (119) found that DA could poten- gion amplifies low-level afferent inputs from neighboring pyra- tiate glutamate-driven bistable states of PFC neurons (Fig. Therefore, the state of the membrane may significantly change the pyramidal neuron from responding primarily to long- loop afferents to a state in which it responds primarily to local influence the response to DA observed. Dopamine receptors for the in several of the behavioral aspects of DA system function D1 and D2 class have been identified in the ventral pal- (121), particular related to drug sensitization (122). DA causes an overall de- crease in the firing rate of presumed projection neurons by two mechanisms: (a) a direct effect on the projection neu- ron, and (b) an activation of the firing of putative interneur- ons, which may be analogous to the interactions occurring in the PFC. In addition, DA produced effects on afferent drive of these neurons that was dependent on the origin of the projection system. Thus, DA attenuates afferents from limbic structures such as the PFC and MD thalamus, whereas afferent input from auditory association cortex (Te3) is potentiated (Fig. Intracellular recordings re- vealed that this was a consequence of a D1-mediated de- crease in PFC-evoked EPSP amplitude, combined with a D2-mediated increase in BLA input resistance that poten- FIGURE 9. In vivo intracellular recordings from a pyramidal tiated Te3 afferent drive (129). PFC stimulation also caused neuron in the frontal cortex of a chloral hydrate anesthetized rat an excitation of BLA interneurons, which lead to a subse- is illustrated. The neuron was located near a microdialysis probe quent attenuation of input arising from Te3; however, in implanted to deliver the compounds to be tested by reverse di- alysis to the environment of the cell. Administration of NMDA (20 the presence of DA stimulation, the ability of the PFC stim- M) increases the number of spikes evoked by brief depolarizing ulation to attenuate responses from Te3 was diminished pulses. Following washout, administration of NMDA DA (30 (129). These data suggest that the PFC is normally capable M) greatly increases the spikes evoked per unit current. This occurs despite the fact that DA did not appear to significantly of attenuating amygdala responses to sensory inputs, which affect current threshold. In the case of NMDA alone, the increase could be a mechanism for decreasing emotional responses to in the number of spikes per unit current occurs with (and may be familiar or nonthreatening stimuli. However, with excessive secondary to) a decrease in current threshold; that is, the cell is simply more excitable. In the case of DA added to NMDA, the cell DA stimulation, the ability of the PFC to suppress amyg- fires more spikes during the current-induced depolarization, but dala-mediated emotional responses may be lost. Because the VP is positioned anatomically at the crossroads of the limbic and extrapyramidal system, DA modulation in this area has the ability to potently influence motivated behavior by its actions in this region (121). Mediodorsal Thalamus Anatomic studies have revealed the presence of a DA inner- vation of the mediodorsal (MD) thalamic nucleus arising from the midbrain. Using in vitro intracellular recordings, DA was found to alter MD neuron activity via a D2-me- diated effect. In particular, quinpirole was found to increase membrane excitability and enhance the low threshold spike FIGURE 9. DA attenuates prefrontal cortex (PFC) modulation in these neurons (127). This was mediated at least in part of basolateral amygdala (BLA) neuronal responses. The PFC pro- via an alteration in potassium conductances.
A more extensive distribution of der may occur in purchase levitra with dapoxetine 40/60 mg with mastercard, or indeed precede cheap 40/60 mg levitra with dapoxetine with mastercard, a range of neurodegen- Lewy bodies typifies DLB buy levitra with dapoxetine 40/60 mg overnight delivery, in which significant -amyloid- erative disorders purchase levitra with dapoxetine 40/60 mg line, including PD and multiple-system atro- osis and senile plaque formation that fall short of what is phy, in the context of degenerative dementia it suggests seen in AD are also usually present. Furthermore, the presence of extrapyramidal regulation of microtubule assembly proteins—tau-related signs in DLB and their value in discriminating DLB from cytoskeletal abnormalities that are not found in most cases AD is unresolved. First, the 'background' population preva- Alzheimer disease and DLB do share the features of - lence of parkinsonism is very common in the age range in amyloidosis, senile plaque formation, and severe depletion which both DLB and AD occur. In one recent community- of acetylcholine, which is even greater in DLB than in AD. CONSENSUS CRITERIA FOR THE 84, and 52% of those 85 and older (36). Second, a wide CLINICAL DIAGNOSIS OF PROBABLE AND range of frequencies (5% to 90%) of extrapyramidal signs POSSIBLE DEMENTIA WITH LEWY BODIES has been reported in patients with AD (37). Although this Consensus criteria for the clinical diagnosis ofprobableandpossible may be related in part to differences in disease severity and dementia with Lewy bodies (DLB) study duration, it also likely reflects imprecision in the clini- 1. The central feature required for a diagnosis of DLB is progressive cal definition of so-called extrapyramidal signs. Thus, pre- cognitive decline of sufficient magnitude to interfere with dominantly cortically determined signs, such as ideomotor normal social or occupational function. Prominent or presistent memory impairment may not necessarily occur in the early stages apraxia, paratonic rigidity (Gegenhalten), and frontal gait but is usually evident with progression. Deficits on tests of disorder, may be mistaken for bradykinesia, parkinsonian attention and of frontal–subcortical skills and visuospatial rigidity, and parkinsonian gait, respectively. Two of the following core features are essential for a diagnosis damentally different from the true parkinsonism deter- of probable DLB; one is essential for possible DLB. Fluctuating cognition with pronounced variations in mined by basal ganglia pathology (38). Finally, the reported attention and alterness rates for parkinsonism in DLB undoubtedly partly reflect b. Recurrent visual hallucinations that are typically well formed case ascertainment biases. Patients collected through neuro- and detailed logic departments, which primarily receive referrals for c. Spontaneous motor features of parkinsonism movement disorders, are more likely to exhibit extrapyrami- 3. Features supportive of the diagnosis are the following: a. Repeated falls dal signs than are DLB cases identified through memory b. Transient loss of consciousness Overall, probably fewer than half of DLB cases have ex- d. Neuroleptic sensitivity trapyramidal signs at presentation, and a fourth continue e. Systematized delusions to have no evidence of them throughout their illness. Hallucinations in other modalities (Depression and REM sleep behavior disorder have been cians must therefore be prepared to diagnose DLB in the suggested as additional supportive features. A diagnosis of DLB is less likely in the presence of tion rates will be unacceptably low. Stroke disease, evident as focal neurologic signs or on brain When extrapyramidal signs do occur in DLB, a number imaging of studies have contrasted them with the signs in PD in an b. Evidence on physical examination and investigation of any physical illness, or other brain disorder, sufficient to account attempt to characterize parkinsonian syndrome and identify for the clinical picture potential diagnostic markers for DLB (39,40). In compari- son with PD, less resting tremor and myoclonus, greater DLB, dementia with Lewy bodies; REM, rapid eye movement. It should be emphasized that any differences international workshop. The positive predictive value of any particular sign, or combination of signs, in differentiating DLB from PD in an individual patient has not been established. It seems probable that the fluctuating attentional bradykinesia, hypophonic speech, masked facies, stooped deficit is linked to dysregulation of central cholinergic posture, and festinant gait have all been reported for DLB. The important hallucinatory symptoms are specified receive neuroleptics but in only 15% of AD patients. Two as visual, recurrent, and detailed, usually occurring most studies have examined interrater reliability and found agree- days of the week; they are typically colorful, three-dimen- ment rates and values to be acceptable for some symptoms sional images of animals and children. Insight into the un- of DLB, such as delusions, hallucinations, parkinsonism, real nature of these hallucinations is usually absent while and falls, but unacceptably low for others, particularly fluc- they occur but is gained after the event. Emphasis is placed of AD, the hallucinations are more persistent and the images on the particular characteristics of the dementia syn- are more likely to be accompanied by vocalization. Sponta- drome—attentional deficits and prominent frontal–sub- neous parkinsonism not attributable to medication is a key cortical and visuospatial dysfunction. Fluctuation is no symptom in most patients with DLB. If two of these three longer essential for the diagnosis, although it is frequently symptoms (fluctuations, visual hallucinations, and parkin- Chapter 91: Dementia with Lewy Bodies 1305 TABLE 91. AUTOPSY VALIDATION OF myoclonus in patients with a rapidly progressive form of CONSENSUS CRITERIA FOR DEMENTIA DLB may lead the clinician to suspect sporadic Creutz- WITH LEWY BODIES feldt–Jakob disease (11). In patients with intermit- tent delirium, appropriate examination and laboratory tests Mega et al. In patients with a prior aClinical diagnoses made prospectively, not by chart review. Other neu- rodegenerative akinetic–rigid syndromes associated with a sonism) are present, a diagnosis of probable DLB is made; poor response to levodopa, cognitive impairment, and pos- if only one is present, a diagnosis of possible DLB is allowed. All find the diagnostic specificity patient with so-called lower-body parkinsonism, cognitive to be relatively high, comparable with that of existing clini- impairment, and urinary incontinence. This high specificity suggests in DLB are often incorrectly attributed to transient ischemic that the DLB clinical criteria are appropriate for confirma- attacks despite an absence of focal neurologic signs. Sensitivity of case rent disturbances in consciousness accompanied by complex detection is reported as more variable and generally lower. However, movements during sleep may meet the criteria for REM two studies prospectively applying consensus criteria (as op- sleep behavior disorder. Both these conditions have been posed to retrospective inspection of previous case records) reported as uncommon presenting symptoms of autopsy- did detect more than 80% of autopsy-confirmed DLB cases confirmed DLB. A prospective validation study in Newcastle re- differ clinically from those without, performing worse on ported on a sample of 50 hospital-referred demented cases attentional tasks (48). If parkinsonian features a clinical diagnosis of probable DLB were 0. Four main categories of disorders should be considered in the differential diagnosis of DLB. These are the following: NEUROTRANSMITTER ABNORMALITIES 1. Sixty-five percent of au- topsy-confirmed DLB cases meet the NINCDS/ADRDA Neurochemical activities have been widely investigated in clinical criteria for probable or possible AD (47), which is AD and PD, including in some instances PD with dementia, the most frequent clinical misdiagnosis applied to patients but fewer reports are available on DLB. These are summa- with DLB presenting with a primary dementia syndrome. Up to a third of DLB cases Reductions in presynaptic cholinergic activities, particu- are additionally misclassified as vascular dementia on the larly in the cerebral neocortex, are more marked in DLB Hachinski ischemic index by virtue of the fluctuating nature than in AD and are similar to those in PD with dementia and course of the illness. As in PD, the cortical cholinergic deficit appears to neurologic signs are usually absent. The development of reflect neuronal loss in the basal nucleus of Meynert (50). NEUROTRANSMITTER ACTIVITIES IN The cortical cholinergic pathology is independent of the DLB, AD, AND PDa extent of Alzheimer pathology, being equally great in DLB cases with and without this type of pathology (51). Cholin- DLB AD PD ergic deficits in DLB extend beyond the cortex to the stria- I. CHOLINERGIC SYSTEM tum and certain nuclei of the thalamus (52).