Cognition in PD and AD 275 to rule out the existence of another entity, which may be treated differently. In a clin- ical setting, functional imaging is basically limited to positron emission tomography (PET), where two modalities are currently used: [18F]fluorodeoxy glucose (FDG) to evaluate brain glucose metabolism (Gonzalez et al., 1995) and more recently imag- ing of amyloid-beta, using Aβ selective carbon-11 labeled thioflavin-T ([C-11]PIB) or stilbene ([C-11]SB-11) compounds. FDG-PET may show hypometabolism in temporoparietal and posterior cingulate regions, or more extensive abnormalities depending on AD stage. PIB/SB-PET studies have proven a valuable method to confirm AD diagnosis or to evaluate response to treatment, nevertheless its use is still limited, because PET compounds have a very short half-life, making the distri- bution to PET facilities difficult. So far in the United States there are only about 40 PET radiochemistry facilities that can provide this service. Research MR-imaging groups have developed several structural analysis programs that allow the quantita- tive evaluation of specific brain regions. Using these methods, it has been found that atrophy rates of entorhinal cortex best correlate with cognitive deficits in AD (Du et al., 2003). Others have used a more visual score to evaluate white matter lesions, the Scheltens score, which also correlates with cognitive decline in AD (Brickman et al., 2008). AD researchers have also extensively used functional imaging. Almost all in vivo techniques that measure brain metabolism are based on Fick’s principle postu- lated in 1870, which has been used to measure blood flow to different organs. This principle describes a relationship between oxidative metabolism and hemodynamic variables—cerebral blood flow, cerebral blood volume, and deoxyhemoglobin— to assess metabolism in the living brain. These techniques include: near-infrared spectroscopy (NIRS), contrast-enhanced computerized tomography (CT) to eval- uate cerebral blood volume (CBV), PET and single-photon emission tomography (SPECT) measurements of cerebral blood flow (CBF), and magnetic resonance imaging (MRI) measurements of CBF, CBV, and deoxyhemoglobin (BOLD sig- nals). To varying degrees, all these approaches have proven capable of detecting AD-related metabolic changes (El Fakhri et al., 2003; Small et al., 2000; Dixon et al., 2002). It is important to note that these techniques can detect metabolic changes caused by diseases in which there is a relative absence of cell loss, includ- ing a range of psychiatric illnesses (Costa et al., 1999) as well as in aging (Noda et al., 2002), establishing that imaging correlates of metabolism can detect cell dysfunction. In a recent study (Moreno et al., 2007) high spatial resolution CBV maps performed in both humans with AD and AD mouse models showed early entorhinal cortex hypometabolism which then extended to the other hippocampal subregions. This correlated with cognitive symptoms. This method was able to detect AD related MRI-changes before Aβ plaques developed in the mouse model (Fig. 11). New imaging approaches applied to AD are under development. One such approach is based on the ability to detect Aβ plaques with MRI by using 19 F and 1 H containing amyloidophilic Congo red-type compounds (Higuchi et al., 2005). This would allow a better spatial resolution in plaque location and earlier detection. The development of longer half-life F-18 label-PET radioligands have advanced 276 I. Bodis-Wollner and H. Moreno Fig. 11 Integrated approach to study neurodegeneration. In the upper panel are shown hippocampal cerebral blood volume (CBV) maps generated in mice (right)and humans (left). In the lower panel an in vitro horizontal brain slice (left) at the same position where the MRI generated images (right). These types of preparations exemplified the techniques that can be used crosssspecies (upper panel) and techniques that complement each other (lower panel) significantly too. In contrast, efforts to develop a SPECT Aβ imaging agent have been largely unsuccessful. To conclude, it seems possible, although still at early stages, that neuronal metabolic changes preceding cell death can indeed be detected by imaging methods. This is a significant advancement, which allows for very early diagnosis and intervention. 11 APP Processing and Its Relation to Cognition 11.1 Amyloid Hypothesis A strong genetic association exists between early onset familial forms of AD (FAD) and the 42 amino acid species of the Aβ peptide (Hutton et al., 1998; Younkin, 1998). It has been determined that autosomal dominant mutations in the genes for amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) increase production of Aβ42 and correlate strongly with the FAD syndrome. In addition, the ε4 isoform of the apolipoprotein E gene, which is the major risk for late-onset dis- ease, affects the rate of Aβ aggregation (Bales et al., 1999). Aβ has been the central point of AD research for over a decade and is generally considered as the upstream causative factor. This has been the basis of the amyloid hypothesis. Recently this hypothesis has been challenged or at least reconsidered by several investigators (Ash, Duff, etc.); some propose a dual hypothesis (Small and Duff, 2008), which Cognition in PD and AD 277 implies an upstream event that initiates both Aβ- and tau-related pathologies. Aβ is a cleaved product of APP via the sequential action of two protease complexes, the β and γ secretases. (Selkoe, 2001). β secretase cleaves APP at the N-terminus producing the membrane-bound moiety C99 and the secreted APPs β segment. Subsequently, C99 is cleaved by the γ secretase to generate the C-terminus of Aβ, resulting in a series of 28 to 43 amino acid length Aβ peptides. Under normal condi- tions such events result in a higher proportion of Aβ40 than Aβ42 moieties. Under altered conditions, such as in transgenic mice harboring human APP mutations, an increased production of Aβ42 develops, followed by many pathophysiological features of AD including amyloid plaques, dystrophic neuritis, and synaptic dys- function. Nevertheless none of the amyloidogenic mice or even mice that develop Aβ- and tau-related pathology have significant neuronal loss. 11.2 Aβ Extra- or Intracellular and in Which Compartment? Amyloidogenic mouse models have shown that overproduction of Aβ leads to dys- trophic axons and dendrites around amyloid plaques (LaFerla et al., 2007). It is also clear that anterograde axonal transport delivers Aβ peptide into plaques (Stokin et al., 2005). Substantial controversy remains over the sites of APP processing and Aβ release (Lee et al., 2005). Some studies implicate the axon as a site of Aβ pro- duction. Consistent with the amyloid deposition hypothesis is the fact that plaque formation increases if poor axonal transport delays the progress of APP and its processing enzymes through the axon (Stokin et al., 2005). Other reports failed to reproduce parts of this model, in which APP and its processing enzymes are cotransported (Lazarov et al., 2005). Some Aβ release occurs at the synapse in an activity-dependent manner, but Aβ can also be released from more proximal sites (Adalbert et al., 2007). A study that evaluated Aβ dynamics in human brain interstitial fluid (ISF) after trauma, reported that Aβ concentrations increased as neu- rological status improved and decreased when neurological status declined. Brain ISF Aβ concentrations were also lower when cerebral hypometabolism was present, reflecting depressed neuronal function (Brody et al., 2008); interestingly most of the normally secreted Aβ detected in this study did not appear to be either Aβ40 or Aβ42. Extracellular accumulation of Aβ represents the foundation of the amyloid cascade hypothesis. The importance of intracellular Aβ accumulation in the patho- genesis of AD has emerged as a possibility in recent studies (LaFerla et al., 2007). These studies, implemented in human and mouse brains were made possible by the development of antibodies that could differentiate Aβ40 and Aβ42 from the transmembrane amyloid precursor protein from which they derived (Gouras et al., 2005). Other studies using transgenic mice harboring constructs that target Aβ either intracellularly or extracellularly showed that only transgenic mice producing the intracellular Aβ developed neurodegeneration (LaFerla et al., 1995). Some experi- mental evidence suggests that intracellular Aβ accumulates because a portion of the Aβ by not being secreted remains in the cytosol. Given that the vast majority of Aβ is 278 I. Bodis-Wollner and H. Moreno normally secreted, such results indicate that Aβ is predominantly cleaved at or near the plasmalemmal inner surface or as part of the secretory pathway (Laferla et al., 2007). Another possible mechanism that explains intracellular Aβ accumulation involves Aβ endocytosis (D’andrea et al 2001). There is strong evidence that Aβ42 is responsible for memory decline in AD, however, in humans the extent of Aβ accumulation correlates poorly with mem- ory abnormalities (Giannakopoulos et al., 2003). Indeed, a specific challenge in addressing Aβ in AD concerned the role of specific pools of Aβ (e.g., extracellular, intracellular, membrane associated, or insoluble) in the genesis of the pathology. Newly reported pathological findings, using sequential brain extraction procedures demonstrated that only the intracellular Aβ42 levels and membrane-bound com- partments were significant higher in the neocortex of AD cases than controls and correlated with neurological deficit, whereas Aβ40 levels were similar in patients with AD and in controls (Steinerman et al., 2008). The relevance of extracellular Aβ toxicity has also been fully documented, with many reports emphasizing two issues: there is no clear relationship between amy- loid plaque number and AD clinical status in humans or behavioral deficit in humans or mouse models, and cognitive deficits occur much before plaque deposit in AD mouse models, and are related to the appearance of oligomeric forms of Aβ, mainly Aβ42. The main Aβ oligomeric subspecies identified have been (1) dimeric forms in CSF from AD patients (Klyubin et al., 2008), and (2) 56-kDa specie, a poten- tial dodecameric Aβ42 assembly in an AD mouse model, that when injected into young rats produced similar deficits in memory as those seen in the AD mouse (Lesné et al., 2006). Finally, it should be pointed out that Aβ40 and Aβ42 are not the only toxic proteolytic products of APP. Indeed, several groups have proposed that other C-terminal fractions (C99 and C88) or CTF50 are also related to AD pathophysiology. 12 Revisiting the Unforgettable Tau 12.1 Aβ and Tau Interaction For more than two decades neurobiologists have known that both Aβ and tau are prominent in the CNS structures targeted by AD. As described above, Aβ hypoth- esis has been favored due to its genetic links. Indeed, no mutations in the tau gene have ever been linked to the disease and even today many tau experts concede that Aβ-related toxicity initiates neuronal dysfunction. Based on these premises several Aβ reducing agents have been or are in the process of being tested (tarenflurbil, tramiposate, active, and passive Aβ immunizations). However, to date these human trials have been largely disappointing. Furthermore, a recent study documenting the long-term effect of Aβ immunization in patients that had been immunized in September 2000 (of note, phase I of the trial was halted because of lethal compli- cations in a small number of patients) who deceased, reports that the immunization Cognition in PD and AD 279 with Aβ42 resulted in a near complete reduction of Aβ pathology, but this clearance did not prevent progressive neurodegeneration. All these patients had severe neu- rocognitive deficits and advanced NFT pathology, even involving primary cortex (Holmes et al., 2008). These two sets of findings—the failure of drugs that reduce Aβ load and the neuropathological study—not only suggest that the focus of AD treatment must also consider tau physiopathology in the equation, but has been the basis for proposing the dual pathway hypothesis, specifically referring to late onset AD (Small and Duff, 2008). This group hypothesizes that Aβ and tau pathologies are driven by single upstream molecular events: potential candidate molecules include Apolipoprotein E ε4-(APO-E4), the glycogen synthase kinase 3 (GSK3), and the retromer complex. Focusing on the interaction tau-Aβ, mice expressing disease-causing double- mutations in APP and varying the number of the mouse tau gene (either, none, one or the normal two copies) have been generated. These mice developed brain amy- loid pathology due to the APP mutation, but as usual in AD mouse models none had NFTs or neuronal loss. As the mice aged, those with two tau gene copies became impaired in spatial memory tests. Animals with one tau copy performed slightly bet- ter and mice with no tau gene had normal memory scores (Roberson et al., 2007). These results suggest that tau reduction somehow can block Aβ mediated neuronal dysfunction. Consistent with these reports, mice bearing a mutant tau that is linked to hereditary tauopathy that can be suppressed with doxycycline developed age- dependent NFTs, where the tau gene is expressed (SantaCruz et al., 2005). These mice developed brain atrophy and abnormal spatial memory. Suppression of the mutant tau gene with doxycycline improved the mice’s spatial memory but did not affect NFT accumulation. Some have even proposed that NFT serves as protective role against cellular toxicity, because phosphorylated tau can sequester redox-active heavy metals (Castellani et al., 2008). This leaves by default one viable hypothesis of a “toxic tau intermediate” yet to be discovered. 13 Synaptic Dysfunction in AD 13.1 Is AD a Neuronal Disconnection Syndrome? In neuropathological studies of synaptic damage, several groups have identified synaptic loss in the hippocampus ∼50%, neocortex 25–30%, whereas in the cere- bellum, an area not affected in AD, there are no changes in synapse number (Bertoni-Freddari et al., 1990; Gylys et al., 2004; Almeida et al., 2005). These changes are accompanied by decreased levels of pre- (synaptophysin) and post- synaptic (synaptopodin and PSD95) proteins in the samples from the AD brains compared to non-AD age-matched controls. The loss of synapses and the loss of synaptic proteins are confined to the brain regions known to be affected in AD. There are several lines of evidence from experiments in vitro and in vivo that sol- uble oligomeric Aβ is responsible for a decrease in long-term potentiation in several 280 I. Bodis-Wollner and H. Moreno synapses, mainly in the hippocampus, and disruption of neuronal synaptic plastic- ity. Further experiments have identified that dimeric and trimeric subspecies of Aβ inhibit LTP (Cleary et al., 2005; Townsend et al., 2006; Puzzo et al., 2005). Thus, although there is evidence for oligomeric Aβ (oβ)-induced synaptic dysfunction, the pre- or postsynaptic sites of action and the specific mechanism responsible for such dysfunction have not been established. Experiments addressing these questions were performed in the squid giant synapse, demonstrating that although intra-axonal oAβ42 peptide produced failure of synaptic transmission, intra-axonal oAβ40 pep- tide produced no significant changes in synaptic transmission. The effect of oAβ42 peptide is mediated by a cascade of events involving caseine kinase activity, abnor- mal fast axonal transport, and the rapid clathrin-independent endocytosis pathway. This set of events resulted in reduction of transmitter release (Moreno et al., 2009). This suggests that a dying-back phenomenon may be occurring in AD, causing synaptic loss, as has been recently proposed. (Pigino et al., 2009). In addition, other factors, such as Aβ-mediated decreased expression of sodium channels in hippocampal GABAergic interneurons, which leads to a hyperactive sate of the hippocampall circuit, have also been proposed (Palop et al., 2008). In agreement with this “exitotoxic event” acute extracellular exposure of hippocampus subicular pyramidal neurons to nanomolar concentrations of oAβ42 produced an increase of spontaneous synaptic events and larger basal dendritic calcium levels, and intra- cellular oAβ42 produced a synaptic failure (Angulo et al., 2008). Interestingly Fig. 12 Model of a “disconnected neuron.” Shown are the events known to occur in different com- partments of the neuron due to amyloid pathology. Note that both the presynaptic and postsynaptic elements are dysfunctional in AD Cognition in PD and AD 281 an upregulation of several neurotransmitter receptors (cholinergic, GABAergic, and glutamatergic) in young AD mouse models, with a subsequent age-dependent decline in their expression levels has also been reported (Bell et al., 2006). The role of tau in synaptic dysfunction has not been as well documented as Aβ. Tau has been reported to change intracellular calcium levels, probably via the inter- action of extracellular tau with muscarinic receptors M1 and M3 (Gómez-Ramos et al., 2008). Also a spatially association of tau modifications with intraneuronal Aβ, in which both pathologies co-occur at synaspses has been reported ( Takahashi et al., 2010). Finally, using two-photon calcium imaging in layer 2/3 of an AD mouse model cortical neurons, an increase in the frequency of spontaneous calcium transients in the vicinity of amyloid plaques was seen (Busche et al., 2008). Taking this information together with the imaging data (MRI-CBV) maps demonstrating a hypermetabolic phase in very young AD and Down-syndrome mice and a later age-dependent hypometabolism (Moreno et al., 2006, 2007), it seems plausible to propose that this series of events leads to a biphasic neuronal discon- nection syndrome, with an initial hyperactive state followed by subsequent synaptic failure phase (Fig. 12). 14 Future Perspectives Although the advances in the understanding of AD and PD pathophysiology have been significant, fundamental issues remain unsolved. The powerful neuropathological arguments concerning the progression of PD based on alpha synuclein predicts late involvement of cortical circuits, presumably responsible for cognitive changes. This needs to be established with a multivariate analysis of longitudinal studies in a large number of demographically well-defined populations. The relationship of PD to frontotemporal dementia (Kertesz et al., 2005) and other neurodegenerative disease remains to be defined. The search for specific protein aggregates characterizing or perhaps defining each diagnostic entity appears promising. More attention to the sensitivity of pre- and postsynap- tic dopamine receptors may help further development of rational pharmacotherapy in PD. The retina is the most accessible part of the central nervous system and its morphology and functional properties have been well characterized. Future neu- ropharmacological/ t herapeutical research may take advantage of the retina in PD. Although the inner retina has been shown to be significantly thinned in over two thirds of PD patients, the presence of alpha synuclein has not been established. There is a demonstrable paucity of rational pharmacotherapeutical agents in the treatment of cognitive dysfunction in PD. The evidence suggests that multiple circuits and multiple neurotransmitter systems are involved: developing therapy will be a challenging task. Potentially targeting specific cognitive dysfunctions and specific pathochemical mechanisms may be rewarding. 282 I. Bodis-Wollner and H. Moreno The possible future directions of AD research may include: (a) more detailed information in the synaptic dysfunction (i.e., localizing the pre- and postsynap- tic events, identification of the “toxic tau subspecies” and its molecular pathway); (b) identification of the molecular/functional basis for the regional sensitiv- ity/specificity: why is entorhinal cortex affected initially in AD and how does it progress? What confers “resistance” to the cerebellum; (c) reconsider therapeutic strategies; we may need a molecular step up; (d) the use of in vivo techniques that allow a better understanding of brain circuitry disarray in AD such as magnetoen- cephalography (MEG); (e) the use of data-based circuits modeling, in which brain oscillations can be investigated and used in conjunction with MEG data, to be able to propose the mechanisms of the cognitive deficits observed more realistically. To finish, I refer to Faulkner. “The past is never dead,” Gavin Stevens says in Requiem for a Nun, and he adds, “It is not even past.” Such fundamen- tal considerations may not remain the same under AD pathological processes, a rather devastating new reality, or perhaps quite the opposite; in any case we must understand it, if an appropriate treatment is to be developed. 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