Cognition in PD and AD 255 Gamma power increase starts at the beginning of the movement, prior to achiev- ing the final eye position and then returns to baseline following the end of the saccade. Power is higher in the absence of visual input. The perisaccadic modu- lation of gamma power we call “phasic” gamma. Conceive of a person sleeping in the dark, awakened and quickly looking for an invisible visual target. Our inten- tion to see even in the absence of visual stimulus, is a prerequisite for the saccades to start. Perisaccadic phasic gamma in the absence of visual stimulation may rep- resent intrasaccadic cerebral processes we called “pre-emptive” (Bodis-Wollner, 2008). The term “pre-emptive” represents that the saccades are directed and not random; they may emerge from a repertoire of an infinite number of trajectories by suppressing unwanted actions. 5.3 Genetic Variability of Catechol-O-Methyltranferase, Prefrontal Cortex, and Cognition Dopamine receptors, in particular D1 receptors, are abundant in the prefrontal cor- tex (Goldman-Rakic et al., 2000). Cathecol-O-amine transferase (COMT) is one of the metabolic enzymes of catecholamines in the tissues, including the brain (Axelrod, 1966). In the last two decades COMT inhibitors have been introduced into clinical practice to enhance the effectiveness of levodopa therapy, without the need to administer higher doses of levodopa. COMT alters dopamine levels in the prefrontal cortex (PFC) dopamine system. The COMT gene contains a functional polymorphism (Val 158 Met) that has been associated with variation in PFC func- tion, including “prefrontal tests” of cognition in PD (Malholtra et al., 2002). The COMT inhibitor medication tolcapone, which easily crosses the blood–brain bar- rier, improved cognition in eight advanced PD patients: in particular improvement was noted in the attentional task, auditory verbal short-term memory, visuospatial recall, constructional praxia, and motoric (Gaspirini et al., 1997). In the dopamine-depleted awake rat model (Tunbridge et al., 2004) tolcapone significantly and specifically improved extradimensional (ED) set-shifting perfor- mance, originally described by Teuber and Proctor (1964) in PD. Microdialysis showed that tolcapone significantly potentiated the increase in extracellular dopamine (DA) elicited by either local administration of the depolarizing agent potassium chloride or systemic administration of the antipsychotic agent clozapine. Although extracellular norepinephrine (NE) was also elevated by local depolar- ization and clozapine, the increase was not enhanced by tolcapone. Apparently COMT activity specifically affects ED set-shifting and is a significant modulator of mPFC DA but not NE under conditions of increased catecholaminergic transmis- sion. The interaction between clozapine and tolcapone may have implications for the treatment of schizophrenia (Inada et al., 2003). Schott et al. (2006) measured dopaminergic midbrain functions in a human episodic memory task. They quantified responses in 51 young, healthy adults using functional magnetic resonance imaging. Their specific question was how 256 I. Bodis-Wollner and H. Moreno polymorphisms in dopamine clearance pathways affect encoding-related brain activ- ity. Successful episodic encoding was associated with activation of the substantia nigra. This midbrain activation was modulated by the number of tandem repeat (VNTR) polymorphisms in the dopamine transporter (DAT1) gene. Despite no differences in memory performance between genotype groups, carriers of the (low- expressing) 9-repeat allele of the DAT1 VNTR showed relatively higher midbrain activation when compared with subjects homozygous for the 10-repeat allele, who express DAT1 at higher levels. The catechol-O-methyl transferase Val108/158Met polymorphism, known to modulate enzyme activity, affected encoding-related activ- ity in the right prefrontal cortex and in occipital brain regions but not in the midbrain. Moreover, subjects homozygous for the (low-activity) metallele showed stronger functional coupling between the PFC and the hippocampus during encoding. Their study provides strong support for a role of dopaminergic neuromodulation in human episodic memory formation. It also supports the hypothesis of anatomically and functionally distinct roles for DAT1 and COMT in dopamine metabolism, with DAT1 modulating rapid, phasic midbrain activity and COMT being particularly involved in prefrontal dopamine clearance. 6 Vision and Visual Cognition 6.1 Short-Term Memory for Visual Stimuli and Spatial Orientation in PD In the definition of dementia memory is one of the three most important defin- ing characteristics by DSM-IV criteria. In the commonly applied experimental paradigms to elicit event-related potentials for a successful response the target stimulus has to be stored in the active working memory. The paradigms r equire a comparison between the stored stimulus and a subsequently presented one for same– different decision making. There has been an attempt to relate neuropsychological deficits to discrete neuranatomical brain areas. Prior to the era of in vivo brain functional imaging, this was based on human and animal lesion studies, with remarkable foresight. Spatial orientation deficits (Teuber and Proctor, 1964) are thought to reflect deficits of the posterior cortices and set-shifting impairment has been thought to reflect mostly frontal functions (Taylor et al., 1986). Aggleton and Brown (1999) proposed two parallel brain systems with quali- tatively different contributions to memory. Pathological anatomical studies in the monkey support the concept of this division of memory systems. Following bilat- eral symmetrical frontal ablations Macaque monkeys are impaired in object–reward association memory (Gaffan and Parker, 2000) and object RM (Kowalska et al., 1991). Thus, the select deficiencies in recall-aware memory reported by Hay et al. and others (Levin et al., 1989; Buytenhuijs et al., 1994; Hugdahl et al., 1991; Daum et al., 1995; Leplow et al., 1997; Knoke et al., 1998; Owen et al., 1998; Dujardin Cognition in PD and AD 257 et al., 2001) appear to arise as a consequence of a breakdown in frontally medi- ated strategic memory processes implicated in intentional and effortful memory processes. Spatial orientation deficit and set-shifting impairment have been noted in neu- ropsychological studies in PD (Raskin et al., 1990). One part of the working memory system, the visuospatial sketchpad, is devoted to the maintenance of visual infor- mation. The visuospatial sketchpad shows a specific selective impairment in PD: even when the visual subsystem responsible for the object-related visual analysis seems to be spared until the later stages of the disease, the visual processing of spa- tial location, motion, and three-dimensional properties is impaired (Moreaud et al., 1997; Owen et al., 1993, 1997; Postle et al., 1997; Lee et al., 1999). Cognitive changes in PD may be independent or precede global dementia. Kuroiwa and his collegues (Wang et al., 1999a,b,2000;Lietal.,2003, 2005) introduced an S1–S2 paradigm (task S) as well as oddball paradigm (task O) visual event-related poten- tials under different interstimulus intervals (ISIs). In several studies they have shown that PD patients have particular difficulty with longer interstimulus intervals. ERP measurements were correlated with motor disability, WAIS-R, and regional cere- bral blood flow ((99)Tc-ECD SPECT) examination. In advanced PD patients, P300 latency to S2-same and reaction time was significantly prolonged, whereas rCBF at bilateral frontal, temporal, and the right parietal lobes was decreased. P300 latency to S2-same was significantly correlated with the rCBF at bilateral temporal lobes. Reaction time was significantly correlated with the rCBF at the right frontal and parietal lobes, as well as the temporal and occipital lobes. They suggested that P300 changes in nondemented PD in the late stage is related to temporal lobe dysfunction, suggesting the importance of a memory task-dependent subdivision of cortico–basal ganglia circuits in PD. Based on the results in humans it is likely that the P300 abnormalities predomi- nantly reflect working memory impairment in PD. Kemps et al. (2004) compared the visuospatial sketch pad and central executive components of working mem- ory as potential cognitive mechanisms of visuospatial dysfunction in PD. Patients performed more poorly in both concurrent task conditions, implicating a reduc- tion in both visuospatial sketch pad and central executive resources. The impact of the concurrent tasks varied with disease severity, with the central executive deficit prominent at disease onset, but the visuospatial sketch pad deficit became apparent only in the moderate stages of the illness. Studies that examined P300 amplitude in PD are few (Wang et al., 1999a). The first positive “hump,” the anterior P3a, is atten- uated in amplitude in patients with PD without dementia (Lagopoulos et al., 1998). This component possibly reflects passive or automatic math/mismatch processing and elicited by the more infrequently appearing stimulus regardless of its target or nontarget status. The reduction of the classical P3b was also found and correlated with a poor performance in the Wisconsin Card Sorting Test (WCST; Tsuchiya et al., 2000). These results suggest that the passive and active orienting responses of PD patients to novel events is impaired and that recording P300 might provide a neuro- physiological and quantitative measure of attentional and cognitive deficits linked to the frontal lobe in nondemented PD. Furthermore, the amplitudes of the NoGo-P300 258 I. Bodis-Wollner and H. Moreno and NoGo-N200 (a negative component appearing around 200 ms after the stimu- lus onset) were also significantly smaller in the PD group than in the control group (Bokura et al., 2005). The NoGo-P300 amplitude was significantly correlated with the WCST and the verbal fluency test scores, as well as with the number of com- mission errors. These data suggest that there is also an impairment of inhibitory function in PD and that this deficit may be related to impaired inhibitory executive function in the frontal lobe. Vi sual perceptual categorization and ERPs were studied by Antal et al. (2000). Classifying visual targets is often difficult for PD patients. Antal et al. (2002) tested 16 de novo, early PD patients. They were shown, one after another, color photographs of either natural scenes or animals, each different. Their task was to categorize each picture as “scene” or “animal”. There was a signifi- cant poststimulus amplitude difference around 200 ms in control, but not in PD patients, suggesting a visual categorization deficit in PD out of 1000 randomly presented Delayed-response tests are well suited to test the spatial location of objects. PD patients even with mild symptoms have difficulty in maintaining, even briefly, the memory trace of spatial locations of irregular polygons, whereas they successfully keep online the shapes of the same stimuli (Postle et al., 1997). However, errors in this kind of task (usually errors in pointing movements to remembered visual tar- gets) can be attributed to various factors, such as the misperception of the target position, errors in spatial memory, errors in the transformation from visual informa- tion to an appropriate motor command, or to a deficit in proprioceptive information processing of the arm. A recent study reports that pointing movements in PD are impaired due to a deficit in processing of proprioceptive information, which appears early in the course of the disease, and by a visual feedback problem, which emerges in later stages of the disease (Keijsers et al., 2005). Although some studies have suggested that the visual subsystem responsible for the object-related visual analysis seems to be spared until the later stages of PD (Lee et al., 1999; Moreaud et al., 1997; Owen et al., 1997; Postle et al., 1997; Amick et al., 2003), others have found that it is not always the case (Antal et al., 2002). Rather, attention-biased object-related weighting and selecting processes can be dysfunctional even in young PD patients. During a visual categorization pro- cess a diminished differential N1 component was observed in de novo and also in treated PD patients. This component represents the basic visual feature encoding and initiating stages of perceptual categorization in the first 200 ms poststimulus period (Thorpe et al., 1996). It is hypothesized that the neostriatum may mediate feature weighting and extraction processes and the differential N1 may refer to this function. In PD, this is possibly dysfunctional, as reflected by the diminished dif- ferential N1 (Antal et al., 2002). In agreement with this hypothesis, in patients with AD, in which the cortico–cortical pathways mediating feedforward mechanisms are impaired, this component was not diminished compared to the controls but appeared later. Cognition in PD and AD 259 6.2 Aging and Cognitive Event-Related Potentials It has been suggested that with age the dopaminergic system progressively weakens in various animal species. However, the generalization of these observations from observing motor dysfunction to the suggestion that PD represents an accelerated form of aging is not generally accepted. Evidence from various sources, includ- ing patients, animals, the effects of experimental pharmacological intervention, and molecular genetics shows that DA is also critically implicated in select higher-order cognitive functioning. It remains to be seen whether DA-dependent select cognitive deficits in PD also characterize the aging process (Bäckman et al., 2006). A delayed P300 in PD is not due to aging per se (Tachibana et al., 1997) and there is a significant inverse relationship of delayed P300 and score of the Mini Mental State (Maeshima et al., 2002). The P300–P100 latency difference calculated from the concurrently obtained visual ERP is significantly longer in younger PD patients and differentiates them from controls (Antal et al., 1996; Sagliocco et al., 1997). 6.3 Neurotransmitters and Cognitive ERP-S in PD Does the P300 abnormality represent only dopaminergic dysfunction? Electrophysiological evidence shows that DA receptors are involved in visual working memory in the prefrontal area (for a review see Goldman-Rakic, 1998), which was also identified as one of the generators of P300 (Halgren et al., 1998). Indeed, levodopa treatment shortens the latency of P300 in some PD patients (Stanzione et al., 1991; Sohn et al., 1998). Contrary to these findings, some inves- tigators have described a prolonged P300 latency in medicated patients (Hansch et al., 1982; Prasher and Findley, 1991). However, medicated patients are more severely affected and the delayed P300 might also correlate with disease severity. In the animal model of PD, in behaving MPTP monkeys the visual P300 is beneficially affected by levodopa treatment (Glover et al., 1988) and in the healthy monkey D2 receptor blockade impairs the latency of the visual ERP but surprisingly it enhances its amplitude (Antal et al., 1997). It is known that task difficulty prolongs ERP latency while enhancing its amplitude. Based on this explanation the D2 receptor blockade may perhaps induce increased noise in the thalamocortical cognitive loop. The modulation of P300 by nondopaminergic agents such as cholinergic sub- stances has been studied in monkeys (Antal et al., 1994) and in healthy subjects (Dierks et al., 1994; Frodl-Bauch et al., 1999). Delayed P300 improved in PD patients following treatment with amantidine, a low-affinity uncompetitive NMDA receptor antagonist (Bandini et al., 2002). In this study amantidine’s effect was noticeable not only as a monotherapy, but also in patients treated with levodopa. It is suggested that amantadine has DA-mimetic properties and it cannot be therefore excluded that amantidine improves cognitive ERP-s in PD as a DA-mimetic agent. 260 I. Bodis-Wollner and H. Moreno 6.4 Dopamine in Visual Processing in the Retina The retina is multilayered, with distinct neural elements in each layer. Receptors in the outer layers convert and use light energy to produce electrical currents, affecting subsequent neurons. There are three major forward synapses before the ganglion cells receive signals in the innermost layer of neurons. In between there are sev- eral lateral and feedback connections. Amacrine cells, including dopamine amacrine cells, are located in the inner layer close to ganglion cells (Fig. 4). The inner retina (IRL) includes the nerve fiber layer, the ganglion cell layer, and the inner-plexiform layer whereas the outer retina (ORL) consists of layers starting from inner nuclear layer up to and including the retinal pigment epithelium. Fig. 4 A TH labeled (dopaminergic) amacrine cell of the rat retina. Note that the receptor layer is on the top and the faintly visible ganglion cell layer is on the bottom (from Mytileneou and Bodis-Wollner, Department of Neurology, The Mt. Sinai School of Medicine, around 1978; unpublished data) Quantitative morphology of gross retinal histology in humans can be measured in vivo using optical coherence tomography (OCT) (Shulman et al., 1996) (Fig. 5). The electrophysiological measure obtained with corneal electrodes in the intact eye, using patterned visual stimuli, such as sinusoidal gratings, the so-called PERG is an average response of foveally located retinal ganglion cells. The amplitude of the pattern electroretinogram as a function of spatial frequency of the sinusoidal grat- ing stimulus also shows the inverted U-shaped function (in both man and monkey) as the CS curve. This PERG output function is the result of the massed averaged response of central retinal ganglion cells (Maffei et al., 1989). The bandpass func- tion is changed to a lowpass function in PD and in the monkey using systemic MPTP (Ghilardi et al., 1988a, b), intraocular 6-Hydroxydopamine (Ghilardi et al., 1989), and D2 receptor blockade (Tagliati et al., l994; Fig. 6). These results lend themselves to the functional interpretation of retinal ganglion cell disorganization in the dopamine-deficient PD retina once the contrast transfer function is understood as the sum (difference) of center and surround responses (Enroth-Cugell and Robson 1966;Fig.7). Based on electrophysiological and func- tional studies in primates, one may accept the existence of two classes of ganglion cells: one center dominated with strong surround, having narrow spatial tuning Cognition in PD and AD 261 Fig. 5 Left: OCT image of 6 mm of the macular retinal layers of a 46-year-old healthy subject with an IOP 15 mmHg and Snellen visual acuity 20/20. Right: OCT image of 6 mm of the macular reti- nal layers of a 50-year-old, moderately advanced (Hoehn and Yahr staging 2.5) PD patient (Unified Parkinsons Disease Rating System motor score 17) prior to any anti-Parkinsonian treatment. IOP was 14 mmHg and Snellen visual acuity 20/25 (from Hajee et al., 2009) 0.6 0.5 0.4 0.3 0.2 0.1 0 0.1 1 10 Spatial Frequency (c/d) P E R G A m p l i t u d e A Fig. 6 The pattern ERG PERG in PD. The normally strongly bandpass PERG amplitude function (top curve) shows lowpass shape in levodopa-treated (middle curve) and untreated PD patients (after Tagliati et al., 1996). Note that the treatment slope on the right side of the curve, representing summation in the center mechanism, is attenuated as a result of D2 antagonist treatment 262 I. Bodis-Wollner and H. Moreno Fig. 7 Antagonistic center/surround interaction is the basic model of a foveal retinal ganglion cell receptive field. Note that the center mechanism is characterized by a narrow and tall response (sensitivity) profile, whereas the surround is broad and has a low, spatially extended profile. The response profiles are e stablished by preganglionic circuitry. The ganglion cell performs the linear operation of subtracting the center and surround signals. If the surround mechanism is selec- tively attenuated it may lead to a response that monotonically grows with center stimulation. As a result the spatial transfer function loses tuning. The exact spatial frequency at which tuning occurs reflects on the diameter and optimal interplay between center and surround (after Enroth-Cugell and Robson, 1966) and another one with larger centers and less sharp tuning. The PERG spatial con- trast response function is understood as the envelope output of all retinal ganglion cells covering the central foveal area with different weights for the two classes of ganglion cells. Based on the results of experimental pharmacological studies and the effect of PD on retinal processing (Bodis-Wollner, 1990) inferred that D1 receptors primar- ily affect the “surround” organization of ganglion cells with large centers, whereas D2 postsynaptic receptors contribute to “center” response amplification of ganglion cells with smaller centers. 6.5 Retinal Model of Dopaminergic Dysfunction in PD Bodis-Wollner and Tzelepi (1998, 2002, 2005) modeled the preganglionic dopamin- ergic circuit based on the results of pharmacological experimental data (see above) in the monkey and in humans. These experiments showed that select dopamine receptor ligands change the spatial transfer function of the retina in a manner which suggests that D1 and D2 receptors modulate the balance of center and surround organization of foveal ganglion cells of the primate. Based on results in vertebrates Bodis-Wollner (1990) assumed that in primates the surround organization of the retinal ganglion cell is under D1 receptor control. D1 receptor activation causes disjunction of horizontal cells, otherwise coupled in Cognition in PD and AD 263 an extended chain (Piccolino et al., 1987). In other words, when D1 activity is present, the horizontal cell signal is more concentrated in a smaller area; it does not get diffused. As a consequence under D1 activity the surround becomes smaller 4 3 2 1 0 0.1 1 5 4 3 2 PERG Amplitude 1 0 10 –1 High Dosage Low Dosage Normal L-Sulpiride 10 0 Spatial frequency (cpd) 10 1 10 4 3 2 1 0 0.1 1 10 Fig. 8 The effect of the selective D2 ligand l-sulpiride on the PERG of a low-dose monkey. Upper left: Note that for a low-dose sulpiride PERG amplitude is higher at low spatial frequencies than in the untreated one and the response to the peak spatial frequency is attenuated. This effect at the optimal spatial frequency is not unexpected, given the role of D2 receptors in center response amplification: the heightened response at low spatial frequencies is surprising. Upper right:The effect of high-dose sulpiride on the PERG: both low and peak spatial frequency responses are attenuated. (Both figures after Tagliati et al., 1994 and Stanzione et al., 1995.) Bottom: a model of the dose and spatial frequency-dependent effect of D2 blocking on the PERG according to the subtractive Gaussian center-surround interactive mechanisms. (Based on the experimental results of Tagliati et al., 1994 and Stanzione et al., 1995, after Bodis-Wollner and Tzelepi, 2002, 2005.) 264 I. Bodis-Wollner and H. Moreno but stronger. D2 receptors promote coupling between rods and cones in the xeno- pus (Krizaj et al., 1998). In our model we assumed that 2–3 neighboring receptors are coupled, thereby amplifying the center strength. Consequently complete lack of D2 activation should lead to a loss of center sensitivity by a factor of 2–3. Tagliati et al. (1994) and Stanzione et al. (1995) found a seemingly paradoxical effect when the effects of a low-dose and a high-dose sulpiride were compared in the healthy subject. The effect of the selective D2 ligand l-sulpiride on the PERG for a low dose shows that PERG amplitude is higher at low spatial frequencies than in the untreated one and the response to the peak spatial frequency is atten- uated. This effect at the optimal spatial frequency is not unexpected, given the role of D2 receptors in center response amplification: the heightened response at low spatial frequencies is surprising. High-dose sulpiride attenuates the PERG for both low and peak spatial frequency responses (Fig. 8; both figures after Tagliati et al., 1994 and Stanzione et al., 1995). These results suggested to Bodis-Wollner and Tzelepi (1998, 2002, 2005) that high-affinity (Skirboll et al., 1977) D2 autorecep- tors are located in the D1 surround pathway and this presynaptic effect dominates the PERG when using low-dose sulpiride. An understanding of the logic performed by retinal D1 and D2 receptors may be useful to discern the functional role of diverse dopamine receptors in DA circuits elsewhere in the CNS. These retinal data may be relevant to an understanding of the logic role of D1 and D2 type receptors (Fig. 9). D 1 D 2 CENTER SURROUND RB IDB IMB FMB A MG MG R R C R R R R C C C A P –– + Fig. 9 Left: a simplified diagram of the retina with principal neurons and interconnections. On top is the receptor layer and the bottom shows the ganglion cells with their axons (“nerve fiber”) which can be seen on ophthalmoscopic examination and quantified using modern retinal imaging in vivo. Right: a schematic representation of the preganglionic dopaminergic connections including pre-synaptic D2 receptor connection . receive signals in the innermost layer of neurons. In between there are sev- eral lateral and feedback connections. Amacrine cells, including dopamine amacrine cells, are located in the inner layer. amantidine improves cognitive ERP-s in PD as a DA-mimetic agent. 260 I. Bodis-Wollner and H. Moreno 6.4 Dopamine in Visual Processing in the Retina The retina is multilayered, with distinct neural. and functionally distinct roles for DAT1 and COMT in dopamine metabolism, with DAT1 modulating rapid, phasic midbrain activity and COMT being particularly involved in prefrontal dopamine clearance. 6