Neurochemical Mechanisms in Disease P29 ppt

Cognition in PD and AD 265 7 Nondopaminergic Signals and Cognition in PD 7.1 GABA and the Subthalamic Nucleus Deep brain stimulation was introduced nearly two decades ago into the treatment of PD. Over the last years it has become a rather widespread treatment modality, with some rather impressive results in carefully selected patients. The effects are seen as motor improvement. However, adverse mood and cognitive effects have been also described and preoperative selection criteria have to be adhered to min- imize the chances for adverse effects (Lang et al., 2006). Some of the results also raised questions concerning our neuroanatomical and neuropharmacological con- cepts of the classical basal ganglia circuitry. One of the evaluating techniques is intraoperative microdialysis which was developed by Stanzione and his collegues (Fedele et al., 2001; Mazzone et al., 2005) as a technique into human intraoperative electrophysiological monitoring and recordings. Their and some other studies have yielded biochemical evidence of the functional role of the subthalamic nucleus in the PD relevant basal ganglia circuitry. It was noted that lesions of the subthalamic nucleus may reverse Parkinsonism (Bergman et al., 1990). Deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson’s disease patients augments STN-driven excitation of the internal globus pallidus (Stefani et al., 2005). Stefani et al. (2006) quantified the biochemical effects of STN-DBS in two basal ganglia mechanisms (putamen, PUT, and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergo- ing surgery, microdialysis samples were collected from GPi, PUT, and VA before, during, and after 1 h of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA ([gamma]-aminobutyric acid) was measured in the VA. During clinically effective STN–DBS, a significant decrease in GABA extracellular concentrations in the VA (–25%) was achieved. Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). The results suggest that DBS differentially affects fibers crossing the STN area: it activates the STN–GPi pathway while inhibiting the GPi–VA one. These findings support a thalamic disinhibition, as the main fac- tor responsible for the clinical effect of STN–DBS. Inhibitory interneuron play is essential for regulating neuronal circuits and behavior by controlling spike timing and neuronal rhythms (see later). However, there is great diversity of GABAergic interneurons and GABAA receptor subtypes. There are indications that region- and domain-specific location of these receptor subtypes are differentially involved in several nonmotor manifestations of PD such as regulation of sleep, anxiety, memory, and sensorimotor processing, in addition to postnatal developmental plasticity (Mohler, 2007). The pedunculopomtine nucleus (PPN) is reciprocally connected to the BG. It input is from the globus pallidus interna, substantia nigra pars reticulata, and STN. Its output is glutamatergic to STN, GPOi, and SNC. It has been reported that in PD about 50% of its intrinsic cholinergic neurons are lost. Combined deep brain 266 I. Bodis-Wollner and H. Moreno stimulation of the subthalamic and pedunculopontine (PPN) nuclei has been recently proposed as surgical treatment of advanced PD. STN stimulation alone has been shown to provide selective improvement of the grammatical aspect of language. In five advanced PD patients combined deep brain stimulation (STN + PPN) did not change the overall cognitive profile, however, language was affected. There was a trend towards reduction of ungrammatical errors (particularly substitution of free and inflectional morphemes) when stimulating t he PPN, even when the STN was switched off (Zanini et al., 2009). The PPN reaches the motor cortex via thalamic nuclei, however, its connections to other cortices are less well explored. 7.2 Cholinergic Mechanisms “Dementia” has been recognized for many decades as one of the nonmotor fea- tures of PD. Research proceeded along several approaches to understand whether dementia in PD represents an overlap syndrome with primarily dementing disorders, such as Alzeheimer disease, diffuse Lewy body disease, and frontotemporal dementia, just to name a few. Both anatomical and neurochemical studies addressed dementia in PD. Dementia, by the definition of Diagnostic Manual (DSM-IV) criteria includes memory dysfunction and one of the following: aphasia, apraxia, agnosia, or disturbance of executive functions. By this standard PD patients rarely have dementia. They have select and specific cognitive impairments such as “log- ical memory” (Pang et al., 1990; Bodis-Wollner et al., l995) which correlate with modality dependent changes in event-related potentials. The earliest cognitive impairment in PD is evident for executive abilities, visu- ospatial orientation, and memory. However, many studies of cognition in PD use the term “dementia” without defining the specific deficits. With this in mind, it is still worth reviewing the contrast between Alzheimer disease and PD, in particular with reference to cholinergic mechanisms. It was suggested that cognitive dysfunction in PD, similarly to AD results from loss of cholinergic neurons in the nucleus basalis Meynert (Whitehouse, 1981). However, it was reported by Perry et al. (1985) that “dementia” in this disease usu- ally occurs in the absence of substantial Alzheimer type changes in the cortex and may be related to abnormalities i n the cortical cholinergic system. Thus, in Parkinsonian patients with dementia there are extensive reductions of choline acetyltransferase and less extensive reductions of acetylcholinesterase in all four cortical lobes. Choline acetyltransferase reductions in temporal neocortex correlated with the degree of mental impairment assessed by a memory and information test but not with the extent of plaque or tangle formation. In PD but not in Alzheimer’s disease the decrease in neocortical (particularly temporal) choline acetyltransferase correlates with the number of neurons in the nucleus of Meynert suggesting that primary degeneration of these cholinergic neurons may be related, directly or indirectly, to declining cognitive function in Parkinson’s disease. In fact the correlation of cholinergic deficits in PD is more evident and is more severe than in AD (Bohnen et al., 2003). In 18 of 22 patients who were diagnosed with Cognition in PD and AD 267 dementia Aarsland et al. (2005) reported on the presence of limbic and neocortical Lewy bodies-associated cholinergic deficits without the presence of changes typical of AD. Thus the evidence suggests that acetylcholine may have an important role in nondopaminergic cognitive changes. If so, some cognitive defects could possibly be treated with choline-esterase inhibitors. Although the ACh inibitor Rivastigmine has been reported to have some benefits in PD (Emre, 2004), up to now there has been a dissonance between the scientific evidence for cholinergic deficiency in PD brains and the clinical use of cholinergic agents in treating cognitive impairment in PD. One reason may be the concern for a potential negative motor effect of cholinergic medication in PD. Treatment of PD with anticholinergic medications precedes the l-dopa era and is still used in some clinical centers Cholinergic interneurons play an essential role in striatal mechanisms and increased acetylcholine release in the striatum is pathognomic for PD (Cragg, 2006). ACh interneurons interact with the dopaminergic system in several ways. Dopamine-dependent long-term potentiation (LTD) is mediated by D2 receptors (in the indirect pathway) but D2 receptors are also reported on cholinergic interneurons. Acetylcholine release activates mainly through M1 muscarinic receptors at glutamatergic axo-spinous synapses (Hersch et al., 1994). It is possible therefore that selective receptor agonist therapy would benefit cognition in PD without causing negative motor effects. Establishing the relationship between select cognitive deficits and nicotinic versus muscarinic neurotransmission may lay the foundation for rational pharmacotherapy of cognitive dysfunction in PD. 7.3 Glutamate, Thalamocortical Processing, and D1 and D2 Dopamine Receptors The results of several imaging studies have shown correction of abnormal motor, but not cognitive, network activity by treatment with dopaminergic therapy and deep brain stimulation. Some nondopaminergic elements of the circuitry, however, are known to contact diverse postsynaptic dopamine receptors. Select psychomotor functions are under the influence of dopamine in modulating cortical and thalamic glutamatergic signals impinging upon principal medium spiny neurons (MSNs) of the striatum. Dopamine D1 receptor signaling enhances den- dritic excitability and glutamatergic signaling in striatonigral MSNs, whereas D2 receptor signaling exerts the opposite effect in striatopallidal MSNs. The functional antagonism between these two major striatal dopamine receptors also extends to the regulation of synaptic plasticity. Furthermore these studies have also shown that long-term alterations in dopamine signaling produce profound and cell-type-specific reshaping of corticostriatal connectivity and function. However, at this point little is known of the effects of selective dopamine receptor ligands on memory performance in PD. 268 I. Bodis-Wollner and H. Moreno 7.4 Adenosine The role of adenosine, originally described by Greengard (1972), is being increasingly emphasized and studied from the molecular to the behavioral level. Furthermore, anecdotical clinical evidence concerning cognitive effects of alpha adenosine A2 type receptor blockers is consistent with the results of animal studies (Takahashi et al., 2010). The molecular role of adenosine is primarily in the postsynaptic phosphorylation cascade in the action of dopamine (Nishi et al., 2008). Phosphodiesterase (PDE) regulates cellular cAMP/protein kinase A (PKA) signaling. The effect of dopamine is largely mediated through the cAMP/PKA signaling cascade, and therefore is con- trolled by PDE activity. PDEs with different substrate specificities and subcellular localizations are expressed in neurons. PDE4 and PDE10A have different roles in the regulation of cAMP/PKA signaling in the striatum. In vitro and in vivo biochemical techniques Nishi et al. (2008) used selective PDE inhibitors to regulate phosphorylation of presynaptic (e.g., tyrosine hydroxylase (TH)) and postsynaptic (e.g., dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP- 32)) substrates for PKA. The PDE4 inhibitor, rolipram, induced a large increase in TH Ser40 phosphorylation at dopaminergic terminals t hat was associated with a commensurate increase in dopamine synthesis and turnover in striatum in vivo. Rolipram induced a small increase in DARPP-32 Thr34 phosphorylation preferen- tially in striatopallidal neurons by activating adenosine A(2A) receptor signaling in striatum. In contrast, the PDE10A inhibitor, papaverine, had no effect on TH phosphorylation or dopamine turnover, but instead robustly increased DARPP-32 Thr34 and GluR1 Ser845 phosphorylation in striatal neurons. Inhibition of PDE10A by papaverine-activated cAMP/PKA signaling in both striatonigral and striatopallidal neurons, resulted in potentiation of dopamine D(1) receptor signaling and inhibition of dopamine D(2) receptor signaling. These biochemical results are supported by immunohistochemical data demonstrating differential localizations of PDE10A and PDE4 in striatum. Over the last decade, adenosine receptors in the central nervous system have been implicated in the modulation of cognitive functions. Despite the general view that endogenous adenosine modulates cognition through the activation of adenosine A1 receptors, evidence is now emerging on a possible role of A2A receptors in learning and memory. Takahashi et al. (2010) reviewed studies using diverse animal models to provide a comprehensive picture of the recent evidence of a relationship between adenosinergic function and memory deficits. They conclude that caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A2A receptor antagonists can improve memory performance in rodents evaluated through different tasks. Their review also suggests that caffeine and selective antagonists may also afford protection against memory dysfunction elicited in experimental models of aging, Alzheimer’s disease, PD, and, in spontaneously hypertensive rats (SHR), a putative genetic model of attention deficit hyperactivity disorder (ADHD) (Fig. 10). Cognition in PD and AD 269 Fig. 10 Regulation of the striatopallidal indirect GABAergic pathway: A 2A receptor-mediated dual excitatory modulation of the indirect pathway. Presumed action of the nondopaminergic adenosine receptor ligand in the basal ganglia circuit. Adenosine A(2A) receptors are localized to the indirect striatal output function (courtesy of Mori and Shindou, 2003) From the clinical point of view the development of nondopaminergic therapy is highly attractive as direct dopaminergic therapy is associated with a number of complications. Whether medications that affect alpha adenosine a-2 type receptors are effective and whether they bypass some of the complications associated with direct dopaminergic therapy, remains to be seen. Current research also suggests that cyclic-nucleotide PDE isoforms could be targets for developing novel therapies for neuropsychiatric and neurodegenerative disorders affecting dopamine neurotransmission. 8 The Alzheimer’s Disease Case: An Overview Listen, stranger; this was myself: this was I. (W. Faulkner, very last sentence in “The Jail”) Alzheimer’s disease has prevalence estimates of approximately 10% in individuals over age 65 and 30% in individuals over age 85 in the United States. Clinically AD presents as a progressive deterioration of selective cognitive domains, with initial symptoms indicating a decline in memory function, particularly a loss of episodic memory, which is considered a subcategory of declarative memory. But it is also well documented that a large number of elderly people have poorer memory perfor- mances, with prevalence of up to 40% in individuals over 60 years (Hanninen et al., 1996) and in many cases other cognitive deficits (di Carlo et al., 2007). Prospective 270 I. Bodis-Wollner and H. Moreno studies show that elderly subjects who exhibit mild cognitive impairment, a proposed transitional stage between “normal aging” and “dementia” go on to develop dementia at a rate of 10–15% per year, which is 5–7 times higher than for age- matched individuals without such impairment (Petersen and Negash, 2008). The challenges in the diagnosis, predictors to conversion to AD, and possible modifiers such as diet and education level are briefly presented in this chapter. From a neuropathology perspective AD is characterized by accumulation of senile plaques (beta amyloid-related pathology) and neurofibrillary tangles (tau- related pathology). Until recently it has been proposed that beta amyloid is an extracellular pathology, and tau is intracellular, but recent studies challenge both of these statements, as discussed in detail below. The cause of the disease still remains unknown but involves abnormal cleavage of a neuronal membrane protein called amyloid precursor protein (APP) and abnormal accumulation of a fragment called B-amyloid (Aβ), which is the substrate for the senile plaques. This constitutes the so-called amyloid hypothesis, which implies a causative model initiated by Aβ.A more recent hypothesis linking Aβ and tau pathologies to a common upstream ini- tiator(s) has also been proposed (Small and Duff, 2008). The mechanism of Aβ and tau-induced changes in neuronal activity and their relationship with cognitive dysfunction are also topics of the present chapter. Thus, the cognitive deficits in AD are covered from both the clinical and basic science perspectives. 9 Cognitive Decline in the Elderly; Is It “Aging”, MCI, or Early AD 9.1 Normal Aging Advanced aging is accompanied by cognitive decline even in the absence of disease. Several theories posit that cognitive deficits arise from alterations in functional properties of co-ordinated brain systems or from subtle anatomical disconnection between brain regions that ordinarily function together, most likely due to white matter abnormalities (O’Sullivan et al., 2001; Pfefferbaum et al., 2005). Based on the structural observation of age-associated white matter degeneration, O’Sullivan proposed the “disconnection” hypothesis: decline in normal aging emerges from changes in functional integration between systems of brain areas in addition to dysfunction of specific gray matter areas. An indirect method based on analysis of spontaneous fluctuations within brain systems has been proposed to detect system integrity (Greicius et al., 2003 in 4). The basis of this technique is that functional MRI (fMRI) detects the spontaneous low-frequency fluctuations that are coherent within large-scale systems, such as motor (Biswal et al., 1995) and sensory (De Luca et al., 2005). Recently this technique was used to measure the integrity of a large-scale system involving frontal and posterior brain regions; this system is often Cognition in PD and AD 271 referred to as the “default network” (Raichle et al., 2001) and is associated with the internally directed mental states including memory, planning, and related cognitive processes. This study demonstrated an age-dependent reduction in the correlation between the anterior and posterior systems, in elderly individuals free of AD. This correlated with poor performance in the following psychometric tests, in order of strength: memory, processing speed, and executive function (Andrews-Hanna et al., 2007). One could propose that this disconnection ultimately leads to corticosubcor- tical dysrrhythmias, such as thalamo-cortical abnormalities, that could potentially explain cognitive deficits (Llinás et al., 2005). In contrast, other researchers proposed that age-related processes, some of which underlie cognitive decline, do not target cortical regions equally, suggesting that the effect of aging is not cognitively diffuse (Small, 2001). Using a different MR imaging technique, in which basal metabolism is measured by cerebral blood volume (CBV), this group (Small et al., 2000) has identified the hippocampal dentate gyrus region as the most sensitive structure to the aging process, which correlated with the memory decline observed in the elderly. These proposed mechanisms— disconnection and site-specific vulnerability—are not mutually exclusive. We can envision a situation in which deafferentation produces specific gray matter dysfunction or neuronal dysfunction may lead to axonal abnormalities in specific circuits. Of note, almost all cases of non-AD causes of memory decline in humans and nonhuman mammalian species are hippocampal-based. The exact cause of non-AD age-dependent memory decline is a matter of debate; many mechanisms have been proposed including: adrenal and gestational hormonal levels, changes in cerebrovas- cular supply, oxidative stress, and disrupted neuronal calcium homeostasis. All these different abnormalities are present at different levels in the elderly, but the extent to which they contribute to memory failure is still unknown. What else to take into account before considering MCI or AD diagnosis: The fact that different life exposures including education, occupation, and leisure, impart a reserve against Alzheimer’s disease in epidemiological studies, raised the possibility of a different brain response to the aging process or to neurodegenerative entities in general. This term is referred to as cognitive reserve (CR). It has been proposed that the neuronal implementation of CR may involve two major components: neuronal reserve and neuronal compensation (Stern, 2006). Neuronal reserve refers to CNS networks or cognitive paradigms that due to their activity become less susceptible to disruption. Using this type of CR would be a normal process that is constantly used in healthy individuals. However, such networks may also help an individual cope with brain pathology. Neuronal compensation refers to the process by which subjects suffering from brain pathology use brain structures or networks not nor- mally used by healthy individuals. These two hypothesized mechanisms have been supported by several fMRI studies (reviewed in Stern, 2006). It is plausible to propose that an individual’s CR may be amenable to change upon specific exposures or interventions. This could potentially be used as the basis for a behavioral therapy to treat AD. 272 I. Bodis-Wollner and H. Moreno 9.2 Mild Cognitive Impairment (MCI) MCI is not a disease per se, but rather it has been defined as a condition of inter- mediate symptomatology between the cognitive changes of aging and very early dementia (Petersen and Negash, 2008). In fact, it can be viewed as a cognitive decline at the normal tail end of a continuum. The rationale for the study of MCI is derived from the idea that the earlier one intervenes in a neurodegenerative process, the more likely the damage done to the CNS can be prevented. The concept of MCI has evolved considerably over the years. The term MCI was initially used by Reisberg to describe individuals with a global deterioration s cale (GDS) of 3. Others have used the clinical dementia rating scale (CDR) of 0.5. But these cutoff values do not necessarily correspond to specific diagnoses. A patient with CDR0.5 can meet the criteria for MCI, mild dementia, or AD. Recently MCI has emerged to represent a stage of impairment beyond what is considered normal for age, but not of sufficient magnitude to warrant the diagnosis of dementia or AD. Originally MCI was defined by memory complaint, memory impairment for age (adjusted for education and socioeconomic background), preserved general cognitive function, and intact activities of daily living. Recently the criteria have been expanded to include two subtypes: amnesic (original criteria) and nonamnesic (nonmemory cognitive domain impaired; Winblad et al., 2004). It has been suggested that nonamnesic MCI patients may have underlying brain pathology different from AD, and the amnesic MCI patients are more likely to be diagnosed with AD over time (Devanand et al., 2008a). Using these criteria it is rather subjective to diagnose MCI versus normal aging; in most cases the appropriate diagnosis becomes clear only with time. 9.3 Predicting Conversion from “Normal Aging” to MCI and from MCI to AD? The clue to this transition seems to be found in the sense of olfaction. Early in the course of AD, degeneration occurs in the entorhinal cortex–hippocampal–subicular complex (Price and Morris, 1999). The olfactory bulb, particularly the anterior olfactory nucleus, shows numerous neurofibrillary tangles (NFTs). Odor identification deficits during life may be associated with NFTs in the hippocampus (Wilson et al., 2007). Clinically, AD patients consistently show deficits in odor identification com- pared to controls (Doty et al., 1991). These deficits have been shown to be a true decline in odor identification ability that cannot be explained by lexical difficulty in interpreting written words in the multiple choice test formats. The University of Pennsylvania has developed a smell identification test (UPSIT), with ranges 0– 40, which is widely used in clinical settings. Recent studies have shown that odor identification deficits predict conversion from normal to MCI, particularly decline of verbal memory (Wilson et al., 2007). Other series (Devanand et al., 2008a)of studies have demonstrated that olfaction has a strong predictive power of MCI to AD in both t ypes of MCI. Many other biomarkers have been used to predict AD Cognition in PD and AD 273 conversion, including neuropsychological tests, cerebrospinal fluid markers (Beta amyloid, hyperphosphorylated tau and isoprostane), and MRI entorhinal cortex volume. Combining several of these markers (i.e., olfactory measures, selective remaining test immediate recall (verbal memory), MRI-hippocampus/entorhinal cortex volumes and functional activities questionnaire values) strongly predicted conversion to AD (Devanand et al., 2008b). 9.4 Diagnosis of AD AD is a genetically heterogeneous disorder. Four genes have been identified (Preselinin 1-PSEN1, Preselinin 2-PSEN2, Amyloid precursor protein-APP, and Apolipoprotein E ε4-APOE4) and additional chromosomal regions and genes are being investigated. The autosomal-dominant genes cause early-onset before 60 years of age. Mutations in these causative genes account for less than 5% of all cases of AD. PSEN1 is the most common causative gene; its mutation is associated with the earliest age at onset, seizures, myoclonus, and language deficits. APP mutations cause dementia typical of AD. Mutations in PSEN2 have been identified only in one family. In most cases the cause of the disease is believed to be complex, resulting from a combination of susceptibility genes interacting with each other as well as with environmental factors. APOE4, the most common of the known susceptibility genes, is distinct from the causative genes, because it is neither sufficient nor necessary to cause AD. Genetic testing for diagnosis and predictive purposes is available for early-onset AD, and appropriate genetic counseling is strongly suggested, almost mandatory. Clinically AD is characterized by a gradual progressive decline in intellectual function, problem solving, language, and perception. Patients manifest character- istic cognitive and behavioral findings. The most common presenting cognitive symptom is short-term memory impairment (mostly episodic memory) and forget- fulness. As the disease progresses long-term memory is also affected. In addition to memory impairment, diagnosis requires impairment of at least one other cognitive domain, including judgment, abstract reasoning, language (primarily word find- ing difficulties or anomia, common symptom) orientation, praxis, and attention. It should be emphasized that some patients with AD may develop memory deficits only very late in the course of the disease. Noncognitive behavioral manifestations include changes in personality and mood or in behavior (paranoia, delusions, anger, aggression, restlessness agitation, wandering, sleep–wake cycle disturbance, hal- lucinations, and illusions). The rest of the neurological examination is relatively normal. Extrapyramidal signs such as rigidity and bradykinesia may portend a more rapid decline. Standardized instruments are available for staging of AD, these include the Clinical Dementia Rating scale (CDR) and the Global Deterioration Scale (GDS). Staging is useful mainly for following disease progression and management. The CDR evaluates memory, orientation, judgment, problem solving, community affairs, 274 I. Bodis-Wollner and H. Moreno home and hobbies, and personal care. This is used to classify AD into categories: mild, moderate, and severe. Many comorbidities, such as dyslipedemias and dia- betes, seem to worsen AD progression, making the approach to this pathology multimodal, and requiring metabolic, neurological, behavioral, and psychosocial interventions 9.5 Diet in AD Diet may play an important role in the causation and prevention of AD (Luchsinger and Mayeux, 2004) but the results may be conflictive. Higher intake of vitamins C, E, and B12, flavonoids, unsaturated fatty acids, fish, and folate, moderate ethanol, and lower total fats, have been related to lower risk of AD. Other studies failed to find association between intake of vitamins C, E, B12, carotenes, fats, or levels of vitamin B12 and AD risk. There is a new and perhaps more ecological approach to this situation, which is to study the effect of dietary pat- terns (rather than individual foods or nutrients) on the risk for AD. One such dietary pattern is the Mediterranean diet (MeDi), which is characterized by high intake of vegetables, legumes, fruits, cereals, unsaturated fatty acids (mostly in the form of olive oil) but low intake of saturated fatty acids and moderately high intake of fish and low to moderate intake of dairy products (mostly cheese and yogurt) and low intake of meat and poultry, and a regular but moderate amount of ethanol, primarily in the form of wine and generally during meals (Trichopoulou et al., 1995). There are several lines of evidence showing that MeDi is related to lower risk of cardiovascular disease, several forms of cancer, and overall mortal- ity. Recently it was reported that higher adherence to the MeDi is associated with a reduced risk for AD, in a cohort of nondemented individuals at baseline where AD was prospectively assessed. The association observed between MeDi and risk for AD was not mediated by vascular comorbidity (Scarmeas et al., 2006a,b).This constitutes another potential nonpharmacological intervention to treat and/or pre- vent AD and suggests that there are multiple metabolic processes related to AD pathophysiology. 10 Imaging AD 10.1 Can Neuronal Dysfunction Be Visualized Before Cell Death? As part of the initial assessment of a patient with dementia, brain imaging is required. With imaging one can get information on structure or function, or a combination of the two. In AD, clinical structural MRI findings are not specific, with reports of neocortical, hippocampal, or global atrophy and white matter hyperinten- sities and/or associated mircovascular disease. The main reason to perform a MRI is . neurons in the nucleus of Meynert suggesting that primary degeneration of these cholinergic neurons may be related, directly or indirectly, to declining cognitive function in Parkinson’s disease. In. under the in uence of dopamine in modulating cortical and thalamic glutamatergic signals impinging upon principal medium spiny neurons (MSNs) of the striatum. Dopamine D1 receptor signaling enhances. PDE4 inhibitor, rolipram, induced a large increase in TH Ser40 phosphorylation at dopaminergic terminals t hat was associated with a commensurate increase in dopamine synthesis and turnover in

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