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Departamento de Investigación, Laboratorios Trinidad, Roma Sur, Mexico, D.F., Mexico
1 To whom requests for reprints should be addressed at Departamento de Investigación, Laboratorios Trinidad, Tlaxcala 90, 1er piso, Roma Sur, Mexico, D.F., Mexico. E-mail: svalemayorga{at}yahoo.com.mx
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Abstract |
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 Top Abstract IntroductionFuture DirectionsFinal RemarksReferences |
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Key Words: Parkinson’s disease • cognitive dysfunction • prefrontal cortex • dopamine • cholinesterase-inhibitors • ampakines
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Introduction |
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TopAbstractIntroductionFuture DirectionsFinal RemarksReferences |
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Cognitive Dysfunction in PD.
Patients with PD have two components of cognitive dysfunction (CD): a generalized subcortical dementia (PDsCD), and a hypothesized, overlapped pattern, suggesting specific prefrontal dysfunction (PDpFCD).
PDsCD.
PDsCD is considered to be multifactorial and comprises the highly selective loss of dopamine (DA) neurons in the SN, as well as losses occurring in other nervous cells such as norepinephrine neurons in locus ceruleus and dorsal motor nucleus of the vagus, the nucleus basalis of Meynert (with a pronounced depletion of cholinergic neurons), epinephrine neurons in the rostral ventral lateral medulla, and serotonin neurons in the dorsal raphe (4, 5). Thus, PDsCD is associated with structural neosubcortical changes in the brain (in frontal, parietal, limbic, and temporal lobes, as well as in midbrain structures), whereas in PD non-demented patients, but with mild cognitive impairment (MCI), there are reduced grey matter areas in the left frontal and both temporal lobes (6).
In addition, pathological examination shows marked accumulation of cytoplasmic inclusions of proteinaceous and lipid material called Lewy bodies (LBs). LBs consist of lipids, ubiquitin, alpha-synuclein, synphilin-1, and other entangled proteins. Alpha-synuclein is a protein of unknown function and a major component of LBs. In the sporadic form of PD, cortical LBs (and Lewy neurites) are widespread and correlate with the severity of the dementia (7). It has been suggested that the accumulated pre-synaptic alpha-synuclein prefibrillar oligomers and protofibrils, not LBs themselves, are the cause of synaptic dysfunction (8), contrasting the traditional hypothesis where LBs containing alpha-synuclein, because of its association with a free radical generating metabolite of DA, initiates neurotoxicity (9). Consequently, it has been hypothesized that inhibition of early alpha-synuclein aggregation may prevent the alpha-synuclein oligomer-related toxicities (10). Amyloid plaques are also present in PD, however, since they may represent some type of comorbidity, are outside the scope of this article. The clinical characteristics of PD subcortical dementia (slowness of mental processing, forgetfulness, apathy, and, in many cases, depression) differ from those of Alzheimer dementia’s type, where prominent cerebral cortical involvement produces aphasia, amnesia, agnosia, and apraxia.
PDpFCD.
Among the complex pathophysiological mechanisms of CD in PD, the non-demented patients at an early stage of PD already show impaired vigilance and significant deficiencies in verb retrieval, abnormalities that can be the consequence of DA depletion in the striatum, disrupting the function of subcortical prefrontal networks even in absence of loss of gray matter (11, 12). These phenomena are thought to arise from de-afferentation of the prefrontal cortex from the basal ganglia. In this regard, three closed frontal-subcortical circuits link discrete areas of the frontal cortex with the striatum and other basal ganglia, and thalamic nuclei (Fig. 1
). These loops are involved in functionally distinct neurobehavioral features. Disruption of projections from the dorsolateral prefrontal cortex, orbitofrontal cortex, and anterior cingulated/mediofrontal cortex correlate with executive dysfunction, social behavioral abnormalities, and poor motivation, respectively. These features overlap with the clinical data of PDsCD, especially in middle and advanced stages of the disease, in such a way that in most occasions it is a theoretical issue to take apart one type of CD from the other. Nevertheless, there is a central role played by prefrontal cortex in the early CD of PD (12). In this hypothesized PDpFCD (preferentially affecting the dorsolateral prefrontal cortex), cognitive deficits can be recognized by neuropsychological tests sensitive for frontal lobe functions.
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Pharmacological Agents Targeting PDsCD.
In PD, the primary cause is yet unknown; consequently, we only have secondary weapons for symptomatic benefit of the patients (Table 1).
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Agents with Mixed Cholinergic and Dopaminergic Properties.
Selegiline: This selective irreversible inhibitor of monoamine oxidase-B possesses a wide range of pharmacological activities. Besides its dopamine-potentiating effect, it renders protection against a number of dopaminergic, cholinergic, and noradrenergic neurotoxins (19). Moreover, selegiline metabolites interferes with early apoptotic signaling events induced by various kinds of insults in cell cultures of neuroectodermal origin, hence protects cells from apoptotic death (20). Interestingly, this drug also increases acetylcholine activity and thus, improved memory-associated synaptic plasticity (21). However, there are no randomized controlled trials (RCT) with this drug in PDsCD as yet. Moreover, in a multicenter trial phase II study of selegiline transdermal system for HIV-associated cognitive impairment, this drug, although well tolerated, failed to improve CD (cognitive modifications were detected by changes in NPZ-8 score, average of norm-adjusted z-scores for Timed Gait, Grooved Pegboard, Trail-making, Symbol Digit [to detect short-memory and attentional dysfunction], and the Subject Clinical Global Impressions using a semistructured interview) (22). In summary, beneficial effects observed in PD patients treated with selegiline are primarily symptomatic rather than cognitive-enhancement.
Dopaminergic Agonists.
Pramipexole and Piribedil: If dopaminergic drugs improve PDsCD, why does L-Dopa exposure seems to affect adversely the course of the disease? Current opinion says that the pulsatile stimulation of the striatal DA receptors caused by the short-live of L-Dopa may be partially responsible.
Accordingly, long-acting dopaminergic agonists will be indirectly neuroprotective and may improve cognition. This is the case of Pramipexole (23). Of note, because of its D3 dopamine-receptor-selectivity, this drug exerts a neurotrophic effect on cultured DA neurons by modulating the production of endogenous glial cell derived neurotrophic factor and brain-derived neurotrophic factor (BDNF), which may participate in neuroprotection (24). However, regarding its long-term cognitive improvement effects, no RCT exists yet. Conversely, research about piribedil profile does exist and is shown below, in the PDpFSD section (25–27).
Antiglutamatergic Drugs.
Memantine, a moderate-affinity, voltage-dependent, uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor, has shown to benefit cognition in patients with moderate to severe Alzheimer’s disease; consequently, it has been evaluated in the symptomatic treatment for the general PDsCD. An isolated report (28) describing three patients, shows improvement of both dyskinesia and PDsCD. In consequence, the hypothetical enhanced effects of adding memantine to cholinesterase inhibitors have been proposed (29), although it must be stressed that there are no hard data recommending this drug in PD CD. Remarkably, riluzole, a more potent glutamate release inhibitor as compared with memantine, have failed to improve parkinsonian symptoms or nonmotor complications like cognition (30, 31). This apparent paradox may depend on the reduced neuronal calcium influx caused by memantine (while riluzole has no effect in this area) and that calcium deregulation may contribute to the pathogenesis of CD by increasing the formation of neurotoxic oligomer forms of the amyloid β-peptide (32).
Other Mixed Antiglutamatergic and Dopaminergic Agents.
Amantadine, which possesses NMDA receptor blocking activity as well as DA releasing properties, apparently has beneficial effects on cognition. Consequently, it has been suggested that amantadine is a reasonable option for improving cognition in several types of neurological insults (Reviewed in 33). Importantly, in one case-control study (34), the duration of amantadine exposure was positively correlated with PD duration-until-dementia as well as attenuation of its severity. Moreover, improved survival with amantadine use also has been reported (35). Amantadine appears to act through many pharmacological mechanisms. It exhibits dopaminergic, noradrenergic, and serotonergic activities, increases the availability of acetylcholine in cortical neurons, blocks monoamine oxidase A and NMDA receptors and seems to raise β-endorphin and β-lipotropin levels (36). So, more than one of these complex effects may be relevant in the treatment of PDsCD and in the presumed general survival improvement. In summary, these preliminary findings suggest that a prospective, controlled, randomized trial of amantadine’s effects on PDsCD is warranted.
Antioxidants and Enhancers of Mitochondrial Functions.
The oxyradical products derived from DA metabolism may initiate selective SN degeneration. This situation may be increased from normal parameters if the DA from synaptic vesicles are redistributed to cytosol as the result of an exogenous toxin (methamphetamines for instance). The resulting oxidized compound, DA-quinone, reacts with the DA-transporter and synuclein. Neurons in SN are characterized by neuromelanin, a proxy of oxidative stress. This pigment is composed of DA-quinone, DA-semiquinone, lipids, and proteins. Neuromelanin avidly binds iron and a variety of other metals, which seems to explain the basis for high iron levels in the SN, and has been suggested to act as a pool for transition metals that could contribute to the oxyradical formation by the Fenton reaction (37). These oxyradical products in turn activate microglia, causing release of nitric oxide, interleukin-6, and tumor necrosis factor-
, thus becoming an important determinant of disease progress. In line with these data, in vitro and in some PD models, native antioxidants (reduced glutathione, N-acetylcysteine, tetrahydrobiopterin, and the enzyme superoxide dismutase) have neuroprotective properties. Unfortunately, in spite of this strong experimental evidence, in the clinic there is no RCT with these substances yet, and only vitamin E has been tested, with negative results (38). Moreover, the antioxidant and "bioenergetic" agent in the mitochondrial respiratory chain, the coenzyme Q10, has no effect either in motor function or in activities of daily living, cognition, or depressive symptoms (39). (Three main tests detected the ineffectivity of this agent: the Parkinson’s Disease Questionnaire, the Global Clinical Impression score, and the Montgomery-Asberg Depression Rating Scale.)
Anti-COX-2 and Other Anti-Inflammatory Agents.
Many persuasive findings support the view that inflammation contributes to the pathogenesis of PD. Reactive oxygen species, cytokines, and prostaglandins are released by activated microglia in experimental lesions of dopaminergic neurons in the SN of PD patients. Consequently, it is reasonable to suppose that activated glial cells can propagate the neurodegenerative process. Therefore, drugs targeting specific aspects of the glia-related cascade may be valuable against and PDsCD (40). Nevertheless, in clinical studies this class of drugs has not proved their capability to improve PD progression nor PD CD. Two recent phase III large RCT studies carried out with aspirin and refecoxib respectively are good examples of negative results using this approach (41, 42). Incidentally, in these studies, cognition modifications were comprehensively searched (41) by: Boston memory test, delayed recall, and category fluency (naming as many animals as possible in one minute); likewise, CD was extensively evaluated (42) by MMSE, Clinical Dementia Rating, Blessed Dementia Rating Scale, and Auditory Verbal Learning Test.
Pharmacological Agents Targeting Prefrontal CD in PD (PDpFCD) (Table 1
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Piribedil.
In PD, converging evidence from behavioral pharmacology and neuroimaging suggests that CD could, at least in part, be related to impairment of the mesolimbic and mesocortical DA pathways (43). However, PD patients are also less proficient in learning the predictive value of reward cues, despite preserved mesolimbic processing of reward prediction errors. Values and probabilities of reward outcomes are coded in a medial prefrontal-mesolimbic network and a deficit in learning expected values might be a result of both mesolimbic neurotransmitter deficiencies, and medial pre-frontal dysfunction. Moreover, a functional disconnection between the prefrontal cortex and the supplementary and premotor cortex in PD patients has been disclosed (44), arguing in favor of combination of both factors PDsCD and PDpFCD, in the early CD of PD. In a brief "proof-of-concept" randomized study, 19 out of 25 patients with severe MCI showed improvement (evaluated for significance with non-parametric statistics with the "Mini-Mental State Examination" scores) taking the DA agonist piribedil (25). Since in addition to its dopaminergic activity, piribedl augments the extracellular levels of ACh in the frontal cortex and dorsal hippocampus, possibly antagonizing the alpha-2A-adrenoceptors, (these receptors exert a tonic inhibitory influence upon cholinergic transmission) (26, 27), this preliminary report deserves further studies to disclose actual usefulness in targeting PDsCD and/or PDpCD.
Amantadine.
An isolated report showed that amanta-dine administration can yield prefrontal, executive function enhancement, as well as increased neuronal activity in pre-frontal cortex (33). Because the study not only included tests of executive function, but also functional image analysis of frontal activity (PET data demonstrating a significant increase in left pre-frontal cortex glucose metabolism), it is reliability is reasonable. However, its open-label design and the limited number of subjects lead one to consider these results as a hypothesis-generating study, and further research is required. Of note, the main tests leading to conclude that there were cognitive improvement consisted in: Trail Making Test Part B and Controlled Oral Word Association Test [to evaluate the executive functions]; to assess the attention domain were the Trail Making Test Part A, and the Digit Span test; and finally, the memory measurements were performed by the California Verbal Learning Test and the Rey Osterreith Complex. As a final point, it is worth noting that when CD is present, amantadine (and overall DA-agonist drugs) can induce important side-effects, among which hallucinations are frequent.
Tolcapone.
Accumulated data from electrophysiological studies in experimental animals indicates that DA "focuses and stabilizes" prefrontal cortical networks by modulating NMDA and GABAergic currents. Neuroimaging studies in pharmacological manipulations with normal humans using indirect agonists such as amphetamine, or with levodopa treatment in patients with PD, have demonstrated that increasing DA activity enhances prefrontal physiologic "efficiency." In contrast to psychostimulant drugs (e.g., amphetamine), which target all biogenic amines throughout the brain, animal studies showed that the COMT activity of the brain appears to specifically affect extra-cellular DA levels, primarily in cortical regions where DA transporters are functionally negligible (45). Consequently, a specific pharmacological approach to regulate prefrontal cortical DA signaling may be achieved by increasing extracellular DA through inhibition of COMT.
Whereas many COMT inhibitors reduce the peripheral enzyme with greater potency than the enzyme present in the central nervous system, tolcapone does penetrate the blood–brain barrier and inhibits the COMT activity of the brain. A recent "proof-of-concept" study shows that this drug enhances memory and executive cognition and the physiologic efficiency of prefrontal cortical information processing in normal volunteers (14). Researchers used tests linked with prefrontal cortical processes, (notably verbal fluency, trail making, and letter number span). This randomized, double-blind, placebo-controlled trial is limited by its small sample (47 individuals). Moreover, improvements on measures of executive function and verbal episodic memory were restricted to individuals with a Val/Val genotype versus diminished cognitive performance in individuals with the Met/Met genotype. Thus, overall, the potential of pharmacologic inhibition of COMT in the long-term treatment of the CD in PD remains to be determined. Nevertheless, tolcapone being an antiparkinsonian agent, the expected next step is to assay it in PDpFCD. It is worth noting that side effects of tolcapone can go beyond diarrhea and hypotension, having the potential to cause hepatotoxicity. However, this complication has been disputed and some authors considered it infrequent (46).
CX516 and Farampator.
The alpha-amino-3-hy-droxy-5-methyl-4-isoxazol-propionic acid (AMPA)-type glutamatergic receptors have been linked to neuronal survival signaling. Although using a glutamate agonist for neuroprotection is counterintuitive, the broad cytoskeletal and synaptic damages caused by a neurotoxin (trimethyltin) can be reduced when AMPA modulation was initiated during the post-insult period. Furthermore, the extent of protection was comparable to that produced by some NMDA receptor antagonists (47). Allosteric potentiators of AMPA receptor function, a class of compounds termed ampakines, are being studied as potential treatments for enhancing cognition in schizophrenia and have also shown to be therapeutically beneficial for treating cognitive deficits in a variety of disorders (reviewed in 48). Multiple molecular pathways are involved in the activity of AMPA agonists, among which an excitatory response in prefrontal cortical neurons and a reciprocal interaction with the BDNF may be relevant for the improvement of PD CD. A recent controlled trial in healthy, elderly volunteers (16 subjects) with the ampakine farampator demonstrated that it has a significant positive effect on short-term memory functioning (using "symbol digit recall test" to measure incidental learning, "N-back task" to evaluate working memory, "verbal memory test" to asses episodic memory, and the "Visual Picture memory task" as a measure of both immediate and delayed recall); nevertheless, this drug appeared to impair episodic memory, and thus, it remains unclear if modulation of AMPA receptors with this agent has therapeutic value in the treatment of PD CD even though this is a highly active area of current research (49).
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Future Directions |
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Three Selected Examples of Clinical Trials Expected to Detect Neuroprotection in PD.
1. The DATATOP Trial.
Selegiline was tested as a potential neuroprotective agent in PD based on its capacity to inhibit DA metabolism, an action that might prevent damage caused by oxidative metabolites besides providing symptomatic benefits (although neuroprotection is now attributed to selegiline’s metabolite desmethylselegiline, which inhibits pro-apoptotic proteins and promotes anti-apoptotic proteins). The DATATOP study failed to demonstrate convincing evidence of a neuroprotective effect of selegiline (because of the incapacity of disentangling the symptomatic effects from true neuroprotection) (50). In a somewhat analogous study (the SIN-DEP-PAR trial) results obtained are consistent with a neuroprotective effect of selegiline, although with analogous caveats. In any event, propargylamines (like selegiline and the recently introduced rasagiline) deserve further research as possible neuroprotectants (51).
2. The Coenzyme Q10 Trial.
In PD there is decreased staining and activity of mitochondrial complex in the SN. Coenzyme Q10 is the electron acceptor for mitochondrial complexes I and II and is reduced in mitochondria isolated from platelets of PD patients (52). In aged mice, CoQ10 attenuates MPTP induced loss of dopaminergic axons. In a preliminary study (53), data are consistent with possible slowing the progression of clinical decline in PD. These observations merit further research in prospective studies.
3. Initial Treatment with a DA Agonist Versus Levodopa.
DA agonists have been shown to protect both dopaminergic and non-dopaminergic neurons from a variety of toxins (54), as well as upregulating neurotrophic factors, inhibiting apoptotic cascades, and reversing ubiquitin/ proteasome-dependent pathology (55). The REAL-PET study assessed PD progression using 18F-dopa PET in 186 patients randomized to treatment with ropinirole versus levodopa (56). The study demonstrated that ropinirole slowed the decline of putamenal DA storage capacity compared to levodopa and is consistent with the possibility that ropinirole slows progression of PD. However, confounding factors (ropinirole symptomatic benefits masking an increased rate of disease progression) yield doubts about a true neuroprotection of ropinirole. An analogous situation is seen in subjects initially treated with pramipexole compared to levodopa (the CALM-PD-CIT study [57]).
Nonpharmacological Interventions Trying to Improve PD.
Deep Brain Stimulation and Cognition.
Chronic bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus interna are effective neurosurgical procedures for treatment of motor symptoms in patients with advanced PD who cannot be satisfactorily treated with pharmacological treatments. Although long-term studies demonstrate that benefits of DBS persist for more than 5 years of follow-up, general disability still progresses from year to year, reflecting degeneration in nondopaminergic sites (58). Data concerning neuropsychological consequences of STN-DBS usually show no global cognitive deterioration, except for small groups of elderly patients where cognitive decompensation is possible or in patients with preoperative cognitive decline (59); consequently, good candidates for DBS should be patients free of dementia, major psychiatric disorders, structural brain lesions, and important general medical problems. Thus, although DBS can disrupt some pathogenic circuits in PD, it can not be considered as neuroprotectant.
Cell Transplantation and Stem Cells Therapy.
Neuroregenerative therapies based on gene and stem cell therapy or a combination of both, we hope, may surpass limitations of the symptomatic treatment that is now used in PD. Transplantation of human fetal mesencephalic tissue from aborted fetuses (rich in primary dopaminergic neurons) in the putamen or caudate nucleus did not prove to be beneficial (60). In addition, a subset of patients developed graft-induced dyskinesias. Therefore, few (if any) cell transplantations have been carried out in PD patients in the last few years, since cell transplantation best results has turned out to be less effective than deep brain stimulation. However, the existence of endogenous neurogenesis is opening possibilities for a second cell-based approach in the treatment of neurodegeneration. It has been demonstrated that levodopa significantly restored the cell proliferation in the sub-ventricular zone (SVZ) of 6-OHDA-lesioned rats, again pointing to an important role of DA in increasing adult neurogenesis (60, 61). Successful endogenous stem cell-based therapy has result in efficient progenitor cell proliferation, dopaminergic differentiation, and survival of newly generated cells in PD models. Therefore, it may be feasible to generate dopaminergic neurons in the striatum by either recruitment of endogenous progenitors from the SVZ or stimulation of resident cells in the striatum with circumvented immunological reactions. However, many challenges still need to be overcome before this strategy can be brought into the clinic (60).
Another fascinating albeit speculative possibility comes from bone marrow-derived mesenchymal stromal cells. Whole adult bone marrow contains a mixture of hematopoietic cells in addition to nonhematopoietic marrow stromal cells (MSCs). The nonhematopoietic stromal cells are capable of differentiating into multiple mesodermal tissues, including bone, cartilage, fat, and muscle, and produce several neurotrophic factors and cytokines (62). Much of the recent interest surrounding the use of stromal cells in CNS injury began with the discovery that MSCs from humans give rise to cells with neuronal morphology and may also express neuronal or astrocytic markers in vitro (63). Importantly, some researchers suggest the transdifferentiation of MSCs into cells of neural lineage in humans is seen at low frequency in vivo (64). However, due to this complex transdifferentiation, other mechanisms of recovery may play a role in CNS lesion-repair including: neuroprotection, creation of a favorable environment for regeneration, expression of growth factors or cytokines, or vascular effects or remyelination (64). One is tempted to hypothesize that the inherent migration of MSCs to areas of neuronal stress-damaged and/or aging, may embrace a general neuronal/glial protecting instrument, addressing also disability related to the non-dopaminergic and neuroinflammatory pathology of PD (65). Again, many challenges still need to be overcome before this strategy can be evaluated beyond traumatic central nervous injury (an intense field of interest using MSCs) and be considered also in preclinical investigations in PD.
Gene Therapy.
Since current therapies do not prevent disease progression, gene therapy in PD may offer the possibility for a significant advance in this unmet area. Adenovirus was the first vector used for gene transfer studies in PD models. However, this vector induces severe inflammatory responses in the area of injection. As a result, recombinant adeno-associated viral vectors (rAAVs) or lentiviruses of human or equine origin have been tested and have been demonstrated to be effective in providing neuroprotection in animal models of PD (66, 67). Since in humans the most important issue to be addressed is safety, a short list of phase 1 clinical gene therapy trials in PD are currently underway: rAAV-glutamic acid decarboxylase delivered to the subthalamic nucleus (Neurologix), rAAV-Aromatic-L-Amino acid decarboxylase carried into the striatum (Avigen), and rAAV-neurturin placed in the striatum (Ceregene). Importantly, while no reports of efficacy have has been presented yet, neither have there been reports of safety concerns (68). If these methodologies can yield safe and significant improvements for PD patients, either in motor symptoms or in neuroprotection, remains to be seen.
Preclinical Studies with Pharmacological Presumed Neuroprotective Agents.
Citicoline has been investigated as a therapy for stroke patients. Three mechanisms are postulated: (a) repair of the neuronal membrane via increased synthesis of phosphatidylcholine; (b) repair of damaged cholinergic neurons via potentiation of acetylcholine production; and (c) reduction of free fatty acid buildup at the site of stroke-induced nerve damage (69). Recent preclinical research has shown neuroprotective effects in the 6-hydroxydopamine-lesioned animal models (70). A Cochrane review concluded that citicoline was more effective than placebo for cognitive impairment in vascular dementia (71) and in a recent proof-of-concept trial of citicoline (44 cocaine-dependent outpatients with bipolar disease) improvement declarative memory come out (72). Accordingly, this agent warrants to be further studied in PD.
Immunophilins are ubiquitous cytosolic proteins particularly concentrated in neural tissue (neuroimmunophilins). GPI-1046 (as well as other synthetic non-immunosuppressive immunophilins derived from the immunosuppressant FK506–tacrolimus) exerts neuroprotective and neuroregenerative actions in several monoamine cellular pathways. One of its relevant actions is the suppression of synaptic glutamate transmission; thus, the prevention of excitotoxicity depends on rapid removal of glutamate by high affinity Na+-dependent transporters. Since GPI-1046 was found to be significantly neuroprotective in a mouse peripheral-sympathetic nerve injury model induced by 6-hydroxydop-amine, it has been speculated that these effects deserve to be explored in the treatment of PD (73). A phase II clinical trial in early PD patient has been funded by the National Institute of Neurological Disorders and Stroke and remains in development (74, 75).
The search of new therapeutic agents for treating PD is intense. Many new pharmacological agents designed to improve cognition in different diseases are in development; however, because of space limitations I refer the reader to recent reviews on the theme (76–79). As a final point, since all of the efforts of drugs development for CD are still focused on symptomatic treatment (not on biological bases) it should be stressed that understanding of the pathogenesis of the CD in PD is urgently needed in order to hasten novel drug discovery.
Differential Diagnosis in Overlapping Diseases.
CD or dementia, rather than constituting discrete entities, are labels for a variety of neurological conditions associated with different patterns of cognitive deterioration, such as Alzheimer’s disease, frontotemporal dementia, and many others. Specific neuropsychological deficits can be related to atrophy or hypoactivity of circumscribed brain regions. Since the outcome of the treatment for these diseases may be different, the correct diagnosis is essential. In this regard, a cognitive bedside assessment useful in differential diagnosis is the Addenbrooke’s Cognitive Examination (82). An area in which this test has been particularly useful is that of atypical parkinsonian syndromes, such as progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and dementia with LB. The main cognitive changes in these patients affect frontal-executive plus visuospatial functions. The cognitive picture of corticobasal degeneration and dementia with LB is complex and characterized, in addition to the reduction in verbal fluency, by deficits in attention/orientation (dementia with LB), language (corticobasal degeneration), and visuospatial functions (corticobasal degeneration and dementia with LB).
Do the Results Discussed in This Paper Support Modifications in Present Therapy for PD?
At present, we have effective dopaminergic agents that can improve the parkinsonian symptoms associated with the progressive loss of the SN and locus coeruleus’ neurons, and they work reasonably well over ~10 years. What is the reason that thereafter an accelerated deterioration in motor and nonmotor symptoms occurs? Therapy directed exclusively at mechanisms specific to dopaminergic cells may slow the loss of these cells but will have little effect on the development or progression of the nondopaminergic features. Consequently, we need innovative therapies directed at the underlying degenerative process (e.g., at oligomers and protofibrils aggregation, or proteasomal dysfunction, etc.) which would be expected to slow the cell damage also in these non-striatum sites. Such combination of neuroprotective strategies directed at both the primary neurodegenerative cellular mechanisms and DA-specific mechanisms might be expected to be more successful in slowing the progression of all the disease’s features (80).
Nevertheless, since the primary cause of PD remains unclear, we do not have true neuroprotective agents that may work in the nondopaminergic area of the disease yet. Therefore, the question of what (if any) role do the already known drugs with limited or putative neuroprotective properties may play in the treatment of PD remains an open one. Maybe we can consider the early addition of citicoline to dopaminergic treatments in PD patients (71, 72). Amantadine or memantine may also deserve consideration in this regard (29, 34, 35). The use of other agents like N-acetylcysteine or some new agents such as sarizotan and others, unfortunately, should await further research.
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Final Remarks |
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TopAbstractIntroductionFuture DirectionsFinal RemarksReferences |
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Received for publication July 22, 2007. Accepted for publication March 12, 2008.
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V, Herling P. List of drugs in development for neurodegenerative diseases. Update June 2007. Neurodegener Dis 4:443–486, 2007.[Medline]This article has been cited by other articles:
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  T. W. Meeks, N. Lanouette, I. Vahia, S. Dawes, D. V. Jeste, and B. Lebowitz Psychiatric Assessment and Diagnosis in Older Adults Focus, January 1, 2009; 7(1): 3 - 16. [Abstract] [Full Text] [PDF]
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