Dementia with Lewy bodies (DLB) was first reported in the 1960’s and 70’s [1,2], long before reports describing larger groups of patients in the late 1980’s and the early 1990’s [3-7] began to highlight the frequency of the syndrome and the characteristic clinical features.
DLB probably accounts for 10-20% of people with dementia [8,9], implying an approximate prevalence of 0.5-1% in people over the age of 65. Dementia eventually develops in the majority of older patients with a diagnosis of Parkinson disease (PD) [10], with an estimated cross sectional community prevalence of Parkinson disease dementia (PDD) of 0.5% in people over the age of 65 [11]. The clinical profile and underlying brain changes in DLB and PDD are similar [12]. The key brain changes observed include widespread Lewy body formation due pathological processing of alpha-synuclein, and cholinergic and dopaminergic deficits. In this article, we are reviewing the clinical presentations of these two syndromes, focusing on management issues.
PROFILE OF COGNITIVE DEFICITS
The cognitive profile of both PDD and DLB has been characterized as including prominent visuospatial, attentional and executive impairment with relatively less impairment of memory [13,14]. The overall profile of cognitive deficits in DLB and PDD is similar and interestingly, even fluctuating attention, a key feature of DLB, is also evident in PDD, but not in patients with Alzheimer’s disease or PD without dementia [15]. Employing qualitative methods, Doubleday [16] reported that 78% of their study cohort of DLB patients experienced symptoms of general inattention. In particular it was reported that patients suffer from incoherence of thought, confabulations, perseverations, as well as impairments in both the establishment of and the shifting between mental sets. These symptoms have been associated with pathology in the dorsolateral prefrontal cortex (DLPFC) and anterior prefrontal cortex in previous studies, where symptoms of perseverations [17,18], distractibility [19,20], shifting between mental sets [21] as well as confabulations [22] were all associated with damage in BA9/46, 10/11 and the basal ganglia.
DLB and PDD patients also show marked fluctuation of consciousness and cognition [15,23,24]. Fluctuating cognition (FC), one of the core diagnostic features for DLB and PDD, is characterized by marked variations in attention and alertness, these being in turn closely related to impairments of consciousness. These fluctuations in cognition range from changes occurring on a week-to-week basis to those that occur with second-to-second frequency and are associated with marked EEG frequency variabilities. As a consequence of fluctuating cognition, the patient’s level of alertness may vary greatly from being perfectly lucid to experiencing severe confusional states.
Visuospatial impairment is more pronounced than in AD and is a key characteristic of the cognitive profile in DLB and PDD. These include visuoperceptual as well as visuospatial impairments, which impact on such skills as object identification, spatial processing and space motion perception [25-27]. These impairments may be related to the frequently observed diminished activity in the occipital lobes in patients diagnosed with DLB in comparison to patients diagnosed with AD [28-30]. A study comparing pentagon copying in patients with DLB and PDD suggested a similar severity of impairment in the two conditions and a pattern of errors indicating executive dysfunction [31].
As a consequence of medial temporal lobe and frontostriatal neuron loss and Lewy body aggregation [32], patients with DLB present with a distinctive pattern of mnemonic dysfunctions. The modules of memory function that are impaired in DLB include semantic and episodic memory as well as working memory components. As a result of these dysfunctions, patients experience difficulties with declarative memory aspects such as the recall of factual, abstract knowledge based information, contextual information as well as personal associations. In addition, patients’ severe attentional impairments have a detrimental impact on working memory function, in particular with regard to the registration aspects of memory. As a result of these sensory/attentional deficits, information is not appropriately gated to short term memory, resulting in the patient’s reduced ability to employ executive control functions.
This combination of marked neuropsychological deficits of attention, consciousness and memory results in the development of the inability to focus attentional resources on ever changing situational requirements. Inability to block irrelevant information from intrusion on current thought processes makes focusing on social interactions and activities of daily living [33] difficult, and considerably limits the patient’s ability to exercise social skills. In summary, the attentional dysfunctions characteristic for patients with DLB constitute a significant part of the clinical picture of the disease as well as play a prominent role in the patient’s everyday experience and therefore require careful psychosocial and clinical management.
NEUROPSYCHIATRIC SYMPTOMS
Psychiatric symptoms are common in all dementia syndromes, but a characteristic psychiatric profile has been reported in patients with DLB and PDD. Visual hallucinations, typically recurrent well-formed images of people, and delusions are much more common in DLB than in Alzheimer’s disease, occurring in 60-70% of patients with DLB [34,35]. They are also more intense [36] and more persistent [36] in DLB patients. In PDD, the phenotype of these symptoms is very similar, and hallucinations (45%) and delusions (25%) are very common [35,37]. REM sleep disorders, including “acting out dreams”, occur more frequently in DLB and PDD than in other dementias. REM sleep disorders are characterized by complex verbal and physical behaviors and the lack of muscle atonia typically present during the REM phase of sleep. Such REM sleep behaviour disorders may actually precede the dementia syndrome in many patients [38]. Depression and anxiety are common in most dementias, but probably have a higher frequency in DLB [35,39] and PDD [39], consistent with the high frequency of depression in PD [40]. Apathy, loss of motivation, interest and effortful behavior, occurs in more than 50% of PD, PDD and DLB patients [37,41].
DIAGNOSIS
Achieving accurate diagnosis is imperative for optimizing overall management and specifically, to avoid severe neuroleptic sensitivity reactions (see treatment section). International operationalized clinical criteria for the diagnosis of DLB were agreed upon at a consensus conference in 1995 and published the following year [8]. These criteria highlighted 3 core diagnostic features: fluctuating cognition, persistent or recurrent visual hallucinations and spontaneous parkinsonism; two of which had to be present in the context of a dementia syndrome to support a diagnosis of probable DLB. Autopsy validation studies indicate that although specificity of diagnosis is generally good (80%), the sensitivity of these criteria for DLB may be as low as 50% in some studies. Aided by emerging scientific data, the international DLB Consortium has therefore recently revised the criteria originally proposed for the clinical and pathological diagnosis of DLB [9], and the role of special investigations was reviewed. Additional clinical features (REM sleep behavior disorder and severe neuroleptic sensitivity) and functional imaging changes (dopamine transporter scan) are now considered to be suggestive of DLB, and a diagnosis of probable DLB can now be made in the presence of one core feature if one or more suggestive features is also present. There is also emerging evidence that myocardial scintigraphy using meta-iodobenzylguanidine (MIBG) can accurately distinguish DLB from AD [42]. The revised criteria have not yet been prospectively validated.
The main reason for the difficulties in applying the operationalized clinical criteria for DLB has been the challenge of identifying fluctuating cognition, with several studies suggesting that agreement between clinicians is barely better than chance [43,44]. Utilizing the rating scales that have now been validated [e.g.,16,23,45] and assessing variability in reaction time on formal assessments of attention should, however, enable more accurate assessment of fluctuation. Other potential difficulties include patients with a combination of cerebrovascular and Lewy body pathology and the assessment of spontaneous parkinsonism in people taking neuroleptics or who have severe dementia.
The revised operationalized criteria [9] may assist with the general diagnostic accuracy. The presence of REM sleep behavior disorder and the results of investigations such as DAT scans now form part of the diagnostic criteria which should help improve sensitivity, although this has not yet been systematically evaluated. Given the particular challenges of managing patients with DLB, the best advice is probably to consider DLB as the most likely clinical diagnosis if there are any suggestive features.
By default, PDD can only be diagnosed in people with more than one year of parkinsonism prior to the onset of dementia. As more than 90% of patients who develop dementia meet operationalized criteria for DLB, and cortical Lewy body pathology is the main substrate of dementia and correlates with the rate of cognitive decline in these individuals [46], differential diagnosis between different dementias is not problematic in the majority of situations, and a simple approach to diagnosis based upon the presence of Parkinson’s disease and the subsequent development of dementia is usually sufficient to accurately diagnose PDD. More recently, specific diagnostic criteria have been developed for PDD to further refine the operationalized clinical diagnosis. According to these criteria, a diagnosis of probable PDD requires a diagnosis of PD, a dementia syndrome with impairment of more than one cognitive domain severe enough to impair daily life, and exclusion of features associated with other abnormalities which may be an independent cause of cognitive impairment [47].
The diagnosis of PDD poses other difficulties. Many people with Parkinson’s disease have subtle cognitive deficits, and it can be difficult to decide when dementia criteria are fulfilled, in particular the determination as to whether the cognitive impairment causes impairment of daily life. However, the distinction between mild cognitive impairment and dementia in PD is not of major clinical importance. Rigorous longitudinal evaluation with cognitive testing is advisable as part of the clinical follow-up to enable the diagnosis of dementia to be made as early as possible.
TREATMENT
Given the complex combination of symptoms in people with DLB and PDD, it is helpful to think about the different treatment targets. Ultimately the goal is to identify therapies which fundamentally impact the disease process. However, DLB and PDD are both progressive neurodegenerative dementias associated with global cognitive deterioration and impairment of self care and other activities of daily living, and consequently, symptomatic improvement and stabilizing self care skills are major treatment goals. The clinician together with the patient and the caregiver should prioritize the variety of neuropsychiatric symptoms (parkinsonism, falls, autonomic dysfunction or sleep disorders), and decide which are the major symptoms for a particular individual and should hence be the primary target. In addition, since drugs may improve one symptom and simultaneously worsen another (i.e., antipsychotic and anti-Parkinson agents), patients and relatives need to be informed about the risk of side-effects as well as the modest symptom improvement or stabilization that can be achieved.
Global symptomatic treatments for DLB and PDD
The main evidence base for treating cognitive symptoms suggests the use of acetyl CholinEsterase Inhibitors (ChEIs). The first trial was a small open label study of 7 patients with PDD treated with tacrine, who experienced improvement in visual hallucinations and cognition, based on the Mini Mental State Examination (MMSE) score. This suggested that contrary to previous concerns, parkinsonian symptoms actually improved. Although the potential utility of tacrine is limited by the high risk of hepatotoxicity, the trial was extremely important in highlighting the potential value of ChEI therapy [48]. Aarsland [49] has summarized the literature between 1996 and 2003 and highlighted 14 small studies with donepezil, rivastigmine and galantamine in patients with Parkinson’s disease including two randomized cross-over trials with a total of 144 patients. Overall MMSE scores improved by approximately 2 points, and more than 90% of patients had an improvement in their visual hallucinations. Although the overall balance of the literature did not support Hutchinson & Fazzini [48] in suggesting an improvement in motor symptoms, only a very modest proportion of individuals experienced a worsening of parkinsonism.
The only large parallel group randomized controlled trial of a cholinesterase inhibitor in PDD, published in 2004 [50], confirmed the impression from the previous preliminary studies and demonstrated that rivastigmine was significantly better than placebo over a period of 24 weeks of treatment in 541 patients with PDD (allocated 2:1 rivastigmine:placebo) on all primary and secondary outcome measures. The rivastigmine treated patients had a 1 point advantage on the MMSE, an almost 3 point advantage on the ADAS-COG, and significant benefits on more specialized assessment of attention and executive function. There were also significant advantages for rivastigmine treated patients on the activity of daily living scale and in terms of neuropsychiatric symptoms. Although there was no overall significant worsening of parkinsonism based on rating scales, there was a significant increase in tremor as a reported adverse event in the rivastigmine treated patients. As expected, the participants receiving rivastigmine were more likely to experience nausea (29% vs. 11%) and vomiting (16.5% vs. 2%). There was no difference in falls, and 75% of participants were able to tolerate rivastigmine for the duration of the study. The mortality rate was significantly lower in the rivastigmine treated patients (1.1% vs. 3.9%).
A similar evolution of studies was seen for DLB, with an initial small case series [51] indicating that two thirds of patients experienced benefit from ChEI treatment, especially with respect to neuropsychiatric symptoms and several reports [52] highlighting improvements in fluctuating confusion. In general, this literature supports the conclusions of the treatment studies in PDD, indicating that parkinsonian symptoms only worsened in a minority of individuals, although in one of the reports [51], 3 of the 9 patients experienced a worsening of their parkinsonism. Again, this literature emphasized the need for a randomized controlled clinical trial and culminated in a multicenter placebo controlled trial [53] involving 120 DLB patients treated with rivastigmine (mean dose 7mg) or placebo for 2 weeks. The primary outcome measure was 30% improvement in a four item sub-score (delusions, hallucinations, apathy, depression), which was attained by 63% of people treated with rivastigmine and 30% of people treated with placebo, a significant difference on the observed case analysis. On the total neuropsychiatric inventory (NPI), there was a non-significant 3 point advantage for the patients treated with rivastigmine. However, it should be emphasized that this difference was not evident at the 12 week assessment point, and the benefit appeared to emerge between 12 and 20 weeks. Significant improvements were also seen in attentional performance, with a nonsignificant 1 point advantage for the rivastigmine treated patients on the MMSE. The reports of adverse events were similar to those in the subsequent PDD trial. The impact on specific psychiatric symptoms and fluctuating cognition has been less well studied.
Overall the literature is encouraging with evidence from 2 large RCTs supported by an extensive case series literature, indicating that rivastigmine is significantly better than placebo for the treatment of cognitive deficits and neuropsychiatric symptoms, with evidence from the PDD study [50] that there are also significant advantages for activities of daily living. Rivastigmine is well tolerated with no significant exacerbation of parkinsonism, although nausea and vomiting can be a problem.
The case series literature suggests that donepezil is also an effective treatment for DLB and PDD [49], and individual studies also indicate benefits with other ChEIs [48]. While in general, this suggests that the treatment efficacy is a ChEI class effect, the only robust RCT evidence is for rivastigmine. In the absence of direct comparative studies, it is difficult to make any firm conclusions about the relative efficacy of the different cholinesterase inhibitors. One large two year RCT comparing rivastigmine and donepezil for the treatment of AD did suggest a modest advantage for rivastigmine in the sub-group of patients who met criteria for possible DLB, but the diagnostic status of these patients is very unclear [54]. The profile of adverse events has not been directly compared in DLB or PDD patients either, although the literature in AD probably indicates that on balance, nausea and vomiting may be more frequent in people treated with rivastigmine, although this may be largely a consequence of too rapid titration in some of the studies. One small crossover study with donepezil in a combined cohort of DLB and AD patients did indicate a significant exacerbation of syncope and carotid sinus hypersensitivity (CSH) and related falls in donepezil treated patients [55]. This is a very real clinical concern given the high frequency of CSH and other aspects of autonomic dysfunction in DLB and PDD patients, but it is unclear whether the propensity to exacerbate these problems differs between the different ChEIs. An ECG, assessment of autonomic function and postural hypotension, and a good clinical history to evaluate syncope should probably be completed before instigating treatment, and any emergent symptoms/features of autonomic dysfunction should be monitored carefully during therapy.
In addition, detrusor instability is common in DLB patients, can occur early in the course of the illness [56] and may be exacerbated by ChEIs. As ChEIs exacerbate rather than ameliorate urinary incontinence, other management approaches may be necessary. Anticholinergics such as oxybutinin, often used to treat urinary frequency, can cross the blood brain barrier and may worsen cognitive function; therefore non-pharmacological approaches are preferable.
Several reports have attempted to evaluate predictors of treatment response within the RCTs. The presence of visual hallucinations [57,58], probably a marker of more severe cholinergic deficit, is associated with preferential treatment response. Although preliminary, patients with the wild type butyrylcholinesterase (BuChE) genotype respond better to rivastigmine than patients with the K variant of BuChE [59].
Other general pharmacological treatments
There is limited or no evidence regarding the use of other candidate therapies such as memantine, vitamin E or selegeline, and clinical trials of these treatments are an important research priority. Preliminary evidence of a preventive effect of amantadine, an N-methyl d-aspartate (NMDA) antagonist, on the development of dementia in PD was provided in a longitudinal non-randomized study [60].
Neuropsychiatric symptoms
When assessing the treatment of visual hallucinations, delusions and accompanying agitation, it is critical to determine whether there is any medical co-morbidity, review potentially contributing medications, assess relevant visual impairments and determine the severity of the symptoms and the level of distress experienced by the patient and their caregivers. In particular, attention should be paid to the potential contributing role of anti-parkinsonian medications, and dose reduction or even discontinuation of some anti-parkinsonian medications may be indicated.
Non-pharmacological interventions have been shown to effectively ameliorate neuropsychiatric symptoms in people with dementia, but have not yet been systematically evaluated in DLB or PDD. Approaches vary in complexity from optimizing the care and support package, promoting good communication and person-centered care to specific tailored interventions involving the patient, caregivers and/or environment. If symptoms are not causing enormous distress, non-pharmacological treatments should probably be the intervention of first choice, although cholinesterase inhibitors prescribed as a more generic pharmacotherapy may confer additional benefit.
When specific pharmacological intervention is required to treat neuropsychiatric symptoms in DLB or PDD, the main options are ChEIs or atypical antipsychotic medications. Case series have suggested that all three generally available ChEIs may improve symptoms such as visual hallucinations, delusions and associated agitation in DLB and PDD [51,52,61]. The RCTs in DLB [53] and PDD [50] have compared rivastigmine to placebo and show a general improvement in neuropsychiatric symptoms, but the specific impact on visual hallucinations has not been reported, and the time course to improvement appears to be 3 to 6 months. Although there is some disparity between the case series and the RCT data, a trial of a ChEI will give general benefits, is well tolerated and is the pharmacological treatment of first choice. As is the case for global symptomatic treatment, there are no comparative data between the ChEIs in PDD or DLB, although given the higher level of evidence, rivastigmine is probably the treatment of choice.
The use of atypical neuroleptics creates a much more difficult clinical dilemma. In addition to the general concerns about the potential for adverse events in people with dementia [62] and the specific risk of severe neuroleptic sensitivity reactions in DLB and PDD patients [7,63-66], McKeith [7] reported that 50% of neuroleptic-treated patients with DLB experienced severe drug sensitivity with symptoms that included marked extra-pyramidal features, confusion, autonomic instability, falls and accelerated mortality. Accumulating literature consisting of case reports and case series, as well as subsequent larger and more systematic series, shows that severe sensitivity reactions occur with a wide range of typical and atypical antipsychotics. These include clozapine [64] in DLB and the related condition, PDD [7,63-66]. Failure of neuroleptic prescriptions to up-regulate dopamine D2 receptors has been highlighted as a major contributing factor contributing to severe neuroleptic sensitivity [67]. However, the largest and most systematic study suggested that the highest frequency of severe neuroleptic sensitivity reactions occurred in olanzapine treated patients [66], raising the possibility that anti-muscarinic properties may also be important. Clinically, severe neuroleptic sensitivity reactions are a major concern, as they can occur after only a few [63] or even single doses of a neuroleptic drug [64].
One re-analysis of an AD trial in which a small proportion of participants met clinical criteria for possible DLB indicated some improvement of neuropsychiatric symptoms with olanzapine [68], and other small open series in DLB patients suggested that quetiapine may confer benefit [69]. However, the only placebo controlled trial has not indicated any benefit in DLB patients from antipsychotic treatment [70].
In AD, there is preliminary evidence from cross-over studies and RCTs that anticonvulsants such as carbamazepine [71] and sodium valproate [72] and antidepressants such as trazadone [73] and citalopram [74] may improve agitation or psychosis. There are no studies of these agents in people with DLB or PDD, and the safety of these treatment approaches has not been established in these individuals. The risk of falls, for example, may be a serious concern. Emerging data from AD trials also suggests that memantine may confer benefit in the treatment of neuropsychiatric symptoms [75], although there have been several case reports of increased confusion in people with DLB or PDD treated with memantine [76]. The potential utility of memantine therapy in DLB/PDD patients needs to be evaluated more systematically.
In a number of circumstances, the problematic situation may arise where people are experiencing ongoing and distressing visual hallucinations or other neuropsychiatric symptoms that have not responded to ChEI treatment or non-pharmacological interventions. Although difficult, providing the appropriate support to enable people to manage and cope with the situation effectively is still probably a better option for most people than the potential risks of atypical antipsychotics.
Mood disorders
Depression is among the most common symptoms in both DLB and PDD, but there have been no systematic studies of its management. At the present time SSRIs and SNRIs are probably the preferred pharmacological treatment, although studies of SSRIs in PD without dementia have been disappointing [77]. Tricyclic antidepressants and other antidepressants with anticholinergic properties should be avoided. Non-pharmacological interventions such as activity programs, exercise and cognitive behavior therapy have been shown to be effective for the treatment of depression in AD [78], but have not been evaluated in DLB or PDD. Anxiety is also frequent, and may be secondary to fluctuating confusion, psychotic features or depression. Treating the underlying neuropsychiatric condition will often result in resolution. There is, however, no specific evidence base that provides information and insight as to the treatment of more severe or persistent symptoms. In studies of ChEIs in AD, anxiety is often one of the symptoms that shows a preferential response [79]. Benzodiazepines should probably be avoided because of the risks of worsening amnesia, decreased alertness and impairment of motor function, with increased risk of falls.
Fluctuating cognition is often a prominent and distressing symptom which adds to impairment in everyday activities and can create major practical problems for planning an appropriate care package. Several of the case series included patients whose fluctuating cognition improved with ChEI therapy, but the data are less clear-cut from the RCTs. In the McKeith et al. [53] study for example, after adjusting for overall improvement in attentional performance, there was no specific improvement of fluctuation. Fluctuating cognition is an important treatment target meriting further research, but may be improved by ChEI treatment.
Parkinsonism
Parkinsonism by definition occurs in all people with PDD, and probably develops in 80% of DLB patients over the course of their illness. The parkinsonian syndrome differs in only subtle ways from PD, PDD and DLB, and progresses at a similar rate in the three disorders. Motor symptoms contribute to the disability experienced by DLB and PDD patients and are associated with an increased risk of falls. Good to excellent response to L-dopa is a defining feature in early PD, and can be used for the motor disorder associated with both DLB and PDD, but doses should be titrated more carefully in these patients. L-dopa is generally well tolerated, but may induce hallucinations and increase confusion in a small proportion of patients [80]. Responsiveness to L-dopa is more limited in both DLB and PDD patients, with significant improvement of parkinsonism seen in approximately half of PDD patients and a smaller proportion of individuals with DLB, although falls may even be reduced in some patients without optimal motor response. Caution should be exercised in adding other parkinsonian medications including selegeline, amantadine, COMT inhibitors and dopamine agonists because of concerns about exacerbating confusion and psychosis (visual illusions, hallucinations and delusions). Anticholinergics should definitely be avoided in both DLB and PDD.
Motor disability including parkinsonism and postural instability may also be improved by physiotherapy and occupational therapy approaches. The unpredictable and fluctuating nature of cognitive and motor impairments can prove particularly frustrating to patients and caregivers. Education, discussion and reassurance on dealing with variable performance can help both parties adopt a flexible approach depending upon the patient’s functional level at a given time.
Falls and dysautonomia
There is a high prevalence of falls in DLB and PDD, with a considerable risk of related injuries. Prevention of falls is therefore a very important management consideration. The cause of falls is multifactorial in dementia patients, with a number of factors including parkinsonism (with or without postural instability), postural hypotension, muscle weakness, posture, confidence/anxiety, medication and the environment all contributing. A broad approach is therefore required which should include an evaluation of the patient’s environment, their need for walking devices and physiotherapy for gait training, and other rehabilitation efforts. Blood pressure (BP) should be checked for orthostatic BP, and minimization of cardiac medications and benzodiazepines is recommended. Management of postural hypotension includes removal of medications which may be causative or additive. If postural hypotension persists following medication adjustment, additional pharmacological treatments including fludrocortisone and midodrine may be useful. Syncope may be a major cause of falls. If suggestive symptoms are apparent, a detailed cardiovascular assessment is recommended including head-up tilt and carotid sinus massage in a specialist facility. Cardiac pacing may be beneficial in some of these patients. Protective underwear and careful attention to flooring may reduce the risk of serious injury for patients at high risk of falling.
Future treatment targets
The next key goal of therapy is to alter the underlying disease process. There is some emerging evidence that cholinesterase inhibitors may reduce concurrent amyloid pathology in DLB patients [81], but there are few reports focusing on potential treatments targeting α-synuclein. α-synuclein is an intracellular protein with unknown function that aggregates into β-sheet–rich fibrils [82]. It is a primary component of Lewy bodies in PD, PDD, DLB and has been proposed to play a pivotal role in Lewy body disorder [83]. Pre-clinical studies conducted in transgenic mice that overexpress human α-synuclein indicate that immunotherapy, i.e., the vaccination of mice and resultant accumulation of antibodies specific for α-synuclein, results in the reduction of α-synuclein positive inclusions within the cerebral cortex and critically blocks the degeneration of neuronal terminals within this region [84]. Future studies of this interesting strategy will need to establish whether this reduction of inclusions has behavioral effects. Immunization remains one of the most promising treatment approaches in AD and human studies are ongoing. Targeting α-synuclein in such a manner represents a viable approach to the treatment of PDD and DLB.
Interesting initial studies have suggested that endogenous neurogeneis is markedly reduced in PD and DLB, and is strongly associated with the cholinergic deficit [85]. The prospect of enhancing endogenous neurogeneis provides an interesting novel treatment target for the future. However, one of the most promising current approaches relates to the proteasome. The proteasome is the primary enzyme complex responsible for the degradation of mutant, abnormal, oxidized or nitrated proteins [86]. The tagging of target proteins with ubiquitin serves to identify them for proteolytic degradation, a process that occurs within the β-subunits of the 20S proteasome [87]. Post-mortem studies in patients with PD have indicated a selective loss of the α-subunit of the 20S proteasome and a reduction in proteasomal activity within the dopaminergic neurons of the substantia nigra [88,89]. Pre-clinical studies have indicated that proteasomal inhibition of dopaminergic cells in vitro [90,91] and in vivo [92,93] gives rise to cell death and the generation of inclusions that stain positive for α-synuclein and ubiquitin. Furthermore, recent work has suggested that injection of proteasome inhibitors into the forebrain nucleus of rodents leads to the development of cortical α-synuclein pathology and cholinergic deficits. The proteasome is hence an exciting potential treatment target, with a number of potential candidate therapies including nicotine, green tea extracts and several anti-myeloma drugs.
CONCLUSION
DLB and PDD are progressive neurodegenerative disorders characterized by cognitive impairment, parkinsonism and prominent neuropsychiatric symptoms. The complex combination of symptoms can be distressing for the patient and problematic for the managing clinician. ChEIs confer significant benefits with respect to cognition, function and neuropsychiatric symptoms, but not all patients respond. Finding the optimal balance between the treatment of key symptoms such as psychosis and parkinsonism, and the risk of adverse events is often a major challenge. There are a number of other potentially exciting avenues of exploration such as the relationship between proteasome function and α-synuclein pathology. However, these remain research questions at the moment, and clinical management therefore needs to focus on symptomatic treatment of the key symptoms.
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