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Parkinson’s disease with dementia (PDD) is now recognised as a major clinical consequence of idiopathic Parkinson’s disease (PD). Indeed the cumulative prevalence of dementia in PD is very high; up to 80% of patients will develop dementia within 10 years of their Parkinson’s diagnosis. The consequences of PDD, including the associated neuropsychiatric, autonomic and sleep symptoms, are profound. With increased survival in PD accurate diagnosis and appropriate management of PDD in neurological, movement disorder and psychiatric services is increasingly important. In this chapter we explore the epidemiology of PDD, risk factors for its development as well as clinical features, diagnostic issues, prognosis and management. We conclude with a synthesis of current theoretical considerations and research into the aetiology of PDD.

An Essay on the Shaking Palsy by James Parkinson is remarkable in its inclusive and thorough description of the motor symptoms of Parkinson’s disease (PD) [1]. However he stated that it was a condition which left the ‘senses and intellects’ ‘uninjured’, and this belief was perpetuated for a significant part of the 20th century.

However perhaps consequent to the development of dopaminergic treatment and increased survival of PD patients, it has now become increasingly recognised that cognitive and neuropsychiatric dysfunction is an integral part of PD. Indeed there is now evidence to indicate that the majority of people with PD will develop so-called Parkinson’s disease with dementia (PDD) within 10 years of diagnosis [2]. Furthermore with the spotlight of modern enquiry, including genetic, neuroimaging and detailed neuropsychological studies, subtle deficits have been observed even in the earliest stages of PD (see chapter 10 for further elaboration).

There is now also a convergence of opinion [3] that PDD shares a common aetiological basis with a closely related condition, dementia with Lewy bodies (DLB) but that they represent different points along a Lewy body disease spectrum. DLB was defined on the basis of people presenting primarily with dementia, who had varying degrees of parkinsonism (often falling short of full PD) and who had alphasynuclein (Lewy body) pathology at autopsy. Traditionally DLB and PDD have been separated on clinical grounds, though clinical, imaging, cognitive, therapeutic and pathological studies suggest considerable overlap between DLB and PDD. Indeed both PDD and DLB are now often collectively referred as the Lewy body dementias (LBDs). In this chapter, we focus on PDD, although we draw upon evidence and data from studies in DLB as appropriate. We explore the epidemiology of diagnostic classification and neuropsychiatric features of PDD as well as briefly cover management of this complex condition. We conclude with a discussion on the proposed aetiology including neuropathological findings and recent genetic determinations. Interest in PDD has burgeoned over the past decade [4], and there is now a significant literature on the condition. This chapter thus provides more of a taster for the reader rather than an exhaustive text; for example, we do not discuss recent innovative developments in LBD biomarkers, as this is beyond the scope of this chapter, but would refer the reader to reviews such as Burn [5] and Johansen et al. [6] on the subject. For an in-depth exploration of all aspects concerning PDD, we would suggest Emre [7], which provides a comprehensive clinical and research overview of PDD. A similarly structured text edited by O’Brien et al. [8] provides a detailed description of DLB.

Prevalence and incidence rates of PDD have varied depending upon the methodologies applied in particular surveys, imprecision in definitions of dementia and cognitive impairment, as well as pathological heterogeneity in the patient populations studied. Nevertheless a comprehensive recent systematic review [9] of the available literature found a mean point prevalence of 31.3% (29.2– 33.6 95% confidence interval) of dementia in PD patients, with community prevalence of PDD in the over 65s between 0.3 and 0.5%.

As discussed in chapter 10, it is becoming increasingly recognised that cognitive impairment is present even in the earliest stages of PD; for example, it was shown that between 19 and 24% of newly diagnosed PD patients had a mild degree of cognitive impairment [10, 11]. These deficits appear to progress over time, and it has been suggested that the mean duration from onset of PD to the development of PDD is around 10 years. A longitudinal study based in Norway suggested that the cumulative prevalence was up to 78% after 8 years of follow-up [2]. Consistent with this are the incidence rates of PDD from longitudinal community-based cohorts which are at least four to six times that of the rate of dementia in age-matched controls with approximately 10% of PD patients developing dementia annually [9, 12].

A variety of risk factors for the development of dementia in PD have been described, and these are summarised in table 1.

Table 1.
Risk factors for PDD

Consensus operational criteria for PDD [31] have recently been developed (see tables 2 and 3), which take account of the constellation of signs and symptoms that are prototypical to PDD. The criteria make two major diagnostic separations: probable PDD and possible PDD. For a diagnosis of either, the presence of core symptoms of (1) diagnosis of parkinsonism, (2) a dementia with an insidious onset and slow progression in the context of established PD, and (3) the absence of features which could suggest other conditions as the cause of mental impairment is required (e.g. evidence for vascular disease on imaging). A diagnosis of probable PDD depends upon the presence of the core symptoms, as well as a cognitive profile typical for PDD (e.g. dysexecutive, visuospatial dysfunction), and at least one behavioural symptom (e.g. visual hallucinations). Less diagnostic certainty is contained by the diagnosis of possible PDD; this still requires presence of the core features, but the associated cognitive impairment may be, for example, atypical, or the behavioural symptoms may not be present.

Table 2.
Features of dementia associated with PD
Table 3.
Criteria for the diagnosis of probable and possible PDD

Such criteria offer significant advantages in providing a framework for both diagnosis and subsequent management. In addition such criteria enhance scientific enquiry regarding the natural history of PDD, its epidemiology, and help elucidate understanding of the relationship between clinical features and pathology, as well as allow rigorous clinical trials to be conducted. Nevertheless it is important to recognise that these criteria are not fixed, and as new insights are gleaned into the pathophysiology of PDD with the development of effective biomarkers, it is likely that the criteria will continue to evolve.

One continuing area of controversy is the diagnostic separation of PDD from DLB on the basis of the onset of the motor relative to the cognitive symptoms. Both the consensus criteria for DLB [32] and PDD [31] recommend that for a diagnosis of PDD, the extrapyramidal motor features need to be present for at least 12 months before the onset of the dementia, but if the dementia precedes the motor symptoms or occurred within 12 months of the motor features then the diagnosis should be DLB. This one year rule has been applied in the research setting but the arbitrary separation of PDD and DLB on this basis has no strong clinical or pathological basis. While differences do exist between DLB and PDD (table 4), they share similar cognitive and motor profiles and have common neuropsychiatric features. In addition, both PDD and DLB patients respond similarly to treatments such as cholinesterase inhibitors [33] and are both exquisitely sensitive to antipsychotics. Thus unitary approaches and use of terms such Lewy body dementias (LBDs) which include PDD and DLB have proven useful for researching common neurobiological and genetic processes in these conditions.

PDD has a recognisable mode of onset, disease progression and displays a distinctive constellation of clinical features; parkinsonism is the initial complaint with the subsequent development over many years of an insidiously progressive cognitive impairment and the manifestation of neuropsychiatric symptoms such as visual hallucinations. Other deleterious non-motor features include sleep behaviour disturbances and autonomic dysfunction. A significant proportion of these symptoms are evident in PD without dementia and elaboration of their occurrence, features, management and underlying aetiopathologies are detailed in other chapters within this book. In the present chapter, we will briefly examine their role and association with PDD.

Table 4.
Summary of differences between DLB and PDD

The predominant motor phenotype associated with PDD is that of postural instability and gait disturbance (PIGD) [34]. Tremor-dominant patterns, which are often evident earlier in the course of PD, tend to evolve into the PIGD pattern over time [30], and this change often concords with the onset of cognitive difficulties [35], autonomic dysfunction [36] and sleep disorders [37, 38]. With the development of dementia in PD there is an associated rapid deterioration in motor function with increased risk of falls [39]. Reduced responsivity to levodopa in PDD may reflect the contribution of ‘non-dopaminergic’ lesions, that is, neuropathological changes outside of the dopaminergic-striatal system. Common pathophysiological processes to both the dementia and axial motor symptoms have been proffered and in part may be mediated by dysfunction of the cholinergic system [34].

Compared to Alzheimer’s disease (AD), those with PDD have disproportionate impairments in attention and executive function [40]. These deficits [41, 42] appear to be most closely associated with the occurrence of visual hallucinations, and attentional dysfunction is the most relevant cognitive predictor for the ability to perform activities of daily living [43].

Regarding memory function, patients with PDD, while impaired compared with similarly aged controls [40] tend to perform better on verbal memory tests than AD patients. In non-demented PD patients it has been suggested that a ‘retrieval deficit’ exists, i.e. free recall is impaired, but cued recall or recognition of material presented is relatively preserved. While memory deficits are less marked in PDD than AD or DLB, PDD patients do have clear recognition memory deficits [44].

Visuoperceptive and visuospatial skills are also severely affected in PDD [40, 45]; this deficit may be partially attributed to attentional and executive dysfunction. Nevertheless intrinsic pathological changes in the visual system are likely to be important, and there is an inherent linkage between visuoperceptual/visuospatial dysfunction and visual hallucinations in PDD, with patients who experience visual hallucinations performing significantly worse on visual tasks compared with non-hallucinators [45].

Language dysfunction in PDD is less well studied, although patients tend to have reduced verbal fluency and dysarthric speech, with the former being attributed to executive problems and the latter to motor impairment [46].

Perhaps one of the most obvious features of the cognitive dysfunction of PDD, affecting up to 85% of patients [47], is the marked tendency for cognitive function to fluctuate. Fluctuations in cognition can occur in other dementias such as AD and vascular dementia. However in PDD, similar to DLB, they appear qualitatively distinct, where there appears to be an interruption of awareness which is often associated with transient episodes of confusion, communicative difficulties and psychotic symptoms, such as visual hallucinations with delusions [48]. Remission to near-normal cognitive function can then occur. The temporal cycles of these fluctuations can vary in duration in terms of minutes, hours or days, and these fluctuations appear to be independent of clear environmental triggers suggesting that the fluctuations in PDD and DLB are internally driven. Although the precise neurobiological locus is unknown, both cholinergic transmitter changes and thalamocortical circuit dysfunction have been implicated [49, 50].

Visual hallucinations and their basis in PD are discussed in chapter 5. Phenomenologically, there are no differences in visual hallucinations between PD patients with and without dementia, although in the former their occurrence appears much more frequent affecting up to 65% of PDD patients [31], and insight is more likely to be lacking, although patients often have better insight into the unreality of the episode when it is over.

Earlier in the course of disease feelings of presence (i.e. that someone or something is nearby although not actually seen) and passage hallucinations (i.e. a feeling of a shadow of a person or animal passing) are common. However as the hallucinations progress, they tend to be become complex and formed, typically of people (often children), animals and body parts that are static, kinetic or indeed the patient is completely immersed in a hallucinatory milieu. The hallucinations can provoke a range of emotional responses from indifference to amusement through to outright fear. In PD visual hallucinations were often initially viewed as a side effect of dopamine replacement therapy [51], with dopaminergic agonists especially implicated.

Auditory hallucinations also occur, but less frequently than visual hallucinations, in about 20% of patients with PDD. Delusional thinking occurs in a minority 20– 25% [31]; this contrasts with patients with DLB where delusions are much more common. Delusions are often based around experienced hallucinations and visuoperceptual disturbances, and their content typically includes persecutory, spouse infidelity, and ‘phantom boarder’ themes.

Depression also appears to be a common neuropsychiatric symptom, although epidemiological estimates of prevalence have varied considerably (7% up to 76%) [52], with diagnosis obfuscated by concurrent apathy, bradykinesia, reduced arousal levels, dopaminergic medication side effects and cognitive fluctuations.

Two major sleep disorders are recognised in PDD: rapid eye movement sleep behaviour disorder and excessive daytime sleepiness; the clinical features and aetiology of these symptoms are described elsewhere (chapter 7).

In both PD and PDD, autonomic dysfunction affects both sympathetic and parasympathetic systems, and the effects are widespread and diverse. Symptoms can include cardiovascular instability leading to orthostatic hypotension and carotid sinus hypersensitivity, and these combined with poor attentional function are likely to contribute to the high frequency of syncope and falls that occur in this population. Other symptoms include urinary retention, constipation and faecal incontinence, erectile dysfunction, and reduced lacrimal, salivary and sweat secretions. These symptoms can significantly affect quality of life and activities of daily living [53].

Aetiologically, alpha-synuclein pathology in PDD is widespread within the autonomic system. This, and the associated acetylcholine deficiency, which impairs effective preganglionic and parasympathetic synaptic neurotransmission, has been speculated as possible cause of the autonomic dysfunction [54]. However clinicians should be aware that other factors may contribute and enhance the autonomic dysfunction including comorbid illnesses, increasing frailty and medication effects (for example, cholinesterase inhibitors and antipsychotics).

In DLB severe antipsychotic sensitivity reactions can occur where patients display acute or subacute changes in response to antipsychotic administration with a sudden worsening of parkinsonism, marked rigidity, confusion and alteration in arousal levels. These reactions can occur even when low doses are used and are so profound that they can prove fatal within days or weeks [55].

Similar reactions have been reported in PDD; in one study by Aarsland and colleagues [56] 39% of PDD patients demonstrated antipsychotic sensitivity, and thus the same caution that is applied to the administration of antipsychotics in DLB should also be applied to PDD.

These effects are thought to be mediated via acute D2 blockade and can occur with both typical and atypical neuroleptic agents. Quetiapine with its low extrapyramidal side effect profile is probably the safest, although an isolated case report for a neuroleptic sensitivity reaction in a DLB patient has been reported [57]. Starting with a very low dose and careful frequent monitoring is probably more important than which specific agent is used.

Beyond this all atypical antipsychotics now include boxed warnings from drug regulatory authorities for increased mortality in older patients with dementia-related psychosis. Additionally, both risperidone and olanzapine have warnings about increased risk of cerebrovascular disease [58, 59]. Overall, while these studies have focussed primarily on AD, it is not unreasonable that clinicians should exercise a high level of caution when prescribing these agents to PDD patients.

The onset of PDD is often unclear, and frequently there is a delay in making the diagnosis of PDD. In some settings routine testing of cognition is not performed, so there may be a lack of awareness or interest in cognitive sequelae, or an unwillingness to label a PD patient as having a ‘dementia’. Development of diagnostic criteria for PDD and the recognised longer survival times of PD patients with the associated increased prevalence of PDD will ameliorate these issues of mind set. A diagnostic delineation of PDD from PD is now supported by a simple five point guideline from the movement task force [60]:

  1. A clear diagnosis of PD according to Queen’s Square Brain Bank criteria

  2. PD develops before the onset of dementia

  3. There is a global decline in cognitive function (Mini-Mental State score <26)

  4. Cognitive deficit is sufficient to impair daily life

  5. Impairment occurs in more than one cognitive domain (e.g. attention, executive, visuoconstructive or memory)

Some thought should be given to the use of appropriate cognitive assessment tools; the Mini-Mental State Examination (MMSE) is often insensitive to the profile of cognitive deficits in PDD. Newer screening tools such as the Montreal Cognitive Assessment may be better [61].

The course of PDD is progressive with no evidence of reversibility. The annual decline in cognitive and motor function scores of PDD patients is about 10% [14], and survival duration from symptom onset (either parkinsonism or dementia) to death has been estimated to be between 5 and 8 years depending upon the population studied [62, 63]; certainly the development of dementia above and beyond the core diagnosis of PD is associated with a twofold increased mortality risk [13]. Plateaus in deterioration can occur, although on other occasions there can be a precipitous decline in functioning. This is sometimes related to co-morbid insults such as infection, but often the cause for the sudden worsening cannot be established and may be intrinsic to the disease process itself. Predictors of a more rapidly progressing course include PIGD motor phenotype, moderate to severe daytime somnolence, greater neuropsychiatric symptom severity (hallucinations and depressive symptoms), older age, cognitive and attentional fluctuations and the presence of comorbid Alzheimer pathology [14, 6467].

Associated neuropsychiatric symptoms, such as visual hallucinations, predict subsequent nursing home placement [68]. Quality of life in PDD is also likely to be poor; in a study in DLB patients [69] it was noted that they had lower quality of life scores and used more resources than AD patients with almost a quarter of patients having scores which defined them as being in a state ‘worse than death’; undoubtedly analogies may be drawn to the quality of life of PDD, particularly given the more severe motor impairments which are evident in this condition.

The management of PDD is complex, given the many symptoms that occur and the problems surrounding early diagnosis. However, recognition and diagnosis of dementia in PD is important because it provides explanation and understanding for patients and carers, allows for future planning, influences management and has major medico-legal implications (advanced care planning, driving, etc.) and can allow access to services, social benefits and financial support.

Evidence for the efficacy of specific non-pharmacological interventions in PDD is currently lacking. Visual hallucinations and decreased arousal may be exacerbated by eye disease or environmental issues. Therefore, there it is reasonable cause to assume that cataract removal and better lighting will be helpful. Exercise may help: one recent small study suggested it improved executive function in PD [70].

Some rationalisation of medication may need to occur, for example, reductions in dopaminergic medications early on in the presentation (in the following order: amantadine, direct dopamine agonists, COMT inhibitors and lastly l-dopa). This may avert later antipsychotic use, at least in the short-term [71]. Stopping anticholinergic agents is also an important consideration given the marked cholinergic deficit in PDD. When treatments are added, clinicians need to be aware that some may produce benefits in one domain (e.g. dopaminergic improvements in motor function) but exacerbate symptoms in another (e.g. dopaminergic worsening of psychosis).

Cholinesterase inhibitors have been widely applied in PDD, and their use to treat cognitive impairment is recommended by a number of expert authorities (for example, American Academy of Neurology Practice [72]), and rivastigmine has been licensed by a number of regulatory bodies for treatment of cognitive impairment in PDD. However the evidence base for their efficacy remains relatively limited: a small number of open label studies have shown that galantamine may be beneficial in PDD, but there is only one major RCT using rivastigmine in PDD (EXPRESS study [73]), which demonstrated improved cognition after 24 weeks of treatment, as well as a significant reduction in neuropsychiatric symptoms (including visual hallucinations) and improved activities of daily living.

Overall, cholinesterase inhibitors are tolerated reasonably well in people with PDD, although theoretically there is a potential antagonism with dopamine function in the striatum and some patients report an increase in tremor. In addition, some cardiac safety concerns have been raised; a community study [74] noted that older patients with dementia who are on cholinesterase inhibitors tended to have more hospital visits for bradycardia, were more likely to have a permanent pacemaker inserted, and more likely to have a hip fracture. Nevertheless while these risks were significant, the absolute numbers of these events was relatively small.

Memantine is an N-methyl-d-aspartate (NMDA) receptor antagonist and is purported to have neuroprotective qualities. Two major studies examined the benefits of memantine in PDD and DLB [75, 76]. However, results were not consistent, with Aarsland et al. [75] finding an improvement in global clinical impression scores in PDD (perhaps more than DLB) participants on memantine compared with placebo, whereas Emre et al. [76] noted improvement in global rating scores and neuropsychiatric symptoms in DLB but not PDD.

Antipsychotics have been used to manage psychotic symptoms in PDD, although their use is not without controversy, and the evidence base for their use has mainly been derived from trials which included PD patients with psychosis but no dementia. Olanzapine, risperidone and aripiprazole are associated with exacerbation of motor symptoms and therefore best avoided. Clozapine or quetiapine have been advocated as preferred agents [77]. However clozapine has notable side effects (e.g. agranulocytosis) and needs regular blood monitoring. The efficacy of quetiapine is equivocal; quetiapine does not overtly worsen parkinsonism, but it appears not to have any demonstrable benefits with regard to agitation or psychosis in DLB or PDD patients [78].

Other treatments for cognitive impairment and dementia in PD have been examined, although currently the evidence for the majority is relatively weak (table 5), and there is still a lack of specific disease-modifying treatments.

The causes for cognitive and neuropsychiatric symptoms in PDD are complex, heterogeneous and unclear. However a number of pathological, neurotransmitter, metabolic and perfusion scan correlates have been associated with the occurrence of dementia in PD. We present some of these findings, as well as emerging new evidence, below.

Table 5.
Examples of alternative pharmacological treatments in PDD

The predominant feature of pathological disturbance in PDD (and indeed in DLB) is the occurrence of cortical Lewy bodies (LB), which are hyaline cytoplasmic inclusion bodies made up of predominantly aggregated α-synuclein bound together with ubiquitin, heat shock proteins and neurofilaments. These cortical LB lack the classical halo, are smaller and are less morphologically distinct compared with the more classical LB that are found in the substantia nigra associated with the motor manifestations of PD. Other neuropathological features have been described, including dystrophic cellular projections called Lewy neurites which are also alpha-synuclein predominant.

LB load in limbic structures has been reported to be correlated with the severity of dementia [84], and their presence in medial temporal lobe and visual areas has been associated with visual hallucinations [22, 85]. While the association of generalised cortical LB pathology and cognitive impairment in PDD has been reported by some, this is however not a consistent finding [86].

Staging of LB pathology and relationship with the clinical phenotype are also not clear. On the basis of sequential autopsy samples of PD brains, Braak et al. [87] proposed that there was a distinct rostrocaudal pathological progression in PD, where LB initially appeared in glossopharyngeal, vagus and olfactory nuclei and then ascended progressively along the neuroaxis. This pattern corresponds to the development of initial parkinsonism followed by cognitive and neuropsychiatric symptoms which emerge as a consequence of LB cortical involvement. However, this pattern of progression has not been observed consistently [88], and the relationship between the different stages with the development of parkinsonism, cognitive impairment or neuropsychiatric symptoms is lacking [89]. While these data may suggest that cortical LB do not cause the dementia, they are likely to be a marker of the condition. More relevant may be alpha-synuclein aggregates which are not specifically localised to LB. These aggregates are great in number and appear more widely distributed in the brains of patients with PDD and DLB than LB. Their presence in pre-synaptic terminals may impair synaptic function and lead to subsequent neurodegeneration [90].

The presence of co-existent AD pathology in PDD has been confirmed both in postmortem and more recently using amyloid imaging techniques [91]. However, the presence of AD pathology only weakly correlates with the occurrence of dementia in PD, in contrast to LB pathology [92]. Interestingly, as a result of the observation that beta-amyloid in the neocortex is associated with more extensive alpha-synuclein related lesions and higher levels of alpha-synuclein, it has been speculated that there may be a synergistic interaction between LB and AD pathology [93].

Another potential contributor to pathology is vascular disease; limited evidence from imaging of white matter, both structural and diffusion tensor imaging has suggested that white matter hyperintensities are more common in PD patients with poor cognition [94] and white matter integrity is perturbed in the frontal cortex of PD patients [95]. However, not all studies [96] found a relationship in PDD between white matter hyperintensities and cognition. Thus it remains uncertain how vascular disease and its associated lesions interact with the neurodegenerative process in PDD and contribute to the cognitive impairment.

LB pathology has an established deleterious effects on a wide range of neurotransmitter systems including dopaminergic (nigrostriatal), cholinergic (nucleus basalis of Meynert), noradrenaline (locus coeruleus), and serotonin (raphe nucleus) systems.

Dopaminergic system dysfunction is likely to be greater in PDD than in PD, reflecting a continued attrition of nigrostriatal neurons. Evidence for this comes from the observation of more severe parkinsonism in PDD compared with PD and also from striatal neuroimaging, for example 123I-N-3-fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl)-notropane (FP-CIT), a dopamine transporter (DAT) single photon emission tomography (SPECT) ligand, has demonstrated DAT binding at 50% of that compared with PD and DLB [97].

This dopaminergic loss is also likely to have a significant role in the cognitive changes of PDD. A progressive reduction in FP-CIT binding has been associated with cognitive decline in PDD [98] and changes in striatal [18F] fluorodopa uptake, a marker for dopamine synthesis, on Positron emission tomography (PET) has been correlated with impaired cognitive performance [99]. As discussed in the chapter by Williams-Gray and Mason, part of this, particularly the executive dysfunction may be mediated via differences in Catechol-O-methyltransferase (COMT) genotype, medication and/or disease stage. In addition to dopamine loss, there are alterations in dopamine receptor densities. Post-synaptic dopamine D2 receptor upregulation in the striatum is a feature of early PD; with disease progression there may be subsequent downregulation [100]. Reduced D2 density, particularly in the temporal lobes has been correlated with cognitive impairment [101], whereas increased thalamic D2 binding appears to be associated with disturbances in consciousness and arousal [102].

Dysfunction in the cholinergic system may be crucial to cognitive impairment in PDD as evidenced by the ability of cholinesterase inhibitors to improve cognitive and neuropsychiatric symptoms in PDD [5]. Other lines of evidence also support this hypothesis: In PDD, there is an extensive, global reduction in choline acetyl-transferase, the enzyme responsible for acetylcholine synthesis. Reductions in this enzyme in the temporal lobe are associated with the severity of cognitive impairment [103]. On functional imaging, acetylcholinesterase activity is depressed in PDD compared with PD [104], and the level correlates with severity of executive dysfunction. Conversely, the use of cholinesterase inhibitors in PDD has been associated with increased regional cerebral metabolism [105].

Cholinergic receptor (nicotinic and muscarinic) disturbances have also been reported in PDD [for overview, see Piggott et al. 106], and this relates to the loss of acetylcholine. Their specific role in mental impairment in PDD still remains to be elucidated, although it has been suggested that receptor alteration may modulate arousal and alertness (nicotinic receptors in thalamus and temporal cortex) and visual hallucinations (nicotinic and muscarinic receptors in occipital cortex).

The role of other neurotransmitter systems is less well understood. Serotonergic neuron loss in the raphe nuclei is an early feature of PD and has been speculated to be associated with the frequent depressive symptoms evident in the disease. However whether there is greater loss of serotonin in PDD than PD is not clear [106]. Neuronal loss in the locus coeruleus (noradrenaline) may be more extensive in PDD than PD and correlate with cognitive decline. This has been suggested to contribute to depressive and behavioural symptoms as well as apathy and attentional dysfunction [106].

More work is needed to clarify the aetiological place of alterations in neurotransmitter systems in PDD; it may in fact be the balance between different systems which is important in dementia [107]. For example, patients with LBD and visual hallucinations show a pattern of decreased cholinergic function, but a relative preservation of monoaminergic function [108].

Reductions in brain glucose metabolism, as measured using 18F-fluorodeoxyglucose (FDG) PET imaging, and in perfusion measured with SPECT, have been found in PD patients with both cognitive impairment and with dementia. Deficits appear global and widespread, affecting parietal, frontal and occipital cortices [109, 110].

Principal component analyses with FDG PET to identify areas of the brain which co-vary in function, have found salient metabolic networks that are disrupted in PDD [111]. One of these covariance networks, the so-called ‘PD-related cognitive pattern’ which includes prefrontal, midline frontal, precuneus and inferior parietal regions is associated with cognitive impairment in PD, and reduced activity in this network is longitudinally associated with declining cognitive function. Perfusion and metabolism deficits in distributed brain areas including frontal [112], parietal [113] and temporal cortex [114] have also been associated with visual hallucinations, although there is a lack of consensus on precisely which brain areas are involved.

New lines of enquiry regarding the molecular basis of PD have been opened up (see for example the discussion by Olanow and McNaught [115]) and by extension are likely to be highly relevant to understanding the pathological basis of PDD.

In particular, there is an increasing recognition that in PD there is an inherent dysfunction of cellular protein clearing processes such as the autophagy and lysosomal clearance system and ubiquitin-proteasome system, which results in the accumulation of toxic intracellular proteins that undermine neuronal function and ultimately lead to neuronal cell death. It has been suggested that compensatory cellular strategies to deal with toxic protein accumulations result in so-called aggresomes of which LB are one type; thus, LB may represent a protective stress response rather than being pathogenic in themselves [116]. Intriguingly, known genetic mutations in PD such as PARKIN, PARK1, LRRK2 [115], as well as glucocerebrosidase mutations [117] have been associated with dysfunction in cellular protein degradation, providing further support for the importance of these cellular systems in the aetiology of PD. Mitochondrial dysfunction may be another important and possibly related player. A number of gene mutations which cause familial PD such as PARKIN and PINK1 appear to have a role in the maintenance of normal mitochondrial function. It has been speculated that, in part, PD may be caused by impaired energy production [for discussion, see 86].

Finally and controversially PD has been suggested to be a prion-like disease. Support for this comes from the observation of Lewy pathology in foetal neurons grafted into the brains of PD patients, suggesting a spread of alpha-synuclein from the host brain tissue to the grafts [118]. At the molecular level, alpha-synuclein can be transmitted via endocytosis to neighbouring neurons and neuronal precursor cells, forming Lewy-like inclusions [119].

There is increasing recognition of the inevitability of dementia developing in PD. Thus, there is a pressing need to be able to diagnose the condition better and to explain mechanistically how the condition arises at a micro- and macro-structural level. Treatments are available, which partially ameliorate some of the symptoms in PDD, but further work is needed to develop disease-modifying agents. However, the first and essential step has been taken in that we now know the ‘shaking palsy’ to be not just a motor disorder but something much more.

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