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Dementia in Parkinson's disease
JNS-15074; No of Pages 6 Journal of the Neurological Sciences xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Review Article
Dementia in Parkinson's disease Hasmet A. Hanagasi ⁎, Zeynep Tufekcioglu, Murat Emre Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul, Turkey
a r t i c l e
i n f o
Article history: Received 26 December 2016 Received in revised form 1 January 2017 Accepted 4 January 2017 Available online xxxx Keywords: Parkinson's disease Dementia Dementia with Lewy Bodies Cholinesterase inhibitors
a b s t r a c t Dementia can occur in a substantial number of patients with Parkinson's disease with a point prevalence close to 30%. The cognitive profile is characterized by predominant deficits in executive, visuospatial functions, attention and memory. Behavioral symptoms are frequent such as apathy, visual hallucinations and delusions. The most prominent associated pathology is Lewy body-type and biochemical deficit is cholinergic. Placebo-controlled randomized trials with cholinesterase inhibitors demonstrated modest but significant benefits in cognition, behavioral symptoms and global functions. © 2016 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . 2. Epidemiology . . . . . . . . . . . . . . . 3. Genetic aspects . . . . . . . . . . . . . . . 4. Clinical features of PD-D . . . . . . . . . . . 5. Pathological and biochemical correlates . . . . 6. Correlates in Neuro-imaging and biomarkers . 7. Diagnosis of PD-D. . . . . . . . . . . . . . 8. Relation of PD-D to Dementia with Lewy Bodies 9. Management of patients with PD-D . . . . . References . . . . . . . . . . . . . . . . . . .
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1. Introduction
2. Epidemiology
Although considered primarily a motor disorder, non-motor symptoms may accompany Parkinson's disease (PD) from early stages onwards and be present even before the manifestation of motor symptoms. Considering its contribution to morbidity and mortality dementia constitutes one of the most significant non-motor disorders. Due to increased survival as a consequence of advances in treatment, incidence and prevalence of dementia in PD has been increasing.
Even though subtle cognitive deficits may be detected in the early stages of PD, overt cognitive deficits usually become manifest in the late stages of the disease, especially as the age advances. The prevalence of dementia estimates varies depending on the nature of the study population and diagnostic criteria used. In a systematic review, the point prevalence of dementia was found to be 24–31% [1]. In a community-based study, 36% of newly diagnosed patients were found to have cognitive impairment based on their performance in three tests (MiniMental State Examination, a pattern recognition task, and the Tower of London task) at the time of diagnosis, while 57% of this cohort developed cognitive deficits within 3.5 (±0.7) years; the incidence of dementia was estimated to be 54.7 per 1000 person-years during the 10 year follow up period [2]. A prospective study showed 32.9% of drug-naive, newly diagnosed PD patients had mild cognitive
⁎ Corresponding author at: Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Çapa, 34390 Istanbul, Turkey. E-mail address: [email protected] (H.A. Hanagasi).
http://dx.doi.org/10.1016/j.jns.2017.01.012 0022-510X/© 2016 Elsevier B.V. All rights reserved.
Please cite this article as: H.A. Hanagasi, et al., Dementia in Parkinson's disease, J Neurol Sci (2016), http://dx.doi.org/10.1016/j.jns.2017.01.012
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impairment (MCI) at the time of diagnosis [3]. Another longitudinal study including 141 PD patients with normal cognition at baseline revealed that 47.7% developed cognitive impairment within 2–6 years observation time and all those who developed MCI progressed to dementia within 5 years [4]. In the prospectively followed-up Sydney PD cohort, 48% of surviving patients had developed dementia 15 years after the diagnosis [5] and the cumulative incidence of dementia had increased to 83% 20 years after the diagnosis [6]. The most established risk factors for Parkinson's disease dementia (PD-D) include old age at disease onset or at the time of evaluation. Older patients and those with severe disease have a 12-fold increased risk of dementia as compared to young patients with mild disease [7]. Along with severe motor disability, long disease duration, atypical neurological features such as early autonomic failure, symmetrical disease presentation and unsatisfactory response to dopaminergic treatment are other risk factors. Low cognitive scores at baseline, early development of confusion or hallucinations on dopaminergic medication, axial involvement including speech impairment, postural imbalance and excessive daytime sleepiness have also been reported to be associated with increased risk of dementia. PD patients with REM sleep behavior disorder (RBD) had a 6 fold higher occurrence of dementia than those without [8]. In a prospective cohort study several other predictors of dementia were reported, including cardiovascular autonomic dysfunction (hypertension or orthostasis) and color discrimination ability [9]. Patients with tremor-dominant phenotype have a lower risk of developing dementia. In one study, impairment in cognitive tests relying on frontal executive functions were associated with a lower risk of dementia whereas impairment in those assessing more posterior cortical functions was associated with a higher risk [2,10]. White matter hyperintensities (WMH) were suggested to be associated with cognitive decline in PD patients [11,12] but another study couldn't demonstrate an independent relationship [13]. Hippocampal volume was also reported to be a predictive factor for cognitive impairment [14]. In a cross-sectional study, heart disease was the only vascular factor significantly more prevalent in PD patients with dementia [15], whereas a longitudinal study revealed that more than two vascular risk factors and white matter leukoaraiosis in brain imaging were associated with cognitive impairment [16].
3. Genetic aspects Presence of apolipoprotein epsilon 4 (ApoE ε4) allele was found to be a predictor of cognitive decline in non-demented PD patients. The associated cognitive profile was more typical of that seen in early Alzheimer's disease (AD) than that seen in PD [17]. Another genetic association study showed that the presence of APOE ε2 allele (the least common allele) might reduce the risk of developing dementia [18]. There is some evidence that variations in the tau (MAPT) gene may determine the genetic risk of dementia in PD, the H1/H1 haplotype being associated with a greater rate of cognitive decline and development of early dementia [2,19,20]. Heterozygote mutations in the glucocerebrosidase gene (GBA) has been reported to be a significant risk factor for PD and DLB. A community-based incident cohort study showed that GBA mutations are present at a frequency of 3.5% in the PD population and progression to dementia is 5.7 fold higher and occurs earlier than in non-carriers [21]. In mutation carriers cognitive dysfunction was found to be present even without motor features of PD at the time of investigation [22]. A large, longitudinal study revealed that GBA E326K polymorphism is associated with a 3.34-fold more rapid progression of cognitive impairment and dementia compared with non-carriers [23]. There is a robust association between cognitive impairment and duplication, and even more so with the triplication of the alpha-synuclein gene [24,25]. The frequency of dementia in autosomal dominant LRRK2 mutations may be lower than that in sporadic PD. The risk of dementia
seems to be lower in patients with PINK1, DJ-1 and Parkin mutations [26]. 4. Clinical features of PD-D Typically, the cognitive profile of dementia in PD-D is a dysexecutive syndrome (characterized by impairment in planning, abstract thinking, mental flexibility and apathy) with early and prominent impairment of attention and visuo-spatial functions, moderately impaired episodic memory and relatively preserved core language functions. Deficits in attention/executive functions, naming, visuospatial/constructional abilities and retrieval in episodic memory are present in early stages [27]. Behavioral symptoms are pervasive, most notably apathy and psychosis. Dementia is preceded by mild cognitive impairment, which may affect a variety of domains. Mild cognitive impairment, it should be noted, may not progress to dementia. In early stages, designated as Parkinson's disease mild cognitive impairment (PD-MCI), the most frequent subtype is multi-domain MCI [28–31], with the most frequently impaired domains being memory and visuo-spatial functions [32–34]. Deficits in more posterior cortical functions, such as visuo-spatial functions, were found to be associated with a higher risk of dementia than frontal-subcortical deficits [2]. PD-D patients are more apathetic, with more prominent impairment of attention as compared to AD patients in comparative studies [35]. Impaired attention is an important determinant of the ability to undertake activities of daily living. Working memory, explicit visual and verbal memory and implicit memory such as procedural learning can all be impaired in PD-D. In typical cases the memory impairment is characterized by a deficit in free recall with relatively preserved recognition, however, memory impairment with impaired recognition resembling that seen in AD, can also be seen in a sub-population of PD-D patients [36]. Impairment in visuo-spatial functions is another early feature, which is typically more severe than in patients with typical, amnestic AD [37]. A wide range of neuropsychiatric symptoms are seen in PD-D. The most common are hallucinations, apathy, depression, anxiety and insomnia. At least one neuropsychiatric symptom is present in more than 90% of PD patients [38]. Visual hallucinations are similar to those seen in Dementia with Lewy Bodies (DLB), with well-formed figures of humans or animals, often with preserved insight and little emotional content. Delusions, usually paranoid in nature are not uncommon. Delusional misidentification syndromes were found in 17% of PD-D patients [39] in one study. Autonomic disturbances including notably urinary incontinence, orthostatic and postprandial hypotension (which can result in syncope and falls) are frequent in PDD, it was suggested that orthostatic hypotension and cognition may be interrelated [40]. Excessive sweating, reduced heart rate variability predisposing to ventricular arrhythmias can also occur [41]. 5. Pathological and biochemical correlates Pathologically, PD-D is characterized by a variable combination of Lewy Body (LB)-type degeneration, cellular loss in subcortical nuclei and cortical AD-type pathology [42]. Dementia and more rapid cognitive decline best correlate with neocortical LB pathology, although some degree of AD-type pathology (more plaques than tangles) usually co-exists, a combination of both pathologies being more detrimental [43–45]. Degeneration of subcortical nuclei results in various neurochemical abnormalities including cholinergic, dopaminergic, serotoninergic and noradrenergic deficits, of which cholinergic loss is the most prominent. Loss of cholinergic cells in the nucleus basalis of Meynert (nbM) is greater than that seen in AD, LBs are frequently found in nbM cells. It has been suggested that the pattern of neuronal loss in the nbM of patients with Lewy body disease is different than that seen in AD [46].
Please cite this article as: H.A. Hanagasi, et al., Dementia in Parkinson's disease, J Neurol Sci (2016), http://dx.doi.org/10.1016/j.jns.2017.01.012
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The noradrenergic locus coeruleus shows neuronal loss especially in demented and depressed PD patients [47]. Degeneration in serotonergic dorsal raphe nucleus has been reported and may contribute to affective symptoms [48].
6. Correlates in Neuro-imaging and biomarkers Structural MRI studies have reported frontal, occipital and parietal gray matter loss and an increased rate of whole brain atrophy in PD-D patients compared with control subjects. A volumetric study suggested a relationship between decreases in caudate volume (but not in hippocampus) and cognitive decline [49]. In a study using structural and resting-state functional MRI (fMRI) in patients with DLB and PD-D, PD-D patients revealed significant bilateral frontal atrophy, whereas DLB was characterized by greater parietal and occipital atrophy. Similar amount of atrophy in caudate nucleus was seen in PDD and DLB compared to PD and healthy controls. Resting state fMRI demonstrated reduced local coherence (synchronization) of frontal regions in PD and in PDD. Whereas DLB patients had reduced local connectivity in posterior and inferior regions [50]. In another resting state fMRI study, corticostriatal connectivity was found to be selectively disrupted in PD-D patients [51]. Other fMRI studies found functional connectivity alterations in attention and motor related seeds in PD-D [52]. In a structural and diffusion tensor MRI study in newly diagnosed, nondemented PD subjects, there were bilateral reductions in frontal and parietal gray matter volume associated with reduced performance on executive function tests. In addition, there were regionally specific increases in central white matter mean diffusivity, suggesting early axonal damage. These reports suggest that diffusion tensor imaging analysis could be a noninvasive biomarker reflecting cognitive impairment in PD [53]. PET in PD-D has usually shown hypometabolism in parietal and temporal cortices, along with hypometabolism in visual areas and the frontal lobes [54]. In PET using MP4A, which assesses cholinergic innervation of the cortex, PD-D patients exhibited a severe cholinergic deficit in various cortical regions including frontal and temporoparietal cortices [55], however, a cholinergic deficit is present in non-demented PD patients as well. In PET studies with Pittsburgh compound B (PIB), mean cortical amyloid load in PD-D patients was comparable to that in controls and non-demented PD patients [56]. Another study with PIB revealed comparable results: 83% of PD-D patients had ‘normal’ PIB uptake whereas 85% of DLB patients had significantly increased amyloid load in one or more cortical regions [57]. Currently, there are no blood or cerebrospinal fluid (CSF) markers that can reliably be used for diagnosis of PD-D, to follow its progression, or as an outcome measure for therapeutic interventions. In early PD, lower CSF Aβ42 was associated with reduced cognitive functions, mainly with memory deficits and may predict future cognitive decline [58]. A population-based prospective cohort study revealed that high CSF neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein at baseline were related to future PD-D [59]. In a large clinical-pathological study, low CSF amyloid β1-42 was associated with low MMSE score in patients with PD-D. In DLB and PD-D groups 67% and 53% of the subjects respectively, had abnormal amyloid β1-42 levels, 28% in both groups had abnormal total tau, 25% and 19% had abnormal phosphorylated tau levels [60]. In a retrospective analysis of approximately 300 patients from the DATATOP study, higher CSF alpha-synuclein levels predicted worse cognitive performance at follow-up, although the average length of follow-up of was only 1.8 years [61]. A prospective cohort study showed that changes in EEG activity during sleep may be predictive of dementia in PD, perhaps as a marker of cholinergic denervation [62].
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7. Diagnosis of PD-D Clinical diagnostic criteria for PD-D and practical recommendations for its diagnosis have been described by a Movement Disorder Society Task Force [63,64]. Diagnostic criteria for mild cognitive impairment in PD (PD-MCI) have also been published by a Task Force of Movement Disorder Society [65] (see Table 1). Diagnosis of dementia in PD can be confounded by various factors, in particular by motor and speech dysfunction, depression, anxiety, systemic/metabolic disorders or adverse effects of drugs. A thorough neuropsychological evaluation, neurological and systemic examination, a review of current medication and use of appropriate auxiliary investigations are helpful in differentiating these conditions from dementia. 8. Relation of PD-D to Dementia with Lewy Bodies PD-D and Dementia with Lewy Bodies (DLB) are both Lewy-body related neurodegenerative dementias affecting cognition, behavior, movement and autonomic function. In terms of molecular pathology, they are both synucleinopathies, characterized by accumulation of mis-folded alpha-synuclein protein in the form of Lewy bodies and Lewy neuritis and loss of tegmental dopaminergic and basal forebrain cholinergic cells, often with a variable degree of co-existing Alzheimer pathology, more so in DLB. They have overlapping clinical, neurochemical, and pathological features; when the clinical picture is fully developed they are indistinguishable [42,66,67]. The main difference is in the temporal sequence of symptoms. In PDD motor features precede dementia or develop within 12 months of the motor features, whereas Table 1 Diagnostic criteria for mild cognitive impairment in Parkinson's disease [65]. I. Inclusion criteria Diagnosis of Parkinson's disease as based on the UK PD Brain Bank Criteria [83] Gradual decline, in the context of established PD, in cognitive ability reported by either the patient or informant, or observed by the clinician Cognitive deficits on either formal neuropsychological testing or a scale of global cognitive abilities Cognitive deficits are not sufficient to interfere significantly with functional independence, although subtle difficulties on complex functional tasks may be present II. Exclusion criteria Diagnosis of PD dementia based on MDS Task Force proposed criteria [63,64] Other primary explanations for cognitive impairment (e.g., delirium, stroke, major depression, metabolic abnormalities, adverse effects of medication, or head trauma) Other PD-associated comorbid conditions (e.g., motor impairment or severe anxiety, depression, excessive daytime sleepiness, or psychosis) that, in the opinion of the clinician, significantly influence cognitive testing III. Specific guidelines for PD-MCI level I and level II categories A. Level I (abbreviated assessment) Impairment on a scale of global cognitive abilities validated for use in PD or Impairment on at least two tests, when a limited battery of neuropsychological tests is performed (i.e., the battery includes less than two tests within each of the five cognitive domains, or less than five cognitive domains are assessed) B. Level II (comprehensive assessment) Neuropsychological testing that includes two tests within each of the five cognitive domains (i.e., attention and working memory, executive, language, memory, and visuospatial) Impairment on at least two neuropsychological tests, represented by either two impaired tests in one cognitive domain or one impaired test in two different cognitive domains Impairment on neuropsychological tests may be demonstrated by:
o Performance approximately 1 to 2 SDs below appropriate norms or o Significant decline demonstrated on serial cognitive testing or o Significant decline from estimated premorbid levels IV. Subtype classification for PD-MCI (optional, requires two tests for each of the five cognitive domains assessed and is strongly suggested for research purposes) PD-MCI single-domain—abnormalities on two tests within a single cognitive domain (specify the domain), with other domains unimpaired or PD-MCI multiple-domain—abnormalities on at least one test in two or more cognitive domains (specify the domains)
Please cite this article as: H.A. Hanagasi, et al., Dementia in Parkinson's disease, J Neurol Sci (2016), http://dx.doi.org/10.1016/j.jns.2017.01.012
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they are co-incident with or follow dementia in DLB. The two disorders represent two entities on a continuum, with many similarities, but some differences. Pathological and imaging evidence suggest that there is greater amyloid pathology in DLB [67,68–71], but amyloid imaging is of limited use in the diagnosis of Lewy Body-related dementias [72]. Recent functional and structural imaging studies revealed greater atrophy and impaired functional connectivity in the posterior regions in DLB as compared to more prominent atrophy in frontal lobes in PD-D suggesting that they may have different networks involved and different underlying pathogenic pathways [50,73]. Consensus guidelines proposed an arbitrary cut-off with regard to chronology of symptoms. Patients who develop dementia after one year following the onset of parkinsonian symptoms should be diagnosed as PD-D, whereas those develop dementia and parkinsonism concomitantly or within one year of each other should be diagnosed as DLB [74]. This “one year rule” may be used for research purposes. In practice, patients who are diagnosed with PD first and subsequently develop dementia should be given the diagnosis of PD-D, whereas those who develop dementia first followed by parkinsonism should be designated as DLB. In cases where the sequence of motor as compared to mental symptoms cannot be determined, a more generic term such as Lewy Body Disease may be preferred. It should also be noted that patients who present to dementia clinics with dementia and no motor features may mistakenly be diagnosed to have AD.
9. Management of patients with PD-D Before considering pharmacological treatment systemic diseases, depression and adverse events of medication should be excluded or appropriately treated. In particular, drugs with anticholinergic properties (i.e. medications to control over-active bladder control), tricyclic antidepressants, and benzodiazepines should be discontinued. Cholinesterase inhibitors (ChE-I) have been investigated in PD-D and PD-MCI patients. A recent placebo-controlled, single site study showed benefit of rivastigmine in PD-MCI on a performance-based measure of cognitive abilities and a trend for improvement on a global rating of cognition, disease-related health status, and anxiety severity [75]. In a smaller randomized, placebo controlled trial in non-demented PD patients, galantamine did not show any significant benefits on tests of cognitive function [76]. There have been two large randomized, placebo controlled trials in PD-D, one with rivastigmine and the other with donepezil. In the rivastigmine trial, both cognitive and overall evaluation scales showed significant improvement compared to placebo; there were also benefits in the behavioral, attentional and executive function test scores [77]. Except for more patients having worsening of tremor there were no significant effects on motor symptoms as compared to placebo. The beneficial effects seemed to last for at least 6 months [78], with consistent benefits on all aspects of attention [79]. In another large placebo controlled trial donepezil 10 mg was also associated with beneficial effects in cognitive and overall scales, with no significant differences on ADLs or behavioral scores. A recent metaanalysis including studies with ChE-Is or memantine in PD-D concluded that both treatments were associated with a positive effect on global assessment whereas treatment with ChE-Is, however, ChE, but not memantine, significantly improved cognitive functions, behavioral symptoms and activities of daily living [80]. Based on the results of the clinical trial described above rivastigmine was approved for the treatment of patients with mild to moderate PD-D. Memantine, a partial NMDA receptor antagonist used in the treatment of AD, was tested in patients with DLB or PD-D in two randomized controlled trials. In the smaller study, there was a significant difference in favor of memantine in the global outcome scale. Patients with PD-D had more benefits as compared to those with DLB [81]. In the larger study the global outcome scale and behavioral scores were significantly better with memantine in the DLB group, whereas there were no
significant differences in the PD-D population [82]. Memantine is not approved for the treatment of PD-D.
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Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Review Article
Dementia in Parkinson's disease Hasmet A. Hanagasi ⁎, Zeynep Tufekcioglu, Murat Emre Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul, Turkey
a r t i c l e
i n f o
Article history: Received 26 December 2016 Received in revised form 1 January 2017 Accepted 4 January 2017 Available online xxxx Keywords: Parkinson's disease Dementia Dementia with Lewy Bodies Cholinesterase inhibitors
a b s t r a c t Dementia can occur in a substantial number of patients with Parkinson's disease with a point prevalence close to 30%. The cognitive profile is characterized by predominant deficits in executive, visuospatial functions, attention and memory. Behavioral symptoms are frequent such as apathy, visual hallucinations and delusions. The most prominent associated pathology is Lewy body-type and biochemical deficit is cholinergic. Placebo-controlled randomized trials with cholinesterase inhibitors demonstrated modest but significant benefits in cognition, behavioral symptoms and global functions. © 2016 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . 2. Epidemiology . . . . . . . . . . . . . . . 3. Genetic aspects . . . . . . . . . . . . . . . 4. Clinical features of PD-D . . . . . . . . . . . 5. Pathological and biochemical correlates . . . . 6. Correlates in Neuro-imaging and biomarkers . 7. Diagnosis of PD-D. . . . . . . . . . . . . . 8. Relation of PD-D to Dementia with Lewy Bodies 9. Management of patients with PD-D . . . . . References . . . . . . . . . . . . . . . . . . .
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1. Introduction
2. Epidemiology
Although considered primarily a motor disorder, non-motor symptoms may accompany Parkinson's disease (PD) from early stages onwards and be present even before the manifestation of motor symptoms. Considering its contribution to morbidity and mortality dementia constitutes one of the most significant non-motor disorders. Due to increased survival as a consequence of advances in treatment, incidence and prevalence of dementia in PD has been increasing.
Even though subtle cognitive deficits may be detected in the early stages of PD, overt cognitive deficits usually become manifest in the late stages of the disease, especially as the age advances. The prevalence of dementia estimates varies depending on the nature of the study population and diagnostic criteria used. In a systematic review, the point prevalence of dementia was found to be 24–31% [1]. In a community-based study, 36% of newly diagnosed patients were found to have cognitive impairment based on their performance in three tests (MiniMental State Examination, a pattern recognition task, and the Tower of London task) at the time of diagnosis, while 57% of this cohort developed cognitive deficits within 3.5 (±0.7) years; the incidence of dementia was estimated to be 54.7 per 1000 person-years during the 10 year follow up period [2]. A prospective study showed 32.9% of drug-naive, newly diagnosed PD patients had mild cognitive
⁎ Corresponding author at: Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Çapa, 34390 Istanbul, Turkey. E-mail address: [email protected] (H.A. Hanagasi).
http://dx.doi.org/10.1016/j.jns.2017.01.012 0022-510X/© 2016 Elsevier B.V. All rights reserved.
Please cite this article as: H.A. Hanagasi, et al., Dementia in Parkinson's disease, J Neurol Sci (2016), http://dx.doi.org/10.1016/j.jns.2017.01.012
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impairment (MCI) at the time of diagnosis [3]. Another longitudinal study including 141 PD patients with normal cognition at baseline revealed that 47.7% developed cognitive impairment within 2–6 years observation time and all those who developed MCI progressed to dementia within 5 years [4]. In the prospectively followed-up Sydney PD cohort, 48% of surviving patients had developed dementia 15 years after the diagnosis [5] and the cumulative incidence of dementia had increased to 83% 20 years after the diagnosis [6]. The most established risk factors for Parkinson's disease dementia (PD-D) include old age at disease onset or at the time of evaluation. Older patients and those with severe disease have a 12-fold increased risk of dementia as compared to young patients with mild disease [7]. Along with severe motor disability, long disease duration, atypical neurological features such as early autonomic failure, symmetrical disease presentation and unsatisfactory response to dopaminergic treatment are other risk factors. Low cognitive scores at baseline, early development of confusion or hallucinations on dopaminergic medication, axial involvement including speech impairment, postural imbalance and excessive daytime sleepiness have also been reported to be associated with increased risk of dementia. PD patients with REM sleep behavior disorder (RBD) had a 6 fold higher occurrence of dementia than those without [8]. In a prospective cohort study several other predictors of dementia were reported, including cardiovascular autonomic dysfunction (hypertension or orthostasis) and color discrimination ability [9]. Patients with tremor-dominant phenotype have a lower risk of developing dementia. In one study, impairment in cognitive tests relying on frontal executive functions were associated with a lower risk of dementia whereas impairment in those assessing more posterior cortical functions was associated with a higher risk [2,10]. White matter hyperintensities (WMH) were suggested to be associated with cognitive decline in PD patients [11,12] but another study couldn't demonstrate an independent relationship [13]. Hippocampal volume was also reported to be a predictive factor for cognitive impairment [14]. In a cross-sectional study, heart disease was the only vascular factor significantly more prevalent in PD patients with dementia [15], whereas a longitudinal study revealed that more than two vascular risk factors and white matter leukoaraiosis in brain imaging were associated with cognitive impairment [16].
3. Genetic aspects Presence of apolipoprotein epsilon 4 (ApoE ε4) allele was found to be a predictor of cognitive decline in non-demented PD patients. The associated cognitive profile was more typical of that seen in early Alzheimer's disease (AD) than that seen in PD [17]. Another genetic association study showed that the presence of APOE ε2 allele (the least common allele) might reduce the risk of developing dementia [18]. There is some evidence that variations in the tau (MAPT) gene may determine the genetic risk of dementia in PD, the H1/H1 haplotype being associated with a greater rate of cognitive decline and development of early dementia [2,19,20]. Heterozygote mutations in the glucocerebrosidase gene (GBA) has been reported to be a significant risk factor for PD and DLB. A community-based incident cohort study showed that GBA mutations are present at a frequency of 3.5% in the PD population and progression to dementia is 5.7 fold higher and occurs earlier than in non-carriers [21]. In mutation carriers cognitive dysfunction was found to be present even without motor features of PD at the time of investigation [22]. A large, longitudinal study revealed that GBA E326K polymorphism is associated with a 3.34-fold more rapid progression of cognitive impairment and dementia compared with non-carriers [23]. There is a robust association between cognitive impairment and duplication, and even more so with the triplication of the alpha-synuclein gene [24,25]. The frequency of dementia in autosomal dominant LRRK2 mutations may be lower than that in sporadic PD. The risk of dementia
seems to be lower in patients with PINK1, DJ-1 and Parkin mutations [26]. 4. Clinical features of PD-D Typically, the cognitive profile of dementia in PD-D is a dysexecutive syndrome (characterized by impairment in planning, abstract thinking, mental flexibility and apathy) with early and prominent impairment of attention and visuo-spatial functions, moderately impaired episodic memory and relatively preserved core language functions. Deficits in attention/executive functions, naming, visuospatial/constructional abilities and retrieval in episodic memory are present in early stages [27]. Behavioral symptoms are pervasive, most notably apathy and psychosis. Dementia is preceded by mild cognitive impairment, which may affect a variety of domains. Mild cognitive impairment, it should be noted, may not progress to dementia. In early stages, designated as Parkinson's disease mild cognitive impairment (PD-MCI), the most frequent subtype is multi-domain MCI [28–31], with the most frequently impaired domains being memory and visuo-spatial functions [32–34]. Deficits in more posterior cortical functions, such as visuo-spatial functions, were found to be associated with a higher risk of dementia than frontal-subcortical deficits [2]. PD-D patients are more apathetic, with more prominent impairment of attention as compared to AD patients in comparative studies [35]. Impaired attention is an important determinant of the ability to undertake activities of daily living. Working memory, explicit visual and verbal memory and implicit memory such as procedural learning can all be impaired in PD-D. In typical cases the memory impairment is characterized by a deficit in free recall with relatively preserved recognition, however, memory impairment with impaired recognition resembling that seen in AD, can also be seen in a sub-population of PD-D patients [36]. Impairment in visuo-spatial functions is another early feature, which is typically more severe than in patients with typical, amnestic AD [37]. A wide range of neuropsychiatric symptoms are seen in PD-D. The most common are hallucinations, apathy, depression, anxiety and insomnia. At least one neuropsychiatric symptom is present in more than 90% of PD patients [38]. Visual hallucinations are similar to those seen in Dementia with Lewy Bodies (DLB), with well-formed figures of humans or animals, often with preserved insight and little emotional content. Delusions, usually paranoid in nature are not uncommon. Delusional misidentification syndromes were found in 17% of PD-D patients [39] in one study. Autonomic disturbances including notably urinary incontinence, orthostatic and postprandial hypotension (which can result in syncope and falls) are frequent in PDD, it was suggested that orthostatic hypotension and cognition may be interrelated [40]. Excessive sweating, reduced heart rate variability predisposing to ventricular arrhythmias can also occur [41]. 5. Pathological and biochemical correlates Pathologically, PD-D is characterized by a variable combination of Lewy Body (LB)-type degeneration, cellular loss in subcortical nuclei and cortical AD-type pathology [42]. Dementia and more rapid cognitive decline best correlate with neocortical LB pathology, although some degree of AD-type pathology (more plaques than tangles) usually co-exists, a combination of both pathologies being more detrimental [43–45]. Degeneration of subcortical nuclei results in various neurochemical abnormalities including cholinergic, dopaminergic, serotoninergic and noradrenergic deficits, of which cholinergic loss is the most prominent. Loss of cholinergic cells in the nucleus basalis of Meynert (nbM) is greater than that seen in AD, LBs are frequently found in nbM cells. It has been suggested that the pattern of neuronal loss in the nbM of patients with Lewy body disease is different than that seen in AD [46].
Please cite this article as: H.A. Hanagasi, et al., Dementia in Parkinson's disease, J Neurol Sci (2016), http://dx.doi.org/10.1016/j.jns.2017.01.012
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The noradrenergic locus coeruleus shows neuronal loss especially in demented and depressed PD patients [47]. Degeneration in serotonergic dorsal raphe nucleus has been reported and may contribute to affective symptoms [48].
6. Correlates in Neuro-imaging and biomarkers Structural MRI studies have reported frontal, occipital and parietal gray matter loss and an increased rate of whole brain atrophy in PD-D patients compared with control subjects. A volumetric study suggested a relationship between decreases in caudate volume (but not in hippocampus) and cognitive decline [49]. In a study using structural and resting-state functional MRI (fMRI) in patients with DLB and PD-D, PD-D patients revealed significant bilateral frontal atrophy, whereas DLB was characterized by greater parietal and occipital atrophy. Similar amount of atrophy in caudate nucleus was seen in PDD and DLB compared to PD and healthy controls. Resting state fMRI demonstrated reduced local coherence (synchronization) of frontal regions in PD and in PDD. Whereas DLB patients had reduced local connectivity in posterior and inferior regions [50]. In another resting state fMRI study, corticostriatal connectivity was found to be selectively disrupted in PD-D patients [51]. Other fMRI studies found functional connectivity alterations in attention and motor related seeds in PD-D [52]. In a structural and diffusion tensor MRI study in newly diagnosed, nondemented PD subjects, there were bilateral reductions in frontal and parietal gray matter volume associated with reduced performance on executive function tests. In addition, there were regionally specific increases in central white matter mean diffusivity, suggesting early axonal damage. These reports suggest that diffusion tensor imaging analysis could be a noninvasive biomarker reflecting cognitive impairment in PD [53]. PET in PD-D has usually shown hypometabolism in parietal and temporal cortices, along with hypometabolism in visual areas and the frontal lobes [54]. In PET using MP4A, which assesses cholinergic innervation of the cortex, PD-D patients exhibited a severe cholinergic deficit in various cortical regions including frontal and temporoparietal cortices [55], however, a cholinergic deficit is present in non-demented PD patients as well. In PET studies with Pittsburgh compound B (PIB), mean cortical amyloid load in PD-D patients was comparable to that in controls and non-demented PD patients [56]. Another study with PIB revealed comparable results: 83% of PD-D patients had ‘normal’ PIB uptake whereas 85% of DLB patients had significantly increased amyloid load in one or more cortical regions [57]. Currently, there are no blood or cerebrospinal fluid (CSF) markers that can reliably be used for diagnosis of PD-D, to follow its progression, or as an outcome measure for therapeutic interventions. In early PD, lower CSF Aβ42 was associated with reduced cognitive functions, mainly with memory deficits and may predict future cognitive decline [58]. A population-based prospective cohort study revealed that high CSF neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein at baseline were related to future PD-D [59]. In a large clinical-pathological study, low CSF amyloid β1-42 was associated with low MMSE score in patients with PD-D. In DLB and PD-D groups 67% and 53% of the subjects respectively, had abnormal amyloid β1-42 levels, 28% in both groups had abnormal total tau, 25% and 19% had abnormal phosphorylated tau levels [60]. In a retrospective analysis of approximately 300 patients from the DATATOP study, higher CSF alpha-synuclein levels predicted worse cognitive performance at follow-up, although the average length of follow-up of was only 1.8 years [61]. A prospective cohort study showed that changes in EEG activity during sleep may be predictive of dementia in PD, perhaps as a marker of cholinergic denervation [62].
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7. Diagnosis of PD-D Clinical diagnostic criteria for PD-D and practical recommendations for its diagnosis have been described by a Movement Disorder Society Task Force [63,64]. Diagnostic criteria for mild cognitive impairment in PD (PD-MCI) have also been published by a Task Force of Movement Disorder Society [65] (see Table 1). Diagnosis of dementia in PD can be confounded by various factors, in particular by motor and speech dysfunction, depression, anxiety, systemic/metabolic disorders or adverse effects of drugs. A thorough neuropsychological evaluation, neurological and systemic examination, a review of current medication and use of appropriate auxiliary investigations are helpful in differentiating these conditions from dementia. 8. Relation of PD-D to Dementia with Lewy Bodies PD-D and Dementia with Lewy Bodies (DLB) are both Lewy-body related neurodegenerative dementias affecting cognition, behavior, movement and autonomic function. In terms of molecular pathology, they are both synucleinopathies, characterized by accumulation of mis-folded alpha-synuclein protein in the form of Lewy bodies and Lewy neuritis and loss of tegmental dopaminergic and basal forebrain cholinergic cells, often with a variable degree of co-existing Alzheimer pathology, more so in DLB. They have overlapping clinical, neurochemical, and pathological features; when the clinical picture is fully developed they are indistinguishable [42,66,67]. The main difference is in the temporal sequence of symptoms. In PDD motor features precede dementia or develop within 12 months of the motor features, whereas Table 1 Diagnostic criteria for mild cognitive impairment in Parkinson's disease [65]. I. Inclusion criteria Diagnosis of Parkinson's disease as based on the UK PD Brain Bank Criteria [83] Gradual decline, in the context of established PD, in cognitive ability reported by either the patient or informant, or observed by the clinician Cognitive deficits on either formal neuropsychological testing or a scale of global cognitive abilities Cognitive deficits are not sufficient to interfere significantly with functional independence, although subtle difficulties on complex functional tasks may be present II. Exclusion criteria Diagnosis of PD dementia based on MDS Task Force proposed criteria [63,64] Other primary explanations for cognitive impairment (e.g., delirium, stroke, major depression, metabolic abnormalities, adverse effects of medication, or head trauma) Other PD-associated comorbid conditions (e.g., motor impairment or severe anxiety, depression, excessive daytime sleepiness, or psychosis) that, in the opinion of the clinician, significantly influence cognitive testing III. Specific guidelines for PD-MCI level I and level II categories A. Level I (abbreviated assessment) Impairment on a scale of global cognitive abilities validated for use in PD or Impairment on at least two tests, when a limited battery of neuropsychological tests is performed (i.e., the battery includes less than two tests within each of the five cognitive domains, or less than five cognitive domains are assessed) B. Level II (comprehensive assessment) Neuropsychological testing that includes two tests within each of the five cognitive domains (i.e., attention and working memory, executive, language, memory, and visuospatial) Impairment on at least two neuropsychological tests, represented by either two impaired tests in one cognitive domain or one impaired test in two different cognitive domains Impairment on neuropsychological tests may be demonstrated by:
o Performance approximately 1 to 2 SDs below appropriate norms or o Significant decline demonstrated on serial cognitive testing or o Significant decline from estimated premorbid levels IV. Subtype classification for PD-MCI (optional, requires two tests for each of the five cognitive domains assessed and is strongly suggested for research purposes) PD-MCI single-domain—abnormalities on two tests within a single cognitive domain (specify the domain), with other domains unimpaired or PD-MCI multiple-domain—abnormalities on at least one test in two or more cognitive domains (specify the domains)
Please cite this article as: H.A. Hanagasi, et al., Dementia in Parkinson's disease, J Neurol Sci (2016), http://dx.doi.org/10.1016/j.jns.2017.01.012
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they are co-incident with or follow dementia in DLB. The two disorders represent two entities on a continuum, with many similarities, but some differences. Pathological and imaging evidence suggest that there is greater amyloid pathology in DLB [67,68–71], but amyloid imaging is of limited use in the diagnosis of Lewy Body-related dementias [72]. Recent functional and structural imaging studies revealed greater atrophy and impaired functional connectivity in the posterior regions in DLB as compared to more prominent atrophy in frontal lobes in PD-D suggesting that they may have different networks involved and different underlying pathogenic pathways [50,73]. Consensus guidelines proposed an arbitrary cut-off with regard to chronology of symptoms. Patients who develop dementia after one year following the onset of parkinsonian symptoms should be diagnosed as PD-D, whereas those develop dementia and parkinsonism concomitantly or within one year of each other should be diagnosed as DLB [74]. This “one year rule” may be used for research purposes. In practice, patients who are diagnosed with PD first and subsequently develop dementia should be given the diagnosis of PD-D, whereas those who develop dementia first followed by parkinsonism should be designated as DLB. In cases where the sequence of motor as compared to mental symptoms cannot be determined, a more generic term such as Lewy Body Disease may be preferred. It should also be noted that patients who present to dementia clinics with dementia and no motor features may mistakenly be diagnosed to have AD.
9. Management of patients with PD-D Before considering pharmacological treatment systemic diseases, depression and adverse events of medication should be excluded or appropriately treated. In particular, drugs with anticholinergic properties (i.e. medications to control over-active bladder control), tricyclic antidepressants, and benzodiazepines should be discontinued. Cholinesterase inhibitors (ChE-I) have been investigated in PD-D and PD-MCI patients. A recent placebo-controlled, single site study showed benefit of rivastigmine in PD-MCI on a performance-based measure of cognitive abilities and a trend for improvement on a global rating of cognition, disease-related health status, and anxiety severity [75]. In a smaller randomized, placebo controlled trial in non-demented PD patients, galantamine did not show any significant benefits on tests of cognitive function [76]. There have been two large randomized, placebo controlled trials in PD-D, one with rivastigmine and the other with donepezil. In the rivastigmine trial, both cognitive and overall evaluation scales showed significant improvement compared to placebo; there were also benefits in the behavioral, attentional and executive function test scores [77]. Except for more patients having worsening of tremor there were no significant effects on motor symptoms as compared to placebo. The beneficial effects seemed to last for at least 6 months [78], with consistent benefits on all aspects of attention [79]. In another large placebo controlled trial donepezil 10 mg was also associated with beneficial effects in cognitive and overall scales, with no significant differences on ADLs or behavioral scores. A recent metaanalysis including studies with ChE-Is or memantine in PD-D concluded that both treatments were associated with a positive effect on global assessment whereas treatment with ChE-Is, however, ChE, but not memantine, significantly improved cognitive functions, behavioral symptoms and activities of daily living [80]. Based on the results of the clinical trial described above rivastigmine was approved for the treatment of patients with mild to moderate PD-D. Memantine, a partial NMDA receptor antagonist used in the treatment of AD, was tested in patients with DLB or PD-D in two randomized controlled trials. In the smaller study, there was a significant difference in favor of memantine in the global outcome scale. Patients with PD-D had more benefits as compared to those with DLB [81]. In the larger study the global outcome scale and behavioral scores were significantly better with memantine in the DLB group, whereas there were no
significant differences in the PD-D population [82]. Memantine is not approved for the treatment of PD-D.
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