Cognitive Pathology in Parkinson's Disease
van der Zee, Sygrid
DOI:
10.33612/diss.172837091
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2021
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
van der Zee, S. (2021). Cognitive Pathology in Parkinson's Disease: a cholinergic perspective. University of Groningen. https://doi.org/10.33612/diss.172837091
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
General Introduction
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer’s disease, with an estimated 10 million individuals with PD globally.1 The onset of the disease is usually after age 60, affecting approximately 1%
of the population over 60.2,3 Incidence rates of the disease increases with age, peaking
between ages 85 and 89 years. PD affects men more frequent than women, with a 1.4:1.0 male to female ratio.4
PD is traditionally viewed as a movement disorder characterized by four motor symptoms, including tremor, rigidity, bradykinesia and postural instability, resulting from dopaminergic degeneration in the substantia nigra. However, additional motor and non-motor symptoms are frequently observed, including freezing of gate, REM sleep behavioral disorder, fatigue, olfactory dysfunction, visual hallucinations, autonomic dysfunction and cognitive impairment.5 A large variability in clinical phenotype, as well as
in the rate of disease progression, is observed between individual patients6, making PD
a heterogeneous disorder in which different clinical subtypes might represent different etiologies.7–9 Non-motor symptoms are present in the majority of cases and are already
frequently present in early PD or even before the onset of motor symptoms.10,11 Cognitive
impairment is among the most common non-motor symptoms and considered an important contributor to the quality of life of PD patients and caregivers alike.12,13
Here, we review the current understanding of the phenotype and etiology of cognitive impairment in PD, including the cognitive profile, recently described definitions, and the underlying pathophysiology with a focus on the role of the dopaminergic and cholinergic systems.
Cognitive impairment in PD
It is well established that PD patients show cognitive impairment compared to control subjects. The clinical syndrome defined as mild cognitive impairment (PD-MCI) is a more profound decrease in cognitive functioning than would be expected based on normal ageing, given that it does not interfere with the individual’s ability to perform activities of daily life.14 Progressive cognitive impairment developing within the context of established
PD, that is severe enough to impair daily life is considered as PD dementia (PDD).15 Over
the past years, several prospective and cohort studies have provided inconclusive data on the prevalence and clinical presentation of PD-MCI.16–19
Epidemiology
A considerable part of non-demented PD patients already have PD-MCI. Despite the frequent occurrence of cognitive impairment in PD, it is often underrecognized in clinical
practice.20,21 Prevalence estimates vary between 20% and 64%22–25, but larger studies,
including a meta-analysis and multicenter pooled analysis, report a 25-40% estimated prevalence.19,26 Longitudinal studies show that the incidence of PD-MCI increases with
disease duration and that it is a risk factor for, or even a potential prodromal state of, PDD.16,27,28 Up to an estimated 78% of PD patients develop PDD over a disease duration
of 10 years.16,27–29 However, cognitive impairment is not limited to more advanced disease
stages only, and research has shown that an estimated 25-36% of PD patients already demonstrate cognitive impairment at the earliest stages of the disease, including de novo patients.22,30
Clinical presentation
PD-MCI is associated with older age, longer disease duration, more impaired motor function, postural instability and gait disorder (PIGD) motor features, as well as with depression and apathy.26,31 The cognitive profile of PD-MCI has been described as a
frontal-subcortical profile with predominantly impairments in the domain of executive functioning.31,32 Executive function is an umbrella term comprising a range of processes
involved in complex goal-directed behavior, including planning, initiation, working memory, inhibition and attentional control.33 However, increasing evidence demonstrates additional
impairments in the domains of mental speed and attention, memory, visuospatial abilities and social cognition, in both de novo as well as more advanced PD.17,22,31,32,34–38 The
language domain is generally less affected.22 Overall, the clinical presentation of PD-MCI
appears to be heterogeneous and the majority of patients show impairments in multiple cognitive domains.26 Differences in cognitive impairment profile may reflect differences
in underlying pathophysiology, which will be discussed further on in this chapter. Assessing cognitive impairment in PD
The use of different diagnostic criteria and assessment methodologies may partly explain variability in incidence estimates and cognitive profile characteristics. The Movement Disorder Society Task Force has proposed uniform diagnostic criteria to allow early recognition of PD-MCI.14 According to these criteria, the diagnosis of PD-MCI is based
on four key features; 1) diagnosis of PD, 2) gradual decline of cognitive ability, in the context of PD, reported by either the patient or informant, or observed by the clinician, 3) cognitive impairment on either formal neuropsychological testing or a scale of global cognitive abilities, and 4) cognitive deficits are not severe enough to interfere significantly with functional independence, although subtle difficulties on complex functional tasks may be present. The presence of cognitive deficits can be established through Level I or Level II criteria. Level I testing includes an abbreviated assessment with a scale of global cognitive abilities validated for use in PD. Level II testing includes a comprehensive neuropsychological assessment that includes at least two test for each cognitive domain
(i.e. attention and mental speed, executive functions, language, memory and visuospatial abilities), with impairment on two neuropsychological tests in one or more domains being considered PD-MCI. PD-MCI can be further subtyped as single-domain or multiple-domain cognitive impairment.14 The use of standardized criteria to identify the clinical
syndrome of PD-MCI may facilitate clinicians to identify PD patients at risk for developing PDD and allows future research to better identify and stratify PD patients in studies on the pathophysiology of cognitive impairment in PD.
Pathophysiology of cognitive impairment
The exact pathophysiology underlying cognitive impairment in PD remains elusive. The classical neuropathological hallmarks of PD include the loss of dopaminergic neurons in the subtantia nigra pars compact (SNc) and the presence of α-synuclein containing Lewy bodies and neurites.39 However, the pathological changes are progressive over
time and include additional interactive effects of protein depositions, neuronal and synaptic changes.5 Moreover, alterations in various neurotransmitter systems have been
described in PD and may contribute to cognitive impairment in PD, including loss of dopamine, acetylcholine, noradrenaline and serotonin.40 The former two, and especially
the cholinergic system, are of particular interest in the context of this dissertation and will be discussed in more detail below.
Dopaminergic system and cognitive impairment in PD
The degeneration of the dopaminergic neurons in the SNc and subsequent dopaminergic depletion of the striatum is of importance for motor control, but also for emotional and cognitive functions.40,41 Moreover, the mesocortical and mesolimbic pathways, consisting of
dopaminergic projections from the ventral tegmental area to the frontal cortical regions and limbic regions respectively, play an important role in these non-motor functions of dopamine.40 However, the exact role of the dopaminergic system in cognitive impairment
in PD is complex and still not fully understood.
Dopaminergic innervation and the relationship with cognitive impairment can be assessed in vivo with positron emission tomography (PET) or single photon emission computed tomography (SPECT), using markers of dopaminergic terminal integrity. Previous nuclear imaging studies demonstrated a dopaminergic role in cognitive impairment, in particular in executive dysfunction. Dopamine transporter (DAT) SPECT imaging and [18F]fluorodopa PET imaging studies showed reduced dopaminergic function
of the striatum, associated with executive dysfunction in both newly diagnosed as well as more advanced PD patients.42–48 In addition, a beneficial effect of dopaminergic medication
on working memory and planning was demonstrated by Lange et al. and Cooper et al.49,50
visuospatial, attention and memory domains.49 These findings suggest that neurochemical
pathology may be different for cognitive impairments in different domains, with a more prominent role of the dopaminergic system in the frontostriatal dysexecutive syndrome. In addition to the dopaminergic system, the cholinergic system is considered an important contributor to cognitive domain functioning in PD.
The cholinergic system
There are four major sources of cholinergic projections in the brain. The first one is the basal forebrain cholinergic cell groups, which is the source of widespread cholinergic projections throughout the brain. It consists of 4 cell groups; Ch1 (medial septal nucleus) and Ch2 (vertical limb nucleus of the diagonal band of Broca) project to the hippocampus, Ch3 (horizontal limb nucleus of the diagonal band of Broca) projects to the olfactory bulb and the Ch4 (nucleus basalis of Meynert) projects to the amygdala and neocortex.51–53
The second cholinergic source, the pedunculopontine nucleus (PPN, Ch5)-laterodorsal tegmental complex (LDTC, Ch6) projects primarily to the thalamus, brainstem nuclei and cerebellum.54 The third major source is represented by cholinergic interneurons mainly
found in the striatum.55 Finally, the medial vestibular nucleus (MVN) is a major source
of cholinergic cerebellar innervation.54 Table 1 provides an overview of cholinergic cell
groups and their major projection area.56
Table 1: Cholinergic cell groups and their projection areas.53,56
Cholinergic cell group Major projection area
Ch1: medial septal nucleus Hippocampus
Ch2: vertical limb nucleus of the diagonal band of Broca Hippocampus Ch3: horizontal limb nucleus of the diagonal band of Broca Olfactory bulb Ch4: nucleus basalis of Meynert Amygdala and neocortex
Ch5: pedunculopontine nucleus Thalamus
Ch6: laterodorsal tegmental complex Thalamus
Striatal interneurons Striatum
Medial vestibular nucleus Cerebellum
Because of its widely distributed projections, the cholinergic system is of importance for many central nervous system functions, including cognitive performance. Interestingly, α-synuclein deposition, the pathological hallmark of PD, was found in the basal forebrain in early PD, concurrent with Lewy bodies and neuronal loss in the substantia nigra.57 This
may indicate early involvement of the cholinergic system in PD pathology. Significant loss of nbM cholinergic neurons is extensive in PD, with more profound cholinergic pathology in PD and Lewy body dementia compared to Alzheimer’s disease.58–61 In addition to nbM
cholinergic losses, degeneration of the cholinergic neurons of the lateral part of the PPN,
pars compacta, is reported in PD.62,63 Although significant and widespread cholinergic
losses are found in PD, there is great heterogeneity in cholinergic denervation.64 This
heterogeneity is may provide an explanation for some of the clinical variability in PD. Cholinergic imaging
In vivo radioligand imaging can provide insight into the underlying cholinergic pathophysiology in PD. The processes of acetylcholine synthesis, storage and degradation provide molecular targets which can be used in the identification of cholinergic neurons and pathways. Figure 1 provides a schematic overview of cholinergic radioligand imaging targets. Currently ligands exist for (1) the vesicular acetylcholine transporter (VAChT), (2) acetylcholinesterase (AChE), the enzyme responsible for acetylcholine degradation within the synapse, and (3) cholinergic receptor targets with ligands selective for either nicotinic or muscarinic receptors.
Figure 1: Cholinergic synapse radioligand targets
AChE is a cholinergic target commonly used in PD research and is considered a reliable marker for the cholinergic system, and can be non-invasively quantified in low and moderate activity areas, such as the neocortex, limbic cortex and thalamus.65–68
However, AChE-based approaches are considered as indirect markers of cholinergic terminal integrity because AChE may have both pre- and post-synaptic expressions. In addition, AChE PET imaging is less accurate for non-invasive quantification of cholinergic
changes in higher binding regions including the striatum and cerebellar vermis.69,70
VAChT ligands, the SPECT tracer (-)-5-[123I]Iodobenzoversamicol ([123I]IBVM) and PET
tracer [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV), on the other hand, are selective
presynaptic markers. [18F]FEOBV has recently been successfully validated for observational
research. In healthy control subjects, [18F]FEOBV shows a pattern of cholinergic binding
consistent with the expected brain distribution.71,72 In addition, the use of [18F]FEOBV
was quantified in patients with Alzheimer’s disease, supporting its use as a marker of cholinergic innervation in this disease.73 [18F]FEOBV allows for more detailed cholinergic
assessment of not only cortical regions, but also the higher binding subcortical regions, such as striatum and cerebellum.71,74 [18F]FEOBV therefore is a promising ligand for the
assessment of the cholinergic system in PD, related to cognitive functioning and possibly other clinical symptoms like gait and balance. However, quantification of [18F]FEOBV as
a cholinergic imaging marker in PD was lacking so far.
Cholinergic pathology of cognitive impairment in PD
The role of cholinergic neurotransmission in cognitive functioning was suggested over 30 years ago, when loss of choline acetyltransferase and acetylcholinesterase was found post mortem in Alzheimer’s disease and later also in PD.75,76 In vivo cholinergic imaging studies,
confirmed by post-mortem studies, revealed cholinergic deficits in PD patients compared to control subjects.58,77,78 This loss is more pronounced in PDD patients compared to
PD patients without dementia, suggesting a direct relationship between the level of cholinergic denervation and the severity of cognitive decline in PD.67,79–81 For example,
Hilker et al. (2005) found significant cholinergic deficits in PD patients compared to controls, in which PDD patients showed more severe and widespread losses than the non-demented PD group.80 In addition, Shimada et al. (2009) found that cholinergic
losses could already be found in early PD compared to control subjects.81 They did not
find a difference in AChE activity between early and advanced PD, with comparable cognitive functioning. However, the PDD group showed more widespread and profound cholinergic dysfunction, and a correlation was found between cortical cholinergic values and scores on the mini mental state examination (MMSE), a global cognitive screening tool. To get a better understanding of the cholinergic role in cognition, Bohnen et al., 2006 showed that overall cortical cholinergic denervation was associated with cognitive tasks in the attention, memory and executive function domains.64,82 These results suggest
that cholinergic degeneration is a key component in overall cognitive decline across multiple domains.
Overall, recent developments in neuroimaging provide compelling evidence that cholinergic denervation is an important contributor to the pathophysiology of cognitive dysfunction in PD, but the exact underlying cholinergic mechanism remains elusive. Unlike traditional views of the cholinergic system as a diffuse cortical neuromodulator
system83, more recent studies emphasize the importance of specific regional activity of
the cholinergic system.55,84,85 Kehagia et al (2010) proposed a “dual-syndrome” hypothesis
that posits sequential involvement of anterior vs. posterior regional brain changes with different driving pathologies. In this model, early fronto-executive dysfunction is more related to dopaminergic losses, and subsequent posterior cortical dysfunction, including memory and visuospatial impairments is associated with non-dopaminergic, in particular cholinergic, denervation. According to this model, conversion to dementia is related especially to posterior cortical changes.86,87
Conclusion
Overall, cognitive impairment is a common and debilitating non-motor symptom in PD. Although the importance of cholinergic innervation in cognitive impairment in PD is well established, previous studies have mostly evaluated global cortical cholinergic innervation, and detailed assessment of the regional cortical and subcortical role of the cholinergic system in cognitive impairment across stages of PD is lacking. Early identification and a better understanding of the pathophysiology underlying cognitive impairment in PD might help to improve efficacy of both pharmacological and non-pharmacological interventions and will support the identification of potential novel therapeutic targets. Moreover, it will offer important information for both patients and healthcare providers to anticipate on future changes.
General aim and outline of this thesis
This thesis aims to improve the understanding of cholinergic pathology underlying cognitive impairment in Parkinson’s disease, by providing new insights on the in vivo assessment of cholinergic imaging, evaluating the cholinergic system in the early stages of the disease and assessing the regional role of the cholinergic system in domain-specific cognitive functioning in more advanced PD patients.
The following hypotheses will be investigated in this thesis:
1. The presynaptic cholinergic tracer [18F]FEOBV allows for reliable and detailed
assessment of the cholinergic system in PD.
2. Altered cholinergic innervation is already present in de novo PD patients.
3. Domain specific cognitive impairment is associated with regional cholinergic denervation patterns in more advanced PD patients.
In chapter 2 we validated the use of the novel cholinergic PET tracer [18F]FEOBV
control subjects on both whole-brain voxel based and volume of interest (VOI) analysis. In addition, we assessed test-retest variability and reliability in both groups.
In chapter 3 and chapter 4 the use of [18F]FEOBV is further explored in newly
diagnosed, treatment naïve, PD patients as part of the DUtch PARkinson Cohort (DUPARC) study. Chapter 3 provides a detailed description of the DUPARC study; a prospective cohort study on de novo Parkinson’s disease. Chapter 4 demonstrates the first results of the DUPARC study by assessing the regional cholinergic innervation status in de novo PD patients, with and without cognitive impairment compared to control subjects.
Chapter 5 and chapter 6 focus on non-demented PD patients with a longer disease duration as part of a cross-sectional study performed at the University of Michigan. These chapters explore the topographic relationship between regional cholinergic innervation and cognitive processing from two a priori perspectives. Chapter 5 explores this relationship from the cognitive domain perspective and evaluates the regional cholinergic correlates of the five predefined cognitive domains on a whole-brain voxel-based level. In chapter 6 the relationship is approached from the cholinergic perspective and primarily aims to identify cholinergic covarying patterns on a principle component analysis.
References
1. Fang C, Lv L, Mao S, Dong H, Liu B. Cognition Deficits in Parkinson’s Disease: Mechanisms and Treatment.
Parkinsons Dis. 2020;2020:2076942. doi:10.1155/2020/2076942
2. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5(6):525-535. doi:10.1016/S1474-4422(06)70471-9
3. Tysnes O-B, Storstein A. Epidemiology of Parkinson’s disease. J Neural Transm. 2017;124(8):901-905. doi:10.1007/s00702-017-1686-y
4. Global, regional, and national burden of Parkinson’s disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17(11):939-953. doi:10.1016/S1474-4422(18)30295-3 5. Kalia L V, Lang AE. Parkinson’s disease. Lancet (London, England). 2015;386(9996):896-912. doi:10.1016/
S0140-6736(14)61393-3
6. Greenland JC, Williams-Gray CH, Barker RA. The clinical heterogeneity of Parkinson’s disease and its therapeutic implications. Eur J Neurosci. 2019;49(3):328-338. doi:10.1111/ejn.14094
7. von Coelln R, Shulman LM. Clinical subtypes and genetic heterogeneity: of lumping and splitting in Parkinson disease. Curr Opin Neurol. 2016;29(6):727-734. doi:10.1097/WCO.0000000000000384 8. van Rooden SM, Colas F, Martínez-Martín P, et al. Clinical subtypes of Parkinson’s disease. Mov Disord.
2011;26(1):51-58. doi:10.1002/mds.23346
9. Marras C, Lang A. Parkinson’s disease subtypes: lost in translation? J Neurol Neurosurg Psychiatry. 2013;84(4):409-415. doi:10.1136/jnnp-2012-303455
10. Khoo TK, Yarnall AJ, Duncan GW, et al. The spectrum of nonmotor symptoms in early Parkinson disease.
Neurology. 2013;80(3):276-281. doi:10.1212/WNL.0b013e31827deb74
11. Postuma RB, Aarsland D, Barone P, et al. Identifying prodromal Parkinson’s disease: pre-motor disorders in Parkinson’s disease. Mov Disord. 2012;27(5):617-626. doi:10.1002/mds.24996
12. Post B, Muslimovic D, van Geloven N, et al. Progression and prognostic factors of motor impairment, disability and quality of life in newly diagnosed Parkinson’s disease. Mov Disord. 2011;26(3):449-456. doi:10.1002/mds.23467; 10.1002/mds.23467
13. Lawson RA, Yarnall AJ, Duncan GW, et al. Severity of mild cognitive impairment in early Parkinson’s disease contributes to poorer quality of life. Parkinsonism Relat Disord. 2014;20(10):1071-1075. doi:10.1016/j. parkreldis.2014.07.004 [doi]
14. Litvan I, Aarsland D, Adler CH, et al. MDS Task Force on mild cognitive impairment in Parkinson’s disease: critical review of PD-MCI. Mov Disord. 2011;26(10):1814-1824. doi:10.1002/mds.23823; 10.1002/mds.23823 15. Goetz CG, Emre M, Dubois B. Parkinson’s disease dementia: definitions, guidelines, and research
perspectives in diagnosis. Ann Neurol. 2008;64 Suppl 2:S81-92. doi:10.1002/ana.21455
16. Pedersen KF, Larsen JP, Tysnes OB, Alves G. Prognosis of mild cognitive impairment in early Parkinson disease: the Norwegian ParkWest study. JAMA Neurol. 2013;70(5):580-586. doi:10.1001/ jamaneurol.2013.2110; 10.1001/jamaneurol.2013.2110
17. Yarnall AJ, Breen DP, Duncan GW, et al. Characterizing mild cognitive impairment in incident Parkinson disease: the ICICLE-PD study. Neurology. 2014;82(4):308-316. doi:10.1212/WNL.0000000000000066 [doi]
18. Williams-Gray CH, Mason SL, Evans JR, et al. The CamPaIGN study of Parkinson’s disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry. 2013;84(11):1258-1264. doi:10.1136/ jnnp-2013-305277
19. Aarsland D, Bronnick K, Williams-Gray C, et al. Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology. 2010;75(12):1062-1069. doi:10.1212/WNL.0b013e3181f39d0e; 10.1212/WNL.0b013e3181f39d0e
20. Kulisevsky J, Pagonabarraga J. Cognitive impairment in Parkinson’s disease: tools for diagnosis and assessment. Mov Disord. 2009;24(8):1103-1110. doi:10.1002/mds.22506
21. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591-1601. doi:10.1002/mds.26424
22. Muslimovic D, Post B, Speelman JD, Schmand B. Cognitive profile of patients with newly diagnosed Parkinson disease. Neurology. 2005;65(8):1239-1245. doi:10.1212/01.wnl.0000180516.69442.95 23. Lawrence BJ, Gasson N, Loftus AM. Prevalence and Subtypes of Mild Cognitive Impairment in Parkinson’s
Disease. Sci Rep. 2016;6(1):33929. doi:10.1038/srep33929
24. Nicoletti A, Luca A, Baschi R, et al. Incidence of Mild Cognitive Impairment and Dementia in Parkinson’s Disease: The Parkinson’s Disease Cognitive Impairment Study. Front Aging Neurosci. 2019;11:21. doi:10.3389/ fnagi.2019.00021
25. Monastero R, Cicero CE, Baschi R, et al. Mild cognitive impairment in Parkinson’s disease: the Parkinson’s disease cognitive study (PACOS). J Neurol. 2018;265(5):1050-1058. doi:10.1007/s00415-018-8800-4 26. Baiano C, Barone P, Trojano L, Santangelo G. Prevalence and clinical aspects of mild cognitive impairment
in Parkinson’s disease: A meta-analysis. Mov Disord. November 2019. doi:10.1002/mds.27902
27. Broeders M, Velseboer DC, de Bie R, et al. Cognitive change in newly-diagnosed patients with Parkinson’s disease: a 5-year follow-up study. J Int Neuropsychol Soc. 2013;19(6):695-708. doi:10.1017/ S1355617713000295; 10.1017/S1355617713000295
28. Aarsland D, Kurz MW. The epidemiology of dementia associated with Parkinson’s disease. Brain Pathol. 2010;20(3):633-639. doi:10.1111/j.1750-3639.2009.00369.x
29. Domellöf ME, Ekman U, Forsgren L, Elgh E. Cognitive function in the early phase of Parkinson’s disease, a five-year follow-up. Acta Neurol Scand. 2015;132(2):79-88. doi:10.1111/ane.12375
30. Foltynie T, Brayne CE, Robbins TW, Barker RA. The cognitive ability of an incident cohort of Parkinson’s patients in the UK. The CamPaIGN study. Brain. 2004;127(Pt 3):550-560. doi:10.1093/brain/awh067 31. Barone P, Aarsland D, Burn D, Emre M, Kulisevsky J, Weintraub D. Cognitive impairment in nondemented
Parkinson’s disease. Mov Disord. 2011;26(14):2483-2495. doi:10.1002/mds.23919; 10.1002/mds.23919 32. Williams-Gray CH, Evans JR, Goris A, et al. The distinct cognitive syndromes of Parkinson’s disease: 5
year follow-up of the CamPaIGN cohort. Brain. 2009;132(11):2958-2969. doi:10.1093/brain/awp245 33. Lezak MD. Neuropsychological Assessment. Oxford University Press, USA; 1995.
34. Stefanova E, Iropadja L, Stojkovic T, et al. Mild Cognitive Impairment in Early Parkinson’s Disease Using the Movement Disorder Society Task Force Criteria: Cross-Sectional Study in Hoehn and Yahr Stage 1.
Dement Geriatr Cogn Disord. 2015:199-209. doi:10.1159/000433421
35. Johnson DK, Langford Z, Garnier-villarreal M, Morris JC, Galvin JE. Onset of Mild Cognitive Impairment in Parkinson Disease. 2015;00(00):1-7.
36. Chen H-B, Wu D-D, He J, Li S-H, Su W. Emotion Recognition in Patients With Parkinson Disease. Cogn
Behav Neurol Off J Soc Behav Cogn Neurol. 2019;32(4):247-255. doi:10.1097/WNN.0000000000000209
37. Bora E, Walterfang M, Velakoulis D. Theory of mind in Parkinson’s disease: A meta-analysis. Behav Brain
Res. 2015;292:515-520. doi:10.1016/j.bbr.2015.07.012
38. McIntosh LG, Mannava S, Camalier CR, et al. Emotion recognition in early Parkinson’s disease patients undergoing deep brain stimulation or dopaminergic therapy: a comparison to healthy participants. Front
Aging Neurosci. 2014;6:349. doi:10.3389/fnagi.2014.00349
39. Dickson DW, Braak H, Duda JE, et al. Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol. 2009;8(12):1150-1157. doi:10.1016/S1474-4422(09)70238-8
40. Halliday GM, Leverenz JB, Schneider JS, Adler CH. The neurobiological basis of cognitive impairment in Parkinson’s disease. Mov Disord. 2014;29(5):634-650. doi:10.1002/mds.25857 [doi]
41. Rodriguez-Oroz MC, Jahanshahi M, Krack P, et al. Initial clinical manifestations of Parkinson’s disease: features and pathophysiological mechanisms. Lancet Neurol. 2009;8(12):1128-1139. doi:10.1016/S1474-4422(09)70293-5
42. Ekman U, Eriksson J, Forsgren L, Mo SJ, Riklund K, Nyberg L. Functional brain activity and presynaptic dopamine uptake in patients with Parkinson’s disease and mild cognitive impairment: a cross-sectional study. Lancet Neurol. 2012;11(8):679-687. doi:10.1016/S1474-4422(12)70138-2
43. Nobili F, Campus C, Arnaldi D, et al. Cognitive-nigrostriatal relationships in de novo, drug-naïve Parkinson’s disease patients: a [I-123]FP-CIT SPECT study. Mov Disord. 2010;25(1):35-43. doi:10.1002/mds.22899 44. Lebedev A V, Westman E, Simmons A, et al. Large-scale resting state network correlates of cognitive
impairment in Parkinson’s disease and related dopaminergic deficits. Front Syst Neurosci. 2014;8:45. doi:10.3389/fnsys.2014.00045
45. Siepel FJ, Brønnick KS, Booij J, et al. Cognitive executive impairment and dopaminergic deficits in de novo Parkinson’s disease. Mov Disord. 2014;29(14). doi:10.1002/mds.26051
46. Pellecchia MT, Picillo M, Santangelo G, et al. Cognitive performances and DAT imaging in early Parkinson’s disease with mild cognitive impairment: a preliminary study. Acta Neurol Scand. 2015;131(5):275-281. doi:10.1111/ane.12365
47. Brück A, Portin R, Lindell A, et al. Positron emission tomography shows that impaired frontal lobe functioning in Parkinson’s disease is related to dopaminergic hypofunction in the caudate nucleus. Neurosci
Lett. 2001;311(2):81-84. doi:10.1016/s0304-3940(01)02124-3
48. Marié RM, Barré L, Dupuy B, Viader F, Defer G, Baron JC. Relationships between striatal dopamine denervation and frontal executive tests in Parkinson’s disease. Neurosci Lett. 1999;260(2):77-80. doi:10.1016/s0304-3940(98)00928-8
49. Lange KW, Robbins TW, Marsden CD, James M, Owen AM, Paul GM. L-dopa withdrawal in Parkinson’s disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction.
Psychopharmacology (Berl). 1992;107(2-3):394-404. doi:10.1007/BF02245167
50. Cooper JA, Sagar HJ, Doherty SM, Jordan N, Tidswell P, Sullivan E V. Different effects of dopaminergic and anticholinergic therapies on cognitive and motor function in Parkinson’s disease. A follow-up study of untreated patients. Brain. 1992;115 ( Pt 6):1701-1725. doi:10.1093/brain/115.6.1701
51. Liu AKL, Chang RCC, Pearce RKB, Gentleman SM. Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer’s and Parkinson’s disease. Acta Neuropathol. 2015;129(4):527-540. doi:10.1007/s00401-015-1392-5
52. Selden NR, Gitelman DR, Salamon-Murayama N, Parrish TB, Mesulam MM. Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain. 1998;121 ( Pt 1:2249-2257. http:// www.ncbi.nlm.nih.gov/pubmed/9874478.
53. Mesulam MM. The systems-level organization of cholinergic innervation in the human cerebral cortex and its alterations in Alzheimer’s disease. Prog Brain Res. 1996;109:285-297. doi:10.1016/s0079-6123(08)62112-3 54. Zhang C, Zhou P, Yuan T. The cholinergic system in the cerebellum: from structure to function. Rev
Neurosci. 2016;27(8):769-776. doi:10.1515/revneuro-2016-0008
55. Ballinger EC, Ananth M, Talmage DA, Role LW. Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline. Neuron. 2016;91(6):1199-1218. doi:10.1016/j.neuron.2016.09.006 56. Bohnen NI, Kanel P, Müller MLTM. Molecular Imaging of the Cholinergic System in Parkinson’s Disease.
Int Rev Neurobiol. 2018;141:211-250. doi:10.1016/bs.irn.2018.07.027
57. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197-211.
58. Bohnen NI, Kaufer DI, Ivanco LS, et al. Cortical Cholinergic Function Is More Severely Affected in Parkinsonian Dementia Than in Alzheimer Disease: An In Vivo Positron Emission Tomographic Study.
Arch Neurol. 2003;60(12):1745-1748. doi:10.1001/archneur.60.12.1745
59. Candy JM, Perry RH, Perry EK, et al. Pathological changes in the nucleus of Meynert in Alzheimer’s and Parkinson’s diseases. J Neurol Sci. 1983;59(2):277-289. doi:10.1016/0022-510x(83)90045-x
60. Rogers JD, Brogan D, Mirra SS. The nucleus basalis of Meynert in neurological disease: a quantitative morphological study. Ann Neurol. 1985;17(2):163-170. doi:10.1002/ana.410170210
61. Tagliavini F, Pilleri G, Bouras C, Constantinidis J. The basal nucleus of Meynert in patients with progressive supranuclear palsy. Neurosci Lett. 1984;44(1):37-42. doi:10.1016/0304-3940(84)90217-9
62. Jellinger K. The pedunculopontine nucleus in Parkinson’s disease, progressive supranuclear palsy and Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 1988;51(4):540-543. doi:10.1136/jnnp.51.4.540 63. Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F. Neuronal loss in the pedunculopontine
tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci U S A. 1987;84(16):5976-5980. doi:10.1073/pnas.84.16.5976
64. Bohnen NI, Mu MLTM, Kotagal V, et al. Heterogeneity of cholinergic denervation in Parkinson ’ s disease without dementia. 2012:1609-1617. doi:10.1038/jcbfm.2012.60
65. Irie T, Fukushi K, Akimoto Y, Tamagami H, Nozaki T. Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AchE) in vivo. Nucl Med Biol. 1994;21(6):801-808. doi:10.1016/0969-8051(94)90159-7
66. Kilbourn MR, Snyder SE, Sherman PS, Kuhl DE. In vivo studies of acetylcholinesterase activity using a labeled substrate, N-[11C]methylpiperdin-4-yl propionate ([11C]PMP). Synapse. 1996;22(2):123-131. doi:10.1002/(SICI)1098-2396(199602)22:2<123::AID-SYN5>3.0.CO;2-F
67. Hiraoka K, Okamura N, Funaki Y, et al. Cholinergic deficit and response to donepezil therapy in Parkinson’s disease with dementia. Eur Neurol. 2012;68(3):137-143. doi:10.1159/000338774
68. Koeppe RA, Frey KA, Snyder SE, Meyer P, Kilbourn MR, Kuhl DE. Kinetic modeling of N-[11C] methylpiperidin-4-yl propionate: alternatives for analysis of an irreversible positron emission tomography trace for measurement of acetylcholinesterase activity in human brain. J Cereb blood flow Metab Off J Int
Soc Cereb Blood Flow Metab. 1999;19(10):1150-1163. doi:10.1097/00004647-199910000-00012
69. Greenfield SA. A noncholinergic action of acetylcholinesterase (AChE) in the brain: from neuronal secretion to the generation of movement. Cell Mol Neurobiol. 1991;11(1):55-77. doi:10.1007/bf00712800 70. Kuhl DE, Koeppe RA, Minoshima S, et al. In vivo mapping of cerebral acetylcholinesterase activity in aging
and Alzheimer’s disease. Neurology. 1999;52(4):691-699. doi:10.1212/wnl.52.4.691
71. Petrou M, Frey K a, Kilbourn MR, et al. In Vivo Imaging of Human Cholinergic Nerve Terminals with (-)-5-18F-Fluoroethoxybenzovesamicol: Biodistribution, Dosimetry, and Tracer Kinetic Analyses. J Nucl
Med. 2014;55(3):396-404. doi:10.2967/jnumed.113.124792
72. Albin RL, Bohnen NI, Muller MLTM, et al. Regional vesicular acetylcholine transporter distribution in human brain: A [(18) F]fluoroethoxybenzovesamicol positron emission tomography study. J Comp Neurol. 2018;526(17):2884-2897. doi:10.1002/cne.24541
73. Aghourian M, Legault-Denis C, Soucy JP, et al. Quantification of brain cholinergic denervation in Alzheimer’s disease using PET imaging with [18F]-FEOBV. Mol Psychiatry. 2017;22(11):1531-1538. doi:10.1038/
mp.2017.183
74. Nejad-Davarani S, Koeppe RA, Albin RL, Frey KA, Müller MLTM, Bohnen NI. Quantification of brain cholinergic denervation in dementia with Lewy bodies using PET imaging with [18F]-FEOBV. Mol Psychiatry.
2019;24(3):322-327. doi:10.1038/s41380-018-0130-5
75. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet (London,
England). 1976;2(8000):1403. doi:10.1016/s0140-6736(76)91936-x
76. Perry EK, Gibson PH, Blessed G, Perry RH, Tomlinson BE. Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J Neurol Sci. 1977;34(2):247-265. doi:10.1016/0022-510x(77)90073-9
77. Kuhl DE, Minoshima S, Fessler JA, et al. In vivo mapping of cholinergic terminals in normal aging, Alzheimer’s disease, and Parkinson’s disease. Ann Neurol. 1996;40(3):399-410. doi:10.1002/ana.410400309
78. Shinotoh H, Namba H, Yamaguchi M, et al. Positron emission tomographic measurement of acetylcholinesterase activity reveals differential loss of ascending cholinergic systems in Parkinson’s disease and progressive supranuclear palsy. Ann Neurol. 1999;46(1):62-69.
79. Klein JC, Eggers C, Kalbe E, et al. Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology. 2010;74(11):885-892. doi:10.1212/WNL.0b013e3181d55f61 80. Hilker R, Thomas a. V., Klein JC, et al. Dementia in Parkinson disease: Functional imaging of cholinergic
and dopaminergic pathways. Neurology. 2005;65(11):1716-1722. doi:10.1212/01.wnl.0000191154.78131.f6 81. Shimada H, Hirano S, Shinotoh H, et al. Mapping of brain acetylcholinesterase alterations in Lewy body
disease by PET. Neurology. 2009;73(4):273-278. doi:10.1212/WNL.0b013e3181ab2b58
82. Bohnen NI, Kaufer DI, Hendrickson R, et al. Cognitive correlates of cortical cholinergic denervation in Parkinson’s disease and parkinsonian dementia. J Neurol. 2006;253(2):242-247. doi:10.1007/s00415-005-0971-0
83. Woolf N. Cholinergic systems in mammalian brain and spinal cord. Prog Neurobiol. 1991;37:475-524. 84. Sarter M, Lustig C, Howe WM, Gritton H, Berry AS. Deterministic functions of cortical acetylcholine.
Eur J Neurosci. 2014. doi:10.1111/ejn.12515
85. Zaborszky L, Csordas A, Mosca K, et al. Neurons in the basal forebrain project to the cortex in a complex topographic organization that reflects corticocortical connectivity patterns: An experimental study based on retrograde tracing and 3D reconstruction. Cereb Cortex. 2015;25(1):118-137. doi:10.1093/cercor/bht210 86. Kehagia AA, Barker RA, Robbins TW. Neuropsychological and clinical heterogeneity of cognitive
impairment and dementia in patients with Parkinson’s disease. Lancet Neurol. 2010;9(12):1200-1213. doi:10.1016/S1474-4422(10)70212-X; 10.1016/S1474-4422(10)70212-X
87. Williams-Gray CH, Evans JR, Goris A, et al. The distinct cognitive syndromes of Parkinson’s disease: 5 year follow-up of the CamPaIGN cohort. Brain. 2009;132(Pt 11):2958-2969. doi:10.1093/brain/awp245; 10.1093/brain/awp245
