An Update on Brain Imaging in Parkinsonian Dementia

review An update on brain imaging in parkinsonian dementia Disturbances of cognition are frequent in Parkinson’s disease (PD). Unlike severe loss of dopamine early in PD, extensive cholinergic losses have been consistently reported in PD with dementia. Cholinergic imaging suggests that basal forebrain cholinergic system degeneration appears early in PD and worsens with dementia development. Cortical cholinergic denervation is similar in PD with dementia and dementia with Lewy bodies, supporting a common disease spectrum, at least with respect to cholinergic pathology. Presence of cerebral amyloidopathy in the setting of parkinsonism may accelerate cognitive decline. Novel MRI techniques illustrate the widespread presence of neurodegeneration in PD with dementia, affecting white matter tracts and connectivity functions. This review will outline current concepts regarding dementia development in PD and discuss their correlation with functional and structural neuroimaging including PET and MRI. KEYWORDS: acetylcholine n amyloid n dementia with Lewy bodies Myria Petrou*, n fluorodeoxyglucose n MRI n Parkinson’s disease n PET n SPECT Vikas Kotagal & Nicolaas I Bohnen Cognitive dysfunction in Parkinson’s recognized that cognitive impairments in early University of Michigan, Ann Arbor, disease PD are heterogeneous, with a number of patients MI, USA *Author for correspondence: Disturbances of cognition are frequent find- exhibiting deficits on posterior cortically based Tel.: +1 734 615 3586 ings in Parkinson’s disease (PD) patients with cognitive tasks. For example, the meta-ana lysis Fax: +1 734 764 2412 point prevalence estimates of frank dementia by Aarsland et al. on MCI in PD suggested that [email protected] (PD with dementia [PDD]) being reported in memory and visuospatial impairments were 40% and more subtle cognitive impairment more common than executive impairment in affecting over 60% of PD patients [1–3]. Older nondemented PD [7]. MCI in PD may repre- age and duration of disease are associated with sent a precursor state to dementia but is quali- increased risk of dementia, with development of tatively distinct from the amnestic-type MCI dementia in 75% and over 80% of PD patients seen in association with Alzheimer’s disease who survive for more than 10 and 20 years, (AD). In this respect, the longitudinal study respectively [4,5]. by Williams-Gray et al. suggests that posterior An arbitrary but generally accepted distinc- cortical deficits herald the dementia of PD [8]. tion is made using current consensus diagnostic The mixed pattern of cognitive decline in criteria between patients presenting with parkin- PD is probably secondary to a combination of sonism prior to the onset of dementia (PDD) different neuropathological processes, which versus those with concurrent development of worsen and become more complex and inter- parkinsonism and dementia or with dementia twined with disease progression. The patho- preceding parkinsonism (dementia with Lewy logical hallmark of parkinsonian dementia is bodies [DLB]). Using the so-called ‘1-year rule’, the presence of extranigral Lewy bodies [9,10], patients with L-Dopa responsive parkinsonism but can be accompanied by other patholo- who develop dementia more than 1 year after gies, such as AD-type findings [11], including their initial PD motor symptoms are classified as b-amyloid plaques and hyperphosphorylated PDD. Patients with onset of dementia and par- tau tangle pathology. In addition, comorbid kinsonism within 1 year or with dementia pre- vascular pathology, manifesting as leukoaraio- ceding parkinsonism are classified as DLB [6]. sis on imaging studies, may also contribute to Mild selective cognitive deficits in PD are PDD [12,13]. These different neuropathological frequently present in the absence of a clinical changes may not only result in local or regional diagnosis of dementia [3]. Although impairments neuronal and/or synaptic dysfunction but can of executive functions have long been consid- also interrupt neuromodulator projection net- ered the cognitive signature of mild cognitive works, including the cholinergic, noradrenergic impairment (MCI) in PD, it is now widely and dopaminergic systems. part of 10.2217/IIM.12.10 © 2012 Future Medicine Ltd Imaging Med. (2012) 4(2), 201–213 ISSN 1755-5191 201 review Petrou, Kotagal & Bohnen This review will: discuss current evidence substantia nigra is seen more commonly in PDD and theory on the etiology of cognitive impair- as opposed to PD without dementia, suggesting ment and dementia in PD; outline alterations an association between dementia, duration of in cerebral blood flow (CBF) and glucose disease and the integrity of nigrostriatal dopami- 18 metabolism in PDD using SPECT, and [ F] nergic pathways [31]. Striatal a-synuclein pathol- Fluorodeoxyglucose (FDG) PET and MR ogy is also seen more commonly in PDD than in perfusion techniques; review brain PET imag- PD without dementia or DLB [32,33]. Although ing findings regarding abnormalities in the duration of disease may be a confounding fac- dopaminergic and cholinergic systems, as well as tor in PD to account for the more severe stria- amyloid deposition in the setting of PD-related tal pathology, this argument may be less valid cognitive impairment; and provide an overview in DLB. of MR findings in PD-associated cognitive In addition to nigrostriatal denervation, impairment. there is evidence for alterations in cholinergic neurotransmission in PD. Loss of cholinergic Post-mortem findings of neurons in the nucleus basalis of Meynert has parkinsonian dementia been reported in both PD and AD brains [34–39]. There are numerous pathologic changes in PDD Interestingly, neuronal forebrain loss may be dementia, including degeneration of subcorti- even more profound in PD compared with AD cal dopaminergic and cholinergic projection [34].Similarly, a post-mortem study found greater systems, as well as direct cortical involvement. reductions of acetylcholinesterase (AChE) in Cortical Lewy bodies and Lewy neurites as well the frontal cortex of PDD compared with non- as AD-type changes with b-amyloid plaques, demented patients with PD [40]. The reduc- and in some instances neurofibrillary tangles, tion in cortical nicotinic cholinergic receptor are present in PDD subjects [14–20]. Some neuro- number in PD parallels the degree of dementia pathology studies suggest that limbic and neocor- observed with progression of the disease [41,42]; tical Lewy body deposition is the main determi- it is hence believed that degeneration of the cho- nant of cognitive decline in PD [10,21–24], whereas linergic system may play a significant role in the others suggest an important role for amyloid development of dementia in PD. plaques and neurofibrillary pathology [25–27]. Striatal amyloid deposition is also reported in Imaging global cerebral cortical the setting of PD and cognitive impairment dysfunction in parkinsonian [20,28]. Interestingly, a recent post-mortem study dementia: FDG-PET & CBF imaging found a greater frequency of striatal b-amyloid FDG -PET and [99m]Tc-ECD, [99m]Tc-HMPAO 123 deposition in PDD compared with PD [28], and or [ I]-iodoamphetamine-SPECT can be used may thus confer increased risk of dementia. A to estimate cerebral glucose metabolism and recent pathologic study by Compta et al. sug- CBF, both of which serve as surrogate mark- gests that the combination of Lewy bodies, amy- ers for regional cortical health and metabolism loid plaques and neuro fibrillary tangles is the in neurodegenerative diseases. More recently, crucial determinant of dementia in PD [29]. The Arterial spin labeling (ASL) MRI has been used complex interplay between amyloid deposition to study perfusion changes [43]. Each of these and Lewy body pathology may become clearer techniques has relative advantages and disad- in the era of in vivo fibrillary amyloid imaging. vantages in the assessment of cerebral perfusion In vitro evidence suggests an interaction between and/or metabolism. FDG-PET is both precise PD-type (a-synuclein) and AD-type (i.e., tau) and accurate but can be expensive and time pathologies [30]. consuming to perform. SPECT is less costly Loss of mesencephalic dopaminergic neurons but offers poorer spatial resolution. ASL does in the substantia nigra pars compacta and nerve not involve the use of ionizing radiation or con- terminals in the striatum is the pathological trast injection but does carry potential for a low hallmark of PD. Significant nigrostriatal dopa- signal-to-noise ratio. minergic cell loss occurs early in symptomatic FDG-PET has been studied extensively in PD. Its severity and universal prevalence early AD where it shows characteristic parietotem- in the disease course may explain why subse- poral and posterior cingulate glucose hypo- quent emergence and worsening of non-motor metabolism [44,45]. While similar findings of symptoms are increasingly attributed to non- posterior cingulate hypometabolism are also dopaminergic degenerations in advancing PD. seen in PDD, the presence of anterior cingulate Despite this, post-mortem cell loss in the medial hypometabolism may be more characteristic 202 Imaging Med. (2012) 4(2) future science group An update on brain imaging in parkinsonian dementia review of DLB than PDD [45,46]. Our group recently and suggest that the pattern of rCBF seen in reported results of a prospective study involving PDD is relatively similar to AD [51,52]. rCBF FDG-PET in 23 nondemented individuals with studies may also differentiate DLB from

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