Imaging Neurodegeneration in Parkinson's Disease

Table 1.

Differential Imaging Findings in Parkinsonian Syndromes

Table 2.

Differential Imaging Findings in Dementias

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Morrish PK et al. (1995) Clinical and [¹⁸F] dopa PET findings in early Parkinson’s disease. J Neurol Neurosurg Psychiatry 59: 597-600
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Whone AL et al. (2003) Plasticity in the nigropallidal pathway in Parkinson’s disease: an ¹⁸F-dopa PET study. Ann Neurol 53: 206-213
Benamer TS et al. (2000) Accurate differentiation of parkinsonism and essential tremor using visual assessment of [¹²³I]-FP-CIT imaging: the [¹²³I]-FP-CIT Study Group. Mov Disord 15: 503-510
Catafau AM and Tolosa E (2004) Impact of dopamine transporter SPECT using ¹²³I-ioflupane on diagnosis and management of patients with clinically uncertain Parkinsonian syndromes. Mov Disord 19: 1175-1182
Jennings DL et al. (2004) (¹²³I) β-CIT and singlephoton emission computed tomographic imaging vs clinical evaluation in Parkinsonian syndrome: unmasking an early diagnosis. Arch Neurol 61: 1224-1229
Booij J et al. (2001) The clinical benefit of imaging striatal dopamine transporters with [¹²³I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism. Eur J Nucl Med 28: 266-272
Scherfler C et al. (2007) Role of DAT-SPECT in the diagnostic work up of Parkinsonism. Mov Disord 22: 1229-1238
Marshall VL et al. (2006) Two-year follow-up in 150 consecutive cases with normal dopamine transporter imaging. Nucl Med Commun 27: 933-937
Brooks DJ (1993) Functional imaging in relation to parkinsonian syndromes. J Neurol Sci 115: 1-17
Eidelberg D et al. (1994) The metabolic topography of parkinsonism. J Cereb Blood Flow Metab 14: 783-801
Su PC et al. (2001) Metabolic changes following subthalamotomy for advanced Parkinson’s disease. Ann Neurol 50: 514-520
Feigin A et al. (2001) Metabolic correlates of levodopa response in Parkinson’s disease. Neurology 57: 2083-2088
Eckert T et al. (2007) Regional metabolic changes in parkinsonian patients with normal dopaminergic imaging. Mov Disord 22: 167-173
Burn DJ et al. (1994) Differential diagnosis of Parkinson’s disease, multiple system atrophy, and Steele-Richardson-Olszewski syndrome: discriminant analysis of striatal ¹⁸F-dopa PET data. J Neurol Neurosurg Psychiatry 57: 278-284
Pirker W et al. (2000) [¹²³I]β-CIT SPECT in multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Mov Disord 15: 1158-1167
Eckert T et al. (2005) FDG PET in the differential diagnosis of parkinsonian disorders. Neuroimage 26: 912-921
Moore RY et al. (2007) Extrastriatal monoamine neuron function in Parkinson’s disease: an ¹⁸F-dopa PET study. Neurobiol Dis [doi:10.1016/j.nbd.2007.09.004]
Doder M et al. (2003) Tremor in Parkinson’s disease and serotonergic dysfunction: an ¹¹C-WAY 100635 PET study. Neurology 60: 601-605
Kim SE et al. (2003) Serotonin transporters in the midbrain of Parkinson’s disease patients: a study with ¹²³I-β-CIT SPECT. J Nucl Med 44: 870-876
Remy P et al. (2005) Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128: 1314-1322
Kuhl DE et al. (1996) in vivo mapping of cholinergic terminals in normal aging, Alzheimer’s disease, and Parkinson’s disease. Ann Neurol 40: 399-410
Hilker R et al. (2005) Dementia in Parkinson’s disease: functional imaging of cholinergic and dopaminergic pathways. Neurology 65: 1716-1722
Bohnen NI et al. (2003) Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch Neurol 60: 1745-1748
Bohnen NI et al. (2005) Cognitive correlates of alterations in acetylcholinesterase in Alzheimer’s disease. Neurosci Lett 380: 127-132
Golbe LI (1990) The genetics of Parkinson’s disease: a reconsideration. Neurology 40 (Suppl 3): S7-S16
Berg D et al. (2001) Relationship of substantia nigra echogenicity and motor function in elderly subjects. Neurology 56: 13-17
Walter U et al. (2004) Brain parenchyma sonography detects preclinical parkinsonism. Mov Disord 19: 1445-1449
Sommer U et al. (2004) Detection of presymptomatic Parkinson’s disease: combining smell tests, transcranial sonography, and SPECT. Mov Disord 19: 1196-1202
Ponsen MM et al. (2004) Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 56: 173-181
Piccini P et al. (1997) Dopaminergic function in familial Parkinson’s disease: a clinical and ¹⁸F-dopa PET study. Ann Neurol 41: 222-229
Hilker R et al. (2002) The striatal dopaminergic deficit is dependent on the number of mutant alleles in a family with mutations in the Parkin gene: evidence for enzymatic Parkin function in humans. Neurosci Lett 323: 50-54
Khan NL et al. (2002) Progression of nigrostriatal dysfunction in a Parkin kindred: an [¹⁸F]dopa PET and clinical study. Brain 125: 2248-2256
Scherfler C et al. (2004) Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism. Brain 127: 1332-1342
Khan NL et al. (2005) Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation. Neurology 64: 134-136
Adams JR et al. (2005) PET in LRRK2 mutations: comparison to sporadic Parkinson’s disease and evidence for presymptomatic compensation. Brain 128: 2777-2785
Stiasny-Kolster K et al. (2005) Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for α-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 128: 126-137
Imamura K et al. (2003) Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol 106: 518-526
Ouchi Y et al. (2005) Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol 57: 168-175
Gerhard A et al. (2004) Microglial activation in Parkinson’s disease—its longitudinal course and correlation with clinical parameters: an [¹¹C](R)-PK11195 PET study. Neurology 62 (Suppl 5): A432
Braak H et al. (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318: 121-134
Summerfield C et al. (2005) Structural brain changes in Parkinson disease with dementia: a voxel-based morphometry study. Arch Neurol 62: 281-285
Ramirez-Ruiz B et al. (2005) Longitudinal evaluation of cerebral morphological changes in Parkinson’s disease with and without dementia. J Neurol 252: 1345-1352
Burton EJ et al. (2005) Brain atrophy rates in Parkinson’s disease with and without dementia using serial magnetic resonance imaging. Mov Disord 20: 1571-1576
Bohnen NI et al. (1999) Motor correlates of occipital glucose hypometabolism in Parkinson’s disease without dementia. Neurology 52: 541-546
Hu MT et al. (2000) Cortical dysfunction in nondemented Parkinson’s disease patients: a combined 31P-MRS and ¹⁸FDG-PET study. Brain 123: 340-352
Klunk WE et al. (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55: 306-319
Edison P et al. (2007) Amyloid load in Lewy body dementia (LBD), Parkinson’s disease dementia (PDD) and Parkinson’s disease (PD) measured with C-11-PIB PET. Neurology 68: A98
Walker Z et al. (2007) Dementia with Lewy bodies: a comparison of clinical diagnosis, FP-CIT single photon emission computed tomography imaging and autopsy. J Neurol Neurosurg Psychiatry 78: 1176-1181
Walker Z et al. (2002) Differentiation of dementia with Lewy bodies from Alzheimer’s disease using a dopaminergic presynaptic ligand. J Neurol Neurosurg Psychiatry 73: 134-140
Walker Z et al. (2004) Striatal dopamine transporter in dementia with Lewy bodies and Parkinson disease: a comparison. Neurology 62: 1568-1572
Ito K et al. (2002) Striatal and extrastriatal dysfunction in Parkinson’s disease with dementia: a 6-[¹⁸F]fluoro-L-dopa PET study. Brain 125: 1358-1365
Rinne JO et al. (2000) Cognitive impairment and the brain dopaminergic system in Parkinson disease: [¹⁸F]fluorodopa positron emission tomographic study. Arch Neurol 57: 470-475

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Dementia and Parkinson's Disease

MRI Volumetry

Summerfield and colleagues used MRI with voxel-based morphometry to localize regional reductions in brain volume in patients who had PD with or without later dementia.^[59] They studied 16 patients with PDD, 13 patients with PD, and 13 age-matched healthy control individuals. The patients with PDD showed decreased bilateral gray matter volumes in the putamen, nucleus accumbens, hippocampus and parahippocampal regions, and in the anterior cingulate gyrus. The left thalamus was also atrophic in these individuals. Patients with PD but without dementia also showed volume decreases in the right hippocampus, the left anterior cingulate gyrus and the left superior temporal gyrus. These researchers concluded that the structural correlate of dementia in PD is hippocampal, thalamic and anterior cingulate gyrus atrophy, and that subclinical volume loss in these areas can be detected in PD. In a subsequent prospective series that involved a 2-year follow-up, Ramirez-Ruiz and co-workers noted that, in PDD, progressive volume loss occurred primarily in neocortical areas, whereas in PD it was seen primarily in limbic and temporal association areas.^[60] By use of the boundary shift integral approach, Burton and colleagues compared whole brain volume reductions over 1 year between patients with PD and those with PDD.^[61] The loss of brain volume in patients with PD (0.31% per annum) occurred at a rate comparable to that seen in healthy controls, but an increased rate, approaching that reported for AD (2% per annum), was seen in patients with PDD (1.12% per annum).^[61] These researchers concluded that MRI could be a useful tool for monitoring the progression of PDD.

Resting Brain Metabolism

In patients who have PD with frank dementia, ¹⁸FDG-PET scans show an AD-like pattern of impaired resting brain glucose utilization, with posterior parietal and temporal asso ciation areas being most affected, frontal association areas being affected to a lesser degree, and primary cortical regions, basal ganglia and cerebellum being spared.^[62] Interestingly, up to a third of patients with established PD but without dementia also show reduced parietal and temporal metabolism, but to a lesser extent than in those with frank dementia, which suggests that these patients with PD might be at risk for later dementia.^[63]

Currently, it remains unclear whether the pattern of resting glucose hypometabolism in patients who have PD with dementia reflects coincidental AD, cortical Lewy body disease, loss of cholinergic projections, or some other degenera tive process. Clinicopathological series suggest that there is considerable overlap in cortical ¹⁸FDG-PET findings between coincidental AD and cortical Lewy body disease, but that patients with cortical Lewy body disease show a greater reduction of resting glucose metabolism in the primary visual cortex.^[62] PET imaging agents that can be used to assess the amyloid-β plaque load in patients with dementia are now available (Figure 4).^[64] By use of PET with ¹¹C-Pittsburgh Compound B, a thioflavin marker of amyloid deposition, Edison and colleagues recently reported that 80% of patients with DLB but only 20% of patients with PDD have significantly raised cortical amyloid loads.^[65] This finding suggests that amyloid pathology contributes to later dementia only in a minority of PD cases.

Figure 4. (click image to zoom) PET scan with ¹¹C-Pittsburgh Compound B, a thioflavin-based marker of amyloid-β plaque load. (A) An elderly individual without Parkinson’s disease and (B) a patient who has Parkinson’s disease with late dementia both show no significant plaque deposition in the brain when compared with (C) a patient with Alzheimer’s disease in whom amyloid-β deposition is extensive. Pictures courtesy of Paul Edison.

Dopaminergic Function

In around 20% of individuals with a clinical picture of AD in the general population, the pathological diagnosis is found to be DLB, whereas many other dementia cases have mixed pathology.^[66] It is unclear whether DLB and PD represent opposite ends of a spectrum. Patients with DLB show not only cerebral cortical neuronal loss, with Lewy bodies in the surviving neurons, but also loss of nigrostriatal dopaminergic neurons. By contrast, nigral pathology is mild in AD.

Walker and colleagues examined striatal DAT binding by use of ¹²³I-FP-CIT SPECT in patients with clinically presumed DLB, patients with AD, drug-naive patients with PD, and healthy controls.^[67,68] Patients with presumed DLB or PD had significantly lower uptake of ¹²³I-FP-CIT in the caudate and putamen than did patients with AD (P <0.001) or controls (P <0.001). The authors were subsequently able to correlate their SPECT findings with 10 postmortem examinations. In all, 9 out of 10 patients with dementia were thought to have DLB in life, but only 4, all of whom had reduced striatal ¹²³I-FP-CIT uptake, had this diagnosis at autopsy. Of the 10 patients, 5 showed AD pathology—4 of these 5 individuals had normal ¹²³I-FP-CIT SPECT scans, and the fifth had concomitant vascular disease.

Walker et al. subsequently extended their postmortem series, collecting data over a 10-year period on 20 patients who had been followed up from the time of their first assessment and ¹²³I-FP-CIT SPECT scan through to death and subsequent detailed neuro pathological autopsy.^[66] Eight patients fulfilled the neuropathological diagnostic criteria for DLB and nine patients had AD; most of the patients with AD had coexisting cerebrovascular disease. The sensitivity of an initial clinical diagnosis of DLB was found to be 75% and the specificity was 42%. By contrast, the sensitivity of ¹²³I-FP-CIT SPECT for the diagnosis of DLB was 88% and the specificity was 100%. The authors concluded that DAT transporter imaging substantially enhanced the accuracy of the diagnosis of DLB compared with clinical criteria alone.

The findings from ¹⁸F-dopa PET scans have also been compared between patients who had PD with dementia and patients who had PD without dementia, but who were matched for locomotor disability.^[69] The two PD cohorts showed equivalent levels of dopamine storage capacity in the putamen, but ¹⁸F-dopa uptake in the cingulate and mesial prefrontal regions was reduced in the PDD group. Frontal ¹⁸F-dopa uptake has previously been shown to correlate with performance on executive tasks by patients who have PD without dementia.^[70]

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Page 8 of 10

Conclusions

Summary and Introduction
Lewy Body Pathology in Parkinson's Disease
Imaging Approaches
Imaging the Presynaptic Dopaminergic System
Serotonergic, Noradrenergic and Cholinergic Function
Detection of Preclinical Parkinson's Disease
Microglial Activation in Parkinson's Disease
Dementia and Parkinson's Disease
Conclusions
Key Points

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Table 1.

Table 2.

Technology Insight: Imaging Neurodegeneration in Parkinson's Disease: Dementia and Parkinson's Disease

Dementia and Parkinson's Disease

MRI Volumetry

Resting Brain Metabolism

Dopaminergic Function

Table of Contents

Table 1.

Table 2.

References

Faculty and Disclosures

Author(s)

David J Brooks, MD, DSc, FRCP, FMedSci

Editor(s)

Heather Wood

Technology Insight: Imaging Neurodegeneration in Parkinson's Disease: Dementia and Parkinson's Disease

Dementia and Parkinson's Disease

MRI Volumetry

Resting Brain Metabolism

Dopaminergic Function

Table of Contents