Genetics

Although most PD is sporadic, a few genetic causes of PD are now well characterized. These mutations including both autosomal dominant PD defects (mutations of α-synuclein SNCA [PARK1/4] and dardarin LRRK2 [PARK8]) and autosomal recessive PD defects (parkin PRKN [PARK2], PINK1 [PARK6], and DJ-1 [PARK7]).

Molecular Biology

PD is one of the synucleinopathies: the hallmark lesions contain the protein α-synuclein. The function of this protein is currently unclear, but it is expressed throughout the brain, particularly in presynaptic nerve terminals. Point mutations or triplications of α-synuclein are known genetic causes of PD. Present studies indicate that the degeneration of dopaminergic neurons involves mitochondrial dysfunction, oxidative stress, and impairment of the ubiquitin proteasomal system, all of which interact at several levels. In sporadic PD this ultimately leads to the deposition of α-synuclein and formation of Lewy bodies (although these are not necessarily found in the genetic forms of PD).

Two-Hit Hypothesis

Recent pathologic staging of PD has led to the speculation that PD is best explained by a “two hit hypothesis”: The theory runs that PD may represent a viral infection that enters the body via the olfactory neurons affecting the olfactory cortex and temporal lobe and via the intestinal tract, affecting Auerbach’s plexus and extending retrograde via vagal fibers to the dorsal vagal nucleus of the medulla. PD appears to affect the dorsal motor nucleus of the vagus and olfactory areas early in the disease and then progresses through the brain stem toward the cortex. The substantia nigra pars compacta (SNc) may become involved only at an intermediate stage of disease.

With normal aging, pigmented neurons of the SNc are lost at a rate of 4.7% per decade. In PD, 45% of SNc cells are lost in the first decade of disease, especially from the lateral ventral tier. On gross inspection, therefore, the SNc and the locus ceruleus are visibly pale to the naked eye in PD (Fig. 46-1). This cell loss leads to selective loss of dopaminergic innervation of the striatum and explains the pattern of reduced presynaptic nigrostriatal uptake seen in PET and SPECT studies (see later). Pathologic correlation remains important, because postmortem series have shown that up to 10% of those clinically diagnosed with PD during life may turn out to have an alternative diagnosis.

FIGURE 46-1 The substantia nigra. A, Macroscopic image showing the black substance (literal translation of substantia nigra) in control subject. B, Luxol fast blue stain for myelin. C, Clusters of neurons containing neuromelanin pigment. D, Macroscopic image in Parkinson’s disease showing medial preservation but lateral loss of pigment. E, Luxol fast blue stain for myelin. F, Location of remaining pigmented neurons of the SNc.

(Photography courtesy of Susan Stoneham, histological stains courtesy of Kate Strand, both of Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, London.)

The pathologic hallmarks of PD are round eosinophilic intracytoplasmic inclusions (designated Lewy bodies) and dystrophic neurites (designated Lewy neurites). Lewy bodies contain the protein α-synuclein (see Fig. 46-1).

Ultrasonography

Transcranial B-mode ultrasonography plays a significant role in the neuroimaging diagnosis of PD and its mimics. Transcranial ultrasonography may be employed successfully in approximately 90% of PD patients, although 10% of patients have temporal acoustic bone windows too small to permit study.⁶ In PD, transcranial ultrasonography characteristically shows an enlarged area of hyperechogenicity in the substantia nigra (Fig. 46-2). In normal controls, the area of substantia nigra hyperechogenicity measures about 0.12 cm². Using a cutoff value of 0.19 to 0.2 cm² to define an area of echogenicity as abnormal (1 standard deviation above the mean), transcranial ultrasonography successfully identifies approximately 90% of patients clinically classified as having PD but also 9% of healthy controls. Increasing the area value to 0.24 cm² (2 standard deviations) increases the specificity for PD but reduces the sensitivity. Notably, the healthy controls who exhibit substantia nigra hyperechogenicity do show abnormalities on functional imaging, suggesting that a positive ultrasonographic sign may indicate a real underlying pathologic process in the substantia nigra. In support of that, hyperechogenicity in the substantia nigra is found more often in cohorts of older controls (46% of 86- to 95-year-old control patients) and is associated in them with subtle extrapyramidal motor deficits.

FIGURE 46-2 Transcranial ultrasound in Parkinson’s disease. A, Hypoechogenic mesencephalon (outlined) and hyperechogenic substantia nigra (arrows). B, Second examination of the substantia nigra (outlined) shows no change in area (0.23 cm²). C, Schematic representation of ultrasound image.

(From Berg D, Merz B, Reiners K, et al. Five-year follow-up study of hyperechogenicity of the substantia nigra in Parkinson’s disease. Mov Disord 2005; 20:383-385.)

Hyperechogenicity in the substantia nigra does not correlate with clinical measures of disease severity. Most monogenetic forms of PD return a lower ultrasound signal than do sporadic, nongenetic forms of PD, although they still show significantly greater echogenicity than do controls. Patients with vascular parkinsonism do not have the characteristic substantia nigra echogenicity and instead resemble control patients. Patients with vascular PD, however, show changes in flow resistance or focal stenoses on transcranial color-coded Doppler ultrasonography, in keeping with the multiple lacunar infarcts or deep white matter abnormalities seen by neuroimaging.

Other conditions are associated with increased echogenicity in the midbrain. Nigral midbrain hyperechogenicity is found in patients with impaired nigrostriatal function unmasked by neuroleptics and in 16% of patients with essential tremor. In one transcranial ultrasound study of depressed patients, 40% had substantia nigra hyperintensity plus hypoechogenicity in the midbrain raphe nuclei. Ultrasonography can also detect differences in substantia nigra echogenicity in PD versus “atypical parkinsonian syndromes” (see later). A prospective blinded study reported a sensitivity of 90.7%, specificity of 82.4%, positive predictive value (PPV) of 92.9%, and a negative predictive value (NPV) of 77.8% for identifying patients with PD in a mixed cohort of patients that also included individuals with atypical parkinsonian syndromes.⁶

The pathologic correlate of increased substantia nigra echogenicity is not clear. It could be related to iron deposition, to H- and L-ferritin, and (inversely) to neuromelanin.⁷ However, hyperechogenicity is not seen in atypical parkinsonian syndromes or other disorders with increased midbrain iron. Furthermore, the globus pallidus is not hyperechogenic despite having a high iron content, so another process is likely to cause the ultrasound echoes.

MRI

On axial T2W MR images of the midbrain, the substantia nigra typically appears as a region of two different signal intensities: (1) a ventrally situated curved band of low signal intensity corresponding to the substantia nigra pars reticularis (SNr) and (2) a dorsally situated curved band of high signal intensity corresponding to the substantia nigra pars compacta (SNc)⁸ (Fig. 46-3). The low signal red nucleus lies dorsomedial to the pars compacta. In PD, the high signal band of the SNc appears to decrease in breadth, owing to loss of dopaminergic melanized neurons in this region and/or to increased iron deposition (and corresponding signal loss) in the surrounding structures. The distance between the SNr and the red nucleus may be reduced and the hypointensity of the SNr may appear “smudged.” PD patients may show regions of hyperintensity within the lateral SNr (i.e., zones with “restoration of the normal signal intensity”). The thickness of the high signal pars compacta shows inverse correlation with the clinical severity of PD.⁹ Overall, these changes in the substantia nigra are inconsistent and difficult to reproduce on present 1.5-T scanners. The values measured significantly overlap with controls and do not correlate well with measures of disease severity. Recently, 3-T multiple gradient-echo pulse sequences designed for rapid single-scan mapping of the proton transverse relaxation rate R₂* have successfully demonstrated changes in the lateral portion of SNc in PD, corresponding to the known topography of PD pathology.¹⁰ In the future, diverse MR techniques such as multiecho T2 and T2* at 3 T, partially refocused interleaved multiple echo (PRIME), and field-dependent increase in R₂ (FDRI) may be used to measure the increase in iron deposition in the substantia nigra in PD.

FIGURE 46-3 A, Axial T2W MR image of the midbrain showing the red nuclei and substantia nigra. Arrow indicates the T2 hypointense region corresponding to the SNr. B, Axial proton-density–weighted MR image of the midbrain. c, crus cerebri; n, substantia nigra; r, red nucleus.

(From Oikawa H, Sasaki M, Tamakawa Y, et al. The substantia nigra in Parkinson disease: proton density–weighted spin-echo and fast short inversion time inversion-recovery MR findings. AJNR Am J Neuroradiol 2002; 23:1747-1756.)

Special Procedures

Functional Imaging

The degeneration of the nigrostriatal projection can be mapped by radiotracers using positron emission tomography (PET) or single photon emission computed tomography (SPECT). Radiotracers have been developed to target both the presynaptic and the postsynaptic nigrostriatal systems^14–17 (Table 46-2). Although PET remains the gold standard, SPECT has practical advantages over PET, such as the longer half-life of SPECT ligands, which eliminates the need for an on-site cyclotron. Presynaptic targets include (1) the dopamine transporter (DAT), (2) the vesicular monoamine transporter-2 (VMAT-2) that packages dopamine into synaptic vesicles, and (3) aromatic amino acid decarboxylase (AAAD), which converts exogenous levodopa and endogenous tyramine to dopamine. Postsynaptic ligands target the dopamine D₂ receptor. Another ligand is directed against activated microglia. Regional metabolic rate can be measured using radiolabeled oxygen or glucose.

TABLE 46-2 Radiotracers Used in PET and SPECT Studies

Presynaptic Tracers

The projections of the nigrostriatal tract are arranged topographically. PD preferentially involves the ventrolateral tier of the substantia nigra, which projects to the dorsolateral striatum (putamen) and shows relative sparing of the ventral tegmental area, which projects to the ventromedial striatum (caudate nucleus). Therefore, patients with PD show greater loss of dopaminergic innervation in the putamen than in the caudate nucleus (Fig. 46-4). Typical PET and SPECT findings in PD are (1) bilateral reduction in striatal uptake of presynaptic tracers that is greatest on the side contralateral to the most severe symptoms and (2) more severe loss in the putamen than in the caudate nucleus. The measured decline in presynaptic nigrostriatal function correlates with clinical measures of disease progression. For example, early asymptomatic disease manifests as reduced uptake of ¹⁸F-dopa on the ipsilateral asymptomatic side in patients with clinical hemiparkinsonism. In families with a history of PD, radionuclide studies show reduced uptake of presynaptic nigrostriatal tracers in those members who subsequently go on to develop PD symptoms and in the asymptomatic monozygotic and dizygotic twins of patients with PD. Functional imaging successfully discriminates PD from essential tremor, wherein presynaptic nigrostriatal dysfunction is unaffected. They distinguish PD from vascular parkinsonism, wherein ¹²³I-β-CIT SPECT is normal or reduced only in accord with the vascular changes seen on MRI or CT. A vascular etiology of disease is suggested by finding reduced uptake on ¹²³I-β-SPECT and MR evidence of a discrete vascular infarct in the striatum. Demonstration of a normal radiotracer scan, indicating no presynaptic dopaminergic dysfunction, is not compatible with PD or other neurodegenerative disease affecting the nigrostriatal tract. In the correct clinical context, such findings point more toward essential tremor, psychogenic parkinsonism, drug-induced parkinsonism, or vascular parkinsonism.¹⁸

FIGURE 46-4 ¹⁸F-Dopa PET images of the striatum in a healthy control (left) and a patient with Parkinson’s disease (right) showing asymmetric loss of tracer uptake more severe in the caudal putamen than the rostral putamen or caudate nucleus.

(From Piccini P, Whone A. Functional brain imaging in the differential diagnosis of Parkinson’s disease. Lancet Neurol 2004; 3:284-290.)

Postsynaptic Tracers

Studies with ¹⁸F-dopa PET reliably discriminate between controls and parkinsonian illnesses but are less reliable for distinguishing among PD, PSP, and MSA. Patients with atypical parkinsonism, particularly PSP, show a tendency toward lower uptake of tracer in the caudate nucleus than is seen in PD and MSA.¹⁹ However, measurements of postsynaptic abnormalities in the striatum using ligands to D₂ receptors and fluorodeoxyglucose (FDG)-labeled PET to detect metabolic abnormalities reveal postsynaptic abnormalities in the putamen in MSA (evident as reduction in raclopride binding on FDG-PET), which correlate with the severity of the illness clinically.²⁰ Putaminal binding of raclopride is increased early in PD and subsequently falls, but not as much as it does in PSP and MSA. However, both PSP and MSA have similar postsynaptic abnormalities, so these two conditions are not distinguished by raclopride-binding studies.

Functional Imaging in Preclinical Disease and as a Marker of Disease Progression

PET studies of ¹⁸F-dopa uptake in the putamen estimate that the dopaminergic function of PD patients deteriorates at about 5% of the normal mean per annum. Calculations based on this estimate indicate that clinical disease begins when mean putaminal ¹⁸F-dopa uptake is about 75% of normal and that the mean period of preclinical disease is about 7 years. Both PET and SPECT have been used as surrogate markers of disease progression in randomized trials of dopamine agonists and levodopa in PD. However, discrepancies between clinical and neuroimaging end points imply that our understanding of the imaging modality is not yet accurate enough to allow us to use it as a surrogate marker for disease. Thus, the use of PET and SPECT for assessing disease progression is not currently recommended.

In the REAL-PET trial of the dopamine agonist ropinirole versus levodopa, ropinirole significantly slowed the decline in putaminal ¹⁸F-dopa uptake by 34%, although the patients on levodopa were clinically better off at 2 years.²¹ The ELLDOPA trial of levodopa versus placebo showed that, at 9 months, higher doses of levodopa are associated with better clinical outcomes but have increased rates of adverse events and increased nigrostriatal deficiency (manifest as greater ¹²³I-β-CIT SPECT loss).²² Interestingly, significant proportions of the PD subjects in these studies had normal PET or SPECT scans, both at initiation into the studies and at follow up. This group has been termed SWEDD (scans without evidence of dopaminergic deficit) and are unlikely to have PD.

Cardiac MIBG

Autonomic dysfunction is a feature of parkinsonian conditions but particularly MSA and PD. Histologic and in vivo studies show that in PD there is postganglionic autonomic failure, whereas in MSA the autonomic impairment is caused by preganglionic or central mechanisms on the whole. ¹²³I-Metaiodobenzylguanidine (MIBG) scintigraphy and SPECT can be used to interrogate postganglionic cardiac sympathetic innervation: ¹²³I-MIBG has a similar structure to norepinephrine and as such it competes for postganglionic adrenergic neuronal transport mechanisms, leading to uptake into cells, storage, and secretion in competition with norepinephrine. Thus ¹²³I-MIBG SPECT can be used to assess the localization, integrity, and function of the postganglionic noradrenergic cardiac innervation.

Static planar imaging is performed 2 to 4 hours after injection of 123I-MIBG, and a ratio of heart to mediastinal (H/M ratio) values is calculated (Fig. 46-5). This ratio compensates for interindividual variation and technical differences between sites and machines. The H/M ratio is lower in PD than MSA, PSP, and controls. All PD patients, including those with less than 2-year disease duration and without autonomic features, can be distinguished from MSA patients. All MSA patients have measurements that fall within normative value ranges, and findings are independent of autonomic function and disease duration.²³ Thus, patients with PD may have earlier cardiac autonomic impairment than is clinically evident (usually this is clinical manifest some years into the disease), although patients with greater autonomic dysfunction may have smaller H/M ratios.²⁴ However, there may be cardiac sympathetic degeneration in MSA, particularly if there are concomitant Lewy bodies, and putaminal measurements of the diffusion tensor may be better at discriminating PD and MSA-P.²⁵

FIGURE 46-5 ¹²³I-MIBG scintigraphy in multiple system atrophy and dysautonomic Parkinson’s disease. Anterior view at 2 hours after injection, with overlaid regions of interest placed in order to calculate the heart to mediastinal ratio (H/R ratio).

(From Courbon F, Brefel-Courbon C, Thalamas C, et al: Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson’s disease. Mov Disord 2003; 18:890-897.)

Ultrasonography

PSP does not show the characteristic hyperechogenicity of the substantia nigra seen in PD. However, transcranial ultrasonography does show hyperechogenicity in the lentiform nucleus in a significantly greater proportion of atypical parkinsonian syndromes than in PD.²⁶ Transcranial ultrasound measurements demonstrate that the widths of the third ventricle and the frontal horn are smaller in multisystem atrophy (8.6 ± 1.5 mm and 15.1 ± 2.3 mm) than in PSP (12.9 ± 3.7 mm and 19.3 ± 4.2 mm), respectively.²⁶

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