The Parkinson's-Reversing Breakthrough

Parkinson Disease Manual

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Illustration of the rationale of diagnostic imaging in PD requires a brief description of the pathological and consequent functional changes induced by the disease. Idiopathic PD is a degenerative disorder characterized by progressive and focal loss of the dopaminergic neurons of substantia nigra (SN), or pars compacta. Their depletion induces functional changes in the circuit of the basal ganglia (dopaminergic deafferentation), whose activity is modulated by SN, and eventually functional deafferentation of frontostriatal circuits [2]. The anatomical and functional changes induced by PD can be represented as a three-level system: (1) mesencephalic (neuroaxonal degeneration); (2) basal ganglia (dopaminergic deafferentation); and (3) cortical (functional deafferentation) (Fig. 16.1).

Dysfunction Striato-frontal

Dysfunction Striato-frontal

Dopaminergic deafferentation

Level I: Substantia Nigra

Loss of dopaminergic neurons

Fig. 16.1. Representation of the anatomical and functional changes of PD. The changes are observed at three levels: I mesencephalic (EPI diffusion-weighted image); II basal ganglia (spin-echo T2-weighted image); III cortical (functional MR, motor task)

Dopaminergic deafferentation

Level I: Substantia Nigra

Loss of dopaminergic neurons

Fig. 16.1. Representation of the anatomical and functional changes of PD. The changes are observed at three levels: I mesencephalic (EPI diffusion-weighted image); II basal ganglia (spin-echo T2-weighted image); III cortical (functional MR, motor task)

At each of these three levels MR can further and significantly contribute to evidencing the anatomical and functional changes induced by PD.

MR imaging is particularly difficult in PD patients owing to the technical limitations of the scanners due to the intrinsic characteristics and the reduced size of the structures involved. As regards the former, the high in-tracellular iron content of SN dopaminergic neurons, which is an essential element of their metabolic processes [31], helps to enhance the contrast between the structures and surrounding tissue. However, the iron deposits also play a significant role in the cascade of events that lead to apoptotic cell death [32]. With regard to the small size of the structures, the mesencephalon contains important bundles of ascending and descending myelin fibres, nuclear structures such as red nuclei and the third pair of cranial nerves, SN and reticular substance. In normal individuals, SN usually measures a few square millimetres, emphasizing the crucial importance of spatial resolution for its precise quantification.

Data obtained using low-, medium- and high-field MR are presented below in relation to each anatomical and functional level involved in PD and the potential of 3.0 T MR imaging is illustrated.

Mesencephalic Level

Low- and Medium-Field MR

The mesencephalon, in particular SN, is the area where focal neuronal degeneration electively takes place. Several acquisition techniques have been applied using low- and medium-field magnets to try and define the parameters for the identification and quantification of SN. These studies, performed in a small number of patients, have demonstrated that identification of the borders and dimension of SN is difficult in healthy as well as PD subjects. These modest results have discouraged large-scale application of such methods in clinical practice, but have had the merit of demonstrating that the integrated use of multiple acquisition techniques capable of enhancing and showing the different mesen-cephalic component structures is essential to identify and quantify SN.

Hutchinson et al. [12, 13] used T1-weighted inversion recovery with two different inversion times to suppress the mesencephalic white and grey matter signal, respectively. The ratio of the signals obtained with the two inversion times allowed the quantification of SN in healthy subjects and the assessment of focal neuron loss in PD patients. Being based on a semiautomatic method, these investigations, which were performed in a small number of subjects and patients, have proved difficult to reproduce. Hu et al. [10] demonstrated that positron emission tomography (PET) with (18)F-dopa was more effective than MR with inversion recovery in discriminating patients with PD from controls in only 83 % of cases.

Oikawa et al. [17], using dual-echo spin-echo and short inversion time inversion recovery sequences, failed to show significant differences in SN dimension between PD patients and control subjects. Other studies have been unable to find significant differences in SN volume using diffusion-weighted (DWI) sequences [1,26]. Finally, indices of SN neuron depletion were calculated in healthy and PD individuals using magnetization transfer ratio (MTR), an MR parameter that is based on the energy transfer from protons bound to macromolecular structures like myelin to free-water protons [7]; other researchers have proposed using the measurement of brain iron by means of T2* maps obtained using gradient-echo sequences [4, 8].

Due to their spatial resolution, these low- and medium-field MR studies have demonstrated limited accuracy in SN evaluation. The slice thickness used was 3-4 mm, which is insufficient to measure the modest quantitative differences induced by the loss of dopami-nergic neurons. High-Field MR

One of the main advantages of high-field MR is its high spatial resolution and consequent greater and more accurate anatomical definition. In addition, magnetic susceptibility artefacts due to the iron selectively deposited in SN are enhanced by the higher magnetic field. Spin-echo sequences allow the acquisition of proton density- and T2-weighted images with 0.9 x 0.9 x 2 mm3 voxels in a few minutes (Fig. 16.2) and the quantification of iron deposits using relaxometry, a technique that greatly benefits from the high magnetic field.

The nigrostriatal degeneration characteristic of PD induces a change in functional connectivity between SN and basal nuclei. This change is held to be associated with a reduction in anatomical connectivity. Fibre tracking techniques allow the reconstruction of the course of axon bundles on DWI images by estimating the preferential direction of the diffusion of water molecules. The fibre tracking technique benefits from a high signal-to-noise ratio (SNR) and therefore from high field intensities (Fig. 16.3). Use of this method, which shows considerable potential in the study of connectivity among brain regions, is limited in the mesen-cephalon by its scarce sensitivity to the minimum deviations of fibre bundles that are found in PD and by susceptibility artefacts induced by the anatomical area, which is adjacent to the air-filled cavities of the splan-chnocranium and petrous bones.

Fig. 16.3. Nigrostriatal tractography. Tractographic images are superimposed on EPI T2-weighted slices (Siemens Allegra, 3.0 T)

Due to their technical characteristics, 3.0 T MR im-agers are thus a promising tool to assess the neuronal and axonal depletion that characterizes PD.

Basal Ganglia Level

Low- and Medium-Field MR

Since PD induces nigrostriatal axon degeneration, do-paminergic deafferentation and pre- and postsynaptic disruption of the basal ganglia, the latter do not undergo neuron depletion but synaptic and metabolic alterations. At this level, nuclear medicine-based techniques such as PET and single photon emission tomography (SPECT) employed with specific tracers selectively binding to pre- or postsynaptic dopaminergic receptors have demonstrated their progressive loss, which is related to disease severity [5].

As regards MR, studies of the basal ganglia (globus pallidus, caudatus and putamen) based on morphological evaluation, size, and metabolic parameters such as iron deposition, have yielded contradictory results. Quantification of the iron deposits, which provides a metabolic index of the pre- and postsynaptic disruption of the basal ganglia, has until now been the main goal of the largest number of studies of PD (see [32] for a review). In MR, the presence of iron in brain parenchyma induces a reduction in transverse relaxation times that can be measured on T2- and T2*-weighted sequences. When comparing PD patients with a control group, this reduction was mainly observed at the level of globus pallidus [4, 30] and putamen [3,4, 30]. However, Graham et al. observed increased putaminal transverse relaxation times induced by the reduction in iron content in patients with PD [8, 22]. In a recent study, Kosta et al. confirmed these data by demonstrating an increase in T2 transverse relaxation times in globus pallidus and putamen. In patients who have had the disease for more than 5 years the putaminal surface was also increased compared with patients with a shorter disease duration, presumably reflecting gliotic neuro-reparative phenomena [15].

MR diffusion techniques have been applied to assess subcortical neurodegenerative disorders such as PD and multisystem atrophy (MSA). Schocke et al. showed that analysis of the apparent diffusion coefficient (ADC) in the basal ganglia allowed PD patients to be distinguished from MSA patients [25] based on a greater ADC - an indirect measure of neuronal depletion and of associated reactive gliosis - in the putamen of the latter [25-27]. Seppi et al. documented an ADC increment in globus pallidus and putamen in patients with progressive supranuclear paralysis (PSP) compared with PD patients [28]. MR diffusion techniques are thus effective in discriminating PD from other subcortical diseases (MSA, PSP), but are unable to differentiate PD patients from control subjects of comparable age without neurological disorders [26, 27].

Magnetization transfer imaging (MTI), or the study of MTR maps, is another technique capable of quantifying the degree of myelination [19] and has been used by Eckert et al. to assess neuronal depletion in basal ganglia [7]. The authors observed significant differences in globus pallidus between PD patients and control subjects in 75-80% of cases. This technique has not been further applied to PD, and these data have not been reproduced in other studies.

The main investigations into basal ganglia dopami-nergic deafferentation in PD have used various MR techniques with contrasting results. None of the methods used at low and medium fields can reliably differentiate PD patients from control subjects. High-Field MR

There are no available studies of the effects of dopami-nergic deafferentation on the basal ganglia circuit. Also with reference to these structures, however, measurement of the iron deposits should benefit from the advantages of high magnetic fields (Fig. 16.4). Compared with SN, where iron deposition is characteristic of the physiological activity of dopaminergic neurons [8,15], in the basal ganglia these deposits are an indirect parameter of the neuronal metabolic changes induced by dopaminergic deafferentation.

Fig. 16.4. Relaxometry using GE with different echo times [6,12, 20,30, 45, 60]

Also in this area, DWI sequences allow the estimation of local axonal depletion and provide the data required to track SN dopaminergic fibres, as recently proposed in medium-field MR studies [16]. Also at this level, tractographic techniques suffer from scarce spatial resolution and from susceptibility artefacts induced by surrounding structures and by the iron deposits themselves, which reflect disease progression.

Cortical Level

Low- and Medium-Field MR

As illustrated above, the prefrontal cortical changes induced by PD are essentially functional and are a consequence of dopaminergic deafferentation in the basal ganglia. The altered cortical activity, i.e. the functional deafferentation due to the dysfunction of striatofrontal circuits, would be the cause of the motor and cognitive deficits characteristic of PD. The classic scheme of Alexander et al. describes the different parallel, independent and recurrent striatofrontal circuits connecting specific prefrontal cortical areas with specific striatal and pallidal regions [2]. Evidence of dementia-like cognitive deterioration in some PD patients in the course of disease suggests that the functional changes in the striatocortical circuits progress towards brain atrophy. The recent introduction of cerebral cortex quantification techniques (voxel-based morphometry) using volumetric acquisitions has not provided univocal data in PD patients in terms of factors predictive of dementia. For instance, some researchers have observed a reduction in the volume of the frontal cortex [6] and others of the hippocampal cortex, superior temporal gyrus and cingulum in non-demented PD patients [29]. MR morphological studies of the cortex are therefore scarcely informative in this disorder, whereas functional investigations using PET, SPECT and functional MR imaging (fMRI) have confirmed the hypothesis of motor and cognitive cortical functional deafferentation.

The early fMRI studies of patients with PD performing a simple motor task have clearly demonstrated reduced activation (reflected in reduced regional cerebral blood flow) at the level of the main cortical regions that receive afferents from the basal ganglia: supplementary motor area (SMA) [14,18,20,21], dorsolateral prefrontal cortex [14,18, 24] and anterior cingulate gyrus [14, 18]. In the same patients, other cortical areas, functionally related to the former, exhibited increased activation: primary sensorimotor, lateral premotor, and parietal cortex [18]. It has been demonstrated that reduction in SMA activity is sensitive to dopaminergic drugs in that it is detected in PD patients not receiving treatment and regresses with therapy administered in the acute phase [20], whereas it is not observed in those receiving chronic dopaminergic treatment [21]. In the first fMRI study of PD patients [23], the authors documented a complex cortical activation during a motor task, confirming on the one hand the results obtained with nuclear medicine techniques [18, 20] showing reduced activation of the rostral portion of SMA, and on the other evidencing increased activation in the caudal portion of SMA, anterior cingulum and primary senso-rimotor cortex and parietal cortical areas. This pattern of cortical activation was reversible with administration of L-dopa both at the level of the rostral SMA and of the other cortical areas, such as primary sensorimotor cortex, lateral premotor and parietal cortex [9].

Overall, these studies have demonstrated the hypothesis of reversible functional deafferentation induced by altered striatal modulation in prefrontal cortical area; this in turn is associated with a complex pattern of cortical activation with reorganization of the areas involved in the planning and execution of movements. High-Field MR

High-field MR has opened up new prospects for the study of the functioning of striatofrontal circuits in PD. On the one hand, fMRI with EPI sequences affords greater spatial and temporal resolution (e.g. 38 slices 2 mm in thickness are acquired in 2.4 s). This enables cortical activation during simple or complex motor tasks to be studied more easily in PD patients (Fig. 16.5). In addition, fMRI data can be correlated to structural studies using dedicated protocols both at the level of the mesencephalon and of the basal ganglia (Fig. 16.5). Identification of activated cortical areas during fMRI can allow the course of corticostriatal circuit fibres to be tracked and their possible depletion in PD to be quantified. Other techniques for the quantification of the extent of deafferentation, like relaxometry and MR spectroscopy, can exploit the better SNR afforded by 3.0 T fields.

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