CHAPTER 74 Neuropathology of Movement Disorders
Movement disorders, can be divided into four major groups according to clinical phenomenology (Table 74-1); only the first two are discussed in this chapter. Most rigid-kinetic and hyperkinetic forms have their origin in dysfunction of the dorsal basal ganglia (BG), which work in tandem with the cortex via complex information circuits of the brain, although virtually the entire nervous system is engaged in motor control. Recent progress has provided insight into the anatomy, functional organization, and pathophysiologic significance of BG in specific types of movement disorders, as well as the role of different neuron subpopulations in mediating different aspects of motor control.1–9
TABLE 74-1 Clinical Classification of Movement Disorders
Functional Anatomy of Basal Ganglia
The interconnections of the nuclei of the BG are shown schematically in Figure 74-1. The three main transmitter systems involved in the integration of BG function are glutamate, γ-aminobutyric acid (GABA), and dopamine (DA).10 Normal movement is controlled by cortico-BG-thalamocortical circuits, in which the striatum receives glutamatergic input from the cerebral cortex. It sends GABAergic output to the substantia nigra reticulata (SNr) and globus pallidus (pars) interna (GPi), which release projections to specific thalamic nuclei and, to a lesser extent, to the deep layers of the superior colliculus and mesencephalic reticular formation. The respective thalamic nuclei have an excitatory glutamatergic input to specific regions of the cerebral cortex involved in motor function. In this major circuit, the GABAergic output of the substantia nigra compacta (SNc) and GPi diminishes the glutamatergic projections from the thalamus back to the cortex. Projections of the globus pallidus (pars) externa (GPe), the dopaminergic SNc, and the subthalamic nucleus (STN) remain primarily within the realm of the BG, and these nuclei modulate the main flow of information through the BG. The functional specialization of the striatum is closely related to its chemical heterogeneity along the dorsoventral and mediolateral axes.11 The topography of cortico-BG projections has led to a model of their function based on parallel and segregated pathways operating through discrete functional channels that are represented in specific regions of each BG structure, whereas others have suggested a more complicated pattern of BG connections that indicate potential complex interactions between these channels.
Corticobasal Ganglia–Thalamocortical Circuits
The BG are tightly linked to the frontal cortex and are thought to be involved not only in motor control but also in learning processes, behavior motivation, and planning.9,12 A bidirectional pattern of cortico-BG communication is differentially patterned across bands and during changes in movement.13 These circuits involve, in a sequential manner, specific parts of the prefrontal cortex, striatum, pallidonigral complex, medial and ventral thalamus, and the frontal or prefrontal cortical area. Five such BG-thalamocortical circuits have tentatively been defined: the motor and oculomotor circuits and the dorsolateral prefrontal, lateral orbitofrontal, and anterior cingulate or limbic circuits involving different parts of the striatum, the pallidonigral complex, and the medial and ventral thalamus.
The indirect pathway includes projections from the glutamatergic cortex to the striatal MSNs (containing enkephalin [ENK] and GABA and expressing the DA D2 receptor) along with sequential striatal projections to the GPe, GABAergic GPe projections to the STN, and glutamatergic STN projections to the GPi and SNr. Activation of striatal neurons in this pathway leads to inhibition of the tonically active neurons in the GPe, thereby inducing decreased inhibition (disinhibition) of the STNs and their thalamic and mesencephalic targets and causing suppression of motor and behavioral output. It is the “stop” pathway. Experimental evidence indicates that the STN is a critical component of complex networks controlling not only motor function but also emotion, cognition, and corticothalamic excitability.1,5
Balance between these two pathways at the level of the pallidum and substantia nigra (SN) appears to be crucial for normal functioning of the BG-thalamocortical circuits, and in pathologic situations (in particular in movement disorders), this equilibrium is disrupted. The circuits subserving abnormal movements in primates and humans with specific lesions may be different from those governing normal movements in intact subjects. This core model has helped explain some of the pathophysiologic mechanisms for the major movement disorders, in which there is either increased inhibition of the thalamocortical pathway, which results in hypokinetic disorders, or decreased inhibition of thalamacortical output, which results in hyperkinetic disorders. DA has opposite effects on the two pathways. The direct pathway has D1 receptors, and when DA binds to them, this pathway is activated. The indirect pathway has D2 receptors, and when DA binds to them, this pathway is inhibited. Therefore, the overall effect of DA is to decrease GPi activity, thereby promoting movement. In contrast, DA depletion, as in Parkinson’s disease (PD), leads to higher neuron activity in the output structures and consequently to inhibition of their thalamic and midbrain targets, with reduced activity in “direct” cortical-putamen-GPi projections. This model provides a reasonable explanation for the origin of the akinetic features in PD and the response to drugs and surgery.14 However, the concept of direct and indirect pathways is likely to be far too simplistic and will probably be modified as more complex organization emerges. Recent studies have led to refinement of the model and the development of a novel hypothesis for better understanding how DA regulates the BG and contributes to BG pathophysiology in PD. Although the striatum remains the main functional target of DA, it is now appreciated that there is dopaminergic involvement of the globus pallidus (GP), STN, and SN. The differential distribution of D1 and D2 receptors on neurons in the direct and indirect striatopallidal pathway has been re-emphasized, and cholinergic interneurons are recognized as an intermediary mediator of DA-mediated communication between the two pathways.15 Recently, two “hyperdirect” pathways were reported. One is a direct excitatory connection from the cortex to the STN, which has an excitatory connection to the GPi. Activity in this pathway will increase GPi activity and reduce thalamic and cortical activity.16 A new dopaminergic-thalamic system has also been uncovered that sets the stage for direct DA action on thalamocortical activity.17 Its degeneration in the monkey model of PD provides further evidence for a critical extrastriatal site whereby DA depletion could induce pathologic changes in neuronal activity and behavior.15 Another ultra-short DA pathway from SNc to SNr regulates the intensity and pattern of these BG outputs by dendritically released DA that excites SNr GABA neurons via D1-5 receptor activation enhancing active TRPC3 channels.17a Parallel processing and integrative networks probably work together rather than in conflict to allow coordinated behavior and motor control to be maintained, as well as to be modified and changed according to the appropriate external and internal stimuli, which are key deficits in BG disorders.8 A model for altered neural network dynamics related to movement disorders in PD has recently been presented.18
Classification of Movement Disorders
Most movement disorders related to BG dysfunction are neurodegenerative diseases that are morphologically characterized by neuronal degeneration and loss accompanied by astrocytosis in various, often disparate parts of the central nervous system (CNS). According to recent genetic and molecular-biologic data, movement disorders can be classified into several groups (Table 74-2).16 They may or may not be associated with cytoskeletal abnormalities, which represent important histologic signposts pointing to the diagnosis (Table 74-3). For some of these disorders, consensus criteria for their clinical and neuropathologic diagnoses have been established.19–25
TABLE 74-2 Morphologic and Biochemical Classification of Degenerative Diseases with Movement Disorders
| α-SYNUCLEINOPATHIES |
| Invariable Forms (Consistent α-Synuclein Deposition) |
TABLE 74-3 Ultrastructure, Immunohistochemistry, Biochemistry, and Distribution of Neuroglial Inclusions
Movement disorders are classified into synucleinopathies, a heterogeneous group of neurodegenerative disorders caused by misfolded α-synuclein (α-Syn) protein that forms amyloid-like filamentous inclusions in many brain areas. They include Lewy body (LB) disorders—sporadic and rare familial forms of PD (brainstem type of LB disease [LBD]), dementia with Lewy bodies (DLB), and pure autonomic failure (PAF)—multisystem atrophy (MSA), and Hallervorden-Spatz disease, renamed neurodegeneration with brain iron accumulation type I (NBIA-I) or pathothenate kinase–associated neurodegeneration (PKAN). Other major groups are tauopathies, all of which feature neurofibrillary pathology (progressive supranuclear palsy [PSP], corticobasal degeneration [CBD], and so on); polyglutamine (CAG) disorders, such as Huntington’s disease (HD) and related disorders; the recently described TDP-43 proteinopathies, such as frontotemporal lobe dementia with ubiquitin (Ub) inclusions (FTLD-U); and other neurodegenerative movement disorders without hitherto detected genetic or specific disease markers (Table 74-4). Movement disorders have additional importance in differentiating Creutzfeld-Jakob disease from Alzheimer’s dementia (AD) and DLB.26
Synucleinopathies
α-Syn is a partially unfolded, 140–amino acid presynaptic protein with potential for self-oligomerization and fibrillary aggregation under pathologic conditions. Its gene, located on chromosome 4, is mutated in rare familial forms of PD.27 For its molecular basis, functions, aggregation modes, interaction with DA metabolites, and relevant animal models, see other sources.28–31 α-Syn assembles into special oligomers and is potentially prone to misfold,32 which may lead to neuronal death,33 but other modes of toxicity have also been proposed.34 The lysosomal protease cathepsin D influences α-Syn processing, aggregation, and toxicity in vivo.35 α-Syn was demonstrated to be a major component of LBs, Lewy-related dystrophic neurites (LNs), and astroglia in PD and DLB36,37 and neuronal and glial inclusions in MSA.38 Given the fundamental nature of the α-Syn–containing lesions, these and other disorders are referred to as synucleinopathies.39 The reliability of assessment of α-Syn pathology and its dysfunction in LBD has been reviewed.29,31,40–44 α-Syn phosphorylated at serine 129 has a central role in both familial and nonfamilial forms of PD in dysregulating the DA synthesis pathway.45 Recently, elevated levels of soluble α-Syn oligomers have been detected in postmortem brains of patients with DLB.46
Akinetic-Rigid Movement Disorders—Parkinsonism
This group includes various forms of parkinsonism, tauopathies, and other hereditary degenerative disorders causing atypical parkinsonian syndromes.47 Parkinsonism describes the presence of extrayramidal movement disturbances manifested by a combination of rigidity and bradykinesia with or without resting tremor and postural instability. It has many causes (Table 74-5), with frequent clinical misclassification even if strict diagnostic criteria are used.
| COMMON CAUSES OF PARKINSONISM |
| Idiopathic Parkinson’s disease |
| Drug-induced parkinsonism |
| Multiple system atrophy |
| Dementia with Lewy bodies |
| Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) |
| UNCOMMON NEURODEGENERATIVE CAUSES OF PARKINSONISM |
| Vascular pseudoparkinsonism |
| Corticobasal degeneration |
| Alzheimer’s disease, Pick’s disease |
| Frontotemporal lobe degeneration (FTDP-17) |
| Wilson’s disease |
| Neuroacanthocytosis |
| Huntington’s disease |
| Multisystem degeneration |
| Dentatorubral-pallidoluysian atrophy |
| Lubag (X-linked dystonia-parkinsonism) |
| Dopa-responsive dystonia |
| Pallidal degenerations |
| Neuronal inclusion body and neurofilament inclusion body disease |
| SECONDARY CAUSES OF PARKINSONISM |
| Space-occupying lesions |
| Hydrocephalus (normal pressure) |
| Drugs (especially dopamine receptor blocker) |
| Toxin-induced disease (manganese, carbon monoxide, carbon disulfide, MPTP, rotenon |
| Boxer’s encephalopathy (dementia pugilistica) |
| Infections and postinfectious diseases—HIV encephalopathy, Creutzfeldt-Jakob disease, neurosyphilis, Japanese B encephalitis |
| Anoxic brain injury |
| Metabolic disorders (e.g., Wilson’s disease) |
| Basal ganglia calcification (Fahr’s syndrome, hypoparathyroidism) |
HIV, human immunodeficiency virus; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Lewy Body–Associated Disorders
The prominent cytoskeletal lesions in this group are α-Syn–positive LBs, cytoplasmic inclusions occurring in many regions of the CNS and autonomic nervous system.48,49 They are the morphologic hallmarks of PD and DLB but are also found in a variety of neurodegenerative disorders, for example, in 7% to 71% of sporadic and familial forms of AD50,51 and in 2% to 61% of aged individuals with or without dementia.52–55 The variation in the estimated prevalence of LB pathology in the older population depends mainly on case selection and the methods used for detecting LBs.53 α-Syn pathology has been encountered in autonomic nuclei, plexuses, and nerves49 and more recently in cutaneous nerves56 as an essential or coincidental feature.
Lewy Bodies
There are two types of LBs: the classic brainstem and the cortical type. Classic LBs are spherical cytoplasmic intraneuronal inclusions 8 to 30 µm in diameter with a hyaline eosinophilic core, concentric lamellar bands, and a narrow pale-stained halo. Although most LBs are single, some neurons contain multiple or polymorphic inclusions. In some brain regions, such as the dorsal motor nucleus of the vagus (DMX), similar inclusions within neuronal processes are intraneuritic LBs. They can be detected in routine histopathologic preparations and should be distinguished from LNs, which are not visible on routine histology. Ultrastructurally, classic LBs are non–membrane-bound, granulofilamentous structures composed of radially arranged, 7- to 20-nm intermediate filaments associated with electron-dense granule material and vesicular structures, with the core showing densely packed filaments and dense granular material and the periphery having radially arranged 10-nm filaments. Cortical LBs—eosinophilic, rounded, angular, or reniform structures without a halo—are more difficult to detect by routine histology. Ultrastructurally, they are poorly organized, granulofibrillary structures with a felt-like arrangement composed of 7- to 27-nm–wide filaments, mostly devoid of a central core.57 They are found in small nonpyramidal neurons in the lower cortical layers, with densest accumulation in the insular cortex, amygdala, and parahippocampal and cingulate gyri. Similar lesions—rounded areas of granular, pale-staining eosinophilic material displacing neuromelanin (NM) in brainstem neurons—are referred to as “pale bodies” and have been considered precursors of LBs.58
Both classic and cortical LBs share immunocytochemical and biochemical characteristics, the major components being α-Syn, Ub, and phosphorylated neurofilaments associated with many other substances, including parkin and synphilin-1 isoforms.22,25,59,60 LBs, the morphologic hallmark of PD and DLB, have a distinct central parkin- and Ub-positive domain with α-Syn in the periphery,61 but it is incorporated into LBs and dystrophic neurites before ubiquitination.62,63 Colocalization of α-Syn and parkin within LBs suggests that parkin plays a role in ubiquitination and posttranslational modification of α-Syn.64 The latter results in changes in protein size, structure, or charge28 (e.g., phosphorylation and nitration, both enhancing fibrillation and formation of LBs65,66). A functional Ub–3-ligase complex consisting of early-onset familial PD associated with parkin, PINK-1, and DJ-1 mutations promotes the degradation of unfolded or misfolded proteins and may be a pathogenetic mechanism for PD.67,68 Full-length leucine-rich repeat kinase 2 (LRRK2) is not a major component of the LBs and tau inclusions in AD. Proteomic analysis of cortical LBs has revealed 296 proteins related to multiple or unknown functions.69 In brainstem LBD, 90 proteins were identified that differ from those in Pick bodies, thus suggesting a complex formation process.70 Classic LBs show an initial intraneuronal appearance of dust-like particles related to NM or lipofuscin that are cross-linked to α-Syn, with homogeneous deposition of α-Syn and Ub in the center. Septin 4 (SEPT4), a polymerizing guanosine triphosphate–binding protein that serves as a scaffold for diverse molecules, has been found to colocalize with α-Syn in LBs. Because it serves as a substrate for parkin, it may play a central role in the etiopathogenesis of PD.71 In the MPTP model of parkinsonism, no Lewy pathology was seen in old monkeys.72
Cortical LBs show diffuse α-Syn and Ub labeling, whereas subcortical LBs have a distinct, central Ub-positive domain with α-Syn occurring primarily in the periphery and ubiquitination being the later event. The developmental stages of cortical LBs include granular accumulation of α-Syn in the neuronal cytoplasm initially, stepwise accumulation of dense filaments, spreading to dendrites, later deformation of LBs, and final degradation by astroglial processes.73 Extraneuronal LBs are related to death and disappearance of the involved neurons.
LBs are associated with coarse, dystrophic neurites—LNs—and also contain α-Syn and Ub as inclusions in axonal processes, which according to recent three-dimentional studies may evolve into LBs.74 They occur in many regions of the CNS and peripheral and autonomic nervous systems; absence of tyrosine hydrolase (TH) immunoreactivity suggests that many of these neuritic processes are not derived from dopaminergic neurons.
Although not all LBs contain Ub, 7% to 10% have only α-Syn, which is more widespread than Ub staining, thus making specific antibodies against α-Syn the best markers for diseases with LBs and other synucleinopathies and for differentiating LBs and LNs from negative neurofibrillary tangles (NFTs), Pick bodies, and other protein inclusions.75 Despite the presence of high Aβ affinity binding sites on α-Syn filaments, no discernible interaction of [3H]–Pittsburgh Compound B (PIB) was detected on amygdala sections from patients with PD that contained frequent α-Syn–immunoreactive LBs and LNs, thus indicating that LB pathology is unlikely to contribute significantly to the retention of PIB in positron emission tomography (PET) studies.76
Intranuclear inclusions, referred to as Marinesco bodies, are found at higher frequency in elderly individuals in the pigmented neurons of the SN and locus caeruleus (LC) that contain LBs than in those without such inclusions, and their frequency appears to have an inverse relationship with striatal concentrations of DA transporter (DAT) and TH.77
Lewy Bodies and Neuronal Cell Death
The biologic significance of these insoluble proteinaceous cytoplasmic inclusions, the mechanism of LB formation, and their impact on neurodegeneration await further elucidation. LBs, which are the sequelae of frustraneous proteolytic degradation of abnormal cytoskeletal elements, may represent—similar to other inclusions such as NFTs in AD or Pick bodies—end products or reactions to unknown neuronal degenerative processes.78 Inhibition of complex I (reduced nicotinamide adenine dinucleotide ubiquitinone oxidoreductase) may be a central cause of sporadic PD, and derangement of complex I causes aggregation of α-Syn, which contributes to the impairment in protein handling and detoxification,79 whereas mitochondrial accumulated α-Syn may interact with complex I and interfere with its functions.80 Complex I deficiency in PD brain is not confined to the SN but has also been demonstrated in the frontal cortex.81
Involvement of the Ub-proteasome system (UPS) and the autophagy-liposome pathway (ALP) suggests that LBs are structural manifestations of a cytoprotective process. Inhibition of proteasomal function or generation of misfolded proteins exceeding the degradative capacity of the UPS causes the formation of aggresomes, which are cytotoxic inclusions formed in the centrosome, or a cytoprotective response to sequester and degrade excess levels of potentially cytotoxic proteins.61,82,83 Aggresomal proteins such as β-tubulin and others have been demonstrated in LBs.84,85 There is no correlation between the density of LB formation and cell loss,86 and the comparatively low number of neurons containing LBs in any brain region would not be expected to result from altered synaptic function. Oligomerization of α-Syn at the initial stage of LB development is well documented,87 and accumulation of α-Syn oligomeres coincides with behavioral and pathologic changes, thus indicating that these oligomeres may initiate protein aggregation, disrupt cellular function, and eventually lead to neuronal death.88 Accumulation of small α-Syn aggregates at presynaptic terminals has been linked to synaptic pathology in LBD,89 a finding suggesting that PD is caused by presynaptic accumulation of α-Syn aggregates and resultant synaptic degeneration and that loss of dopaminergic neurons is rather an epiphenomenon after the loss of synapses. LRRK2 expression is found widely in the human brain and may be associated with early-age α-Syn pathology in the brainstem in PD.90 Fragmentation of the Golgi apparatus, seen in 5% of PD nigral neurons with LBs and 3% of those without LBs and in 19% of neurons containing pale bodies, suggests that the cytotoxicity of α-Syn aggregates is reduced by the process of LB formation,91 whereas SN neurons showing DNA fragmentation have no somal LBs. LBs bear similarities to some intermediate filament inclusions, such as Mallory bodies, Rosenthal fibers, and others, which have been proposed as a structural manifestation of a cytoprotective response designed to confine and eliminate damaged cellular elements.91,92a Nevertheless, significant intracellular protein aggregation, such as LB formation, is a pathologic process reflecting changes in the cellular environment that may contribute to dysfunction of the involved cells. Recent studies have shown the development of LBs in grafted neurons in individuals with PD, thus suggesting host-to-graft disease propagation.93,94 In the SN, the proportion of LB-bearing neurons appears to be stable, with 3.6% of neurons involved on average. This suggests that destruction of LBs may be equal to their production, and with the hypothesis that neuronal death is related to LBs, their life span was estimated to be around 6.2 months (15.9 months for any type of α-Syn inclusion).95 Thus, neuronal loss of 71%, necessary for the manifestation of motor symptoms, would be reached after about 20 years, which is in line with standard progression of the disease.95
Deposition of tau can be demonstrated in a proportion of LBs and is greatest in neurons vulnerable to both LB and NFT formation, such as in the LC, nucleus basalis of Meynert (NBM), and amygdala.96,97 Tau phosphorylation at Ser396 has been observed in synaptic-enriched fractions of the frontal cortex in patients with PD and DLB and in advanced stages of AD with and without amygdala LBs.98 Aβ inhibits the proteasome and enhances amyloid and tau accumulation.99 This suggests that α-Syn and tau may be related to several pathologic processes (bystander effect), which may explain the frequent overlap between synucleinopathies and tauopathies.100–102 Interactions between Aβ, α-Syn, and tau may be a molecular mechanism in the overlapping pathology of AD and PD/DLB.103,104
Sporadic Parkinson’s Disease
PD or the brainstem type of LBD, the most common neurodegenerative disorder in patients with advanced age, is manifested clinically by bradykinesia, rigidity, tremor at rest, postural imbalance, and various nonmotor features.105 Subtle cognitive dysfunction and depression are often present early in the disease,105 whereas dementia is common in later stages.106 PD is characterized by progressive degeneration of the dopaminergic nigrostriatal system and other cortical and subcortical networks associated with widespread α-Syn pathology, and the resultant striatal DA deficiency and multiple other biochemical deficits produce a heterogeneous clinical phenotype.107 Accepted clinical criteria for the diagnosis of possible and probable PD108–110 have high sensitivity but a specificity of just 75% for identifying and differentiating PD from other LBDs.111 For the diagnosis of definite PD, histopathologic confirmation is required. Although LBs are not specific to PD and occur in a variety of conditions as secondary pathology, a positive diagnosis of PD can usually be made by inspecting two unilateral sections from the midportion of the SN and finding LBs. If no LBs are found, two further sections should be examined. If LBs are not seen in either the SN or LC, the diagnosis of PD of the LB type can be excluded. In case of cell loss in the SN and LC in the absence of LBs or other α-Syn–positive inclusions, an alternative cause of parkinsonism should be pursued.22,25 Several clinicopathologic studies have shown that LBD accounts for 73% to 83% of cases of parkinsonism, including 42% to 63% of cases of PD, whereas other degenerative disorders masquerading as PD, such as DLB, MSA, or PSP, account for 9% to 33%.59 Awareness of the high rate of misdiagnosis and refinements in the clinical diagnostic criteria for PD seem to have improved the accuracy of diagnosis.109 Although data on the lesion pattern of α-Syn pathology and the multisystem degeneration in PD have provided insight into its course and the pathophysiology of its clinical subtypes, the cause and pathogenesis of PD remain unclear.112,113
Neuropathology of Parkinson’s Disease
The brain is usually grossly unremarkable or may show mild cortical atrophy, enlargement of the ventricles, and pallor of the SN and LC. Histopathologic examination reveals widespread α-Syn–immunoreactive deposits in neurons (LBs) and dystrophic neurites throughout the CNS. Recent studies have demonstrated α-Syn–positive deposits in presynaptic terminals of the cerebral cortex.89 Although PD is generally considered a disease of the CNS, LBs may also be found in sympathetic and parasympathetic neurons in PD patients, including the heart83,114 and the enteric nervous system.49 These findings have been related to gut dysmobility and cardiac disorders in many PD patients. For the distribution of LBs in PD, see other sources.25,59
Glial pathology is present in PD, with argyrophilic, α-Syn–positive, tau-negative inclusions in both oligodendroglia and astrocytes, including Bergmann glia.115–117 Ultrastructurally, they are composed of approximately 23- to 40-nm filamentous structures.118
There is variable neuronal loss in the midbrain and other subcortical nuclei, in particular the SNc, LC, and NBM: severe depletion of melanized neurons (45% to 66%) and dopaminergic neurons immunoreactive for TH (60% to 85%) in the A9 group of the SNc, particularly in the ventrolateral tier (area A, 91% to 97%) projecting to the striatum, followed by the medioventral, dorsal, and lateral areas. The susceptibility of dopaminergic neurons, among others, depends on their distribution within compartments of the SN defined by calbindin (CAB) immunoreactivity. The CAB-rich matrix is separated from the CAB-poor zones of nigrosomes, which show greater cell loss in the caudal and mediolateral region (98%) than in the adjacent matrix. From there it spreads to other nigrosomes and finally to the matrix along a caudorostral, lateromedial, and ventrodorsal progression.119 This temporospatial disorder corresponds to a somatotopic pattern of dopaminergic terminal loss that is more severe in the dorsal and caudal putamen than in the caudate nucleus (CN). The degree of A9 SNc cell loss and the resulting reduction of TH and DAT immunoreactivity in the putamen followed by the CN and nucleus accumbens show close correlation with the duration and severity of motor dysfunction.120,121 DAT immunoreactivity in the striatum is inversely correlated with the total α-Syn burden in the SN, but not with the LB count; nigral TH immunoreactivity does not correlate with α-Syn immunopositivity.122 These data support the concept of synaptic dysfunction and impairment of axonal transport by pathologic α-Syn aggregation.
A close relationship between decreased TH-negative neurons, LBs, and neuronal loss has been shown for the SN.123 The reduced intensity of DAT mRNA in the remaining SNc neurons is associated with decreased α-Syn mRNA expression in the SN and cortex with loss of the vesicular monoamine tranporter VMAT2 (a dopaminergic neuronal marker) in the striatum, orbitofrontal cortex, and amygdala, but not in the SN in the early stages of PD,124 whereas α-Syn inclusions and neuritic changes in the neostriatum increase with progression of PD.125 Akinesia and rigidity are linked to neuronal loss, but the percentage of LB-bearing and α-Syn–positive neurons in the SN is not correlated with disease duration and is apparently stable over time, with 39% of the neurons being involved on average. Such stability suggests that during the course of disease the destruction of LBs is equal to their production and that they are destroyed with the afflicted neurons.
The A10 group of dopaminergic neurons—ventral tegmental area, nucleus parabrachialis, and nucleus parabrachialis pigmentosus—projecting to the striatal matrix,126 thalamus,127 and cortical and limbic areas (mesocorticolimbic system) show less severe involvement (40% to 50% cell loss), whereas the periretrorubral A8 region, which contains only a few dopaminergic but CAB-rich neurons, and the central periventricular gray matter show little or no degeneration.128 Others have reported greater cell loss in the LC (area A6) than in the SN in both PD and AD patients.129 These changes differ from the age-related lesions in the dorsal tier of the SNc, which is involved only in the late stages of PD.130,131 Morphometric studies have shown a 35% to 41% reduction in pigmented SN cells, with severe loss of DAT-immunoreactive neurons in older persons132 and an increase in the volume of these cells.133 Some studies have estimated the loss to be 4.3% per decade,133 whereas others have reported almost 10% per decade.134 Recent morphometric stereologic studies of the human SN have revealed a significant loss of pigmented (−28.3%) and TH+ (−36.2%) neurons in older controls versus younger individuals, with hypertrophy of cells in older controls being intepreted as a compensatory mechanism to allow normal motor function despite neuronal loss. Patients with PD had a massive loss of SN neurons with significant atrophy of the remaining cells (20% of controls), but most of the patients examined were in the end stage of the disease.135
Degeneration of the nigrostriatal system causes dopaminergic denervation in the striatum progressing from the ventrorostal to the posterior putamen and CN. These changes are preceded by a preclinical phase ranging from 4.6 years for the anterior putamen to 6.6 years for the posterior putamen,136 with an annual decline of striatal DA intake of 8% to 10% and of DAT between 5.7% and 6.4% or 10% to 13%. Higher striatonigral dopaminergic neuron loss is suggested in early-onset than in late-onset PD.137 There is marked loss of DA (−89%) in the CN and more severe loss in the putamen (−98.4%), whereas DA loss in the GPi (−89%) and GPe (−51%) is not related to the pattern of putaminal DA loss.138 Reduction of striatal DA by 57% to 80%139 and DAT loss of 56% cause motor symptoms. Therefore, about 50% of dopaminergic striatal innervation appears to be sufficient for normal motor function.140 Striate DA release was reduced by 60% in PD patients, whereas frontal DA release was within the normal range, thus indicating that it remained preserved even in severe stages of disease.141 Sprouting of DA terminals and decreased DAT, which prevent the appearance of parkinsonian symptoms until about 60% loss of SN neurons takes place, also contribute to altered DA release and increased DA turnover and predispose to the occurrence of motor complications and dyskinesias as the disease progresses.142
SN cell degeneration is preceded by loss of neurofilament proteins; neuronal TH immunoreactivity; TH, DAT, and neurofilament mRNA; TH and DAT proteins; and cytochrome c oxidase—findings indicative of functional neuronal damage.143 Neuronal loss is accompanied by extracellular release of NM with uptake into macrophages, rare neuronophagia or phagocytosis of neurons by macrophages, astroglial reaction, and an increase in major histocompatibility complex class II–positive microglia, which may release proinflammatory cytokines and other substances that mediate immune reactions.144,145 Microglial reaction, together with the 35% to 80% pigmented neuronal loss reported in normal aging human SN, indicates the presence of a pathologic process that may be additive with specific age-related changes.146 Activated microglia may also be a source of trophic factors that upregulate neurotrophins in response to signals received from failing nigral neurons and may protect against reactive oxygen species and glutamate.147 Demonstration of microglial activation and corresponding dopaminergic terminal loss in the affected nigrostriatal pathology in early PD (and DLB) by PET and in the rat SN suggests that neuroinflammatory reaction contributes to the progressive degenerative process.145,148–150
Development of Lewy Body–Related Pathology
A hypothetic staging of brain pathology related to sporadic PD with ascending progression has been proposed.151–153 LB pathology may begin in the lower brainstem and involve the DMIX/DMX, intermediate reticular zone, and anterior olfactory nucleus, with the NBM and midbrain regions being preserved (stage 1), and then extend to the caudal raphe nuclei, gigantocellular reticular nucleus, and ceruleus-subceruleus complex (stage 2). These initial stages are considered asymptomatic or presymptomatic and may explain the early nonmotor (autonomic and olfactory) symptoms that precede the somatomotor dysfunctions.154,155 In stage 3, the LC, the central nucleus of the amygdala, the nuclei of the basal forebrain, and the posterolateral and posteromedial SNc are the focus of cytoskeletal changes and neuronal depletion, whereas the allocortex and isocortex are preserved. In stage 4, the anteromedial temporal limbic and neocortex and amygdala are additionally affected. Stages 3 and 4 have been correlated with clinically symptomatic stages, whereas in the terminal stages 5 and 6, the pathologic process reaches the neocortex, with the high-order sensory association cortex and prefrontal areas being affected first and later progressing to the primary sensory and motor areas or involving the entire neocortex (Fig. 74-2).
Recent studies have only partly confirmed this staging by showing that all brains of individuals with clinical PD reveal α-Syn–positive inclusions and neuronal loss in the medullary and pontine nuclei and SN and additional lesions in the NBM (90% to 98.5%), olfactory bulb (70%), limbic cortex (50% to 60%), cingulate area (32% to 46%), frontal cortex (29% to 31%), and amygdala (25%), which corresponds to LB stages 4 to 6.156 Although one study revealed significant interrater and intrarater reliability and supported the suitability of the staging procedure for application in routine neuropathology and brain banking,157 more recent studies have shown that some early PD symptoms may occur in rare patients with LB stage 2 (e.g., autonomic and bladder dysfunction, sleeping disorders, constipation, orthostatic hypotension, and depression) and more often in stage 3, in which most patients clinically manifested stiffness, asymmetric rigidity, and mild hypomimia but no tremor.153 In one study, only 6.3% of PD brains diverged from the hypothetic staging scheme of α-Syn pathology,61 whereas others revealed that between 17% and 47% of all cases of autopsy-proven PD did not follow the predicted spread of α-Syn inclusions and that in 7% to 8.3% of cases, the DMX was not involved despite definite α-Syn inclusions in the higher brainstem or even cortical regions.53,156,158,159 In contrast, in large autopsy samples, 49% to 55% of individuals with widespread α-Syn pathology were neurologically intact and lacked clinical symptoms or were not classifiable.53,160
Therefore, the predictive validity of these concepts was suggested to be doubtful because there was no relationship between Braak stage and the clinical severity of PD,161 and their relationships to coincidental other pathologies are unclear.61,62 A new unifying system for LB disorders was proposed recently that correlates with nigrostriatal degeneration, cognitive impairment, and motor dysfunction.163 Although the previous classifications left 42% to 50% of elderly individuals unclassified, all were classifiable into one of the following stages: I, olfactory bulb only; IIa, brainstem predominant; IIb, limbic predominant; III, brainstem and limbic; and IV, neocortical (Fig. 74-3). Progression of individuals through these stages was accompanied by stepwise deterioration in terms of striatal TH concentration, SN pigmented cell loss, Mini-Mental Status Examination (MMSE) score, and Unified Parkinson’s Disease Rating Scale (UPDRS) part 3. There were significant correlations between these measures and LB-type α-Syn pathology. If validated in a greater proportion of patients, the proposed staging system would improve on its predecessors by allowing classification of a greater proportion of patients.
Early brainstem cell loss in PD is mainly confined to A9 neurons in the SN and is associated with more widespread formation of LBs that rapidly infiltrate the brain, particularly in patients with short survival, whereas those with disease onset at a younger age and longer survival usually have a typical clinical course consistent with the Braak PD staging scheme, which is not consistent with the unitary concept of the pathogenesis of LB pathology.164
Incidental LB disease (iLBD) is the term used when LBs are found in the nervous system in individuals without clinically documented parkinsonism. The distribution of LBs is similar to that in PD, with one or multiple brain areas involved, and some also have sparing of LBs in the limbic or temporal cortex (average Braak PD stage of 2.7), whereas in definite PD cases, more numerous LBs are found in all regions and the Braak PD stage is significantly higher (4.4). Decreased TH immunoreactivity was shown in the striatum and epicardial nerve fibers in comparison to normal controls, but not to the same extent as in PD.165,166 These findings suggest that iLBD is probably a precursor to or a preclinical form of PD and that the lack of symptoms is due to subthreshold pathology.
Single clinicopathologic case reports suggested that random eye movement (REM) sleep behavior disorder (RBD) may represent iLBD or an early clinical manifestation of PD167 or may precede or coincide with Parkinson’s disease dementia (PDD).168
Neuronal Vulnerability
The neurodegenerative lesions in PD show a selective vulnerability of SN neurons rich in NM and caspase-3, which have high expression of DAT mRNA, unrelated to their intrinsic capacity for DA synthesis.143 The majority of midbrain neurons severely affected in PD are melanized cells located in the densely packed ventral tier of the SNc; they contain CAB and glycolytic enzymes but are poor in DAT and arborize profusely in the extrastriatal components of the BG and sparsely in the striatum. Dopaminergic neurogenesis, intracellular and extracellular substances, and interactions among these factors have been discussed as essential causes of selective death of dopaminergic neurons in PD.169 The susceptibility of nigral dopaminergic neurons may further lie within the transcription profile of these cell populations.170 Neurons in the STN and GABAergic cells in the SNr, rich in calcium-binding proteins (calcineurin and parvalbumin) are either not affected or involved only in the terminal stages of PD. A close relationship among SN cell loss, α-Syn accumulation, and decreased TH immunoreactivity was seen, whereas the majority of pigmented SN but not LC neurons bearing α-Syn aggregates lacked TH reactivity, which leads to a decrease in cytotoxic α-Syn oligomeres. The decreased TH immunoreactivity in pigmented neurons can be considered a cytoprotective mechanism in PD,123 but it can also be preserved in neurons with early α-Syn accumulation.122
In the midbrain A9 area, the region of greatest vulnerability in PD, intracellular NM lipid changes, increased concentrations of α-Syn, and interactions with increased iron make dopaminergic nigral neurons susceptible to oxidative stress.171–175 Dysfunction of the BG circuitry in PD may affect the iron content not only in the SN but also in other BG as well.176 In the later stages of degeneration, SN neurons show a significant reduction in intracellular pigment, whereas those of normal morphologic appearance exhibit increased pigment density associated with an increased concentration of α-Syn with respect to its lipid component and loss of cholesterol. No such changes were observed in other NM-containing neurons in the A2, A6, and A10 areas in early PD, which emphasizes the selectivity of the early NM changes in A9 neurons.20
Symptom-Related Specific Lesion Patterns in Parkinson’s Disease
The major clinical subtypes of PD show specific morphologic patterns of pathophysiologic importance.
In the rigid-akinetic type, which occurs in about 50% of all patients, the ventrolateral SNc projecting to the dorsal putamen degenerates more severely than the medial parts projecting to the CN and anterior putamen. There is ventromedial gradient loss of TH- and DAT-immunoreactive fibers and endings from the dorsal to the ventral putamen, with prominent involvement of the met-ENK and SP-rich acetylcholinesterase-poor striosomes of the putamen projecting to the severely involved ventrolateral SNc. DA loss in the GPe and GPi does not match the more severe DA loss in the putamen.138 Preservation of the CAB-positive somatostatin-rich matrix, which shows increased somatostatin mRNA expression and projects to the GABAergic neurons of the SNr and motor thalamus, suggests that the endings richest in DAT are most sensitive to degeneration.177 Dopaminergic denervation of the striatum causes severe loss of dendrites on type I MSNs, the principal targets of dopaminergic input from the SN,178 and loss of convergent nigrostriatal DA and corticostriatal glutamate axon integrity, and the abundant α-Syn pathology in the neostriatum,125,179 dystrophic neurites in the CN, progressive loss of TH- and DAT-immunoreactive nigrostriatal fibers, and reduced met-ENK immunostaining suggest transsynaptic degeneration as a substrate for the severe motor deficits and decreased efficacy of DA-mimetic treatment in the late stages.180,181 Reduced dopaminergic input to the putamen causes increased activity of the GABAergic indirect striatal efferent loop via the SNr and GPi to the ventrolateral thalamus projecting to the cortex (Fig. 74-4; also see Fig. 74-1). Excessive excitatory glutamatergic drive from the STN and Gpi/SNr leads to an akinetic-rigid syndrome through reduced cortical activation. The increased GABAergic activity is reduced by levodopa treatment and disappears in the course of the disease, and changes in N-methyl-D-aspartate (NMDA) receptors and glutamatergic synapses may be generated, events favoring drug resistence and motor complications.182,183 Free endogenous DA may induce a relative hyperstimulation of dopaminergic receptors, which may account for the develoment of motor fluctuations and dyskinesias after levodopa treatment (see Fig. 74-4); it has also been related to increased pro-ENK mRNA levels in the striatum.184,185 Dyskinesia is critically related to the levodopa dosage via loss of synaptic depotentiation.186
