Neuropathology of Movement Disorders

Cortico–Basal Ganglia–Thalamocortical Circuits

Current concepts about the organization of the basal ganglia emphasize the existence of “internal” mechanisms that modulate input/output activity and sustain normal execution of movements. A bidirectional cortico-BG communication is differentially patterned across bands and during changes in movement. These circuits involve, in a sequential manner, specific parts of the prefrontal cortex, striatum, pallidonigral complex, and medial and ventral thalamus. Five such basal ganglia (BG)–thalamocortical circuits have been defined, forming a topographically organized integrated functional network: motor and oculomotor circuits, dorsolateral prefrontal circuits, lateral orbitofrontal circuits, and anterior cingulate or limbic circuits involving different parts of the striatum, pallidonigral complex, and thalamus.

A nigrostriatal circuit in which the SNc receives a GABAergic inhibitory projection from the striatum feeds back to the striatum with a modulating dopaminergic input; it provides the major source of dopaminergic innervation of the striatum. The retrorubral field (A8) and ventral tegmental area (VTA; A10) also participate in the mesostriatal and mesolimbic dopaminergic projections. Dopamine causes excitation of striatal neurons that project to the GPi and SNr (by dopamine ₁ [D ₁ ] receptors) and inhibits thalamic nuclei to maintain normal movements. Dopamine also inhibits neurons that project to the GPe or STN (by dopamine ₂ [D ₂ ] receptors) to check the normal negative effect on motor speed and tone associated with high output from the STN. Its outputs project to the GPi, SNr, GPe, striatum, and pedunculopontine nucleus (PPN). Dopamine, an important modulator of basal ganglia function, may also modulate it outside of the striatum, and these changes contribute to the symptoms of Parkinson disease (PD) and other disorders. The GPe receives GABAergic input from the striatum and sends glutamatergic projections to the STN, which in turn sends glutamatergic projections to the SNr, GPi, and GPe to inhibit glutamatergic excitation of the cortex. The STN-GPe system is considered a central pacemaker of the basal ganglia as a major input relay station receiving projections from various cortical and subcortical regions, including the hyperdirect cortico-subthalamo-GPi pathway, ^, with implications for their (dys)function.

Activity of basal ganglia output structures is controlled by two opposing striatal motor loops, originating from distinct populations of medium spiny projection neurons (MSNs) and projecting to different output structures. The striatal projecting neurons in the “direct” pathway express dopamine D ₁ receptors, whereas D ₂ -bearing neurons project to the globus pallidus and are part of the “indirect” pathway. The two receptors are associated with distinct G proteins and different intracellular signal pathways that support the dichotomous effect of their activation.

The direct pathway is a monosynaptic inhibitory projection from the glutamatergic cortex to the MSNs, which contains GABA, substance P, and dynorphin and expresses the dopamine D ₁ receptor projecting to GABAergic neurons in the GPi and SNr. Activation of striatal MSNs leads to inhibition of the inhibitory GPi/SNr output and to disinhibition of basal ganglia target structures in the thalamus and midbrain. This facilitates thalamocortical activity and thereby promotes movement and behavior.

The indirect pathway includes isopolysynaptic disinhibitory projections from the glutamatergic cortex to striatal MSNs (containing enkephalin and GABA and expressing the dopamine D ₂ 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 leads to inhibition of GPe neurons, thereby reducing inhibition of the STN and its thalamic and mesencephalic targets, causing suppression of motor and behavioral output resulting in inhibition of movements. A signal through the indirect pathway (cortex-striatum-GPe-STN-GPi) terminates the movement. The SNr is an inhibitory GABAergic nucleus that works in conjunction with the GPi as the final output of the basal ganglia’s direct and indirect pathways. Excitatory glutamatergic drive of STN neurons along the corticosubthalamic pathway triggers GABAergic inhibition of pallidothalamic inputs. The STN is a critical component of complex networks controlling not only motor function but also emotion and cognition.

Balance between these two pathways at the level of the globus pallidus and substantia nigra is crucial for normal functioning of the BG-thalamocortical circuits, and in pathologic situations this equilibrium is disrupted. This core model explains some of the mechanisms for the major movement disorders, in which there is either increased inhibition of the thalamocortical pathway, resulting in hypokinetic disorders, or decreased inhibition of thalamocortical output, which induces hyperkinetic disorders. ^, The function of these networks is modulated by the release of dopamine in the striatum. When dopamine binds to D ₂ receptors, the indirect pathway is inhibited to decrease GPi activity, thereby promoting movement. In contrast, dopamine depletion, as in PD, leads to an increase in basal ganglia output that inhibits their thalamic and midbrain targets, with reduced activity in the “direct” striatocortical-nigral-GPi projections, inducing the akinetic features in PD, ^, although abnormalities outside the motor and dopaminergic pathways may be associated with akinesia. Recent concepts explain how dopamine exerts modulatory signals on cortico-BG circuits to enable flexible motor and behavior control. There is differential distribution of D ₁ and D ₂ receptors on neurons in the striatopallidal pathways, and cholinergic interneurons acts as mediator of dopamine-mediated communication between the two pathways. ^{, ,} They are not separate parallel systems, but are structurally and functionally intertwined inside and outside the striatum, where basal ganglia collaterals may bridge the two pathways. ^, According to other models, they are not alternatively but concomitantly active, and the pattern of coordinated activity across the two pathways regulates movement initiation and execution.

Two “hyperdirect” pathways include a direct excitatory connection from the cortex to the STN, which has an excitatory connection to the GPi. Activation in this corticosubthalamic-pallidal pathway will increase GPi activity and inhibit thalamocortical targets by the action of the indirect pathway, causing suppression of all movements. The thalamostriatal system is a dual system, with one projection originating from midline and intralaminar nuclei and another one arising from ventral and relay nuclei using glutamate transporters. The reciprocity between basal ganglia structures is established by expanded circuitry of the GPe, which projects to the STN, and sends direct collaterals to the GPi and SNr and feedback projections to the striatum. The midbrain locomotor region, crucial for normal gait and posture, encompasses the cholinergic PPN that is interconnected with basal ganglia and delays basal ganglia activity to thalamic and brainstem nuclei, spinal effectors, and cerebellum, indicating their role in motor and cognitive control. Loss of the modulatory influence of STN on intracerebellar connectivity in PD may contribute to pathologic activities within the cerebellum.

Classification of Movement Disorders

Most movement disorders related to basal ganglia dysfunction are neurodegenerative diseases morphologically characterized by neuronal degeneration and loss accompanied by astrocytosis in various, often disparate parts of the nervous system. Conventional classification, based on pathophysiologic mechanisms involving the basal ganglia, distinguishes several movement disorders (see Box 104.1 ): (1) parkinsonian syndromes, characterized by rigidity, akinesia/bradykinesia, resting tremor, and postural instability; (2) chorea, in which fragments of movements flow irregularly from one body segment to another, to cause a dance-like appearance; (3) dystonia, characterized by prolonged muscle spasms and abnormal posture; (4) ballism, featuring high-amplitude movements of the proximal extremities; (5) myoclonus, with brief, quick movements; and (6) athetosis, which can be considered a “slow chorea” with lower amplitude.

Based on recent genetic and molecular-biologic data, movement disorders are classified into several groups ( Table 104.1 ). They are associated with cytoskeletal abnormalities, which represent important histologic signposts pointing to the diagnosis (see Box 104.1 ). Consensus criteria for their clinical and neuropathologic diagnoses have been established for most of these disorders.

Movement disorders are also classified into morphologic and biochemical groups ( Box 104.2 ). The α-synucleinopathies are a heterogeneous group of neurodegenerative disorders caused by misfolded α-synuclein (αSyn) protein that forms amyloid-like filamentous inclusions. ^, They include Lewy body (LB) disorders—sporadic and rare familial forms of PD (brainstem type of Lewy body disease [LBD]), dementia with Lewy bodies (DLB), and pure autonomic failure—multiple system atrophy (MSA), and neurodegeneration with brain iron accumulation type 1 (NBIA 1) or pantothenate kinase–associated neurodegeneration (PKAN). Other major groups are tauopathies, featured by neurofibrillary tau pathology (progressive supranuclear palsy [PSP], corticobasal degeneration [CBD], frontotemporal lobe degeneration with tau pathology [FTLD-tau]); polyglutamine disorders linked to cytosine-adenine-guanine (CAG) trinucleotide repeats, such as Huntington disease (HD); and those associated with neuronal antibodies, paraneoplastic forms, or those without hitherto detected genetic or specific disease markers. The various phenotypes are related to the deposition of pathologic (misfolded) proteins in distinct brain areas and neuron populations. ^,

Lewy Bodies

LBs occur in two types: the classical brainstem type and the cortical type. Classical 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. Some brain regions, such as the dorsal motor nucleus of the vagus nerve (dmX), contain intraneuritic LBs. Ultrastructurally, classical 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 ultrastructurally poorly organized, granulofibrillary structures with a felt-like arrangement composed of 7- to 27-nm-wide filaments. They are found in small nonpyramidal neurons in lower cortical layers, with accumulation in the insular and entorhinal cortex, amygdala, hippocampal sector CA2/3, and cingulate gyri. ^, Similar rounded areas of granular, pale-staining eosinophilic material displacing neuromelanin in brainstem neurons (“pale bodies”) are precursors of LBs. αSyn is the best marker to decorate LBs and LNs, selectively detected by antibodies that recognize N-terminal epitopes (synucleins 505, 506, and 514).

Both types of LBs share immuno- and biochemical characteristics. ^{, ,} The major components are αSyn, ubiquitin, and phosphorylated ubiquitin associated with many other substances: structural fibrillary elements; αSyn-binding proteins; proteins implicated in the ubiquitin-proteasome system; synphilin-1; aggresome- and mitochondria-related proteins; cytoskeletal, cytosolic, and cellular response proteins; and others. ^, LBs have a central parkin- and ubiquitin-positive domain with αSyn in the periphery. Colocalization of αSyn, synphilin, and parkin within LBs suggests that parkin plays a role in ubiquitination of αSyn, its oligomers inducing parkin nitrosylation. Synapsin III, a key component of αSyn fibrils, tyrosine hydoxylase (TH), and choline acetyltransferase (ChAT) are colocalized in cortical LBs. Brainstem LBs have TH and ChAT reactivity in the core, surrounded by a peripheral rim of αSyn. LBs and pale bodies are reactive for autophagic proteins p62 and NBR1, ^, and for the TIGAR protein that regulates tumor protein 53, which is absent in MSA inclusions. They contain 14-3-3 proteins that interact with αSyn, are involved in signal transduction pathways, and have multiple cellular functions. Leucine-rich repeat kinase 2 (LRRK2) is not a major component of LBs. αSyn aggregates in LBs are refractory to clearance and degradation. Purified inclusions contain approximately 50 isoforms of αSyn, including multiple truncated species. Regional levels of physiologic αSyn were directly associated with LB-related pathology (LBP). Proteomic analysis of cortical LBs has revealed 296 proteins related to multiple or unknown functions and 204 proteins in the brainstem of patients with PD, suggesting a complex formation process.

The formation of LBs runs through several stages. Classical LBs show an initial intraneuronal appearance of dust-like particles related to neuromelanin or lipofuscin that are cross-linked to αSyn, with homogeneous deposition of αSyn and ubiquitin in the center, showing diffuse, pale or fine granular cytoplasmic staining. The next step is condensation of dense filamentous inclusions, forming “early LBs” that later develop into classical LBs. Extraneuronal LBs, after disappearance of the involved neuron, are degraded by astroglia.

Cortical LBs show diffuse αSyn and ubiquitin labeling, whereas subcortical LBs have a distinct, central ubiquitin-positive domain with αSyn occurring in the periphery. Initial granular accumulation of αSyn in the neuronal cytoplasm is followed by stepwise accumulation of dense filaments, spreading to dendrites, later deformation of LBs, and final degradation by astrocytes.

LBs are associated with coarse LNs that also contain αSyn and ubiquitin as inclusions in axonal processes, which may evolve into LBs with ubiquitin at the core and neurofilaments at the outermost layer. LBs and LNs occur in virtually all brainstem nuclei and fiber tracts, with significant correlations between LBs and LNs, and LBs and coiled bodies, in both PD and DLB.

Intranuclear inclusions, referred to as Marinesco bodies, are frequently found in elderly individuals in pigmented neurons of the substantia nigra and locus ceruleus that contain LBs, and their frequency appears to have an inverse relationship with striatal concentrations of dopamine transporter (DAT) and TH. Their frequency decreases as duration of PD increases.

Pathobiologic Role of Lewy Bodies

The biologic significance of LBs and their impact on neurodegeneration are poorly understood. As sequelae of frustraneous proteolytic degradation of abnormal cytoskeletal elements, they represent—similar to other inclusions such as neurofibrillary tangles (NFTs) or Pick bodies—end products or epiphenomena of unknown responses to cellular stress. Inhibition of complex I (reduced nicotinamide adenine dinucleotide ubiquitinone oxidoreductase) causes aggregation of αSyn due to impairment in protein handling and detoxification, whereas mitochondrial accumulated αSyn may interfere with complex I function. Small αSyn intermediates termed soluble oligomers lead to synaptic dysfunction, whereas insoluble aggregates may function as reservoirs for bioactive oligomers. Oligomerization of αSyn in the initial state of PD ^, may induce protein aggregation, disrupt cellular function, and lead to neuronal death due to mitochondrial energy deficit and oxidative stress. ^{, , ,}

The ubiquitin-proteasome system and the autophagy-liposome pathway that render damaged proteins less toxic than their soluble forms contribute to αSyn turnover, while alterations in these proteolytic pathways result in αSyn accumulation due to impaired clearance. The degree of the mitophagy marker phospho-ubiquitin increased in the early but decreased in late stages of LB or tangle aggregation, indicating mitochondrial damage. Proteinaceous inclusions also form as a consequence of fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their protein contents. Ubiquitinated proteins in LBs may be a manifestation of a cytoprotective response in order to eliminate damaged cellular components and to delay the onset of neuronal degeneration. LBs also interact with DNA to cause nuclear degeneration as a major cause of cell death. Mitochondrial DNA deletion was highest in LB-positive neurons, suggesting increased mitochondrial damage, whereas accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms. ^{, ,} LBP is direct evidence of αSyn misfolding, but it is not yet clear whether LBs are an indicator of toxicity or neuronal protection. ^{, ,}

The uptake and clearance of misfolded/aggregated αSyn, reciprocally regulated by SUMOylation and ubiquitination, is a key process to control extracellular deposition of αSyn aggregates. All main brain cell types are able to internalize and degrade extracellular αSyn, but glial cells appear to be the most efficient scavengers. Impairment of clearance leads to accumulation of toxic species and dysfunctions of glia. αSyn-reactive astrocytes, the distribution of which parallels the spread of neuronal pathology in PD, ^, may be involved in the progressive neurodegeneration.

Sporadic Parkinson Disease

PD or the brainstem type of LBD, the most frequent neurodegenerative movement disorder (prevalence of 100 to 572 per 100,000; incidence of 4.5 to 21 per 100,000 person-years ), is manifested clinically by bradykinesia, rigidity, rest tremor, postural imbalance, and various nonmotor features. Subtle cognitive dysfunction and depression are often present early in the disease, dementia being common in later stages. PD is characterized by progressive degeneration of the dopaminergic nigrostriatal system and many cortical and subcortical networks associated with widespread αSyn pathology. The resultant striatal dopamine deficiency and other biochemical deficits produce a heterogeneous clinical phenotype. The accuracy of clinical diagnosis, according to a meta-analysis, was 73.8% to 79.6%. Using UK Parkinson’s Disease Society Brain Bank Research Center criteria, the pooled diagnostic accuracy was 82.7%. For the diagnosis of definite PD, histopathologic confirmation is required. Although LBs are not specific to PD and occur in a variety of conditions, a positive diagnosis of PD can usually be made by inspecting two unilateral sections from the midportion of the substantia nigra and finding LBs. If no LBs are found, two further sections should be examined. If LBs are not seen in either the substantia nigra or locus ceruleus, the diagnosis of PD of the LB type can be excluded. In case of cell loss in the substantia nigra and locus ceruleus in the absence of LBs or other αSyn-positive inclusions, an alternative cause of parkinsonism should be pursued.

Lewy Body Pathology Staging

Three current major staging systems are in use for LB disorders, one for PD, ^, another for DLB, and revised guidelines for LBD. Based on semiquantitative assessment of LB distribution in a large autopsy series, a staging of the chronologic spread of LBP (the Braak stages) was proposed to designate the predictable sequence of lesions in the nervous system ( Fig. 104.2 ).

LBP initially involves the olfactory bulb and related olfactory nuclei of the brain, the peripheral autonomic system, and the adrenal medulla in neurologically unimpaired subjects, referred to as incidental Lewy body disease (iLBD). It involves the dmX and intermediate reticular zone, with the NBM and midbrain regions being preserved (stage 1). In stage 2, LNs occur in the enteric nervous system, in parasympathetic and sympathetic nerves, and in medullary nuclei of the level setting system (e.g., lower raphe nuclei, gigantocellular reticular nucleus, and ceruleus-subceruleus complex). These initial stages are considered asymptomatic or presymptomatic and may explain nonmotor (olfactory and autonomic [e.g., gastrointestinal and urinary]) symptoms that precede motor dysfunctions. ^{, , ,} In stage 3, LNs and LBs occur in the PPN, locus ceruleus, amygdala, nuclei of the basal forebrain, upper raphe nuclei, magnocellular nuclei of the basal forebrain, hypothalamic tuberomammillary nucleus, posterolateral and posteromedial SNc, and spinal cord, whereas the allocortex and isocortex are preserved. This stage is associated with disturbed sleep, early motor dysfunction (asymmetrical tremor, rigidity, and hypokinesia), and several nonmotor symptoms. In stage 4, midline and intralaminar nuclei of the thalamus, anteromedial temporal limbic cortex (transentorhinal and entorhinal region), hippocampal formation, and second sector of the Ammon’s horn are involved, associated with severe motor dysfunction. In stage 5, LNs and LBs occur in the superordinate cortical areas for regulation of autonomic functions, in higher order sensory association areas and prefrontal fields. They are associated with late-phase motor disability and fluctuations. In terminal stage 6, the first-order sensory association areas and premotor fields, primary sensory, and motor areas or the entire neocortex are involved, ^, causing late motor disability, fluctuations, and cognitive impairment.

Nigral cell loss (12%) has been observed in stages 1 and 2 before the appearance of αSyn aggregates, and progression from stage 3 to stage 4 shows significant decrease in substantia nigra cell density (46%). An increase in the density of αSyn aggregates and LBs from stages 3 to 6 correlated negatively with the decrease in neuronal density. Metabolic and functional abnormalities in the brain occur in early stages of PD, not yet accompanied by LBP. ^{, ,} Many of the regions containing LBP early in PD had no obvious cell loss even over time, while some became involved with increased disease severity. Stereologic studies showed no overall loss of neocortical neurons in end-stage PD, although there were many cortical LBs.

The validity of the Braak staging scheme, which corresponds roughly to the original classification of LB disorders into three phenotypes—brainstem predominant, limbic/transitional, and diffuse neocortical —has gained acceptance, but has been a matter of debate. ^{, ,} It often but not consistently shows correlations between morphologic and clinical data, mainly in a subgroup of patients with early onset and prolonged duration. Studies have shown that 51% to 83% of PD and DLB cases were compatible with this staging, ^, whereas between 6.3% and 47% of autopsy-proven PD cases did not conform to it. ^{, , , ,} In 7% to 8.3% of PD cases, the dmX was not involved despite αSyn inclusions in higher brain stem or cortical regions, ^{, , ,} whereas in large samples, 49% to 55% of individuals with widespread αSyn pathology lacked clinical symptoms or were unclassifiable. ^,

The Braak hypothesis, suggesting predictable caudorostral spreading of LBP, is based on distribution of LBs but not on neuronal loss, which have no significant relationship, and is not identical with the spreading of αSyn. ^, It is valid for PD patients with young onset and long duration with motor symptoms, but not for others (e.g., late onset and rapid disease course). Between 10% and 15% of PD cases associated with genetic mutations show a pattern of LBP that is distinct from the Braak scheme. A recent theory proposed that corticostriatal activity may represent a critical somatotopic “stressor” for nigrostriatal terminals, driving retrograde degeneration and leading to focal motor onset and progression of PD. It may promote secretion of striatal extracellular αSyn, favoring its pathologic aggregation at vulnerable dopaminergic synapses. A similar process may occur at corticofugal projections to the medulla, contributing an integrative top-down perspective for the factors that impinge upon the vulnerability of dopaminergic cells in PD. A new staging system, the Lewy pathology consensus criteria (LPC) (based on the McKeith system but applying a dichotomic approach for the scoring of Lewy pathology [i.e., “absent” vs. “present”]), allows classification of all cases of LBD into distinct categories.

Incidental Lewy Body Disease

The term incidental Lewy body disease is used when LBs are found in the nervous system in subjects without clinical parkinsonism. The distribution of LBs is similar to that in PD, but some brains have sparing of LBs in the limbic cortex (average Braak stage of 2.7), whereas in definite PD cases, more LBs are found in all regions (Braak PD stage 4.4). A 70% substantia nigra cell loss and decreased TH immunoreactivity were shown in striatum and epicardial nerve fibers, but not to the same extent as in PD. ^{, ,} Such cases must have reduced vulnerability to substantia nigra cell loss in the context of equal LBP load. Some cases of random eye movement sleep behavior disorder may represent iLBD, suggesting that it is a preclinical form of PD and that the lack of symptoms is due to subthreshold pathology.

Between 5% and 55% of neurologically unremarkable elderly people have shown abundant LBP with a distribution pattern similar to that seen PD, while the pigmented substantia nigra neurons were relatively well preserved ^{, ,} or LBP was confined to the olfactory bulb. Others had sparse, but widespread LBP involving the cortex, ^, which would violate the theory of upward progression from the brainstem and perhaps fit better with a multicentric disease progression from the onset. LBP in the spinal cord and dorsal root ganglia in elderly persons was associated with that in the lower brainstem due to retrograde spread.

New Guidelines for Lewy Pathology

A new unifying system for LB disorders correlates with nigrostriatal degeneration, cognitive impairment, and motor dysfunction. Whereas the previous classifications left 42% to 50% of elderly individuals unclassified, this system allows all cases to be 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. 104.3 ). Progression through these stages was accompanied by stepwise deterioration of striatal TH concentration and substantia nigra pigmented cell loss, showing significant correlation with clinical and psychometric data.