Cerebellum in Neurodegenerative Disorders: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Igor Iskusnykh.

An important part of the central nervous system (CNS), the cerebellum is involved in motor control, learning, reflex adaptation, and cognition. Diminished cerebellar function results in the motor and cognitive impairment observed in patients with neurodegenerative disorders such as Alzheimer’s disease (AD), vascular dementia (VD), Parkinson’s disease (PD), Huntington’s disease (HD), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia (FRDA), and multiple sclerosis (MS), and even during the normal aging process. In most neurodegenerative disorders, impairment mainly occurs as a result of morphological changes over time, although during the early stages of some disorders such as AD, the cerebellum also serves a compensatory function. Biological aging is accompanied by changes in cerebellar circuits, which are predominantly involved in motor control.

  • cerebellum
  • neurodegeneration
  • aging
  • brain
  • neuron

1. Alzheimer’s Disease (AD)

The amyloid plaques characteristic of AD appear in the cerebellum primarily during the later stages of the disease [91,92][1][2]. The cerebellum is more resistant to the neurotoxicity caused by the soluble amyloid-beta (Aβ) protein, as shown by the lower levels of synapse loss in the cerebellum relative to other brain structures [93,94][3][4]. During the early stages of AD, the cerebellum compensates with enhanced activity that results in the improvement of some forms of memory [95,96][5][6] but the worsening of others, such as the topographic working memory that is functionally related to cerebellar memory [97,98][7][8]. The effects of AD on the cerebellum differ from those on other brain structures. For example, the GABAergic synapse and retrograde endocannabinoid signaling pathways are not downregulated in the cerebellum of AD patients [99][9], and in AD patients, the signs of neurological aging, including increased inflammation and reduced neuronal expression that are present in other brain structures, are absent in the cerebellum [100][10]. Interestingly, in familial AD, the earlier onset and greater severity of the disease correlate with cerebellar pathology [16][11]. In late-stage AD, noticeable cerebellar atrophy is demonstrated by an evident decrease in the volume of the ML and GC layers of the cerebellar cortex and a reduced number of PCs [101,102][12][13]. In the AD neocerebellum, the activation of microglia and development of neurovascular inflammation are not associated with Purkinje cell count or neuronal degeneration, as measured through immunoreactivity to tau and ubiquitin proteins [103][14]. Therefore, the presence or absence of neuronal degeneration in the cerebellum of AD patients is most likely associated with the degree of AD progression. This suggestion is supported by Pellegrini (2021), who showed that specific alterations of DNA methylation in the brain during AD are dependent on age, highlighting the accelerated epigenetic aging that occurs in AD [104][15]. This is consistent with the observation that pronounced changes in the memory performance of AD patients are associated with the extent of cerebellar damage, not the number of amyloid plaques [105][16]. The cognitive dysfunction in AD is likely to be related to accelerated cerebellar synaptic aging characterized by ultrastructural damage to synapses, including a loss of dendritic spines and synaptic boutons and a decrease in the number of synaptic vesicles and mitochondria in the presynaptic termini of cerebellar neurons [63][17]. Notably, a study performed in a mouse model of AD demonstrated electrophysiological alterations in the PCs and neurons of the DCN that were associated with a decrease in memory and poor performance in the water-maze test [106][18].
In addition to synaptic function, the efficiency of cognitive functions in the brain depends on the frequency and timing of neuronal spikes. Using the Purkinje cell model, it has been shown that the regulation of spike rate is mediated by rate-dependent subthreshold membrane potentials that trigger the activation of Na+ channels [107][19]. Cheron et al. showed that in mice with AD, there was evidence of electrophysiological changes in both PC and DCN, which could significantly contribute to behavioral deficits. These changes were associated with Aβ deposition in the molecular layer of the cerebellum [106][18].

2. Parkinson’s Disease (PD)

In PD, cerebellar dysfunction is associated with resting tremor, impaired balance, and unstable gait. PD is characterized by aggregations of alpha-synuclein protein in the pre-cerebellar brainstem and the cerebellar nuclei [108][20]. The severity of the resting tremor is associated with the iron content of the cerebellar dentate nuclei. Excessive cellular iron is a root cause of ferroptosis, a nonapoptotic cell death pathway that leads to the degradation of cerebellar neurons [109][21]. PD patients and patients with PD-PIGD (postural instability and gait disorders) exhibit cerebellar atrophy, specifically the reduced volume of the right Crus II, right lobules IV and V, lobules VIII and IX, vermis VIII and IX, pyramis, and culmen [110,111,112][22][23][24]. Changes in the volume of cerebellar lobules are typical for PD patients, where an increased volume of the lobule IV is positively correlated with resting tremor and the severity of total tremor, and a decreased volume of the lobule VIIb is positively correlated with a more severe tremor [113,114][25][26].
Functional MRI studies demonstrate the impact of cerebellar dysfunction on such PD symptoms as tremor and motor instability. Tremor-dominant PD patients exhibit reduced functional connectivity between the cerebellar dentate nucleus and the ventral lateral posterior nucleus of the thalamus [115][27], the sensorimotor cortex and vermis [116][28], the dorsal attention network, and the cerebellar somatomotor network [117][29]. However, tremor-dominant PD patients converting to the more aggressive PD-PIGD form demonstrate increased functional connectivity in the temporal and occipital lobes and in the cerebellum and pontomedullary junction relative to patients who do not convert to PD-PIGD [118][30]. PD-PIGD patients also demonstrate increased activity in non-motor cerebellar areas during gait-simulating tasks, most likely as a compensatory response to the functional failure of the motor areas of the cerebellum and basal ganglia [112][24]. PD patients who experience gait freezing during lower-limb movements demonstrate reduced theta oscillations and attenuated cue-triggered theta-band power via the mid-cerebellar Cbz electrode in electroencephalography (EEG) studies during motor tasks [119,120][31][32].
One of the most important complications of PD is cognitive decline, a hallmark of poor prognosis. In non-amnestic PD patients, cognitive function studies using MRI studies have shown that cerebellar lobule VII participates in networks within the visuospatial-executive and attention domains and have suggested that lobule VII may play an important role in the development of PD cognitive decline [121][33]. PET studies on the cerebellum in PD patients demonstrate increased local glucose metabolism in the posterior cerebellar vermis that is associated with impaired memory, attention, and executive function [122][34]. Similarly, increased glucose metabolism in the right crus I, crus II, and vermian lobule VI is associated with the severity of cognitive impairment [123][35].

3. Huntington’s Disease (HD)

HD is characterized by uncontrollable movement (chorea), abnormal body posture, and functional deficits in behavior, cognition, emotion, and personality changes. In HD, pronounced cerebellar degeneration was observed in the right Crus I lobule, bilateral Crus II lobules, and the left VIIb and VIIIa lobules [124][36], while another study noted significant volume loss in the cerebellar grey and white matter [125][37]. Cerebellar volume loss is associated with a reduced number of PCs and GCs [126,127][38][39]. Notably, there was a detrimental change in gene expression, particularly of those factors that are responsible for exocytosis and vesicular fusion in GCs [128][40].

4. Amyotrophic Lateral Sclerosis (ALS)

ALS, also called Lou Gehrig’s disease, is a fatal motor neuron disease associated with progressive cerebellar degeneration [129][41]. The specific role of the cerebellum in this disorder may be related to the cerebellum-specific repeat expansion of several genes that determine ALS pathology, including the NIPA magnesium transporter 1 (NIPA1), chromosome 9 open reading frame 72 (C9ORF72), and ataxin-1 (ATXN1) genes [130][42]. The localization of ALS-related cerebellar atrophy varies. For example, sporadic ALS patients demonstrate atrophy of lobules I-V in the cerebellar anterior lobe. At the same time, carriers of the C9ORF72 gene mutation (expansion of a GGGGCC repeat to as many as 1600 copies) demonstrate atrophy of the posterior lobe and vermis, while patients with intermediate expansions in the ATXN2 gene do not demonstrate significant cerebellar atrophy [131][43].

5. Friedreich’s Ataxia (FRDA)

FRDA is a hereditary disorder characterized by progressive motor dysfunction, altered tactile sensation/sensitivity, and impaired speech [132][44]. The cerebellum of FRDA patients exhibits a moderate reduction in volume and patchy atrophy, especially of the dentate nucleus and Lobule IX, based on the results of MRI studies [133,134][45][46]. Mild atrophy of the medial parts of lobule VI may be related to speech impairment [133][45]. Moreover, an impaired visuospatial function in FRDA is directly correlated to the volume of cerebellar lobule IX [135][47]. Voxel-wise seed-based functional connectivity fMRI analysis was used to show that connectivity between the anterior cerebellum and bilateral pre/postcentral gyri and between the superior posterior cerebellum and left dorsolateral prefrontal cortex (PFC) was significantly reduced and that these changes correlated with disease severity [135][47]. Changes in cerebellar morphology in FRDA patients may result from chronic inflammation and glial activation in the dentate nuclei [132][44]. In a mouse model of FRDA, the affected animals exhibited loss of cerebellar PCs and principal neurons of the large dentate nuclei and selective degeneration of climbing fiber synapses, identified using the glutamatergic synaptic marker VGLUT2 [136][48].

6. Spinal Muscular Atrophy (SMA)

SMA affects spinal cord motor neurons, causing their atrophy from inactivity. The development of the loss of motor control in SMA patients involves the neurodegeneration of several brain regions, including the cerebellum [137,138][49][50]. SMA patients exhibit volume loss of cerebellar lobules VIIIb, IX, and X and gray matter atrophy of lobule IX, as determined through MRI studies without correlation with clinical manifestation [139][51]. In a mouse model of SMA, affected mice demonstrated neuronal dysfunction of the cerebellum that was manifested in lower spontaneous firing and lower cerebellar network activity, most noticeably, lower spontaneous excitatory and inhibitory synaptic activities of cerebellar PCs, relative to the control animals [140][52].

7. Juvenile Batten’s Disease (JBD)

The progressive neurodegenerative disorder JBD, also known as the juvenile form of neuronal ceroid lipofuscinosis (JNCL), is characterized by defects in lysosomal storage caused by mutations in the ceroid lipofuscinosis neuronal 3 (Cln3) gene, leading to the degeneration of cerebellar and retinal neurons [141][53]. Cerebellar atrophy in JBD causes motor function deficiency, disturbed balance and coordination, and abnormal EEG findings [142,143,144,145][54][55][56][57]. The severity of cerebellar atrophy positively correlates with the level of dysfunction [143][55]. Although earlier studies on the Cln3-knockout mouse model for JBD showed that the dysregulation of the granular cell AMPA receptors played a role in cerebellar degeneration [144][56], while more recent studies demonstrated presynaptic changes in the mossy fibers that project from BS/SC to the cerebellar IGL (Figure 1) but did not observe postsynaptic AMPAR dysfunction [141][53].

8. Multiple Sclerosis (MS)

In patients with MS, cerebellar dysfunction starts in the early stages of the disease [146][58]. The walk ratio (WR) of step length/cadence serves as a speed-independent index of the neuromotor control of gait [147][59]. During the development of ataxia, the volume of the cerebellum correlates with the walk ratio [148][60]. An analysis of the cerebellar damage in MS patients using MRI showed that the reduced volume of cerebellar lobules I-IV, reduced volume of GM in the lower vermis, lesions of the cerebellar superior peduncle, and increased volume of GM in cerebellar lobules VIIIb and Crus II correlate with physical disability and cognitive disfunction [149][61]. Another MRI study of MS patients showed a relationship between cognitive deficiency and diminished cerebellar functional connectivity, where patients with secondary progressive multiple sclerosis (SPMS) showed the most severe cognitive impairment and cerebellar damage and exhibited changes in cerebellar functional connectivity [150][62]. A separate MRI study showed an association between reduced functional connectivity in the cerebellum, greater loss of cerebellar volume, and more severe lesion burden. And a loss of white matter volume reduced functional connectivity in the sensorimotor cerebellum lobes, while a loss of cortical grey matter volume was linked to increased connectivity of both sensorimotor and cognitive cerebellum tissue [146][58].
An assessment of postural sway deficits and cerebellar peduncle lesions in MS patients using diffusor–tensor imaging (DTI) showed that peduncles in the inferior cerebellum contribute to the control of standing balance with visual input (somatosensory information), while those in the superior cerebellum contribute to reactive balance control without visual input. Notably, MS patients exhibit cerebellar lesions even at the prodromal stage of the disease, when cerebellar motor symptoms have not yet appeared [151][63]. Interestingly, patients who participated in a 12-week high-intensity balance training program exhibited improved balance due to changes in postural sway and DTI parameters. The mechanism by which such improvement occurs is believed to be compensatory training-induced transient structural plasticity in the white matter (WM) tracts that form the cerebellar peduncles, resulting from improved myelination. Although the changes in clinical findings and imaging parameters persisted only for the 12 weeks of the training program, these results provide hope that high-intensity task-oriented exercises will prompt positive changes in the cerebellar microstructure and improve the clinical outcomes of MS [152][64].

9. Vascular Dementia (VD)

Cerebrovascular diseases, especially VD, are increasingly prevalent in aging, tremendously impacting a patient’s quality of life. Cerebrovascular diseases such as stroke can impact the cerebellum due to cerebellar bi-directional interconnection to numerous brain regions, severely decreasing cerebellar function. Conversely, the activation and consequent increase in the function of the cerebellum can effectively alleviate symptoms of a disease such as vascular dementia [153][65]. Nevertheless, the precise mechanism by which metabolic and circulatory disturbances in the cerebellum affect cognition remains to be uncovered.
Evidence suggests that individuals with cerebral small vessel diseases may develop compensatory cerebellar hyperconnectivity in the regions that relate to the frontoparietal cognitive networks and sensorimotor areas of the brain, demonstrating hypoconnectivity in frontoparietal brain regions [154][66]. On the contrary, Ruan and colleagues demonstrated that individuals with vascular mild cognitive impairment in certain areas of the cerebellum demonstrated significantly decreased functional connectivity between the cerebellum and regions of the brain in the default mode network, sensory-motor network, and frontoparietal network [155][67]. It has been demonstrated that subcortical vascular mild cognitive impairment is associated with anatomical atrophy and reduced functional connectivity to the striatum in specific cerebellar regions that are involved in cognitive function [156][68].
Quantitative MRI in VD indicates generalized cerebellar atrophy [157][69]. Additionally, various studies have proposed that cerebellar-mediated cognitive decline is more severe in VD patients than in those with AD [158][70]. It is speculated that greater cerebellar atrophy in VD may serve as a valuable diagnostic marker to differentiate between VD and AD [159,160][71][72].
Morphological alterations in the cerebellum during VD result from the increased susceptibility of Purkinje cells to ischemia. While the precise mechanisms of cerebellar atrophy in hypoxia are not clear, there is evidence that VD leads to a reduction in cerebellar metabolism [161][73], which is not a typical trait among AD patients [162][74]. Mielke’s research showed that the regional cerebral glucose metabolism rate in the cerebellum dropped solely in VD patients but not in those with AD [163][75]. Postmortem studies by De Reuck et al. support the specific role of VD in cerebellar damage. Brain samples from patients with AD, AD associated with cerebellar amyloid angiopathy, frontal degeneration, amyotrophic lateral sclerosis, Levi’s disease, progressive supranuclear palsy, and VD were studied. The findings indicate an appreciable rise in microhemorrhages and microinfarcts in the cerebellum solely among VD patients [164][76].
Experimental studies confirmed the role of hypoxia in cerebellar damage. A mouse model of VD demonstrated increased expression of inflammasome receptors, adaptor, and effector proteins, markers of inflammasome activation, proinflammatory cytokines, and apoptotic and pyroptotic cell death proteins in the cerebellum [165][77].
Ischemic white matter damage is considered a significant factor in cognitive decline [166][78]. Cultured organotypic slices of the cerebellum were utilized to create an in vitro model of chronic ischemic white matter damage. Prolonged hypoxic injury was employed to accurately reproduce the predominant axonal degeneration. This model enables to elucidate the mechanisms of cerebellar atrophy in hypoxia and to effectively test potential drugs that can attenuate axonal degeneration.

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