Cerebello-Parietal Functional Connectivity in Amnestic Mild Cognitive Impairment

Abstract

The role of the cerebellum in amnestic mild cognitive impairment (aMCI), typically a prodromal stage of Alzheimer’s disease, is not fully understood. We studied the lobule-specific cerebello-cerebral connectivity in 15 cognitively normal and 16 aMCI using resting-state functional MRI. Our analysis revealed weaker connectivity between the cognitive cerebellar lobules and parietal lobe in aMCI. However, stronger connectivity was observed in the cognitive cerebellar lobules with certain brain regions, including the precuneus cortex, posterior cingulate gyrus, and caudate nucleus in participants with worse cognition. Leveraging these measurable changes in cerebello-parietal functional networks in aMCI could offer avenues for future therapeutic interventions.

Keywords

Alzheimer’s disease cerebellum functional MRI mild cognitive impairment resting state functional connectivity

INTRODUCTION

The two hallmark Alzheimer’s disease (AD) pathologies, amyloid-β and hyperphosphorylated tau, follow distinct patterns of propagation in various regions of the cerebral cortex [1]. The progression of these neuropathological changes, especially amyloid-β pathology, does not correspond with the severity of clinical symptoms [2]. This disparity between pathology and symptoms has led to the recognition that compensatory mechanisms likely come into play, necessitating a more intricate perspective on AD as a complex brain network issue. Modulating the brain network compensation, especially in the early disease stage, amnestic mild cognitive impairment (aMCI), is a promising strategy as the relevant brain circuitry is more preserved from primary pathology and may therefore exhibit a more uniform response to treatment.

The cerebellar lobules VI, VII, Crus I, and Crus II have been identified as the cognitive cerebellum, and injury to these areas can result in cerebellar cognitive affective syndrome in diverse neurological disorders [3, 4]. The cerebellum is an appealing candidate for network compensation in AD that deserves in-depth study because the cerebellum a) is not one of the primary brain regions affected by tau and amyloid-β pathologies [5, 6], b) has dense connections with cortical and subcortical brain regions, including basal ganglia to modulate cognitive and behavioral functions [7, 8], c) can modulate a constellation of cognitive and behavioral functions [9], and d) is a brain region where neuromodulation could provide cognitive improvement in AD [10 –13]. The cerebellum exhibited a lobule-specific volume change in AD compared to other neurodegenerative disorders, such as frontotemporal degeneration, progressive supranuclear palsy, and multiple system atrophy [14]. Additionally, cerebellar volume change also demonstrated a strong correlation with cognitive outcomes in aMCI, indicating a likely role for the cerebellum in early AD [15].

While the cerebellum has gained attention in AD, its functional changes in AD remains to be explored. We hypothesized that 1) the lobule-specific cerebello-cerebral functional connectivity (FC) change can be identified in aMCI, and 2) the cerebellum may have a compensatory role in aMCI compared to the cognitively normal state. Thus, we conducted this proof-of-concept study to determine the characteristics of cerebello-cerebral FC as well as its clinico-imaging correlates in aMCI.

METHODS

Participants and cognitive measures

We recruited 15 cognitively normal and 16 aMCI participants, approved by the institutional review board and all participants signed informed consents. The diagnosis of aMCI was made according to the most updated National Institute on Aging-Alzheimer’s Association diagnostic guidelines [16]. All study participants received the Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR) scale, and AD Assessment Scale-Cognitive subscale 13 tasks (ADAS-Cog-13). We first studied the cerebello-cerebral FC by diagnostic groups (i.e., cognitively normal versus aMCI). To avoid arbitrarily categorizing the participants by the diagnosis only, especially considering that some of the aMCI and cognitively normal participants might have overlapping scores on the MoCA, a measure for global cognitive function, we further stratified our sample by the MoCA score obtained at the time of scanning. Based on our study participants’ age and education level [17, 18], the cutoff we used was 25 to alternatively define cognitively normal (n = 12, MoCA≥25) versus cognitively impaired with mild severity (n = 16, MoCA = 21–24), and participants with a MoCA score≤20 were removed (n = 3).

Functional MRI, imaging, and statistical analysis

Lobule-specific cerebello-cerebral resting-state FC was conducted using seed-to-voxel analysis. Images were obtained on a 3-Tesla Siemens Prisma Magnetom system. A 12-minute eyes-open resting-state was collected using a Human Connectome Project high-resolution, multiband-accelerated imaging sequence with full brain coverage. Functional images were acquired (2.2 mm isotropic) with two phase encoding directions (anterior-to-posterior and posterior-to-anterior). The details of acquisition parameters and co-registration methods were fully described in the Supplementary Table 1. Preprocessing was performed using the CONN Functional Connectivity toolbox Version 20b (http://www.nitrc.org/projects/conn) within SPM12 (http://www.fil.ion.ucl.ac.uk/spm/). We first placed the cerebellar seeds/region of interests in the cognitive cerebellar lobules, specifically, lobule VI, VII, Crus I, and II as the primary analysis to test our hypothesis that cerebello-cerebral FC alterations will be present at the aMCI stage before progressing to dementia. In order to examine the specificity for the cerebellum’s cognitive contribution in aMCI, we next conducted an additional, exploratory study for the remaining cerebellar lobules (i.e., vermis I to X and lobule III, IV, V, VIII, IX, X). The individual and group-level analysis using one-way ANOVA was conducted per standard fMRI protocol [19]. The functional MRI peak voxel coordinates of all cerebellar region of interests in the primary and exploratory analyses were listed in the Supplementary Table 1.

We then compared the cerebello-cerebral FC between aMCI versus controls (i.e., by diagnosis) and between participants with higher (MoCA≥25, n = 12) versus lower cognitive function (MoCA = 21–24, n = 16). Clinico-imaging correlates between the CDR sum-of-boxes (CDR-SB), MoCA, and ADAS-Cog with cerebellar FC were also studied in all study participants. An additional exploratory subgroup analysis on the aMCI participants was conducted as well. The association between the correlation coefficient from the clusters and the different cognitive measures was examined using linear regression models. Multiple comparison correction was used and pFWE < 0.00625 was considered Bonferroni-significant. SPSS v.25 was used for statistical analysis.

RESULTS

The average age for our study participants was 73.44±8.21 and education level was 17.04±2.13 years. The controls and aMCI participants did not differ significantly on age (70.94±9.10 versus 75.53±7.77, p = 0.128), sex (female/male=7/9 versus 8/9, p = 0.563), and educational attainment (17.5±1.7 versus 16.9±2.4 years, p = 0.430). The aMCI participants had higher neuropsychiatric inventory questionnaire score than controls (0.75±2.24 versus 3.59±4.09, p = 0.020). As expected, aMCI participants had significantly lower MoCA (25.88±2.25 versus 21.71±2.73, p < 0.001), higher CDR sum-of-box (0.34±0.67 versus 1.47±1.32, p = 0.004), higher global CDR (0.19±0.53 versus 0.53±0.12, p < 0.001), and higher ADAS-Cog scores (12.77±5.57 versus 21.14±6.34, p < 0.001).

Characterization of cerebello-cerebral FC

We first studied if the alteration of cerebello-parietal FC can be observed and reliably measured in early AD disease process. Using the complete set of significance with peak voxel p < 0.001 and cluster threshold size p-FWE<0.05, we identified that when compared to controls, aMCI demonstrated significantly weaker FC between the cerebellar left Crus I and right supramarginal gyrus, as well as a significantly weaker FC between the Left Crus II and bilateral supramarginal gyrus of the parietal lobe (Table 1A, Fig. 1A, B). Compared with participants with higher cognitive function (MoCA≥25, n = 12), those who had lower cognitive function (MoCA = 21–24, n = 16) demonstrated significantly weaker FC between the cerebellar left Crus II and bilateral supramarginal gyrus as well as superior parietal lobe (Table 1A, Fig. 1 C). Interestingly, the aMCI demonstrated stronger, instead of weaker FC between Vermis III and left parietal operculum (Table 1A).

Table 1

A) Comparison between the cerebellar-parietal functional connectivity differences in study participants categorized by diagnosis and by MoCA. B) Association between the clinical dementia rating scale and MoCA with functional connectivity changes in all study participants. C) Association between the ADAS-Cog with functional connectivity changes in amnestic MCI cases

A
Participants	Cerebellar ROI	Cerebral cortical region	Side	Cluster size (voxels)	P-FWE	MNI peak coordinates (x, y, z)
Amnestic MCI versus control	Left Crus I	Supramarginal gyrus	R	392	0.0053^**	+52	–30	+38
	Left Crus II	Supramarginal gyrus	R	327	0.0088^*	+44	–34	+38
			L	–58	–42	+34
High versus low MoCA^#	Left Crus II	Supramarginal gyrus and superior parietal lobe	R	536	0.0005^**	+40	–48	+58
			L	669	0.0001^**	–54	–30	+34
	Vermis III	Parietal operculum	L	229	0.0252^*	–54	–28	+14
B
Cognitive and functional measure	Cerebellar ROI	Cerebral cortical region	Side	Cluster size (voxels)	P-FWE	MNI peak coordinates (x, y, z)
CDR-FC correlates	Left VI	Precentral gyrus	R	425	0.0035^**	+26	–16	+54
			L	462	0.0022^**	–24	–20	+54
	Vermis III	Precuneus cortex	B	246	0.0190^*	+04	–48	+36
Frontal pole	L	326	0.0048^**	–30	+42	+04
MoCA-FC correlates	Vermis IV/V	Caudate and putamen	L	275	0.0177^*	–22	+18	+02
C
Cognitive and functional measure	Cerebellar ROI	Cerebral cortical region	Side	Cluster size (voxels)	P-FWE	MNI peak coordinates (x, y, z)
ADASCog Total-FC correlates	Vermis IV/V	Inferior temporal gyrus (anterior division) and temporal fusiform cortex (anterior division)	L	349	0.0012^##	–42	–02	–36
ADASCog Word recall-FC correlates	Left III	Angular gyrus and lateral occipital cortex	L	617	<0.001^##	–46	–62	+32
			R	359	<0.001^##	+46	–54	+38
	Left VIIb	Posterior cingulate gyrus	N/A	320	0.0016^#	+00	–36	+44
	Left VIII	Angular gyrus and lateral occipital cortex	R	359	<0.001^##	+46	–54	+38
ADASCog Orientation-FC correlates	Right IX	Putamen	L	399	<0.001^##	–28	+02	+02
			R	256	0.0037^#	+22	+02	+00

^#High MoCA group refers to score≥25; low refers to score = 21–24. ^*Significant (p < 0.05). ^**Bonferroni significant (p < 0.00625). ^# Significant for the subgroup analysis (p < 0.01). ^##Bonferroni significant for the subgroup analysis (p < 0.00125). ADAS-Cog, AD Assessment Scale-Cognitive subscale; CDR, Clinical Dementia Rating scale score; FC, functional connectivity; MCI, mild cognitive impairment; MoCA, Montreal Cognitive Assessment scale; MNI, Montreal Neurologic Institute coordinates for predefined region of interests in CONN toolbox; ROI, region of interest; L, Left; R, Right; B, bilateral; N/A, non-applicable.

Fig. 1

Cerebello-parietal functional connectivity. A) Participants with amnestic mild cognitive impairment exhibited weaker functional connectivity between the cerebellar left Crus I and right supramarginal gyrus, as well as (B) left Crus II and bilateral supramarginal gyrus. C) Lower cognitive function participants, defined as a MoCA score between 21 and 24, showed weaker functional connectivity between the cerebellar left Crus II and bilateral supramarginal gyrus and superior parietal lobes.

Clinico-imaging correlates

We next asked if the cognitive function is associated with the cerebello-cerebro FC change. Interestingly, we found that participants with worse cognitive and functional impairment, represented by higher CDR-SB, showed stronger, instead of weaker FC between the Left lobule VI and bilateral precentral gyrus (Table 1B, Fig. 2A). Notably, in the exploratory analysis, higher CDR-SB demonstrated stronger FC between Vermis III and the precuneus cortex (Table 1B, Fig. 2B), and the lower MoCA group demonstrated stronger FC between Vermis IV/V and the left caudate and putamen (Table 1B, Fig. 2 C). On the other hand, there was no significant correlation identified between the total ADAS-Cog score and cerebello-cerebral FC in both primary and exploratory analyses.

Fig. 2

Stronger functional connectivity was identified between (A) the left VI and bilateral precentral gyrus in participants with higher CDR, (B) cerebellar vermis III and precuneus cortex as well as left frontal pole in participants with higher CDR, and (C) cerebellar vermis IV/V and left caudate nucleus as well as putamen in study subjects with lower MoCA. CDR, Clinical Dementia Rating scale; MoCA, Montreal Cognitive Assessment scale.

As to our subgroup analysis of the aMCI participants, we chose to strictly lower the significance level of the p-FWE to <0.01 for study rigor to avoid false positive findings in an exploratory analysis, and pFWE < 0.00125 was considered Bonferroni-significant. Our finding showed that higher ADAS-Cog word recall score demonstrated stronger FC between the Left lobule VIII with angular gyrus and between the Left VIIb with cingulate gyrus. In addition, higher ADAS-Cog orientation exhibited stronger FC between the Right lobule IX with bilateral putamen. The full clinico-imaging correlate findings of the aMCI group is listed in the Table 1 C.

DISCUSSION

In our study, we aimed to characterize and explore the cerebello-cerebral FC in the early stages of AD. Our results demonstrated that the alteration of cerebello-cerebral FC, specifically, the cognitive cerebellum and parietal lobe FC alteration was measurable in aMCI, the early AD stage. The significance of the supramarginal gyrus of the parietal lobe in phonological word processing has been well-documented [20], and this discovery may offer a potential explanation for the common early occurrence of word-finding difficulties in aMCI/early AD.

The network-based neurodegeneration highlights the importance of the less affected brain region subserving the main, already damaged principal disease network [21 –23]. The cerebellum, with its dense connections to the cerebral cortex and subcortical regions, has the capacity to influence various cognitive functions impaired in AD. In aMCI, larger cerebellar volume was found associated with worse cognitive function, indicating that the cerebellum might undergo compensatory or neuroplastic change in the aMCI stage [15]. Our results at the functional imaging level partially resonate with this finding: in our cohort, lower cognitive function was correlated with the enhanced FC between the cognitive cerebellum and bilateral precentral gyrus. While the precentral gyrus has been traditionally known as the primary motor cortex, it is also responsible for modulating several non-motor functions, including working memory, emotion-drive action, and response inhibition [24, 25]. In addition, reduced precentral gyrus gray matter volume was also found in major depressive disorder [26, 27]. Early involvement of the parietal lobe in AD may manifest with symptoms such as geographical disorientation and navigation difficulty, and the cerebellar lobule VI, Crus I, and Crus II are related to spatial processing [8]. Consistent with this notion, our exploratory analysis of the cerebellar vermis revealed stronger FC between 1) Vermis III and the precuneus cortex, a brain region involved early in AD, which is pivotal in the default mode network of AD that were also targeted for transcranial magnetic stimulation [28], 2) Vermis IV/V and the caudate/putamen, a brain region less affected in AD which is strongly connected with cognitive cortical regions, especially dorsolateral and orbitofrontal cortex via the striato-cortical circuitry [29, 30], and 3) lobule VIIb and the posterior cingulate gyrus, a cortical region well known affected early in AD [31] when the worse short-term memory function was identified by the ADAS-Cog word recall.

Recent imaging studies have revealed the possibility of resilience or compensatory change of the brain structures in AD, including the cerebellum and anterior cingulate cortex [15, 32]. In individuals with PD, hypermetabolic activity of the posterior cerebellum was seen on FDG-PET, independently associated with impaired attention, executive function, and memory, while the cortical area demonstrated hypometabolism as expected [33]. Additionally, in resting-state fMRI, stronger FC between the cerebellar vermis and parietal area were seen in PD patients with visuospatial dysfunction, and the cerebello-caudate FC was correlated with motor/cognitive performance in PD [34, 35]. These findings, suggestive of disruption in functional coupling and the compensatory activation of the cerebello-cerebral network in PD cognitive processing, resonate with our study’s findings in aMCI due to AD. We thus postulate that in early AD process, the non-motor cerebellum can modulate the precentral gyrus by offering a compensatory effect to the precentral gyrus via the cerebello-parietal circuit while the above-mentioned cognitive and behavioral dysfunction related to the precentral gyrus start to emerge when disease progresses. Our proposal is also consistent with the recent understanding of the cerebellum’s role in modulating the traditional networks related to diverse cognitive and emotional symptoms, such as transcending the excitatory signals from the dentate nucleus to the ventral tegmental area to modulate the reward system related to impulsivity and compulsivity [15 , 36–41]. Along this line, a recent randomized clinical trial in AD showed that by enhancing the cerebello-cortical FC through repetitive transcranial magnetic stimulation on the cerebellum, general and domain-specific cognitive improvement were seen at the end of the study [42]. This finding overall indicates that by leveraging the cerebello-cerebral FC using neurostimulation, novel and customized therapeutics for early AD can be developed in the future.

Among the four non-motor cerebellar lobules in our primary analysis, the lobule VII was the one which did not show significant results on disease stage comparison and clinico-imaging correlation. Whether the cerebellar lobule VII, a region related to language and emotional processing, should be taken as an outsider in classic AD relies on future studies to investigate. Our study has several limitations, including its cross-sectional nature, the relatively smaller sample size, and the homogenous recruitment from local Greater Houston Area population. Additionally, because participants were recruited from a clinical practice setting, biomarkers for the full AT(N) classification suggested by the 2018 National Institute on Aging-Alzheimer’s Association Research Framework could not be applied to confirm AD pathology [43].

Our study highlights that the alteration of cerebello-parietal functional network is already present in aMCI, and the stronger FC seen in worse cognitive function indicates the potential compensatory effect from the cerebellum. Future studies are required to investigate: 1) how the cerebello-cerebral FC will evolve when AD process enters the mild and moderate dementia stage, and 2) whether augmenting these FC through neuromodulation on the specific cognitive cerebellar lobules may inform future therapeutic development for AD.

AUTHOR CONTRIBUTIONS

Chi-Ying R. Lin (Conceptualization; Data curation; Funding acquisition; Investigation; Methodology; Supervision; Writing – original draft; Writing – review & editing); Shayla S. Yonce (Data curation; Formal analysis; Investigation; Methodology; Project administration; Writing – review & editing); Nat J. Pacini (Data curation; Investigation); Melissa M. Yu (Data curation; Writing – review & editing); Jeffrey Bisho (Data curation); Valory N. Pavlik (Conceptualization; Investigation; Methodology; Validation; Writing – review & editing); Ramiro Salas (Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Resources; Supervision; Validation; Writing – review & editing).

Footnotes

ACKNOWLEDGMENTS

The authors acknowledge the support by the Baylor Junior Faculty Seed Award, Mike Hogg Fund Award, and DeBakey Veterans Affairs (VHA, grant number: I01CX001937) for this project.

FUNDING

Dr. Lin received funding from the Baylor Junior Faculty Seed Award and Mike Hogg Fund Award for this research project. Dr. Salas received research funding from the Veterans Health Administration (VHA, grant number: I01CX001937).

CONFLICT OF INTEREST

Lin CR, Yonce S, Pacini N, Bishop JA, Pavlik VN, and Salas R reported no disclosure relevant to the manuscript. An immediate family member of Yu MM has received personal compensation for serving as an employee of CVS/Aetna. The institution of Yu MM has received research support from Alzheimer’s Association. The institution of Yu MM has received research support from Biogen. The institution of Yu MM has received research support from Eisai.

DATA AVAILABILITY

The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

The supplementary material is available in the electronic version of this article: .

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