New Frontiers for the Understanding of Aging: The Power and Possibilities of Studying the Cerebellum

Abstract

Understanding behavior in aging has benefited greatly from cognitive neuroscience. Our foundational understanding of the brain in advanced age is based on what now amounts to several decades of work demonstrating differences in brain structure, network organization, and function. Earlier work in this field was focused primarily on the prefrontal cortex and hippocampus. More recent evidence has expanded our understanding of the aging brain to also implicate the cerebellum. Recent frameworks have suggested that the cerebellum may act as scaffolding for cortical function, and there is an emerging literature implicating the structure in Alzheimer’s disease. At this juncture, there is evidence highlighting the potential importance of the cerebellum in advanced age, though the field of study is relatively nascent. Here, we provide an overview of key findings in the literature as it stands now and highlight several key future directions for study with respect to the cerebellum in aging.

An Overview of the Cerebellum in Aging

The human cerebellum contributes to behavior across domains. From controlling smooth and coordinated movements [1,2], to cognitive processing [3,4], and contributions to social cognition and affect [5], its contributions are wide. During typical function in the absence of disease, cerebellar computations are thought to primarily focus on forward and inverse internal models of behavior [6–9]. Given the consistent cytoarchitecture of the cerebellum, it has been suggested that the computations themselves are universal, but the cerebellum acts on distinct inputs from the cortex to process motor, cognitive, and affective computations [6–8]. Though the universal cerebellar transform has been called into question more recently [9], it is the case that healthy cerebellar function is critical for behavior. Cerebellar differences and functional deficits are observed across disease and psychopathology where deficits in these domains are observed [10,11]. Advanced age is also marked by changes and differences in both cognitive and motor behavior [12,13]. The cognitive neuroscience of aging field works to understand the brain bases of these differences and changes. Several decades of research in this domain have provided foundational knowledge regarding many of the differences and changes seen in advanced age. There are known age differences in brain volume across regions, with particularly notable findings in the prefrontal cortex and hippocampus [14–16], resting state functional connectivity is altered [17–19], and functional activation differs as well. The latter is characterized largely by more bilateral patterns of activation in the cortex in older adults, when in young adults activation is typically more unilateral [20,21]. There are also more general changes in the hemodynamic response function, where in the time to reach the peak of the function is longer, and the peak is lower in older adults relative to young [22,23]. Across these investigations however, the focus has been largely, though not exclusively, on the prefrontal cortex and hippocampus. In recent years, an emerging literature has provided novel insights into cerebellar contributions in aging. This has expanded our foundational knowledge of the aging brain and its relationships to behavioral differences and declines, and now presents new opportunities and frontiers for research in the cognitive neuroscience of aging.

Evidence of the impact of aging on the cerebellum has demonstrated structural differences, both at a global and lobular level [14,16,24–26], differences in resting state functional connectivity [27,28], and differences in functional activation during task performance [29,30]. Broader theoretical accounts suggest that the differences in cerebellar volume, function, and connectivity result in disrupted processing of internal models in the cerebellum [31]. This in turn accounts, at least in part for some of the behavioral differences seen in aging, and the associations therein with cerebellar metrics [24,27,31]. A more recent theoretical framework, based on the scaffolding theory of aging and cognition [32] has further incorporated the cerebellum into frameworks of cognitive aging more broadly [33]. Because older adults are seemingly less able to rely upon cerebellar resources during task performance, this also means that more automated processing associated with internal models is not available. As such, additional cortical resources are needed to maintain performance. Thus, automated processing in the cerebellum may serve as critical scaffolding for function and processing, and the bilateral activation patterns seen in older adults [21], may at least in part, be related to the decreased cerebellar processing in aging [33]. At this point, there is a foundation of literature implicating the cerebellum in aging and the associated behavioral changes that occur therein. However, we have only just scratched the surface, and are only beginning to understand the role this structure plays across the lifespan. Here, we present several areas that stand to be particularly informative for our study of the cerebellum in advanced age as this area of research expands and matures. We will focus on menopause and estrogen, Parkinson’s and Alzheimer’s Disease, and the potential of the cerebellum as a target for remediation in advanced age. As explicated further below, these three topics are areas of emerging or growing interest and impact broad swaths of the aging population, either directly, or for caregivers. Menopause, for example, impacts nearly half of the population. Alzheimer’s Disease is the most common form of dementia, and per the Alzheimer’s Association in 2023, impacts approximately 6.7 million Americans over the age of 65. Parkinson’s Disease is a highly prevalent neurological disorder that primarily impacts older adults. While we would contend that more focus on the cerebellum across populations and diagnoses would be broadly beneficial, these three areas are of particular interest and importance to aging populations.

Menopause, estrogen, and cerebellum

Females in later life experience more negative outcomes, as evidenced by both a higher incidence of Alzheimer’s Disease (AD) and more severe falls [34,35]. There is an increasing recognition of the importance of women’s health broadly defined, and the necessity of understanding how the endocrine system and changes therein might impact brain and behavioral outcomes [36,37]. With respect to the cerebellum, this is an emerging area of particular interest. The cerebellum is dense with receptors for both estrogens and progesterone [38], providing a mechanism by which gonadal hormones may be able to influence structure and function. Further, work investigating resting state functional connectivity of the cerebellum across a 28-day menstrual cycle demonstrated that network dynamics were associated with progesterone and 17β-estradiol [39]. In the context of aging, initial clues suggesting that there may be sex differences came from work looking at volume across adolescence through middle age [40]. In the lateral and posterior cerebellum, females showed a quadratic relationship with age such that volume was largest at mid-life, followed by a downturn [40]. The timing of this point of flux was seemingly overlapping with peri-menopause. Subsequent volumetric work also confirmed some sex differences in the cerebellum with aging [25]. More recently, an investigation of cerebellar connectivity demonstrated that connectivity with the cortex in females differs based on reproductive stage, with differences emerging during the peri-menopausal stage [41]. There were also significant interactions when looking at age-matched male groups, suggesting that differences in females are above and beyond those associated with age alone [41]. Connectivity associations with age in the dentate nucleus of the cerebellum also seem to differ in males and females [28]. Finally, there are emerging suggestions to indicate that levels of gonadal hormones (17β-estradiol and progesterone) interact with sleep in middle-aged and older adult females to predict cerebello-cortical connectivity [42]. Given the widespread behavioral contributions of the cerebellum [3], including in domains that may be more negatively affected in aging females, we propose that investigating sex hormones and the menopausal transition in the cerebellum is a particularly exciting future area of research that stands to provide novel insights into both the cerebellum and aging.

The Cerebellum in Parkinson’s Disease

Parkinson’s Disease (PD) results from degeneration of dopaminergic cells in the midbrain [43]. While traditional approaches to investigating PD focused primarily on dopamine and the basal ganglia to understand parkinsonian deficits, Wu & Hallett [44] and Mirdamadi [45] argue pathology and compensatory mechanisms in the cerebellum also play a critical role. Alpha-synuclein Lewy bodies found in the Purkinje cells in the cerebellum [46] and iron accumulation in the dentate nuclei [47] result in alterations of white matter and deep nuclei damage leading to functional impairments. Work using resting state functional connectivity has demonstrated that in PD patients, cerebellar connectivity is altered, but in a medication-dependent manner [48]. That is, patients were examined on and off L-DOPA medication, and connectivity patterns differed as a result [48]. When off medication, cerebellar connectivity was higher relative to older adult controls, and when on, it was lower. Festini and colleagues argue that perhaps that L-DOPA medication resulted in an overcorrection within cerebellar networks [48]. Given the potential scaffolding role of the cerebellum in advanced age [33], the interactive effects of disease in the case of PD make further investigation particularly important. While there have been suggestions of pathology in this region in PD for over a decade or more, this area has remained relatively understudied.

The Cerebellum in Alzheimer’s Disease

Much like the broader literature on the cognitive neuroscience of aging, work on Alzheimer’s Disease (AD) has not provided as much consideration of the cerebellum. However, new work in this area has highlighted the potential of the cerebellum in this field (for reviews see [49], [50], and [51]). While the cerebellum was long thought to be spared from Alzheimer’s Disease due to a lessened presence of typical AD pathology, particularly senile plaque deposition and neurofibrillary tangles, emerging research shows changes in the cerebellum even when typical pathology is not present. At the cellular level, Purkinje cells are negatively impacted in AD [52]. More globally, recent findings show decreased cerebellar gray matter volume throughout the progression of MCI and AD [53,54]. Findings from Toniolo et al. [54] show initial declines in cerebellar gray matter volume in amnesiac mild cognitive impairment (a-MCI) with progressive volumetric decline in AD patients. More recently, Lin and colleagues [53] used cerebellar gray matter volume to predict the odds of progression from MCI to AD in amyloid negative a-MCI patients. Cerebellar volume was also associated with cognition in MCI, suggesting the cerebellum as a modulator of cognitive function in early stages of cognitive impairment [53]. Finally, functional connectivity of the cerebellar dentate is also altered in AD [55].

Amyloid beta is present in the cerebellar cortex in early onset AD, but not in other dementia types or brains unaffected by dementia (reviewed in [49]). However, the cerebellum does not typically show tau deposition. One notable exception of cerebellar tau deposition is in those with early familial onset AD due to the to presenilin-1 mutation E280A [56]. This unique pathology further asserts the importance of examining the cerebellum in AD and suggests examination of the cerebellum as a way of distinguishing between clinical phenotypes.

While the cerebellum may appear spared from AD pathology, Xu et al. [57] examined changes in protein expression in AD and found a 20% change in protein expression in the cerebellum, even without tau pathology present. Further, though the cerebellum was thought to be relatively spared, results demonstrated impacts comparable to regions thought to be severely affected such as the hippocampus and entorhinal cortex [50]. This further underscores the potential impacts of AD on the cerebellum. Much like in PD, research in this area is nascent, but stands to be fruitful for improving our understanding of age-related neurodegenerative disease.

Cerebellum as an Intervention Target

Given the purported scaffolding role that the cerebellum plays with respect to aging [33], and its connections with both motor and cognitive regions of the cortex [58,59], the cerebellum may be a particularly effective target for remediation of deficits in advanced age. Brain stimulation is a particularly promising area in this regard. Indeed, recent work using cerebellar transcranial direct current stimulation (tDCS) in conjunction with fMRI demonstrated that cortical activation is altered relative to sham in young adults [60], while work using transcranial magnetic stimulation (TMS) targeting the cerebellum has resulted in alterations in cortical brain network connectivity [61]. In patients with schizophrenia, cerebellar stimulation again modulated network connectivity, which in turn improved symptom severity [62]. This provides proof of principle that cerebellar stimulation can impact cortical activation and network connectivity, which in turn can potentially impact behavior. While psychiatric symptoms are distinct from the motor and cognitive deficits discussed here, we suggest that stimulation may have analogous impacts on behavior. Further, modulating the cortical excitation of the primary motor cortex indirectly affects the cerebellum [63]. We suggest other emerging non-invasive brain stimulation techniques such as transcranial focused ultrasound (tFUS) and transcranial unfocused ultrasound (tUS) [64] could also be used to modulate subcortical excitability and in turn improve behavioral outcomes for older adults, or those with age-related neurodegenerative disease. tFUS and tUS can be used to reach more focal or deeper brain sites relative to other stimulation techniques. This is also potentially promising for targeting the deep cerebellar nuclei. With that said, because tFUS and tUS are relatively new techniques, current challenges and future research directions remain unclear [65]. Though we have suggested approaches primarily focused on brain stimulation, other avenues for remediation exist. Medication, training and exercise, or brain stimulation are beneficial approaches, individually, and a combination of these approaches could have greater efficacy for behavioral outcomes. No matter the approach however, we suggest that the cerebellum may be a particularly useful and effective target in this regard.

Summary

The last several decades of research on cerebellar function have firmly established a role for this structure in non-motor behavior. In the cognitive neuroscience of aging, research on the cerebellum remains a nascent area, but one with a great deal of potential. There is a strong foundation of work in this area demonstrating that cerebellar structure, network connectivity, and functional activation are all impacted in advanced age [16,24,25,31,33], and in many cases are related to behavioral performance [24,27]. Recently, the cerebellum has been conceptualized as crucial scaffolding for cortical function in advanced age [33], integrating it into broader frameworks in the cognitive neuroscience of aging. Here, we have highlighted future directions in this field, with a particular emphasis on the cerebellum in the female brain in the context of menopause and the menopausal transition in mid-life, in PD and AD, and as a target for remediation via non-invasive brain stimulation. This is an exciting area of research, with great potential for our understanding of behavioral differences in aging, and for improving quality of life in older adults.