Lateralized Deficits in Motor,Sensory,and Olfactory Domains in Dementia

INTRODUCTION

If we can reach an early diagnosis of preclinical or prodromal dementia, or better yet, predict the condition altogether, we can administer therapies aimed at preserving the function of crucial cognitive and motor domains affected, thereby minimizing sequelae. Over the past ten years, dementia research has focused on the identification of biomarkers. Recent research has focused on the efficacy of cerebrospinal fluid (CSF) as the means to identify early Alzheimer’s disease (AD) [personal communication, March 26–31 Lisbon, Portugal]. Potential biomarkers, in the CSF, include total tau, phosphorylated tau, and amyloid-β (Aβ) 42 amino acid form, which as suggested in recent research, seem to be applicable to clinical AD patients as well as prodromal patients with mild cognitive impairment (MCI) [1]. However, large scale use of these markers is hampered by their failure to predict AD and other dementias in preclinical patients, imperfect results in MCI patients, and impracticalities associated with the invasive collection of CSF [2]. Current studies focus on potential clinical markers such as olfactory, sensory, and motor function deficits as these three domains are severely impaired during the course of AD [2]. If we can identify earlier, non-invasive clinical markers, before significant tau or amyloid levels can be noted, we can better understand the clinical course and develop proper therapies to minimize later dementia functional losses.

Motor impairment in dementia worsens during disease state, as well as developing years before any cognitive impairment. Furthermore, results have suggested that motor impairment is a potential predictor to separate an MCI group from a normal age matched group [3]. From CSF-based biomarkers, overexpression of AβPP and Aβ, and presence of APOE4, has been associated with significant motor neuronal impairment [2]. Research has shown that fine and complex motor functions are impaired in an MCI group, whereas gross motor function is severely impaired in AD patients [3]. Thus, gross motor function has emerged as a viable dementia clinical marker.

Sensory impairments as potential clinical markers in dementia may be used in practice; however, further research is required in order to determine sensitivities and selectivities of these clinical deficits for use as clinical markers [4]. Clinical research in dementia has largely focused on visual and olfactory functional deficits. Despite studies demonstrating that tactile recognition and learning is severely impaired in AD when compared to other neurological diseases, little work has been performed regarding loss of tactile recognition as a potential marker [5]. Other studies have noted deficits in tactile angle discrimination in AD and MCI groups, as well as the association of both astereognosis and agraphesthesia with cognitive decline in AD [6,7, 6,7].

Research has determined that AD pathology is present in both the peripheral and central olfactory neural network, with significant decline in odor identification [2]. This possibly extends to other dementia types. Furthermore, olfactory impairment has been associated with reduced hippocampal volume by structural MRI testing, suggesting that a measure of olfactory odor identification can predict AD, as well as the progression toward prodromal AD in the preclinical population [2]. Thus, olfactory function has emerged as a viable dementia clinical marker.

Lateralized deficits of body functions in these domains has been noted in some neurodegenerative diseases. In Parkinson’s disease (PD), a significant relationship is found between right sided motor impairment and verbal memory, visual perceptual skills, and verbal fluency, which is not found for left-sided motor impairment [8]. Other PD studies have shown that when left-sided motor symptoms develop first, there is a significant association with poor cognitive outcomes [9]. While lateralization studies in PD are inconsistent for their association with cognitive decline, this served as motivation to study their lateralization in the context of dementia. In neurodegenerative disease patients, lateralized deficits extend to the olfactory domain. Left olfactory function appears more compromised in PD, whereas an age matched control group showed no such lateralization [10]. It is important to note that the connection of functional lateralizations to neurodegenerative outcomes in PD has been found in some but not all studies. The question arises as to whether these body lateralizations in olfactory, sensory, and motor domains are unique to PD or are also shared by AD and other dementias. Understanding this potential lateralization would lead to both the development of clinical, non-invasive markers, and subsequent therapies aimed at strengthening these three domains. This study examines the lateralizations in olfactory, sensory, and motor function deficits in dementia. These functions were selected due to their clinical relevance as potential clinical markers as well as recent studies showing the existence of a motor, sensory, and olfactory neural circuit governing behavior [11, 12]. In addition, we seek to identify correlates of lateralizations to support clinical markers and strengthen therapeutic interventions. For our study, lateralization is used to refer to body, not brain, function deficit.

METHODS

In this Institutional Review Board (IRB) approved study, consent for the subject’s participation was acquired from the subject’s Power of Attorney (POA). Recruitment was done with the help of the memory care communities that the study took place at, using emailed flyers and in person talks with POA. Exclusion criteria included: no POA approval, below age of 55, above age of 100, hospitalized during time of study, subject declining study (respecting dissent), aggressive/labile behavior, delirium, presence of acute medical issues (i.e., chest pain, shortness of breath, active ulcer disease) as these could bias results. Inclusion criteria included: presence of any non–acute dementia for over 1 year, residence at a long–term memory care community, POA approval, subject assent, ability to perform functional clinical testing.

Each participant was given a one-time administration of the Mini-Mental Status Exam (MMSE) to evaluate their current level of dementia (the study did not exclude participants with specific types of dementias) [13]. Furthermore, functional (e.g., number of falls in the past 90 days), medical (e.g., use of psychotherapeutic agents), and laboratory (e.g., HbA1C) data were collected from the subjects’ medical records (Table 1). These data were used to analyze correlates of functional lateralizations.

Lateralized sensory and motor deficits are very common after certain neurological conditions such as: stroke, transient ischemic attack, multiple sclerosis, traumatic brain injury, anoxic brain injury, cerebral palsy, chronic regional pain syndrome, amputation, or post–polio syndrome. To the authors’ knowledge, two subjects had a history of stroke: both subjects did not have any significant residual effects (motor or sensory) and were therefore included. None of the subjects suffered from the other listed conditions.

Discrete left and right motor grip strengths were measured using a Baseline^® LITEtrademark Hydraulic Hand Dynamometer 12–0241 set to the second position (considered comfortable grip for this population). This one grip setting was used for all subjects to maintain consistency and chosen due to being more comfortable. Subjects were sitting with their forearm at a 90-degree angle and asked to grip the dynamometer as strong as possible (Fig. 1). This was performed twice on each side. The first side tested was selected randomly.

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Fig.1

Motor Functional Test. Demonstrating right-side grip strength measured by dynamometer.

To measure tactile response to sensory stimuli, discrete left and right upper extremity sensory tactile functional tests were performed using a Von Frey test with Aesthesio^® filaments. Subjects were seated with their forearm at 90 degrees. Researchers applied the Von Frey filaments to the subjects’ posterior forearm 10 cm from the wrist extension crease (Fig. 2). The test started with the smallest filament (0.008 g, 1.65 evaluator size) and incrementally increased until the subject reported sensation (minimum recognized sensory threshold). The test was administered once to each arm and both verbal and non-verbal cues, such as recoil, were recorded. The first side tested was selected randomly.

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Fig.2

Von–Frey Sensory Tactile Functional Test (left and right arm).

Discrete left and right olfactory functional tests were performed using AuraCacia Cooling Peppermint Essential Oil. The subject occluded one of their nostrils, while the bottle of peppermint oil was held 10 cm horizontally, at nostril level, on the non-occluded side by the researcher (Fig. 3). By noting either verbal or non-verbal response from the subject, the time taken to sense the olfactory stimulus was recorded, by another researcher. This was repeated for the opposite side and done twice for each nostril; the first nostril tested was randomly selected.

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Fig.3

Olfactory Functional Test.

None of the administered motor, sensory, or olfactory tests resulted in any irritation to the subjects. POA was encouraged to attend examinations, and both POA and subjects always had the right to refuse testing.

Subjects with missing data for the dynamometer, Von Frey, and/or oil smell tests were excluded from data analysis.

To determine motor sided deficits, the two dynamometer trials for both left and right grip strength were respectively averaged, and a one-tail paired T–test was used. All dynamometer values fell within a reasonable range and thus were included in data analysis.

To determine sensory sided deficits, the Von Frey score for right tactile sensory threshold was paired to the Von Frey score for left tactile sensory threshold for each participant. Using the paired Von Frey scores for each subject, a one-sided paired T–test was used. So as to avoid outlier bias and to maintain exact values, any participants who did not exhibit response up to, and including, the maximum Von Frey diameter filament were not included in the data analysis.

To determine olfactory sided deficit, the two trials of olfactory latency for both the left and right nostrils were averaged, and a one-tail paired T–test performed. To avoid outlier bias, if participants were not able to smell the peppermint stimulus, after one-minute exposure, this latency was not included in the data analysis.

To determine correlates, clinical variables that make the lateralization more pronounced, correlations were calculated between potential correlate and the right-left sided deficit difference in domain function (Table 3). These clinical variables were selected from patient medical charts. Continuous variables were done with the Pearson correlation and continuous versus binary variables were done with the Point–Biserial correlation. Then p–values were calculated twice: once for the group filtered by the presence of a correlate, and once for the group filtered by the absence of a correlate. This was done in order to approximate what other factors can be affecting this lateralization.

RESULTS

Shown in Table 1 is the study population including demographic, clinical, and biohumoral characteristic of the cohort.

From Table 2, a lateralization of loss of function of sensory and olfactory is found to the left body side (p = 0.0387, p = 0.0515). When taking into account the actual difference in filament sizes, a one-tailed paired T–test demonstrates that the sensory deficit is more severe on the left (Table 4). Of the 37 participants who were included in the analysis, 25 (67.6%) had a greater latency for recognition of stimuli presented to the left nostril than when presented to the right nostril.

A lateralization of loss of function of motor ability is found to the right body side (Table 2). Peterson et al. demonstrated that in non-dementia, right-hand dominant subjects, right grip strength is significantly greater than left grip strength [14]. From our study (dementia population), there is no significant relationship (p = 0.127) between handedness and grip strength for right-hand dominant subjects. Of the 57 right–handed participants, only 29 (50.9%) had a greater dynamometer score for right grip strength.

In an effort to further characterize the lateralization of the functional deficits, correlates (factors that cause lateralization to be more extreme), were identified. To predict which variables could possibly be associated with lateralization of deficits for each of the three domains (motor, sensory, and olfactory) the correlation was calculated between lateralization results and each clinical variable (medical, laboratory) (Table 3).

Clinical correlates of the motor right sided deficit are: female (p = 0.434, n = 32), depression (p = 0.455, n = 29), MMSE <15 (p = 0.382, n = 24), and diabetes (p = 0.451, n = 13). Clinical correlates of the sensory left sided deficit are: use of psychotherapeutic agent (p = 0.0514, n = 47), age ≥85 (p = 0.070, n = 30), MMSE <15 (p = 0.0732, n = 30), and male (p = 0.0826, n = 25). Clinical correlates of the olfactory left sided deficit are: age <85 (p = 0.00262, n = 24), number of medications >10 (p = 0.0725, n = 24), and male (p = 0.0742, n = 15).

DISCUSSION

In AD and other dementias, the discovery of lateralizations of loss of function of the motor, sensory, and olfactory domains offers exciting opportunities for the development of non-invasive clinical markers, functional therapies, and new perspectives to study pathology.

We demonstrate that the right motor domain is weakened more severely than the left motor domain in patients with dementia. In the context of Lewy body dementia, frontotemporal dementia, and vascular dementia, this can potentially be used to track dementia severity; cognitive symptoms develop before motor in this dementia and therefore, once a motor lateralization is noted, disease severity can be categorized. This imbalance in upper–motor–ability leads to decreased strength and thereby decreased activities of daily living such as bathing, eating, dressing, grooming, and personal hygiene. Occupational–therapy programs aimed at restoring ability in upper motor domains through right–side strengthening can have great social and clinical impact by improving independence.

Analogous to the upper–motor imbalance, lower–motor ability may be similarly affected by the dementia process. The primary left motor cortex is responsible for much of the right motor domain, not only controlling grip strength but lower limb strength as well. Sided impairment of the primary motor cortex may lead to chronic falls, loss of ambulation, need for equipment, increased energy demands, and general fatigue related issues. Specifically, chronic falls have been documented as a severe sequela in dementia that carries a high morbidity; based on lateralized motor loss, physical therapies, such as balance and strengthening programs, can work to reduce chronic falling, thus reducing fractures and emergency department visits that themselves can advance the dementia process [15].

We demonstrate that the left tactile sensory ability is weakened more severely than right tactile sensory ability in dementia. This lateralization may be due to right–sided lesions to the primary sensory cortex. This sided imbalance in sensory ability may contribute to a loss of proprioception and loss of sensory input resulting in potential for injury. To prevent potential injuries, patients with dementia can be encouraged to rely on their right side for needed sensory–related input; at the same time, sensorial therapies can retrain their left side.

Common to both AD and PD is the early development of sided deficits of olfactory, sensory, and motor functioning in the preclinical and early disease states [2,3,6,16,17 , 2,3,6,16,17]. The early development of a functional deficit has been discussed as a potential clinical marker. AD and PD share similar characteristics, including substantial reduction of hippocampal nicotinic binding, reduction in choline acetyltransferase level, and increased risk and decreased age of onset with apolipoprotein E-4 allele variant [18 , 20]. Specifically, decreased odor detection was suggested as a preclinical test, as decreased odor detection was found significantly related to both de novo and long-term PD patients [16]. Due to pathologic similarities in AD and PD, decreased odor detection may act as a marker for the preclinical AD population. Olfactory dysfunction correlates to Aβ and hypothesized that the mechanisms for accumulation of Aβ likely contribute to early olfactory loss in AD [21]. Crucially, Aβ deposition first occurs in the olfactory bulb, before any other brain region, in mice overexpressing a mutated form of the human amyloid-β protein precursor [21]. Our study showed that loss of function in olfaction, in the dementia population, is more severe on the left nostril. To further develop olfactory dysfunction as a clinical marker for AD, we suggest specifically testing deficits of both the left and right nostrils. The difference between right and left olfaction could act as an early marker of dementia and can be charted longitudinally by a clinician. As this difference becomes more significant, it may serve as an indicator of dementia.

By examining these three domains, clinicians may use these simple, clinical tests as markers for dementia. Furthermore, the combination of these can be used as a therapeutic program to improve function. This study has limitations of not discriminating among different dementia types due to a low population size; the cohort was limited by only including assisted–living subjects. Future research should segregate by dementia types; the ability to use these clinical tests for disease prediction and tracking would be greatly expanded, as the current study analysis of lateralization is complicated by including all dementias. Future studies should also include differential diagnosis, handedness, larger population sizes, age matched non–dementia control group, explore lower limb for sensory and motor domains, and perform longitudinal studies.

This study provides clinical evidence for the lateralization of motor, sensory, and olfactory deficits in patients with dementia.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/20-1216r1).