This study revealed that the resistance and perfusion components of the ultrasonographic parameters unequally contribute to the MMSE and FAB scores (Fig. 3B). The MMSE score was predicted by the perfusion component, which has a close relationship with local ultrasonography parameters (DA, PSV, EDV, and MV). Meanwhile, the FAB score was predicted by the resistance component, which has a close relationship with downstream ultrasonography parameters (PI and RI) (Fig. 4).
The concept of dementia has existed throughout recorded history. It was long considered a consequence of healthy aging23, whereas now, it is regarded an outcome of a disease, such as Alzheimer's disease. Although memory loss (i.e., dysfunction of the temporal lobe) was considered the major symptom of DAD24, with the preservation of frontal function till the late stage24, recent studies have revealed that impairment in executive function (i.e., dysfunction of the frontal lobe) presents from an early stage25. It is consistent with the fact that MMSE cannot screen one third of all patients with mild cognitive impairment26. Hence, it is important to assess frontal and temporal function to appropriately diagnose dementia, especially at an early stage. A previous review introduced the concept that cognitive impairments associated with the temporal lobe arise from the pathology of Alzheimer's disease, while impairments associated with the frontal lobe occur in healthy ageing27. Although this concept provides a new insight, it has two limitations for clinical use: (i) it is not possible to quantify the degree of contribution of causative diseases in vivo as it requires autopsy, which is not available in clinical practice. (ii) The definition of 'healthy ageing' is vague (e.g., brain age is affected by lifestyle and does not correspond to the biological/chronological age28).
In this study, we showed that the two aspects of cognitive impairment (i.e., learning/memory and executive function) can be quantified using ultrasonography, which is an objective measurement tool available at ordinary clinics and hospitals. Six ultrasonographic parameters were subdivided into resistance and perfusion components using PCA (Fig. 3A). The LMEM analysis showed that the MMSE and FAB scores were predicted by the perfusion and resistance components, respectively (Fig. 3B). The mismatch between the MMSE and FAB scores (Fig. 1) indicates that they reflected dysfunctions in different cognitive domains, such as memory and executive function. This supports our hypothesis that two subtypes of vascular risk factors (perfusion and resistance components) are associated with different types of cognitive impairment (MMSE and FAB) (Fig. 4). The FAB is a neurophysiological assessment originally developed for rapid and easy assessment of frontal functions, such as executive function16,29. The frontal lobe is susceptible to atherosclerosis15,30, which is associated with downstream factors (PI and RI). The PI represents the hyper-pulsatility of the carotid blood flow and reflects the transmission of pulsatile energy into the cerebral microcirculation. It is positively associated with the development of stroke31, which is a major risk factor for VaD. Patients with VaD tend to show executive dysfunction dependent on the frontal lobe and show little or no memory impairment32, which heavily depends on the temporal lobe. The RI reflects impaired blood flow caused by the microvascular bed, and is correlated with arteriosclerotic risk factors12,14. In short, there is an interplay between the resistance component, downstream parameters (PI and RI), atherosclerosis, the frontal lobe, and executive dysfunction (Fig. 4, left). We speculate that the FAB score is sensitive to cognitive impartments as atherosclerosis mainly affects the frontal lobe rather than the temporal lobe. The MMSE is another neurophysiological assessment originally developed for dementia screening33. It primarily evaluates learning and memory resources, which depend on medial temporal lobe structures such as the hippocampus34. The MMSE score is associated with grey matter atrophy, mainly in the medial temporal lobe34, a region not susceptible to atherosclerosis15. This study showed that the MMSE score was associated with the perfusion component, which is closely associated with local parameters such as PSV. Previous studies showed that PSV was correlated with MMSE scores10,35 and cerebral blood flow, especially in the mesial temporal area13. Further, cerebral blood flow measured using positron emission tomography was negatively associated with changes in MMSE scores during a 3-year observation period7. Cerebral blood flow is associated with the hippocampal volume36, and the left hippocampal volume is correlated with the MMSE score37. Furthermore, hippocampal blood flow is associated with the memory function38. Taken together, there is an interplay between the perfusion component, local factors (e.g., PSV), cerebral blood circulation, temporal lobe (i.e., hippocampus), and learning and memory (Fig. 4, right). It is reasonable to assume that the perfusion component is associated with the MMSE score via its involvement in temporal functions. On the other hand, the temporal lobe is not susceptible to atherosclerosis15, which is associated with the resistance component. This is consistent with the present finding that the MMSE score was not predicted by the resistance component.
Conventional classification of dementia depends on the pathology of the causative diseases. However, it has some limitations. Accurate pathological diagnosis requires autopsy, which is not available in clinical practice. A previous autopsy study revealed that up to 75% of cases had multiple brain pathologies39. So far, we have few effective treatment strategies that act directly on the causative pathology. Meanwhile, dementia is intrinsically defined by its neuropsychological symptoms. Therefore, it is desirable to have a classification system based on an objective and practical medical examination, which corresponds to the assessment of its symptoms rather than causative disease to prevent and treat cognitive impairment and dementia.
There are three potential limitations of this study. First, we chose the MMSE and FAB because these assessments are routinely used in medical health-check services. However, we believe that the arbitrary selection of neuropsychological assessment scores does not affect our results in a major way, and the combination of the MMSE and FAB evaluations comprehensively proved the proposed hypothesis. Second, the MMSE and FAB scores are not entirely dependent on temporal and frontal lobe functions, respectively 40,41. The MMSE was originally developed for distinguishing old individuals with and without neuropsychiatric disorders and it is insensitive to frontal dysfunction42. The FAB was intendedly developed as an assessment tool for evaluating frontal function16. In this study, we focused on cognitive functions based on the individuals’ symptoms during task performance that was measured by neuropsychological assessments, rather than scrutinizing the pathology or anatomy of dementia. Our approach is consistent with the concept of dementia, which is a syndrome rather than a disease defined by a pathology. Finally, the number of individuals was limited, since it was not easy to enroll more individuals without severe cognitive impairment (See Methods). However, increasing sample size was not imperative for this study, because bootstrap statistics allowed us to obtain robust results even with small sample sizes.
This study showed that carotid ultrasonography could contribute to the development of a new classification for dementia. Herein, we have proposed a novel concept that cognitive impairment falls into two distinct subtypes: the hyper-resistance and hypo-perfusion subtypes, regardless of the underlying brain disease. The hyper-resistance type is pathologically associated with atherosclerosis mainly in the frontal lobe, while the hypo-perfusion type is associated with the temporal lobe and is caused by low cardiac output or lesions in the main blood vessels (Fig. 4). This concept allows us to evaluate the degree of cognitive impairment quantitatively along two axes (i.e., hypo-perfusion and hyper-resistance) to overcome the difficulties faced in diagnosing the type of dementia due to an overlap between the various types (DAD, VaD, DLB, and FTD) in individual patients. The two subtypes proposed here should be considered when designing therapeutic strategies for cognitive impairment. Non pharmacological treatment is the first option for cognitive impairment, and previous studies have demonstrated their effectiveness43. Proper hydration or revascularization therapies (i.e., carotid artery stenting and carotid endarterectomy) improve cerebral perfusion44,45, and physical exercise reduces cerebrovascular resistance46. The outcome of these treatments can be regularly monitored using ultrasonography to maximise their outcome; this is suitable because ultrasonography is non-invasive, has a low running cost, and is available at ordinary clinics and hospitals. The proposed concept is treatment oriented and provides novel insights into the treatment of cognitive impairment and dementia.