In this study we sought to compare NPS rates across multiple neurodegenerative and cerebrovascular diseases and determine the relative contribution of cortical atrophy and white matter lesion load to NPS. The major findings included: (1) NPS were common across all diseases which was consistent with the literature; and (2) focal cortical atrophy was significantly associated with NPS subsyndromes across all disease groups. Moreover, although there was a significant association between WMH burden and NPS subsyndromes in the univariate analyses, it was not maintained in the multivariate analyses signifying that across these diseases, focal atrophy contributed more to NPS.
We observed that participants with FTD had higher rates of agitation, anxiety, apathy, appetite changes, delusions, disinhibition, euphoria, irritability, aberrant motor behaviour, and nighttime behaviours than the other neurodegenerative or cerebrovascular groups. This is consistent with other research that showed that FTD was associated with higher rates of behavioural symptoms including NPS than other neurodegenerative diseases [79–83]. This finding may be related to the early alterations in the fronto-subcortical structures seen in FTD that are responsible for various behavioural functions [84]. Such alterations are often observed in bvFTD which accounted for a large portion of our FTD sample (40%), and several reports have indicated that the manifestation of certain NPS like apathy are early and frequent signs of bvFTD [85,86]. These signs may appear in isolation or concomitantly with executive dysfunction thus, aiding in differentiating bvFTD from other neurodegenerative conditions [85,87]. Nighttime behaviours were significantly higher in PD whilst there was only a trend for higher hallucinations in that group. Our results support the findings of Liew [88] which observed that whilst psychotic symptoms were rarely reported by caregivers, they were associated with all subtypes of dementia compared to affective and agitation symptoms. Furthermore, the presence of psychotic symptoms was associated with higher risk of developing non-AD dementia than AD dementia [88]. This is consistent with the notion that visual hallucinations and sleep disorder have been documented in PD and FTD-parkinsonian syndromes, but are more common in PD and most common in Dementia with Lewy Body (DLB) [89–91]. Likewise, the frequencies of the aforementioned psychotic symptoms are strong indicators of PD and DLB and their absence could serve to suggest another diagnosis [92–94]. DLB patients were excluded in our study based on 90 – 100% PD diagnostic certainty.
The most prevalent NPS across all groups in our study was depression. This is in keeping with prior studies that have reported no significant difference in depressive symptoms across neurodegenerative diseases [80–82,95]. Both anxiety and depression can be presenting symptoms and probable risk factors of neurodegenerative disease as well as strong predictors of cognitive decline [96–101]. Furthermore, depression and anxiety may be more apparent in early to middle stages of dementia as they can be both early symptoms as well as a reactive response [101–103], and less pronounced at later stages as the cognitive functions essential to maintain them decline [81,101].
Our study found that irritability and nighttime behaviours were more frequent in males than females across the entire sample, in AD/MCI, FTD, and PD. Additionally, males with FTD or PD were more likely than females to experience NPS, such as delusion, apathy, and depression whilst females with AD/MCI were more likely than males to experience depression. Studies examining the sex/gender differences in presentation of NPS in dementia have mostly been in AD/MCI and have reported inconsistent findings [104–108]. The higher frequency of depression in females with AD/MCI are in line with previous studies that reported that females more often display affective disorders, compared to males [106,109–111]. Milani et al. [107] found that females had higher odds of dysphoria/depression or anxiety compared to males in community-dwelling older adults. Another study found that depressive symptom was two-fold associated with a greater risk of AD in females but not males [112]. Furthermore, the observed higher irritability, nighttime behaviours, delusion, and apathy in males are similar to several studies that reported higher frequencies of the aforementioned NPS in males compared to females [104,113–115], whilst contradicting others that have showed the opposite [104,105,111,114]. These discrepancies may be attributed to multiple factors such as the genetic predisposition to AD including the interaction between sex and apoE4 in AD/MCI [105,116], sex-related hormonal levels, or the use of pharmacological treatments [115]. For instance, about 30% of individuals with AD/MCI experience psychotic symptoms [117] compared to 50% of individuals with PD or DLB, the latter two which are more prevalent in males than females [118,119]. Moreover, bvFTD which appears to be more prevalent in males [120], has been reported to have more apathy and psychotic symptoms and less empathy as major predictors of disease progression [71,96,121]. A recent study found that females with bvFTD performed better on executive function task and displayed fewer NPS, particularly apathy, sleep disturbance, and appetite changes than males, despite showing similar amount of atrophy burden [122], which may support the neuroprotective role of oestrogen hormone in females [123]. Conversely, the progression of AD in which females account for majority of the diagnosis [124], has been more frequently associated with the presence of depressive symptoms [112], in line with the notion that females use more antidepressants and males more antipsychotics [106,115]. Another possible explanation could be differences in disease severity across studies, the use of different NPS assessment instruments, and/or participants’ demographics, including age and ethnicity may affect sex-related NPS manifestation across neurodegenerative and cerebrovascular disorders.
Cortical atrophy was implicated in NPS across all groups. Although we obtained several brain regions within each NPS subsyndrome, we concentrated on those that appeared across subsyndromes and analyses like the pars-triangularis, prefrontal, cingulate, temporal and frontal poles, and insula cortices. Apathy is a multifaceted syndrome representing deficits in cognition, emotion, and initiation [125]. It is not surprising that several studies report similar neuroanatomical correlates of apathy regardless of the underlying pathologies. Apathy is associated with changes in the fronto-striatal circuits (the dorsal anterior cingulate cortex and ventral striatum) in addition to the orbitofrontal cortex, ventral pallidum, thalamus, basal ganglia, and ventral tegmental area [126]. In PD, the neural correlates of apathy have been structurally and functionally linked to a broad range of regions modulated by dopamine like the ventral striatum, prefrontal cortex, anterior cingulate, bilateral inferior frontoparietal, nucleus accumbens, and ventral tegmental area [127–133]. Likewise in AD/MCI, Guercio et al. [20] found apathy was associated with decreased inferior temporal and increased anterior cingulate thickness in MCI whilst other studies found atrophy of the bilateral anterior cingulate, left prefrontal, left caudate nucleus, and bilateral putamen regions were associated with apathy in AD [39,134–136]. These findings in AD/MCI have been corroborated in some functional imaging studies that observed a relationship between apathy and hypometabolism in the anterior cingulate cortex and medial prefrontal cortex [137–139] in addition to being linked with increased neurofibrillary tangles in the anterior cingulate cortex [140].
The anterior cingulate has been implicated in apathy in FTD, ALS, and CVD. In FTD, apathy was related to atrophy in the ventral striatum and caudate nucleus in addition to anterior cingulate, orbitofrontal, middle frontal, and insula cortices in bvFTD [12,141,142]. Similar regions associated with apathy in participants with ALS-FTD [143] and ALS without dementia [15]. Lesions in the fronto-striatal circuits result in apathy [144,145] and so it is a common symptom of both ischaemic and haemorrhagic strokes [145] with lesions involving the medial frontal gyrus and its surrounding regions like the cingulate, frontal pole, and superior frontal cortices resulting in apathy or related disorder abulia [impaired volition] [126]. Moreover, functional neuroimaging has demonstrated decreased functional connectivity in the cingulo-opercular network due to dysfunction of the connecting regions [146]. Together, these results imply that the manifestation of apathy across multiple neurodegenerative and cerebrovascular diseases results from the disruption of critical and interconnected regions – mainly anterior cingulate cortex and ventral striatum – that are necessary for goal-oriented behaviours.
Psychosis was also associated with fronto-cingulate and left precuneus atrophy. The inferior frontal and precuneus cortices have been implicated in visual hallucination and delusion [147]. Lower grey matter volume in the left frontal lobes, right frontoparietal cortex, and left claustrum were associated with delusions in AD [135] whilst cortical thinning in the supramarginal gyrus was found in both AD and PD with visual hallucinations [19,148]. Additionally, Sanchez-Castaneda et al. [149] found visual hallucinations were associated with atrophy in the left precuneus and right inferior frontal areas in DLB and left orbitofrontal in PD with dementia. Another study found patients with PD with formed visual hallucinations showed grey matter atrophy in the inferior parietal lobule adjacent to the precuneus [150]. One possible theory regarding the mechanism of psychosis in neurodegenerative diseases is that they stem from dysregulation amongst the frontoparietal networks. In keeping with this concept, Shine et al. [151] found an increase in connectivity between the default mode and ventral attention networks and a decrease in the default mode network (DMN) in patients with PD with visual hallucinations compared to patients without. In AD/MCI, Qian et al. [152] reported decreased connectivity of the inferior parietal lobule of the DMN, left superior temporal, and orbitofrontal were associated with greater delusion severity in patients with AD with delusions compared to without. Thus, suggesting that the disruption between top-down dorsal attention and bottom-up ventral attention and default mode networks processing can result in psychosis [153]. In relation to FTD, ALS and CVD, only a few studies have explored the neural mechanism of psychosis [154,155]. Devenney et al. [154] reported a predominant frontal and temporal pattern of atrophy extending to cerebellum and anterior thalamus across all ALS-FTD continuum, particularly in C9orf72 carriers. Whilst Stangeland et al. [155] found the majority of post-stroke patients with psychosis had right hemisphere lesions mainly in frontoparietal and basal ganglia regions. Since these are network-based diseases, it is possible that psychosis can result from dysfunction of core neural networks that are associated with perception and beliefs in addition to interacting with other associative networks, thereby leading to disease-specific psychotic symptoms [156].
We found that increased right basal ganglia/thalamus WMH volume was associated with psychotic, affective, and hyperactivity subsyndromes whilst increased left frontal WMH volume was associated with apathy subsyndrome, albeit a lesser contributor than cortical atrophy. Our results are in contrast to two recent longitudinal studies that showed that WMH contributed more to the progression of NPS subsyndromes than focal atrophy in individuals with AD/MCI [39,157]. Previous studies have demonstrated that lacunes and WMHs in the fronto-striatal circuitry were correlated with affective disorders [29,40,158–160], psychosis [31,161], and reduction in goal-oriented behaviours [29,32,162] in neurodegenerative and cerebrovascular diseases disease. Kim et al. [32] reported that lacunes and WMH, especially in the frontal lobe, were associated with depression and apathy in subcortical-vascular cognitive impairment. In the aforementioned study, BGT WMH were included as part of the frontal lobe. Similarly, a study on individuals with autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) found that basal ganglia and thalamus lesions were associated with apathy [162] whilst another reported an association between depression and frontal and temporal WMHs in community dwelling older adult [158]. In probable AD, increased frontal WMH was associated with apathy whilst increased right parietal WMH was associated with depression [29] which was supported in an autopsy-confirmed FTD and AD study that showed increased right parietal WMH was associated with depression, subcortical WMH was associated with euphoria, and apathy was associated with bilateral frontal WMH [163].
The few studies that have investigated the association between WMH and NPS in PD have reported mixed results. Kraft et al. [164] found no association between global and occipital WMH with visual hallucinations in PD although, patients with visual hallucinations were more disabled. Also, two studies found that increased WMH was associated with depression and anxiety in PD [38,165], particularly in fronto-striatal region [38] whilst another study found that baseline WMH volume was a risk factor for apathy progression in PD [166]. These inconsistences in the localisation of WMH in relation to NPS echoes the notion that injury to any site in a network may contribute to the disruption of cortico-subcortical circuits and the manifestation of NPS across many clinical constructs [167], as well as difficulty in capturing multiple NPS as a singular concept, e.g. affective.
Limitations and Strengths
The current study has several limitations and strengths. Firstly, the generalisability of our findings might be impacted due to the lack of healthy controls in our study. Secondly, we were limited from addressing the cause-effect relationships amongst WMH, cortical atrophy, and NPS due to the cross-sectional nature of our study. However, as discussed above from a recent longitudinal study, WMH may contribute more to NPS progression than grey matter atrophy, at least in individuals with AD/MCI [39,157]. This may suggest that at baseline, focal cortical atrophy may have the greatest influence of NPS but that WMH may impact NPS progression. Thirdly, we did not account for the use of antipsychotics, antidepressants, anticholinergics, and stimulants for treatment of NPS (which might affect symptom severity in our cohorts). Lastly, since clinical and neuroimaging parameters were used to make the diagnoses of disease categories without diagnostic biomarkers, some observed relationships in our cohorts might have been influenced by mixed pathology because it is very common and increasingly recognised in neurodegenerative diseases [168].
A main strength of our study was the inclusion of multiple neurodegenerative disease groups, especially participants with ALS, FTD, and PD. Prior research examining atrophy and/or WMH correlates of NPS have mostly focused on AD/MCI and CVD [31,32,39], occasionally on PD and FTD [163,165], and rarely on ALS [143]. Thus, our study provides an opportunity to investigate these associations across several disease groups. Also, we were able to adjust for several factors associated with atrophy and WMH in our models.