Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer’s Disease

DISCUSSION

NPS are frequent across all AD stages, adding substantial burden for caregivers and patients [8–21]. By employing a large population-based postmortem sample of cases over 50 years of age, encompassing healthy controls and individuals across the AD spectrum, this study is well-positioned to investigate how NPS correlate with AD pathological hallmarks, particularly in precognitive stages. All cases were free of non-AD pathology, minimizing confounders introduced by co-occurring pathology. We found significant positive associations between NFT burden and several NPS, as early as Braak stages I/II, at which time the NFT are confined to subcortical and allocortical areas and, in most cases, the burden of amyloid-β plaques is very low (Fig. 1) [42, 61]. These results support the hypothesis that NFT-related neurodegeneration constitutes the biological basis of NPS in AD, beginning in pre-cognitive stages. OPEN IN VIEWER

An increasing number of studies highlight that early vulnerability of brainstem and hypothalamic nuclei to NFT pathology occurs before involvement of the entorhinal cortex in AD [12, 38–44]. This burden of NFT pathology in subcortical nuclei increases with Braak stage. Taken together with the literature documenting the functional anatomy of these regions, our results showing that AD pathology may manifest first as NPS— agitation, anxiety, appetite dysfunction, depression, and sleep disturbances— are not surprising [12, 38–45]. Given the functional correlates of these regions affected by early NFT pathology, we can develop testable hypotheses to guide further research on mechanisms that drive early NPS in AD.

For example, dysregulation of norepinephrine due to early NFT accumulation in the locus coeruleus may contribute to the increased odds for agitation in Braak I–IV [62–64]. Several experimental studies have demonstrated increased agitation in response to dysfunction of norepinephrine-producing neurons, including those of the locus coeruleus [65–67]. In a review of neuroanatomical correlates of NPS in AD, Rosenberg and colleagues highlight studies correlating agitation with volumetric loss in the frontal cortex, anterior and posterior cingulate cortices, insula, amygdala, and hippocampus, rather than subcortical pathology [63]. Other studies detected a correlation between agitation and NFT burden in the orbitofrontal and anterior cingulate cortices in postmortem samples [48, 52]. While these studies suggest that NFT in these regions contribute to agitation, they were confined to examination of cortical regions in symptomatic individuals. Thus, it is challenging to tease out the contribution of early subcortical and cortical pathology with the patients at more severe disease stages with possible co-occurring pathology.

In fairly large clinicopathological studies, depression has been correlated with an increased burden of cortical plaques and tangles [50, 51]. Similar to agitation, NFT burden in the orbitofrontal and anterior cingulate cortices has also been correlated with depression, but this effect was only seen in later stages [48, 52]. Instead, early NFT-induced dysfunction of neurons in the locus coeruleus and dorsal raphe nucleus is likely driving our findings of increased odds for depression in Braak stages I/II, in line with the monoamine hypothesis of depression [53, 68–70].

Anxiety has been described as an early symptom in AD and a risk factor for dementia [26, 72]. Historically, the norepinephrine-producing locus coeruleus has been viewed as central in modulating networks involved in anxiety [73, 74]. So-called “anxiety cells” have also been identified in CA1 of the hippocampus, an early cortical site to accumulate NFT (Braak stage II) [5, 75]. Thus, both locus coeruleus and hippocampal involvement in Braak stages I/II align with our findings of increased anxiety at these stages [38, 41]. Donovan and colleagues have recently shown that anxiety is an early clinical manifestation of AD [36]. While this investigation was based on neuroimaging measurements of amyloid-β, the findings may be driven by concurrent subcortical NFT pathology, which could not be measured in vivo. Other neuroimaging studies correlate changes in the amygdala, insular cortex, and anterior cingulate cortex (Braak stage III) with several anxiety disorders in symptomatic patients, suggesting that these regions may also contribute to anxiety, in addition to earlier subcortical pathology [76, 77].

The ventromedial and lateral hypothalamus modulate satiety and hunger, respectively, as well as the locus coeruleus [78–83]. These nuclei are known to develop NFT early in AD, which may be driving the higher odds of appetite dysfunction we detect in Braak stages I/II, suggesting that there is a neuropathological basis driving dysfunction related to eating habits and preferences that has been associated with Alzheimer-type dementia [38, 84]. Further work is needed to refine the features of these appetite changes.

Many AD patients experience sleep disturbances even preceding cognitive decline [85–87]. Wakefulness is governed by high firing rates of wake-promoting neurons including neurons of the locus coeruleus, dorsal raphe nucleus, tuberomammillary nucleus, and lateral hypothalamus, all of which are susceptible to NFT in early AD [38, 88–90]. Recent evidence linking poor sleep to exacerbation of cortical pathology suggests existence of a positive-feedback loop leading to an overall increase in pathology [91, 92].

Finally, we detected high odds of delusions in subjects at Braak stages V/VI. Delusions manifest in several neurodegenerative conditions including Lewy body disease and frontotemporal dementia, and their anatomical correlates are complex [63, 93–95]. In AD, delusions have been associated with degeneration in the right inferior frontal gyrus, inferior parietal lobe, and claustrum, aligning with our findings of delusions beginning late in Braak stages V/VI [96]. As delusions are infrequent in healthy individuals and remain low until late stages, the odds ratio for delusions at Braak stages V/VI is very high, even after controlling for possible confounders (Table 1). Delusions in AD patients are often considered to be an indication of overlapping Lewy body disease [97]. However, in this series, any cases with α-synuclein positivity were excluded, suggesting that at late stages, delusions may be driven by cortical NFT pathology itself.

Clinical and epidemiological studies suggest a correlation between apathy and Alzheimer-type dementia [8–11, 19–21], but we failed to find such correlations here. Most studies of apathy in AD have been conducted in vivo, without autopsy verification. For this reason, they likely included mixed pathologies, such as Lewy body disease, which can increase the risk of apathy [31, 99]. Inflammatory dysregulation, which is not captured by Braak staging or CERAD-NP, is another possible underpinning of apathy [100–103]. The neuroanatomical basis of apathy in AD has also been suggested to include dysfunction of the anterior cingulate, dorsolateral prefrontal cortex, and left medial frontal cortex [48, 104]. Atrophy in the caudate, temporoparietal junction, temporal gyri, and frontal operculum-anterior insula region, detected by neuroimaging, has been associated with apathy in frontotemporal dementia [105]. Studies of apathy in AD focus on cortical changes and typically do not correct for cognitive status or co-pathologies which may explain the differences with our findings. Further, protein hallmarks such as NFT may only be related to mild apathy symptoms, to which the NPI-informant report may be insensitive, compared to direct clinical assessment.

The negative associations between amyloid-β severity, measured by CERAD-NP, and NPS have been observed previously [48, 106]. There are several possible explanations for this finding. In more advanced neuropathological AD stages, the severe cognitive impairment may overshadow NPS detection by informants. Additionally, in early AD stages, amyloid-β pathology is confined to neocortical regions that are less likely to modulate NPS than the subcortical regions already carrying substantial NFT burden, making possible correlations between amyloid-β and NPS very weak and the results artificial. Evidence that soluble amyloid-β pathology is a better predictor of clinical symptoms than plaques could also explain the negative relationships [107]. It is also possible that our correction of each model for Braak, due to the collinearity between CERAD-NP and Braak stage, could drive the negative relationships we are finding. Nonetheless, these findings add to mounting evidence that NFT, rather than amyloid-β plaque pathology drives the clinical phenotype of AD.

Despite our efforts to minimize weaknesses in the study design, remaining shortcomings should be noted. First, as neuroimaging studies have shown more robust associations between NPS and pathology longitudinally than cross-sectionally, the inherent cross-sectional design of clinicopathological studies prevents us from tracking domain-specific changes and longitudinal relationships among NPS. However, neuropathology remains the gold standard for diagnosing neurodegenerative disease; despite recent advances, methods for staging AD pathological markers in vivo fail to reach the same level of sensitivity and specific pathological prediction. This discrepancy is particularly prominent at early AD stages when tau burden is primarily subcortical. Second, clinicopathological studies such as this one are often criticized for being descriptive or correlational rather than mechanistic. However, clinicopathological studies play an important role in the advancement of medicine by providing the foundation and context for mechanistic studies. Third, despite universal use in clinical and research settings to evaluate NPS, NPI informant reports may not be sensitive to mild symptoms such as dysthymia. Furthermore, NPI scores are informant-dependent and thus, may be imprecise. To minimize potential bias related to this limitation, the BBAS-USP requires informants to have had close weekly contact with the deceased in the six months prior to death. Fourth, some NPS (i.e., hallucinations and elation) were infrequent in our sample, possibly yielding imprecise estimates for the association of these symptoms with neuropathology. Finally, a lack of correlation between amyloid-β plaque scores and NPS may be derived from bias caused by the metric used to assess amyloid-β burden. CERAD-NP measures the highest cortical density of amyloid-β neuritic plaques, which represents a different, albeit related, quality of amyloid-β than the anatomically-defined Braak stage represents for NFT. CERAD-NP scores have a strong ceiling effect and estimate plaque burden in only a small fraction of the brain. Despite this shortcoming, CERAD-NP is sensitive to the earliest brain area to develop neuritic plaques. In our sample, 63% of individuals lack any amyloid neuritic plaques, and the remaining cases represent all CERAD-NP scores. Thus, we would expect to find positive association with amyloid-β burden and NPS in early AD stages if existing. Moreover, extensive literature including clinicopathological and biomarker studies suggests little impact of amyloid-β pathology and several other cognitive metrics [7]. Thal phase is an alternative and perhaps more appropriate metric to use for measuring amyloid-β pathology; however, as this metric was only introduced in 2011, it is unavailable for the majority of our cases. Nevertheless, a need to investigate possible contributions of amyloid-β to NPS further remains.

This study also offers several considerable strengths. We studied a unique population-based clinicopathological series free of biases typically found in convenience samples that are usually enriched for later AD stages and oldest-old individuals. 28% of our large series of individuals over 50 years of age lacked cortical AD changes and another 44% had AD-tau changes limited to the limbic areas and low amyloid-β burden, which is unprecedented. Moreover, due to the comprehensive postmortem examination, we were able to exclude all cases with non-AD pathology to isolate the independent effects of AD-tau and AD-amyloid-β deposition, a feat not achievable by other available methods. Additionally, in the population sampled, the rates of antipsychotic and antidepressant use are low, which could otherwise mask NPS [108].

In this study, we identify increased risk for five NPS associated with NFT pathology, four of which were associated with early stages (Fig. 1). Our results strongly support the hypothesis that NPS are part of the AD clinical spectrum and are a manifestation of NFT-related neurodegeneration. Further research is needed to clarify the relationships between subcortical pathology and early NPS, as well as determine the prevalence of specific NPS subtypes. By understanding the pathophysiology driving early symptoms, better strategies can be developed to diagnose, target, and effectively treat AD before significant cognitive decline in advanced stages. In similar fashion, neuropathological evidence that Parkinson’s disease develops in non-dopaminergic nuclei, preceding substantia nigra involvement, recharacterized Parkinson’s disease as a multi-systemic disease with important non-motor components that precede motor symptoms. Such a change in paradigm opened room for improved management of non-motor symptoms and encouraged basic and clinical research to properly treat these symptoms. The positive outcomes from this revised view of Parkinson’s disease illustrate the importance of understanding the relationships between NPS and AD pathology and will hopefully encourage the field to follow suit.