Insular Alzheimer’s disease pathology as a cause of “age-related” autonomic dysfunction and mortality in the non-demented elderly

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Summary

Only a few brain structures have been implicated in the autonomic control of blood pressure and heart rate. Among them are heteromodal association areas in the cortex, especially the insular cortex. Ischemic insular lesions have been associated with both cardiac arrhythmias and mortality. However, stroke may not be the only insular pathology with the potential to disrupt autonomic function. Alzheimer’s disease (AD) is associated with both insular pathology and autonomic dysfunction.

Alzheimer’s dementia is merely the final stage of a pathological process that spans decades. Recent studies have demonstrated a hierarchichal sequence of AD pathology that includes the insular cortex. This may explain why AD has effects on BP and central autonomic cardio-regulatory functions. However, AD reaches the insular cortex at a “preclinical” stage in its development (i.e., before “dementia” can be diagnosed). Thus, AD pathology should also be considered as a possible explanation for autonomic morbidity and mortality in non-demented elderly persons.

We hypothesize that autonomic dyscontrol, commonly seen in non-demented well elderly persons without significant cardiovascular disease (CVD), reflects subclinical stages of AD pathology affecting the insular cortex. If true, then preclinical AD pathology should be considered as a possible explanation for arrhythmia/fall related morbidity and mortality in non-demented elderly persons.

Introduction

Only a few brain structures have been implicated in the autonomic control of blood pressure (BP) and heart rate [11], [60], [76]. Among them are heteromodal association areas in the cortex, especially the insular cortex. The insulae have been specifically implicated in electrophysiological studies involving rodents, primates, and humans [48]. Insular infarction has been associated with both cardiac arrhythmias and mortality [50]. However, stroke may not be the only insular pathology with the potential to disrupt autonomic function. Alzheimer’s disease (AD) is associated with both insular pathology and autonomic dysfunction.

Alzheimer’s dementia is merely the final stage of a pathological process that spans decades [9]. Braak has demonstrated a hierarchichal progression of AD pathology that includes the insular cortex. This may explain why AD has effects on BP and central autonomic cardio-regulatory functions. However, AD reaches the insular cortex at a “preclinical” stage in the Braak sequence (i.e., before “dementia” can be diagnosed). Thus, AD pathology should also be considered as a possible explanation for autonomic morbidity and mortality in non-demented elderly persons.

The following observations support this possibility:

  • (1)

    Clinical AD is associated with a wide range of dysautonomic phenomena. These can already be demonstrated at the initial diagnosis, suggesting a preclinical onset.

  • (2)

    There are only a limited set of brain regions capable of affecting autonomic control. Brainstem nuclei are affected too late in the Braak sequence to explain preclinical dysautonomic symptoms. Instead, AD pathology in the cortical insulae, particularly the right, is a more likely origin of autonomic dyscontrol in early AD. The insulae are affected at a preclinical stage in the Braak sequence (i.e. stage III of six).

  • (3)

    Right hemisphere metabolic changes, and performance on cognitive tasks that are associated with the right hemisphere, are significant independent predictors of mortality in AD. Similar measures are associated with autonomic dyscontrol in head injury, epilepsy, and stroke.

  • (4)

    We recently examined 5-year survival curves among healthy, non-institutionalized, non-demented well elderly retirees living in a single comprehensive care retirement community (CCRC). Baseline right hemisphere constructional tasks and clinical features related to preclinical AD (e.g. anosmia) were significant independent predictors of mortality. Moreover, the majority of deaths occurred among residents who never transitioned out of their original (independent) levels of care, suggesting a sudden, unexpected death that was not preceded by a period of increasing frailty and debility.

  • (5)

    Absolute reductions in right insular cerebral blood flow (CBF) and relatively reduced right vs. left insular rCBF are associated with orthostasis in non-demented elderly.

These observations could have important implications: (1) The prevalence of preclinical AD is likely to be higher than the number of demented cases. Many apparently well elderly persons may be at risk solely on the basis of subclinical AD pathology. (2) Tests of right hemisphere function may be useful in detecting those at risk. (3) AD treatment is known to delay the progression of symptoms and to decrease mortality. These medications may also impact AD related autonomic problems. (4) Conversely, the association between other medications and cardiac arrhythmias/sudden death may be mediated via effects on insular function.

Section snippets

Hypothesis

We hypothesize that autonomic dyscontrol, commonly seen in non-demented well elderly persons without significant cardiovascular disease (CVD), reflects subclinical stages of AD pathology affecting the insular cortex. If true, then preclinical AD pathology should be considered as a possible explanation for arrhythmia/fall related morbidity and mortality in non-demented elderly persons.

Preclinical AD pathology is widespread

The prevalence of clinical dementia is high. However, the prevalence of subclinical AD may be even higher. The number of persons with “mild cognitive impairment” (MCI), many of whom can be expected to transition into frank AD in the near-term [45], has been estimated at 38% of community dwelling older persons [69].

Unfortunately, very little is known about the preclinical history of AD. The Nun Study suggests that AD may have detectable effects on cognition decades before the recognition of

Cognitive correlates of mortality in non-demented elderly

Since 1994, we have been studying executive impairment in a cohort of well elderly retirees (N = 546, Age = 78.2 ± 5.0) as part of the Air Force Villages’ Freedom House Study (FHS). The FHS is a longitudinal study of cognition related disability in a single (1500 bed) CCRC (the Air Force Villages). The FHS sample is unusual in that is culturally homogeneous (99% Caucasian), highly educated (15.1 ± 2.4 years), healthy (81% self-rated good-excellent; <10% diabetic or report h/o stroke) and affluent. 93%

Acknowledgements

The author wishes to acknowledge the important cooperation and support he has received from the Air Force Villages. This work has been supported by NINDS R21 Grant NS45121-01A1.

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