Neuropsychiatric Disturbances in Alzheimer's Disease: What Have We Learned from Neuropathological Studies?

Abstract

Neuropsychiatric symptoms (NPS) are an integral part of the dementia syndrome and were therefore recently included in the core diagnostic criteria of dementia. The near universal prevalence of NPS in Alzheimer's disease (AD), combined with their disabling effects on patients and caregivers, is contrasted by the fact that few effective and safe treatments exist, which is in part to be attributed to our incomplete understanding of the neurobiology of NPS. In this review, we describe the pathological alterations typical for AD, including spreading and evolution of burden, effect on the molecular and cellular integrity, functional consequences and atrophy of NPS-relevant brain regions and circuits in correlation with specific NPS assessments. It is thereby clearly established that NPS are fundamental expressions of the underlying neurodegenerative brain disease and not simply reflect the patients' secondary response to their illness. Neuropathological studies, moreover, include a majority of end-stage patient samples, which may not correctly represent the pathophysiological environment responsible for particular NPS that may already be present in an early stage, or even prior to AD diagnosis. The burdensome nature and high prevalence of NPS, in combination with the absence of effective and safe pharmacotherapies, provide a strong incentive to continue neuropathological and neurochemical, as well as imaging and other relevant approaches to further improve our apprehension of the neurobiology of NPS.

Fig. (1)

The accumulation of misfolded proteins in Alzheimer disease follows characteristic and predictable patterns as illustrated by the increasing intensity and spreading of color. (A) Amyloid plaques first appear in neocortex, followed by allocortex and finally progressing to subcortical regions. The three brain schemata reflect Montine A scores 1 – 3 from left to right. (B) Neurofibrillary tangles appear first in the allocortex of the medial temporal lobe and spreads to the associative isocortex, relatively sparing the primary sensory, motor, and visual areas. The three brain schemata reflect Montine B scores 1 – 3 from left to right. Reprinted with permission from [52].

Fig. (2)

At least three frontal-subcortical circuits mediate human behavior: (i) the dorsolateral prefrontal circuit mediating planning, organization, and executive function, (ii) the lateral orbitofrontal circuit mediating inhibitory control and (iii) the anterior cingulate circuit mediating motivated behavior. The prototypic structure of all circuits is an origin in the frontal lobes, projection to striatal structures, connections from striatum to globus pallidus and substantia nigra, projections from these two structures to specific thalamic nuclei, and a final link back to the frontal lobe. Indirect pathways projecting from striatum to globus pallidus externa, then to subthalamic nucleus, and back to the globus pallidus interna/substantia nigra, as well as connections of the substantia nigra and the subthalamic nucleus are not shown for. Legend: BA, Brodman area. Adapted from [124].

Fig. (3)

Illustration of a magnetic resonance imaging-based analysis technique to determine the pattern of cortical thinning (measure of cortical atrophy) as a function of disease progression. Age-matched control individuals, mild cognitive impairment (MCI) and Alzheimer’s disease (AD) groups were compared. Panel A: cortical thickness differences between the control and MCI group with the most significant difference seen in the (left) medial temporal region. Frontal and posterior parietal areas show differences in a more bilateral fashion. Panel B: Cortical thickness differences between the control and AD group clearly indicating bilateral medial and lateral temporal lobe differences are present bilaterally. Occipital, primary motor and primary sensory cortices show the least significant differences. Reprinted with permission from [134]. Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impairment.

Fig. (4)

Neurochemical correlates of neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD). Scatter plots representing significant monoaminergic neurotransmitter correlates of NPS in the cerebellar cortex of autopsy-confirmed AD patients. Panel A: positive correlation between the DOPAC/DA ratio, indicative of DA turnover, and physically nonaggressive behavior (R=+0.497; p=0.003). Panel B: positive correlation between MHPG levels, the major noradrenergic metabolite, and affective disturbances (R=+0.562; p=0.0005). Panel C: positive correlation between the DOPAC/DA ratio and activity disturbances (R=+0.595; p=0.00026). Although the cerebellum has historically been considered to be a brain region principally involved in motor control and coordination, more recently, higher cognitive functions have been attributed to its physiological functions as well. A strong and sustained reciprocal connection between the deep cerebellar nuclei to the thalamus and then on to the (prefrontal) cerebral cortex, called cerebello-thalamic-cortical pathway, neuroanatomically accounts for the role of the cerebellum numerous behavioral processes. Cerebellar pathology and subsequent neurochemical alterations may underlie certain NPS. Abbreviations: AD, Alzheimer’s disease; Behave-AD, Behavioral Pathology in Alzheimer’s Disease Rating Scale; CMAI, Cohen-Mansfield Agitation Inventory; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; MHPG, 3-methoxy-4-hydroxyphenylglycol. Reprinted with permission from [173].