- Alzheimer’s Disease. Epidemiology, Neuropathology, Neurochemistry, and Clinics - Semantic Scholar
- Alzheimer’s Disease. Epidemiology, Neuropathology, Neurochemistry, and Clinics
- Ebook: Handbook of Depression in Alzheimer's Disease
- Recommended for you
Comparison of cell loss in the three different areas. Both total neurone number and relative neurone loss in each of the regions were plotted against those in the other two. Still, only a few original reports, reviews or meta analyses have directly compared the extent of cell loss in the NbM and LC. To the best of our knowledge none of them has compared neurone loss in these subcortical areas to those in the entorhinal cortex within the same subjects analyzing different stages of the disease.
Based on neuropsychological assessment and neuropathological examination, AD patients were allocated to one of 5 stages reflecting increasing disease progression.
- Preventing Mold-Related Problems in the Indoor Workplace - A Guide for Building Owners, Managers and Occupants.
- Inhibitory Regulation of Excitatory Neurotransmission.
- Neuropathology and Genetics of Dementia | Markus Tolnay | Springer.
- خرید: Alzheimer’s Disease. Epidemiology, Neuropathology, Neurochemistry, and Clinics |جی یو.
- Careers for number crunchers & other quantitative types?
- Translational Research in Biophotonics: Four National Cancer Institute Case Studies?
- Passar bra ihop.
For the cohort of healthy controls, we determined neurone numbers in the NbM, LC and entorhinal cortex layer II which are in very good agreement with previous studies. This is very close to previous estimates by unbiased stereological techniques where cell counts varied between 15, and 18, [ 30 , 81 ]. For comparison, previous studies applying various different stereological and non-stereological counting methods to the LC reported on mean cell numbers between 11, and 19, with individual cell counts ranging from about 6,, to about 27,, [ 28 , 30 , 33 , 37 , 81 - 86 ].
For comparison, previous stereological studies obtained mean numbers between , and , [ 87 - 90 ]. To some extent, this variability can be explained by differences in the age and disease stage of the patients which not always has been controlled for as well as by different sampling and counting protocols [ 90 ]. Still, even within each of the 5 stages of AD defined by neuropsychological and neuropathological criteria we have analyzed here separately, cell number shows a rather wide variability.
Also, a meta-analysis [ 93 ] reported on similar magnitudes in effect size when comparing stereological to non-stereological studies on NbM and LC, suggesting that the observed differences might reflect true biological variability. In this meta-analysis, effect size ranged from 0. In the present study, we obtained a comparable effect size between 0. In all three brain areas analyzed, neurone loss, still insignificantly small by statistical means, became detectable already at preclinical AD. The simultaneous presence of AT8 positive NFTs strongly suggests a pathogenetic link towards fibrillary tau pathology.
It must remain open, however, at present to what extent these degenerative changes represent localized disease-specific pathology or might be attributed to an accelerated aging process [ 94 ]. A few studies described a somewhat greater neurone loss in the NbM compared to LC. Jellinger et al. Similarly, Moll et al. In a comprehensive meta-analysis, Lyness et al. Mann et al. Also, Zarow et al. In a prospective study, they observed in a subgroup of AD patients with a history of depression a significantly lower neurone number in the LC and slightly higher neuronal density in the NbM.
Still, Syed et al. Our study clearly shows that at more advanced stages of AD, i. AD with moderate or severe dementia, cell loss is most pronounced in the NbM, while the layer II entorhinal cortex neurons are least affected and the LC shows an intermediate extent of cell loss. Still, the situation is much less conclusive for the very early, i. The question where the pathological process in the brain originates is still controversial. Early studies in the eighties of the last century had documented a contribution towards cortical pathology of ascending cholinergic innervation arising in the basal forebrain, suggesting a subcortical origin of AD pathology [ 8 , 9 , 11 ].
Still, the currently prevailing concept postulates an origin within the transentorhinal cortex from where pathology spreads throughout the cortex [ 1 ]. Consequently, Braak et al. He, thus concluded on an origin of tauopathy associated with sporadic AD in the lower brainstem nuclei rather than in the transentorhinal region [ 4 , ]. Still, there are arguments which call into question an origin of pathology in the LC.
While the severity of tau pathology in the LC increases with increasing NFT stages, there are still cases with considerable entorhinal tau pathology and only minimal amounts of tau pathology seen in the LC: It has, thus, been argued [ ] that the LC becomes increasingly involved during AD progression rather than being the site initially affected. First hints of cell loss, albeit still insignificantly small, even occur already at preclinical stages, i.
We thus failed to observe a systematic pattern which would allow to conclude on an early site of lesion and a subsequent progression of pathology from one area to another. To identify an initial site of degeneration if it exists, it might be necessary to go even further back on the preclinical time scale. Then, however, we run into the problem of how to recognize prospective AD subjects. It might, thus, be too early to draw any conclusion on whether AD pathology is of cortical or subcortical origin.
Also, we need to consider that there might be more than one way of speading of pathology from its site of origin giving rise to different neuropathologically defined subtypes of AD [ ]. We even can not rule out at present that degeneration occurs independently at several sites in parallel. Acta Neuropathol — Neurology — Alzheimers Dement — J Neuropathol Exp Neurol — J Neurosci — Neurosci Lett — Neurosci — Oxford University Press, Oxford, pp — Science — Brain — Lancet Br J Psychiatry — Br Med J — Raven Press, New York, pp — Bigl V, Woolf NJ, Butcher LL Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital, and cingulate cortices: a combined fluorescent tracer and acetylcholinesterase analysis.
Brain Res Bull — Wenk H, Bigl V, Meyer U Cholinergic projections from magnocellular nuclei of the basal forebrain to cortical areas in rats. Brain Res — J Neurol Neurosurg Psychiatry — Neuropathol Appl Neurobiol — The cortical limbic components can be separated into limbic and paralimbic zones that display increasing anatomical complexity, ranging from the corticoid areas of the amygdaloid complex, substantia innominata, septal and olfactory nuclei, over the allocortex of olfactory and hippocampal regions, up to the paralimbic or mesocortex including the piriform cortex, entorhinal cortex, the parahippocampal cortex on the medial surface of the temporal lobe, and the cingulate cortex [ ].
Based on functional imaging data and insights from neurological disorders associated with limbic pathology, the limbic network model has recently been updated and further divided in i the hippocampal-diencephalic and parahippocampal-retrosplenial network dedicated to memory and spatial orientation; ii the temporo-amygdala-orbitofrontal network for the integration of visceral sensation and emotion with semantic memory and behaviour; iii the default-mode network involved in autobiographical memories and introspective self-directed thinking.
As extensively reviewed by Trillo et al. For extensive illustration of the different monoaminergic pathways, we refer to the highly detailed first three figures included in the review by Trillo et al. The ascending dopaminergic system has been classically divided in the nigrostriatal pathway originating in substantia nigra and targeting striatum caudate-putamen , and the mesolimbic and mesocortical pathways originating in the ventrotegmental area and projecting towards limbic region and cortical regions, respectively. In more detail, the mesencephalic dopaminergic system targets cortical and subcortical structures including the medial and dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, dorsal and median raphe nucleus, tuberomammilary nucleus, nucleus basalis of Meynert, the external segment of the globus pallidus, putamen, caudate nucleus, medial septum, amygdala, entorhinal cortex, and dentate gyrus.
The main norepinephrinergic projections arise from neuronal population in the locus coeruleus which widely project to the telencephalon, including the olfactory bulb, hippocampus, amygdala, thalamus, hypothalamus, ventral striatum, basal forebrain nucleus basalis of Meynert and various neo cortical areas, among which anterior cingulate cortex, orbitofrontal cortex and dorsolateral prefrontal cortex.
Finally, ascending serotonergic fibers arise from the raphe nuclei, which target neo cortical areas for example anterior cingulate cortex, orbitofrontal cortex and dorsolateral prefrontal cortex , hippocampus, striatum caudate nucleus and putamen and the external segment of the globus pallidus, medial septum, thalamus and hypothalamus, and the tuberomammillary nucleus.
Overall, monoaminergic fiber projections are composed of generally poorly myelinated axons to innervate the extensive forebrain including the cortex, basal ganglia, thalamus, and amygdala [ ]. According to this theory, monoaminergic neurons are able to induce modulatory and trophic effects on a large number of neighboring cells through diffusion to distant extra-synaptic sites [ ]. By combining wire and volume transmission-based innervation, the monoaminergic system imposes a strong modulatory influence on most of the regions of the brain, and, hence many aspects of behavior [ ]. Moreover, different monoaminergic systems share similar input and output regions and directly project to each other, thereby further substantiating the highly complex and selective modulatory functions of these systems.
Over time, the AD-affected brain shrinks dramatically due to widespread cell death, affecting consequently nearly all its functions. Whole brain atrophy rates differ among normal aging individuals and those diagnosed with mild cognitive impairment MCI and AD [ ]. The spatial pattern of neocortical atrophy associated with normal versus pathologic aging is not uniform and depends on the degree of disease severity Fig. Atrophy is not uniform across cortical and subcortical regions Fig.
The spatial pattern and rate of decline across the spectrum from normal aging to AD is of course paralleled by the development of various cognitive, functional and behavioral symptoms. 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. 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 [ ]. The different pathways, circuits and networks involved in the regulation of behavior as described in section 3 are logically also affected by AD-related pathology and subsequent atrophy, which may underlie the development of cognitive and NPS-related symptomatology.
Various brain regions included in the frontal-subcortical circuits mediating human behavior section 3. Some structures of the hippocampal-diencephalic and parahippocampal-retrosplenial network section 3. In addition, imaging studies have documented altered metabolism and reduced functional activation of this network also in age-related neurodegenerative disorders such as MCI and early stages of AD [ , ], while damage to the temporo-amygdala-orbitofrontal network manifests with cognitive and behavioural symptoms characteristic of for example temporal lobe epilepsy, mood disorders, traumatic brain injury, psychopathy and neurodegenerative dementias, including advanced AD [ ].
In addition to the cholinergic degeneration in AD [ ], extensive neuropathological studies have established a compelling link between abnormalities in structure and function of subcortical monoaminergic systems and the pathophysiology of AD for review: [ , ]. While the rostral raphe complex is especially susceptible to NFT formation, other monoaminergic nuclei frequently exhibit both pathological markers SP and NFT [ ].
An additional link between the monoaminergic systems and AD pathophysiology is based on genome-wide association studies indicative of relationships between polymorphisms in each monoaminergic system and AD symptomatology for review [ ]. Brain imaging, electrophysiological, neurochemical and neuropathological approaches constitute the major tools to investigate brain-behavior relationships in general and hence also the biological underpinnings of NPS. Several lines of evidence suggest that depression shares complex pathophysiological routes with dementia. Several cross-sectional studies were indicative of brain changes associated with AD, including reduced temporal lobe [ ], hippocampal, and amygdala volume [ , ] in depressed elderly.
In line with the observation that depressive symptoms may indeed be a clinical marker of prodromal AD, depressive symptoms were found to be associated with AD-related neuroanatomical changes, particularly in white matter regions causing brain atrophy [ ]. Compared to other common NPS, as for example apathy, depression is indeed considered an early sign of a more aggressive neurodegenerative process or considered to lower brain reserve capacity, allowing for more rapid progression of AD neuropathology [ ].
Nevertheless, this presumed link was not observed in all studies linking depression and conversion to clinical AD. A lifetime history of major depression in AD was particularly linked to increased plaque and tau-related pathological alterations within the hippocampus. Patients with concurrent major depression present at the time of first diagnosis of AD exhibited an even larger number of hippocampal amyloid plaques and NFT [ ].
Default mode network dysfunction has been proposed to be an important factor in the association between depression and AD [ - ]. In addition, depression is considered to be significantly more prevalent in dementia with Lewy bodies DLB as compared to AD [ - ], potentially reflecting a manifestation of LB pathology. Analogously, a higher likelihood of depression has also been observed in the Lewy body variant of AD versus AD patient cohorts [ ], which is apparently associated with the presence of LBs in the amygdala [ ], the limbic brain region most closely associated with depression in the general population [ ], or in cortical areas [ ].
The presence of LBs is accompanied by neuronal cytoskeleton changes, which may influence neuronal connectivity via alterations to the synaptic network [ , ]. Also other brain regions affected by AD pathology have been implicated in depression.
Alzheimer’s Disease. Epidemiology, Neuropathology, Neurochemistry, and Clinics - Semantic Scholar
A disproportionate loss of noradrenergic locus coeruleus neurons for example has been considered to represent an important organic substrate of depression in AD [ , ], which was further substantiated by reduced cortical noradrenergic levels in demented patients with major depression [ , ]. In addition, an impaired noradrenergic neurotransmission in the cerebellar cortex might also be associated with depression in AD [ ] Fig.
Interestingly, AD-related neuroinflammation might also at least partially lie at the basis of certain NPS, including depression. There is for example mounting evidence that the enzyme indoleamine 2,3-dioxygenase IDO , which metabolizes the serotonin 5HT precursor tryptophan into kynurenine, is a prominent player in the relation between chronic inflammation and depression [ , ].
IDO activity is upregulated by neuroinflammatory processes, leading to kynurenine catabolization and an overproduction of quinolinic acid, the neurotoxic end product of the tryptophan pathway which may contribute to the excitotoxic effects in AD brain. Moreover, decreased tryptophan levels consequently affect 5HT synthesis, which is a neurochemical hallmark in the etiology of depression. Increased IDO activity can therefore play an important link between neuroinflammation and depression in AD [ ].
Interestingly, plasma NGAL levels are significantly increased in elderly depressed patients with cognitive impairments [ ] and in serum of people with DS [ ], which are both known population groups at risk to develop AD. Neuroinflammation may indeed play a role in depression, or perhaps even in NPS in general.
Cerebral blood flow and metabolism appear to be reduced in depressed compared with non-depressed AD patients in pre frontal, temporal and parietal areas [ - ]. Depression in AD has also been associated with a significantly larger volume of right parietal white matter hyperintensities [ ]. It is well established that abnormalities in serotonergic neurotransmission are central to the pathophysiology of depression in younger adults, but few studies have examined serotonergic pathological changes in elderly patients and especially in elderly patients in which depression occurs in dementia.
One study found no evidence for loss of serotonergic neurons or the presence of neuritic pathology in the dorsal raphe nuclei in older people with depression, with or without comorbid AD [ ], whereas significantly lower cortical 5-HT reuptake sites, as well as hippocampal 5-HT1A receptors and serotonergic compounds were measured in depressed AD patients [ , - ]. Predictors of depression-related behavior immobility in a forced swim test and tail suspension test in mouse models of AD presumably also involve monoaminergic neurotransmitter alterations.
It is defined as diminished motivation for at least 4 weeks, accompanied by two of the following symptoms: reduced goal-directed behavior, reduced goal-directed cognitive activity, and reduced emotions [ 9 ]. Several studies have indicated an overlap between apathy and executive dysfunction [ , ], both presumably related to dysfunction of thalamic-prefrontal-subcortical circuitry. Since the basal ganglia and their connections with prefrontal cortex are essential to decision-making, fronto-striatal circuit dysfunction may be responsible for the emergence of apathetic behavior in a wide range of neurological disorders [ ].
Apathy is rather difficult to isolate from depression given the frequent comorbidities and a considerable overlap in key symptoms [ ]. Nevertheless, apathy can occur without depression in AD and when depression and apathy co-occur in AD patients, both NPS have been shown to be clinically and anatomically independent [ , ]. Response to treatment is also different: antidepressants, in particular selective serotonin reuptake inhibitors SSRI , seem to have no therapeutic benefit in apathetic patients or can even increase the apathy severity [ ], which may be indicative of differential underlying neurobiological and neurochemical substrates.
Evidence from MCI patients and pre-dementia depressive syndromes has led to the hypothesis that in early AD, apathy may be the result of dysfunctional affective-emotional processing [ ], which takes place in ventromedial prefrontal cortex, and its connections with amygdala and nucleus accumbens. Correspondingly, neuropathological progression in AD targets ventromedial parts of frontal cortex in an early stage [ - ]. Apathetic patients have been shown to display significantly greater NFT burden and cortical thinning in left caudal anterior cingulate cortex and left lateral orbitofrontal cortex, as well as left superior and ventrolateral frontal regions, than AD patients lacking apathy symptoms [ - ].
Involvement of the anterior cingulate and related frontosubcortical structures, indicative of default mode network dysfunction, in patients with apathy has also been confirmed in various imaging studies [ , - ]. Besides imaging studies, also several postmortem studies support the hypothesis that dopaminergic circuits linking the basal ganglia with the anterior cingulate and frontal cortices, default mode network structures, normally involved in motivation and reward, may be dysfunctional in people with AD and apathy [ , ].
Alzheimer’s Disease. Epidemiology, Neuropathology, Neurochemistry, and Clinics
For example, decreased dopamine levels have been reported in the mesolimbic and mesocortical pathway [ - ], as well as changes in dopamine receptor density and distribution in apathy-related brain regions [ - ]. Pharmacological interventions have also indicated that cholinergic mechanisms may underlie the development of apathy.
Improvements in apathy have been noted following cholinesterase inhibitor treatment which has been associated with activation of the ventral striatum [ , ]. Especially physical aggression is a common cause for institutionalization and an important factor in overmedication and the use of physical restraint [ ]. Agitation and aggression in AD have been associated with brain changes in frontal and limbic regions including amygdala, cingulate cortex, and insula.
Increased burden of NFT in the orbitofrontal cortex has been linked to agitation and aberrant motor behavior, latter defined as fidgeting, wandering, pacing or rummaging [ ], while aggressive behaviors have been associated with neuronal loss in the rostral noradrenergic locus coeruleus [ ]. Also increased hippocampal NFT load was associated with increased severity of aggressive behaviors and presence of chronic aggression [ ].
Aggressive AD subjects were also shown to display significant hypoperfusion in the left anterior [ ] and right medial temporal cortex [ ]. Greater AD pathology-related amygdala atrophy was also associated with more prominent aberrant motor behavior [ ]. Both agitation and aggression in MCI and AD have been associated with neurodegeneration affecting the anterior salience network, in particular greater atrophy of frontolimbic regions, right posterior cingulate, and left hippocampus, that may reduce capacity to process and regulate behaviors properly [ ].
Cholinergic deficits appear more severe in AD patients displaying agitation or aggression [ ]. In particular, loss of choline acetyltransferase and acetylcholinesterase enzyme activity has been reported in association with this particular NPS item [ , , ]. Additional evidence comes from the robust clinical improvement of aggression or agitation observed in AD patients receiving cholinesterase inhibitors [ , , ]. Several neurochemical studies have also linked serotonergic alterations with aggression. Specifically, reduced levels of 5HT and its metabolites were measured in the frontal lobes of aggressive AD patients [ ], in addition to preserved or up-regulated serotonin re-uptake 5-HTT sites in hippocampus [ ], and an inverse correlation between hippocampal 5-hydroxyindoleacetic acid 5-HIAA; main metabolite of 5-HT levels and agitation scores [ ].
In addition, the prolactin response to d,l-fenfluramine as an index of central serotonergic function positively correlated to agitation and aggression scores in probable AD patients with severe cognitive impairment and behavioral disturbance, moreover, having interactions with gender and cognitive impairment [ ].
Serotonin transporter 5-HTT gene-related polymorphisms have been studied with regard to aggression and agitation in AD [ - ]. A preservation of cerebellar TH-positive fibers in physically agitated AD subjects, might correspond to preserved or even upregulated dopaminergic neuronal endings or fiber sprouting [ ]. Furthermore, physical signs of anxiety are restlessness, pacing and stereotyped behavior.
Alternative postulated signs of anxiety include sudden feelings of panic and worrying thoughts [ ]. Results from the Cache County study indicated that 7. This difference might be due to distinct assessment scales and study populations [ ]. There are few studies on structural or metabolic correlates of anxiety in AD. A relatively preserved amygdala volume has been associated with the development of anxiety and irritability in AD, which is in agreement with the relationship between the amygdala and anxiety-related behaviors in non-AD subjects with primary anxiety disorders.
In the setting of a reduced ability to interpret the environment and regulate emotional responses, AD patients with relatively preserved amygdala function may exhibit heightened and possibly less differentiated emotional responses that seem inappropriate to caregivers, such as anxiety and irritability [ ]. Anxiety scores correlated with lower metabolism in bilateral entorhinal cortex, anterior parahippocampal gyrus, and left superior temporal gyrus and insula [ ].
Symptoms of AD psychosis are delusions, hallucinations and misidentifications. Criteria for psychosis of AD were proposed by Jeste et al. Although some level of pathology is necessary to give rise to psychoses, patients need to be moderately intellectually preserved in order to elaborate the context of their delusions [ ].
As for depression, psychosis, and particularly visual hallucinations and delusions, seem to have different pathological substrates in DLB versus AD. In AD patients a significant positive association between the presence of neocortical NFT and the occurrence of psychotic symptoms, defined as either visual hallucinations or delusions, was described [ ], while an inverse association between visual hallucinations and NFT staging was observed in DLB [ ].
Visual hallucinations in AD have been linked to lesions in and atrophy of occipital cortex visual cortex and association areas compared to AD patients without visual hallucinations [ , ], while delusions have been linked to atrophy in frontal, temporal and limbic regions, including also hippocampus [ , ].
- Creating successful communities : a guidebook to growth management strategies.
- Waffen-SS Encyclopedia!
- Hospital English: Brilliant Learning Workbook for International Nurses.
- The Social Organization of Work.
- Petroleum Geology of the South Caspian Basin.
Delusional misidentification symptoms in particular have been linked to right frontal lobe atrophy, a reduced number of CA1 pyramidal cells [ , ], as well as white matter changes in the bilateral frontal or parieto-occipital region and left basal ganglia [ ], while delusions and hallucinations were observed in AD patients with less cell loss in the parahippocampal gyrus and the dorsal raphe nucleus [ ].
Zubenko et al. Psychosis defined as the presence of delusions or hallucinations was associated with significantly increased densities of SP and NFT in the prosubiculum and middle frontal cortex, respectively, with trends toward increased densities of these lesions in the superior temporal and the entorhinal cortex. Noradrenergic, dopaminergic and serotonergic compounds were measured in the same four cortical regions, as well as in the substantia nigra, thalamus, amygdala, and caudate nucleus.
Psychosis was also associated with the relative preservation of norepinephrine in the substantia nigra, with trends in this direction for the majority of the remaining brain regions examined, and a significant reduction of 5HT in the prosubiculum that was accompanied by trends toward reduced levels of serotonin and 5HIAA in the remaining regions [ ].
Disruption of a cohesive noradrenergic locus coeruleus-thalamus linked system, due to advanced locus coeruleus neurodegeneration, has been proposed to potentially lead to psychotic-like behavior in AD [ ], which was, at least partially, substantiated by the observation that thalamic MHPG i. Also cholinergic alterations have been linked to psychosis; An increase in M2 muscarinic cholinergic receptors was noted in frontal and temporal cortices of AD patients with psychotic symptoms [ ]. Moreover, treatment with cholinesterase inhibitors also reduced psychotic symptoms in addition to their documented benefits on cognition and global function [ , , ].
Recently, a decreased dopaminergic neurotransmission and increased dopaminergic catabolism, specifically in the amygdala, was suggested to function as a monoaminergic substrate of psychosis in AD, whereas a generally increased dopaminergic neurotransmitter activity in the prefrontal, temporal and mesolimbic cortices, as well as locus coeruleus and hippocampus, could closely relate to psychosis in DLB. The complexity of an altered coupling between serotonergic and dopaminergic pathways might, additionally, also account differently for the presence of psychosis in DLB compared to that in AD [ ].
Overall, patients with AD who manifest psychosis may have disproportionate dysfunction of frontal lobes and related subcortical and parietal structures [ ]. Moreover, stronger right hemispheric dysfunction in frontal and limbic regions [ ], as well as in the temporal horns [ ] has been associated with the presence of psychosis in AD. Delusional misidentification symptoms have been linked to hypometabolism in paralimbic orbitofrontal and cingulate areas bilaterally and left medial temporal areas, and significant bilateral normalized hypermetabolism in sensory association cortices superior temporal and inferior parietal without right left asymmetry [ ].
Pronounced brain dysfunction associated with psychosis was also substantiated by electroencephalogram EEG abnormalities [ , ], with spectral analysis indicating increased delta [ , ], and theta [ ] activity, in addition to decreased alpha power [ ]. Increasing evidence suggests that alterations in circadian rhythms can have profound consequences on emotional behavior and mental health.
The hypothalamic suprachiasmatic nucleus SCN is considered to be the endogenous clock of the brain. Circadian rhythms not only govern sleep-wake cycles but also rhythms in cognitive processes including subjective alertness, mathematical ability, and memory [ ]. The SCN displays a senescence-related decrease in volume, which is especially pronounced in AD [ ]. Nevertheless, indices for amyloid deposition i. Several lines of evidence implicate alterations in melatonin levels in AD as a possible neurochemical mediator of circadian changes.
Decreased night-time melatonin in the pineal gland of AD brain is accompanied by neurotransmitter abnormalities relevant to melatonin regulation [ ]. Another brain area that undergoes neurodegeneration in AD and might be important for circadian rhythm disturbance is the cholinergic basal forebrain. Cells of the nucleus basalis project to the SCN, and cholinergic agents act in the SCN to modulate circadian rhythms [ ]. An AD mouse model study has reported alterations in non—rapid eye movement sleep that could be due to alterations in cholinergic transmission [ ], but clinical studies concerning the role of cholinergic depletion in circadian disturbance in AD are still lacking.
Sleep disturbance has been associated with vascular pathology in studies examining the incidence and severity of NPS [ - ]. Of interest is the fact that rapid eye movement sleep behavior disorder, in which acting out of dream behavior is associated with preservation of body tone, is more common in synucleinopathies than in tauopathies, to the extent that some suggest that its presence may be a diagnostic feature [ ].
A large body of evidence, of which only a sample set of studies were discussed in this review, clearly indicates that NPS in AD are associated with neurodegeneration affecting specific neural pathways, networks and circuits and that they are based on the interplay of neuropathological and neurochemical factors in the pathogenesis of AD.
Nevertheless, further refinement of the nosology of NPS is required since we are only beginning to understand the underlying pathophysiology. In addition, it is important to take into consideration that interpretation and comparison of biological NPS-related studies can be restricted by relatively small sample sizes e. The burdensome nature and prevalent occurrence of NPS, in combination with the fact that effective and safe treatment options are still lacking, provide a strong incentive to continue neuropathological and neurochemical, as well as of course imaging and other relevant approaches to further improve our apprehension of the neurobiology of NPS.
Scatter plots representing significant monoaminergic neurotransmitter correlates of NPS in the cerebellar cortex of autopsy-confirmed AD patients. 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. All authors have contributed substantially to the design and writing of the review, as well as inclusion and interpretation of included research.
The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Bentham Science Publishers. Curr Alzheimer Res. Published online Oct. PMID: Dekker , 1, 2 Petrus J. Alain D. Petrus J. Peter P. De Deyn. This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.
This article has been cited by other articles in PMC. Abstract Neuropsychiatric symptoms NPS are an integral part of the dementia syndrome and were therefore recently included in the core diagnostic criteria of dementia. Keywords: Aggression, amyloid, depression, neurofibrillary tangles, neuronal loss, psychosis, neurotransmitter.
Open in a separate window. Tau-Related Pathology NFT consist of abnormally paired fibrils that are wound around each other, also referred to as paired helical fragments. Topographic Distribution NFT accumulation starts in the allocortex of the medial temporal lobe i. Other Protein Inclusions The misfolding, aggregation and accumulation of proteins in the brain, resulting in synaptic dysfunction and neuronal loss is a seminal pathological mechanism in diverse neurodegenerative diseases [ 65 ]. Neuroinflammation Clinical manifestations preceding the dementia stage support an early and substantial involvement of an innate neuroimmune response in AD pathogenesis [ 85 - 87 ].
Neuronal and Synaptic Loss The mechanisms underlying AD-related neuronal and synaptic loss are very complex and different in nature. Brain circuits, networks and systems involved in regulation of behaviour The fact that with progression of the disease, AD affects nearly all brain regions, including the epicenters of emotions and cognition and their extensive and reciprocal neuronal connections, forms a logical foundation for the development of both cognitive and NPS-related manifestations.
Studies linking pathology — NPS Over time, the AD-affected brain shrinks dramatically due to widespread cell death, affecting consequently nearly all its functions. A B A lifetime history of major depression in AD was particularly linked to increased plaque and tau-related pathological alterations within the hippocampus. Graham N. Distinctive cognitive profiles in Alzheimer's disease and subcortical vascular dementia. Geda Y. Neuropsychiatric symptoms in Alzheimer's disease: past progress and anticipation of the future.
Alzheimers Dement. Reisberg B. Cummings J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Mega M. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients.
Ebook: Handbook of Depression in Alzheimer's Disease
Lyketsos C. Finkel S. Behavioral and psychological signs and symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. Okura T. Neuropsychiatric symptoms and the risk of institutionalization and death: the aging, demographics, and memory study. The stress and psychological morbidity of the Alzheimer patient caregiver. Emanuel J. Trajectory of cognitive decline as a predictor of psychosis in early Alzheimer disease in the cardiovascular health study.
Douglas A. A systematic review of accidental injury from fire, wandering and medication self-administration errors for older adults with and without dementia. Herrmann N. The contribution of neuropsychiatric symptoms to the cost of dementia care.
Recommended for you
American Psychiatric Association. Gauthier S. Van Dam D. Drug discovery in dementia: the role of rodent models. Drug Discov. Animal models in the drug discovery pipeline for Alzheimer's disease. Lansbury P. Pearson H. Physiological roles for amyloid beta peptides. Parihar M. Amyloid-beta as a modulator of synaptic plasticity. Alzheimers Dis.
Harper J. Observation of metastable Abeta amyloid protofibrils by atomic force microscopy. Lambert M. Diffusible, nonfibrillar ligands derived from Abeta are potent central nervous system neurotoxins. Roher A. Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer's disease.
Iwatsubo T. Visualization of A beta 42 43 and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42 Serrano-Pozo A. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Selkoe D. Alzheimer's disease. Cruz L. Aggregation and disaggregation of senile plaques in Alzheimer disease. Thal D. Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer's disease. Acta Neuropathol. Lacor P. Goate A. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
Tandon A. Molecular genetics of Alzheimer's disease: the role of beta-amyloid and the presenilins. Vilatela M. Genetics of Alzheimer's Disease. Blennow K. Hardy J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Teipel S. Neuroanatomy of Down syndrome in vivo : a model of preclinical Alzheimer's disease. Zigman W. Atypical aging in down syndrome.
Wiseman F. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Patterson C. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. Holtzman D. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Jack C. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
Lancet Neurol. Borchelt D. Duff K. To contribute to the identification of the early site of degeneration, here, we address the question whether cortical or subcortical degeneration occurs more early and develops more quickly during progression of AD.
During early AD, however, the extent of cell loss is fairly balanced between all three areas without clear indications for a preference of one area. We can thus not rule out that there is more than one way of spreading from its site of origin or that degeneration even occurs independently at several sites in parallel. The underlying pathological process is characterized by neuronal cell death, accompanied by typical neuropathological hallmarks, i. Recent evidence [ 3 ] indicates that the pathological process begins years if not decades before clinical symptoms occur.
Exact knowledge on the pathological process occurring during this preclinical phase, however, is difficult to obtain. In a recent systematic survey on more than nonselected autoptic cases, Braak et al. Only a subset of subjects with these changes early in life seem to progress to AD [ 5 ]. Even a PHF-like pattern of tau hyperphosphorylation is not necessarily associated with a conversion into aggregated PHF-tau and can occur under certain physiological conditions such as hibernation [ 6 ], hypothermia and anesthesia [ 7 ] where it is fully reversible. As the human cerebral cortex does not contain cholinergic or noradrenergic neurons, these transmitter deficiencies were correctly attributed to a dysfunction in the ascending cholinergic and noradrenergic innervation of the cortex arising in the basal nucleus of Meynert [ 18 , 19 ] and locus coeruleus, respectively.
A corresponding loss of neurons in the NbM was first reported in [ 20 ] and rapidly confirmed by others [ 9 , 21 - 24 ]. Systematic studies clearly indicated that loss of cholinergic NbM neurons occurs early during the course of AD [ 25 , 26 ] and very unlikely is an event secondary to cortical degeneration [ 10 ]. The critical role of cholinergic dysfunction in early AD is clearly documented by the fact that pharmacological inhibition of acetylcholinesterase still is the only treatment available for a modest symptomatic therapy during early stages of the disease.
In parallel with descriptions on the cholinergic dysfunction in AD, a neurone loss has consistently been reported for the locus coeruleus [ 22 , 27 - 44 ]. These cells of the locus coeruleus and nucleus basalis of Meynert share a non-specialised, isodendritic pattern [ 25 , 26 , 45 - 48 ] which have led to the suggestion that they may represent a pool of relatively undifferentiated cells with a high susceptibility to degeneration [ 47 , 49 ].
Formation of cortical plaques and tangles and cortical dysfunction where, thus regarded as phenomena secondary to the loss of the ascending inputs [ 8 - 11 , 48 ]. Accordingly, a pathogenetic concept has been formulated assuming the process of degeneration starts in the transentorhinal cortex from where it spreads throughout the brain [ 56 ]. Until now, only a few studies with a restricted number of patients have compared neuronal loss as a direct quantitative measure of degeneration in the NbM and LC, and to the best of our knowledge there is no study comparing cell loss in the ascending projection neurons of the NbM and LC with those in the entorhinal cortex.
Therefore, to contribute to the identification of the early site of degeneration in AD, here, we address the question whether cortical or subcortical degeneration occurs more early and develops more quickly during progression of the disease. We have assessed by stereological methods neurone counts in the NbM, LC and entorhinal cortex of the same individual autopsy cases covering a wide spectrum of disease stages from preclinical AD to severe dementia. Cases with history of stroke as well as other central nervous system disorders such as tumors, inflammation, Lewy body disease or frontotemporal dementia and premortem hypoxia related to agonal states were excluded from the present study.
Cases with substantial microvascular pathology such as cortical microinfarcts, deep white matter and periventricular demyelination, silent lacunar infarcts and extensive leukoaraiosis as well as cases with argyrophilic grain disease were also excluded. Case recruitment, autopsy and data handling have been performed in accordance with the ethical standards as laid down in the Declaration of Helsinki and its later amendments as well as with the convention of the Council of Europe on Human Rights and Biomedicine and had been approved by the responsible Ethics Committee of Leipzig University.
Based on neuropsychological assessment CDR and neuropathological examination [ 63 , 64 ], cases were allocated to one of the following six groups. Preclinical AD. AD dementia. Every 10th section was collected for sampling. Total neurone number in the NbM, LC and Layer II of the entorhinal cortex was determined by the unbiased stereological method of the optical fractionator [ 70 ].
Cholinergic neurons of the nucleus basalis Meynert complex, consisting of the medial septal nucleus Ch1 , nucleus of the vertical limb of the diagonal band Ch2 and substantia innominate Ch4 were identified by immunocytochemical detection of choline acetyltransferase [ 26 , 71 ] using a goat anti-choline acetyltransferase polyclonal antibody AB P Chemicon as described [ 72 ]. Boundaries of the NbM complex were identified based on a previous three-dimensional reconstruction comprising the subpopulations of Ch1, Ch2, Ch4am, Ch4al, Ch4i and Ch4p [ 9 , 73 ].
Neurons were sampled over the entire length of the NbM complex extending from the septum Ch1 to its most posterior parts Ch4p at the premammillary level posterior to the ansa peduncularis. Neurons of the locus coeruleus were identified by the presence of neuromelanin [ 74 , 75 ]. In the present study, the term locus coeruleus LC refers to both the nucleus coeruleus and nucleus subcoeruleus. For outlining layer II of the entorhinal cortex, we followed the criteria of Amaral and Insausti [ 76 ] and Insausti et al. The anatomical boundaries of the considered region were outlined using a 5x lens and the reference volume for each structure was determined from these areas encircled on each section averaged over the entire length of the structure principle of Cavalieri.
On average, — profiles were counted with a 20x lens in each case and region. The intra individual coefficient of error CE for the individual estimates of cell numbers ranged from 0. The inter-individual coefficient of variation CV within each of the six different groups ranged from 0. In the normal aged brain mean age In AD, there occurred a progressive loss of neurons in all three areas which paralleled the progression of the disease.
Also, there was a large individual range in neurone count for each group. At preclinical stages of AD, neurone count in all three areas tended to be reduced. Cell loss, however, was insignificantly small NbM: 4. Neurone loss further progressed in the groups of mild dementia NbM: At the most advanced stages AD severe dementia , average neurone loss reached Comparison of effect size d for neurone loss in the nucleus basalis of Meynert, locus coeruleus and entorhinal cortex layer II.
Overall, there was a very high degree of correlation of neurone loss in each of the three areas with those in the other two areas correlation coefficient r ranging from 0. Comparison of cell loss in the three different areas. Both total neurone number and relative neurone loss in each of the regions were plotted against those in the other two.
Still, only a few original reports, reviews or meta analyses have directly compared the extent of cell loss in the NbM and LC. To the best of our knowledge none of them has compared neurone loss in these subcortical areas to those in the entorhinal cortex within the same subjects analyzing different stages of the disease. Based on neuropsychological assessment and neuropathological examination, AD patients were allocated to one of 5 stages reflecting increasing disease progression. For the cohort of healthy controls, we determined neurone numbers in the NbM, LC and entorhinal cortex layer II which are in very good agreement with previous studies.
This is very close to previous estimates by unbiased stereological techniques where cell counts varied between 15, and 18, [ 30 , 81 ]. For comparison, previous studies applying various different stereological and non-stereological counting methods to the LC reported on mean cell numbers between 11, and 19, with individual cell counts ranging from about 6,, to about 27,, [ 28 , 30 , 33 , 37 , 81 - 86 ]. For comparison, previous stereological studies obtained mean numbers between , and , [ 87 - 90 ].
To some extent, this variability can be explained by differences in the age and disease stage of the patients which not always has been controlled for as well as by different sampling and counting protocols [ 90 ]. Still, even within each of the 5 stages of AD defined by neuropsychological and neuropathological criteria we have analyzed here separately, cell number shows a rather wide variability.
Also, a meta-analysis [ 93 ] reported on similar magnitudes in effect size when comparing stereological to non-stereological studies on NbM and LC, suggesting that the observed differences might reflect true biological variability. In this meta-analysis, effect size ranged from 0. In the present study, we obtained a comparable effect size between 0. In all three brain areas analyzed, neurone loss, still insignificantly small by statistical means, became detectable already at preclinical AD.