Mitchell K.P. Lai

Psychosis of Alzheimer’s disease is associated with elevated muscarinic M2 binding in the cortex

Objectives: Results from recent drug trials suggest a role for the cholinergic system in the manifestation of neuropsychiatric symptoms in AD. To date, the status of muscarinic acetylcholine receptor subtypes in AD in relation to accompanying behavioral disturbances is unknown. This study aimed to measure alterations of muscarinic M1 and M2 receptor binding in the frontal and temporal cortex of AD and to correlate the neurochemical findings with clinical features. Methods: The cognitive and behavioral features of 26 patients with AD were assessed prospectively using standardized tests. Together with 14 matched controls, the status of muscarinic M1 and M2 receptors in the postmortem frontal and temporal cortex of these patients were measured by radioligand binding assays and were correlated with clinical data. Results: Compared with controls, M2 receptor density was reduced only in the frontal cortex of AD, whereas M1 was unaffected. Within the AD group, the neurochemical variables were not affected by demographic factors, disease severity, or cognition. Instead, M2 receptor density was increased in the frontal and temporal cortex of patients with AD with psychotic symptoms compared with those without these symptoms. Conclusions: This study suggests a role for M2 receptors in the psychosis of AD and may provide the rationale for treatment of behaviorally perturbed patients with AD with cholinomimetics and M2 antagonists.

Neurochemical basis for symptomatic treatment of Alzheimer's disease

Neuron and synapse loss together with neurotransmitter dysfunction have, along with Abeta deposition and neurofibrillary tangles, been recognized as hallmarks of Alzheimers disease (AD). Furthermore, clinical and preclinical studies point to neuronal loss and associated neurochemical alterations of several transmitter systems as a main factor underlying both cognitive and neuropsychiatric symptoms. Treatment for the cognitive decline in AD, based on early findings of a cholinergic deficit, has been in the clinic for more than a decade but provides only modest benefit in most patients. Therefore there is still considerable scope for new treatments that demonstrate greater efficacy against cognitive dysfunction in spite of the fact that the mainstays of current treatments, the cholinesterase inhibitors Aricept, Exelon and Reminyl (Razadyne) will become generic over the next few years. However, the most important area for drug development is for the treatment of behavioural disturbance in AD since many existing treatments have limited efficacy and have potentially life-threatening side effects. This review examines the neurochemical underpinning of both cognitive and neuropsychiatric symptoms in dementia and provides some basis for rational drug development.

Genome wide profiling of altered gene expression in the neocortex of Alzheimer's disease.

Alzheimers disease (AD) is characterized by a complex neurodegenerative process affecting multiple genes and proteins in the neocortex, many of which have not been well‐studied. In this study, we investigated genome‐wide gene alterations in the temporal cortex of a well‐characterized cohort of AD patients using a recently developed microarray platform, and compared some of the transcript changes with immunoblotting. Of the 5485 genes found to be significantly altered in AD, there were consistent patterns of changes which show that the AD transcriptome in neocortex is characterized by changes indicative of synaptic dysfunction, perturbed neurotransmission and activation of neuroinflammation. We also highlighted several genes of potential pathogenic significance which have not been well studied in AD. The current study aims to add to the growing body of knowledge relating to gene changes in AD and provide further insights into pathogenic mechanisms and potential targets of pharmacotherapy.

Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias.

Dementia with Lewy bodies (DLB) and Parkinsons disease dementia (PDD) are characterized by the presence of α‐synuclein‐containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimers disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α‐synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi‐quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α‐synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α‐synuclein‐positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α‐synuclein‐induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.

Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer's disease.

RationalePrevious studies have demonstrated reductions of serotonin 5-HT2A receptors in the neocortex of Alzheimer’s disease (AD) patients. However, it is unclear whether such losses play a role in the cognitive decline of AD.ObjectivesTo correlate neocortical 5-HT2A receptor alterations with cognitive decline in AD.MethodsPostmortem frontal and temporal cortical 5-HT2A receptors were measured by [3H]ketanserin binding in aged controls as well as in a cohort of AD patients who had been longitudinally assessed for cognitive decline and behavioral symptoms.Results5-HT2A receptor densities in both regions were reduced in severely demented AD patients compared to age-matched controls. In the temporal cortex, this reduction also correlated with the rate of decline of Mini-Mental State Examination (MMSE) scores. The association between 5-HT2A receptor loss and cognitive decline was independent of the effects of choline acetyltransferase (ChAT) activity and presence of behavioral symptoms.ConclusionsOur data suggest that loss of neocortical 5-HT2A receptors may predict for faster cognitive decline in AD, and point to serotomimetics as potentially useful adjuvants to cholinergic replacement therapies.

Postmortem serotoninergic correlates of cognitive decline in Alzheimer's disease

Serotonin1A receptor density and serotonin concentration were measured in the postmortem neocortex of 17 AD patients who had been prospectively assessed every four months with the Mini-Mental State Examination (MMSE) for a mean of 2.6 years till death. In the frontal cortex, serotonin levels correlated negatively with the annual rate of MMSE decline, while serotonin1A receptor density was positively correlated with the rate of MMSE decline. Our study suggests that reduced serotonin levels and increased serotonin1A receptor density are markers for accelerated cognitive decline in AD, and provides support for the use of serotonin1A antagonists in the treatment of AD.

Ageing and the telomere connection: An intimate relationship with inflammation

Telomeres are the heterochromatic repeat regions at the ends of eukaryotic chromosomes, whose length is considered to be a determinant of biological ageing. Normal ageing itself is associated with telomere shortening. Here, critically short telomeres trigger senescence and eventually cell death. This shortening rate may be further increased by inflammation and oxidative stress and thus affect the ageing process. Apart from shortened or dysfunctional telomeres, cells undergoing senescence are also associated with hyperactivity of the transcription factor NF-κB and overexpression of inflammatory cytokines such as TNF-α, IL-6, and IFN-γ in circulating macrophages. Interestingly, telomerase, a reverse transcriptase that elongates telomeres, is involved in modulating NF-κB activity. Furthermore, inflammation and oxidative stress are implicated as pre-disease mechanisms for chronic diseases of ageing such as neurodegenerative diseases, cardiovascular disease, and cancer. To date, inflammation and telomere shortening have mostly been studied individually in terms of ageing and the associated disease phenotype. However, the interdependent nature of the two demands a more synergistic approach in understanding the ageing process itself and for developing new therapeutic approaches. In this review, we aim to summarize the intricate association between the various inflammatory molecules and telomeres that together contribute to the ageing process and related diseases.

Serotonergic Therapies for Cognitive Symptoms in Alzheimer’s Disease: Rationale and Current Status

Alzheimer’s disease (AD) is the most common cause of dementia in elderly people. Research focused on identifying compounds that restore cognition and memory in AD patients is a very active investigational pursuit. Cholinesterase inhibitors for the symptomatic treatment of cognitive decline in AD have been in use for more than a decade but provide only modest benefits in most patients. Preclinical research is constantly providing new information on AD. The involvement of the serotonergic system in higher cognitive processes such as memory and learning has been widely described and extensive serotonergic denervation has been reported in AD. This review aims to explain the rationale behind testing serotonergic therapies for AD in terms of current knowledge about the pathophysiology of the disease. Based on preclinical studies, certain serotonin (5-HT) receptor ligands have been suggested to have the ability to modify or improve memory/cognition, specifically 5-HT receptors acting at 5-HT1A, 5-HT4 and 5-HT6 receptors. This article summarizes the pharmacology, efficacy, safety and tolerability data for the various serotonergic agents currently in clinical development for AD.

Characterization of histamine H3 receptors in Alzheimer's Disease brain and amyloid over-expressing TASTPM mice

Background and purpose:  Histamine H3 receptor antagonists are currently being evaluated for their potential use in a number of central nervous system disorders including Alzheimers Disease (AD). To date, little is known about the state of H3 receptors in AD.

The brain lipidomes of subcortical ischemic vascular dementia and mixed dementia

Despite its importance as the leading cause of vascular dementia, the primary pathogenic mechanisms in subcortical ischemic vascular dementia (SIVD) have remained elusive. Because of the lack of approved therapeutic agents for SIVD, there is a pressing need to identify novel therapeutic targets. Comparative lipidomic analyses of SIVD and mixed dementia (i.e., SIVD and Alzheimers disease, MixD) may also confer new insights pertaining to the possible interaction between neurodegenerative and vascular mechanisms in the pathogenesis of dementia. Liquid chromatography coupled to mass spectrometry was used to comprehensively analyze the lipidomes of white and gray matter from the temporal cortex of nondemented controls, SIVD, and MixD subjects. Detailed molecular profiles highlighted the pathologic relevance of gray matter sphingolipid fatty acyl chain heterogeneity in dementia. In addition, the levels of sulfatides and lysobisphosphatidic acids were progressively increased in the temporal cortex gray matter from control to SIVD to MixD. White matter phospholipid profiles indicated possible adaptive mechanisms (i.e., increased unsaturation) to chronic ischemia in SIVD and elevated membrane degradation in MixD.