Increased Neocortical Neurofibrillary Tangle Density in Subjects With Alzheimer Disease and Psychosis

Farber, Nuri B.; Rubin, Eugene H.; Newcomer, John W.; Kinscherf, Dorothy A.; Miller, J. Philip; Morris, John C.; Olney, John W.; McKeel, Daniel W.

doi:10.1001/archpsyc.57.12.1165

Cited by 146 publications

(89 citation statements)

References 44 publications

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“…On the basis of the present findings, it is tempting to speculate that psychotic symptoms in AD are underpinned by disruption of the cholinergic/dopaminergic axis within frontostriatal circuits, with additional pathology in the ventral visual pathway in patients with the misidentification subtype. Postmortem studies have shown a greater pathological (neurofibrillary tangle) burden in frontal cortical regions (Farber et al ., 2000; Koppel et al ., 2014a; Murray et al ., 2014). There is also evidence of greater tau pathology in frontal (Ferman et al ., 2013) and limbic/paralimbic regions (Ferman et al ., 2013; Forstl et al ., 1994; Mukaetova‐Ladinska et al ., 1993) in AD patients with misidentifications, including hippocampal/parahippocampal regions that are functionally connected with the ventral visual pathway.…”

Section: Discussionmentioning

confidence: 99%

Cognitive phenotype of psychotic symptoms in Alzheimer's disease: evidence for impaired visuoperceptual function in the misidentification subtype

Reeves

Clark-Papasavas

Gould

et al. 2015

Int J Geriatr Psychiatry

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BackgroundEstablishing the cognitive phenotype of psychotic symptoms in Alzheimer's disease (AD) could localise discrete pathology and target symptomatic treatment. This study aimed to establish whether psychotic symptoms would be associated with poorer performance on neuropsychological tests known to correlate with striatal dopaminergic function and to investigate whether these differences would be attributed to the paranoid (persecutory delusions) or misidentification (misidentification phenomena +/− hallucinations) subtype.MethodsSeventy patients with probable AD (34 psychotic and 36 nonpsychotic) were recruited to the study. Analysis of covariance was used to compare motor speed and the rapid visual processing test of sustained visual attention, after adjusting for potential confounding factors. Multivariate analyses were used to compare performance across other cognitive domains. Significant findings were explored by separating patients on the basis of subtype.ResultsRapid visual processing performance accuracy was reduced in patients with psychotic symptoms (F 1,58 = 5.94, p = 0.02) and differed significantly across subtypes (F 2,51 = 3.94, p = 0.03), largely because of poorer performance in the misidentification compared with nonpsychotic group. Multivariate analyses (corrected for multiple comparisons) showed poorer performance on the incomplete letters task in psychotic patients (F 1,63 = 8.77, p = 0.004) and across subtypes (F 2,55 = 10.90, p < 0.001), similarly attributed to the misidentification subtype.ConclusionsThese findings provide further support of the involvement of dopaminergic networks in the psychosis endophenotype in AD and, in addition, implicate the ventral (temporo‐occipital) pathway in the misidentification subtype. Future studies should investigate the early trajectory of neuropathological change in vivo across psychosis subtypes.© 2015 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

Cognitive phenotype of psychotic symptoms in Alzheimer's disease: evidence for impaired visuoperceptual function in the misidentification subtype

Reeves

Clark-Papasavas

Gould

et al. 2015

Int J Geriatr Psychiatry

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“…MukaetovaLadinska and colleagues [28] reported that a positive history of misidentification delusions is related to an increased density of neuritic plaques in fronto-parieto-occipital lobes. Farber and colleagues [29] observed 109 patients with AD and after their death compared the pathology in those with and without psychosis. Delusions occurred in almost all patients with psychosis (94%), and hallucinations in the absence of delusions were very rare (6%).…”

Section: Neuropathologymentioning

confidence: 99%

Neurobiology of Delusions in Alzheimer’s Disease

Ismail

Nguyen

Fischer

et al. 2011

Curr Psychiatry Rep

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Alzheimer's disease (AD) is associated with cognitive and functional impairment as well as neuropsychiatric sequelae, including psychotic symptoms such as delusions and hallucinations. Strong evidence supports the need to study delusions separate from hallucinations. Integrating the epidemiology, clinical correlates, and neuropathological and genetic literature for delusions in AD allows us to speculate on etiology and mechanisms. Plaque and tangle deposition in individuals with susceptible alleles of serotonergic, muscarinic, nicotinic, or Apoε4 genes appears to result in disruption of cortical circuitry, culminating in delusions. While delusions in AD correspond to a phenotype distinct from AD without delusions, subtypes of delusions may also define further distinct clinical entities.Persecutory delusions may occur earlier in the illness and have a more significant genetic component than misidentification delusions, which are associated with increased cognitive impairment and advanced dementia. Clearly distinguishing between these two syndromes is essential to making progress in the area of delusions in AD.

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“…19 Post-mortem studies, which have the potential advantage of recording a complete cumulative incidence of AD þ P, have similarly reported rates of approximately 40-60%. [20][21][22] However, all of the studies described above have conducted either cross-sectional assessment for AD þ P, or longitudinal assessments with a limited duration of follow-up. Better estimates of the rate of AD þ P could be obtained by thorough longitudinal assessments of subjects through their course of illness.…”

Section: Evidence For a Distinct Phenotypementioning

confidence: 99%

“…The cumulative incidence of AD þ P is only 40-60% of all AD cases. [19][20][21][22] Second, AD þ P is associated with excess cognitive burden in AD subjects matched on other clinical variables, including dementia duration. 31,33 Third, AD þ P is not only associated with increased cognitive impairment, but with a more rapid rate of cognitive deterioration.…”

Section: Evidence For a Distinct Phenotypementioning

confidence: 99%

Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype

et al. 2003

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Though efforts to identify the genetic etiology of Alzheimer disease (AD) have made substantial progress, to date only some of the genes contributing to AD risk have been identified. Utilization of more etiologically homogeneous subphenotypes represents one strategy to facilitate the identification of novel risk genes in complex disorders. In this review, we evaluate the hypothesis that psychotic symptoms, such as delusions and hallucinations, define a suitable subphenotype in AD patients for gene-mapping efforts. Psychotic symptoms occur in 40-60% of patients with AD and are associated with more severe cognitive deficits and a more rapidly deteriorating course. The presence of psychotic symptoms in AD confers increased risk of similar symptoms to affected siblings. Candidate gene association analyses and initial linkage analysis have yielded significant results. We discuss possible genetic models of psychotic symptoms in AD, and suggest strategies for further investigation. Identification of such genetic factors may facilitate gene-mapping studies for both AD and idiopathic psychoses. OverviewThe genetic basis of Alzheimer disease (AD) is unknown, although considerable strides have been made using gene-mapping efforts. Success has been most notable for the highly heritable early onset form, which comprises a minority of the entire population of AD cases. 1 While the impact of apolipoprotein E e4 alleles (APOE4) is well established, the genetic architecture of the more common late-onset AD (LOAD) is unclear. Like other genetically complex disorders, such as diabetes mellitus, progressively greater attention has been paid to utilizing defined subgroups of AD (eg late age-of-onset, APOE4 presence, autopsy confirmation) for mapping liability genes. 2,3 We have previously proposed that the presence of psychotic symptoms, delusions and hallucinations, define a subgroup of AD 4 that may be suitable for genetic investigation. 5,6 To our knowledge, however, the available evidence pertaining to whether AD with psychosis (AD þ psychosis (AD þ P)) identifies a phenotype suitable for genetic study has not been the subject of critical review.Stedman's Medical Dictionary defines phenotype as 'the observable characteristics, at the physical, morphologic, or biochemical level, of an individual, as determined by the genotype and environment '. 7 The genes associated with a behavioral phenotype, however, are unknown. The task for the psychiatric geneticist, therefore, is to identify a behavioral phenotype that varies according to alleles at a restricted set of genes. As in all psychiatric nosology, a behavioral phenotype must be readily and reliably identifiable in all patients of interest. If this behavioral phenotype has clinical relevance (eg bipolar illness) it provides a measure of face validity, and adds significance to its use in the search for causative genes. Tsuang et al. 8 enumerated additional criteria for determining that a behavioral phenotype has a substantial genetic basis, including state independence, biolog...

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Increased Neocortical Neurofibrillary Tangle Density in Subjects With Alzheimer Disease and Psychosis

Cited by 146 publications

References 44 publications

Cognitive phenotype of psychotic symptoms in Alzheimer's disease: evidence for impaired visuoperceptual function in the misidentification subtype

Cognitive phenotype of psychotic symptoms in Alzheimer's disease: evidence for impaired visuoperceptual function in the misidentification subtype

Neurobiology of Delusions in Alzheimer’s Disease

Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype

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