Impact of Less Common and “Disregarded” Neurodegenerative Pathologies on Dementia Burden in a Population-Based Cohort

Keage, Hannah A.D.; Ince, PG; Matthews, Fiona E.; Wharton, Stephen B.; McKeith, Ian G.; Brayne, Carol; Mrc, Cfas

doi:10.3233/jad-2011-111268

Cited by 32 publications

(26 citation statements)

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“…By using a NPC score and analyzing it against CDR-SOB, IQCODE, and NPI, we showed that neuropathological comorbidity is related to increased risk of dementia and the severity of neuropsychological symptoms. These results are in line with other cohorts from HICs [9,10,19,20,83]. One open question refers to whether neuropathological comorbidity results in a synergistic effect of worsening cognition in humans, as has been shown in animal models [55].…”

Section: Discussionsupporting

confidence: 88%

Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study

et al. 2017

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BackgroundClinicopathological studies are important in determining the brain lesions underlying dementia. Although almost 60% of individuals with dementia live in developing countries, few clinicopathological studies focus on these individuals. We investigated the frequency of neurodegenerative and vascular-related neuropathological lesions in 1,092 Brazilian admixed older adults, their correlation with cognitive and neuropsychiatric symptoms, and the accuracy of dementia subtype diagnosis.Methods and findingsIn this cross-sectional study, we describe clinical and neuropathological variables related to cognitive impairment in 1,092 participants (mean age = 74 y, 49% male, 69% white, and mean education = 4 y). Cognitive function was investigated using the Clinical Dementia Rating (CDR) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE); neuropsychiatric symptoms were evaluated using the Neuropsychiatric Inventory (NPI). Associations between neuropathological lesions and cognitive impairment were investigated using ordinal logistic regression. We developed a neuropathological comorbidity (NPC) score and compared it to CDR, IQCODE, and NPI scores. We also described and compared the frequency of neuropathological diagnosis to clinical diagnosis of dementia subtype. Forty-four percent of the sample met criteria for neuropathological diagnosis. Among these participants, 50% had neuropathological diagnoses of Alzheimer disease (AD), and 35% of vascular dementia (VaD). Neurofibrillary tangles (NFTs), hippocampal sclerosis, lacunar infarcts, hyaline atherosclerosis, siderocalcinosis, and Lewy body disease were independently associated with cognitive impairment. Higher NPC scores were associated with worse scores in the CDR sum of boxes (β = 1.33, 95% CI 1.20–1.46), IQCODE (β = 0.14, 95% CI 0.13–0.16), and NPI (β = 1.74, 95% CI = 1.33–2.16). Compared to neuropathological diagnoses, clinical diagnosis had high sensitivity to AD and high specificity to dementia with Lewy body/Parkinson dementia. The major limitation of our study is the lack of clinical follow-up of participants during life.ConclusionsNFT deposition, vascular lesions, and high NPC scorewere associated with cognitive impairment in a unique Brazilian sample with low education. Our results confirm the high prevalence of neuropathological diagnosis in older adults and the mismatch between clinical and neuropathological diagnoses.

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Section: Discussionsupporting

confidence: 88%

Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study

et al. 2017

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“…Amygdala predominant disease may reflect an alternate progression of LB pathology. Whilst it is commonly proposed that neocortical and limbic Lewy body pathology are central in determining cognitive impairment and dementia [115,120], others have challenged this to suggest Lewy body pathology in the brainstem may also be important correlates of cognitive impairment [65]; however this finding is not replicated in all studies [115]. Some propose the importance of AD pathology burden, and suggest neocortical Lewy body pathology is not sufficient to cause severe global cognitive impairment and that AD pathology must be present, reflecting a synergistic relationship [92].…”

Section: Mixed Lewy Body and Ad Pathologiesmentioning

confidence: 99%

Impact of multiple pathologies on the threshold for clinically overt dementia

2017

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Longitudinal clinical-pathologic studies have increasingly recognized the importance of mixed pathologies (the coexistence of one or more neurodegenerative and cerebrovascular disease pathologies) as important factors in the development Alzheimer’s disease (AD) and other forms of dementia. Older persons with AD pathology, often have concomitant cerebrovascular disease pathologies (macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy) as well as other concomitant neurodegenerative disease pathologies (Lewy bodies, TDP-43, hippocampal sclerosis). These additional pathologies lower the threshold for clinical diagnosis of AD. Many of these findings from pathologic studies, especially for CVD, have been confirmed using sophisticated neuroimaging technologies. In-vivo biomarker studies are necessary to provide an understanding of specific pathologic contributions and time course relationships along the spectrum of accumulating pathologies. In this review, we provide a clinical-pathological perspective on the role of multiple brain pathologies in dementia followed by a review of the available clinical and biomarker data on some of the mixed pathologies.

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“…The distribution of TDP-43 pathology varies remarkably (range 13 to 46%), partly due to the fact that different antibodies are used and also due to how the presence of TDP-43 immunoreactivity is specified [ 35 ]. Furthermore, less common NDDs – such as multiple system atrophy, PSP, corticobasal degeneration, tangle-predominant dementia, FTLD-TDP [ 72 ] and even Pick bodies – are also reported in a subset of their subjects (usually below 5 to 10%) [ 5 , 27 , 36 , 41 , 45 , 51 ]. Application of phospho-tau immunostaining in several anatomical regions allowed the VITA study to identify a spectrum of further tau pathologies associated with the aging brain, including their association with cognitive decline [ 5 , 6 ].…”

Section: Frequency Of Neurodegenerative Conditions In the Aging Brainmentioning

confidence: 99%

Prevalence of mixed pathologies in the aging brain

2014

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The spectrum of mixed brain pathologies expands beyond accompanying vascular pathology in brains with Alzheimer’s disease-related pathology. Co-occurrence of neurodegenerative non-Alzheimer’s disease-type proteinopathies is increasingly recognized to be a frequent event in the brains of symptomatic and asymptomatic patients, particularly in older people. Owing to the evolving concept of neurodegenerative diseases, clinical and neuropathological diagnostic criteria have changed during the last decades. Autopsy-based studies differ in the selection criteria and also in the applied staining methods used. The present review summarizes the prevalence of mixed brain pathologies reported in recent community-based studies. In these cohorts, irrespective of the clinical symptoms, the frequency of Alzheimer’s disease-related pathology is between 19 and 67%, of Lewy body pathology is between 6 and 39%, of vascular pathologies is between 28 and 70%, of TDP-43 proteinopathy is between 13 and 46%, of hippocampal sclerosis is between 3 and 13% and, finally, of mixed pathologies is between 10 and 74%. Some studies also mention tauopathies. White-matter pathologies are not discussed specifically in all studies, although these lesions may be present in more than 80% of the aging brains. In summary, community-based neuropathology studies have shown that complex constellations of underlying pathologies may lead to cognitive decline, and that the number of possible combinations increases in the aging brain. These observations have implications for the prediction of the prognosis, for the development of biomarkers or therapy targets, or for the stratification of patient cohorts for genome-wide studies or, eventually, for therapy trials.

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Impact of Less Common and “Disregarded” Neurodegenerative Pathologies on Dementia Burden in a Population-Based Cohort

Cited by 32 publications

References 0 publications

Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study

Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study

Impact of multiple pathologies on the threshold for clinically overt dementia

Prevalence of mixed pathologies in the aging brain

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