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F4‐02‐02: The influence of severity of total comorbidity on cognitive decline and conversion to dementia in memory clinic visitors
Author(s) -
Hamel Renske E.G.,
Ramakers Inez H.G.B.,
Oosterveld Saskia M.,
Melis René J.F.,
Olde Rikkert Marcel G.M.,
Sistermans Nicole,
Flier Wiesje M.,
Scheltens Philip,
Aalten Pauline,
Jansen Willemijn J.,
Visser Pieter Jelle,
Verhey Frans R.J.
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.07.334
Subject(s) - comorbidity , dementia , medicine , cognition , proportional hazards model , psychiatry , psychology , clinical psychology , disease
Background:Clinical trials in vascular dementia (VaD) are plagued by heterogeneity in etiologies, baseline, and progression patterns, and lack of standardized biomarker and clinical tools to measure outcome.MRI biomarkers are usually required [eg strategic or multiple cortical infarcts, subcortical lacunes/extensive white matter hyperintensities (WMH)], but not advanced MR measures (eg connectivity). Diagnostic criteria struggle to balance sensitivity and specificity. Methods: Using NINDS-AIREN criteria to study cholinesterase inhibitor efficacy in VaD, clinical trial designs either excluded Alzheimer’s Disease (AD) clinically or allowed mixed AD-VaD. Conversely, AD trial inclusion criteria allow a few lacunes but limit severity of WMH, and anti-amyloid trials limit microbleeds. Results: Results showed modest cognitive benefits, but several factors defeated regulatory approval. These factors included attribution to co-existing AD, insensitivity to executive dysfunction, and difficulty disentangling functional decline from cognitive vs physical deficits. Consensus has been developed for standardized investigations of VCID (e.g. NINDS-CSN Standards 2006; ASA/ AHA Statement on VCID 2011) and classification of small vessel disease, with variable impact. At autopsy, AD -vascular pathology relationships (additive/interactive) with pre-morbid dementia vary. Surveying whole brain pathologically (eg microinfarcts/ vessel wall disease) is challenging, and benefits fromMRI-guidance. Molecular PET reveals amyloid, tau pathology, and inflammation invivo, enabling novel insights into co-morbidities. Conclusions: The neurovascular unit (endothelium, neurons, glia and microglia) unifies experimental models (eg BBB dysfunction, amyloidosis in ischemia models, and microvasculature in AD transgenics), yielding new targets, that may translate into human protection and repair. Novel candidates may emerge (eg vasculotide, to reduce endothelial permeability). Repurposing trials (e.g. cilostazol, telmisartan, propentofylline, nimodipine) may fare better in designs which optimize imaging biomarker and clinical outcomes.