Accepted Manuscript Reversible sub-acute cognitive deterioration in cerebral amyloid angiopathy: A case report Marco Pasi, Li Xiong, Andreas Charidimou, Anand Viswanathan PII: DOI: Reference: S0022-510X(18)30001-7 doi:10.1016/j.jns.2018.01.001 JNS 15727 To appear in: Journal of the Neurological Sciences Received date: Revised date: Accepted date: 3 November 2017 28 December 2017 2 January 2018 Please cite this article as: Marco Pasi, Li Xiong, Andreas Charidimou, Anand Viswanathan , Reversible sub-acute cognitive deterioration in cerebral amyloid angiopathy: A case report. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2018), doi:10.1016/j.jns.2018.01.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. 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ACCEPTED MANUSCRIPT Reversible sub-acute cognitive deterioration in cerebral amyloid angiopathy: a case report Marco Pasi, MD,1 Li Xiong, MD, PhD#,1 Andreas Charidimou, MD, PhD,1 Anand Viswanathan, MD, PhD;1 1 Hemorrhagic Stroke Research Program, Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, MA, USA # AC CE PT ED M AN US Marco Pasi mpasi@mgh.harvard.edu Li Xiong lxiong2@partners.org Andreas Charidimou andreas.charidimou.09@ucl.ac.uk Anand Viswanathan aviswanathan1@partners.org CR IP T Corresponding author: Dr Li Xiong, MD, PhD, Massachusetts General Hospital, Stroke Research Center 175 Cambridge Street #300, Boston, MA 02114; Tel: +1 617 643 2713 Fax: +1 617 643 3939 Email: lxiong2@partners.org ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T Key words: Cerebral amyloid angiopathy, Dicyclomine, Cognitive impairment ACCEPTED MANUSCRIPT Introduction CR IP T The pathologies of cerebral small vessel disease (SVD) and Alzheimer’s disease (AD) are the most important contributors to cognitive impairment and dementia in the elderly 1. However, the clinical trajectories of individual patients are affected not only by the underlying brain pathology but also by other reversible environmental factors2. For instance, one population based study demonstrated that APOE ɛ4 magnified the effect of physical inactivity, high dietary fat intake, alcohol drinking and smoking on dementia3. It is likely that the combination of pathological and environmental factors leads to the clinical phenotype in individual patients. Identification and removal of potential precipitating factors may have significant implications on the clinical course in patients. We present a case of reversible subacute cognitive deterioration in the context of probable cerebral amyloid angiopathy (CAA) and likely Alzheimer type neuropathology. In this case report we discuss the role of anticholinergic drugs as a precipitating cause of cognitive deterioration. Case report US A 76-year-old female with a two years’ history of subjective memory complaints presented to a local memory clinic for subacute worsening of cognitive function with a dramatic impact on her functional AN independence and social activities starting from December 2016. An extensive neuropsychological evaluation demonstrated an overall impairment in cognition with greater deficits in visuospatial processing and executive function. Blessed dementia scale (BDS) was 5/37. Global clinical dementia M rating (CDR) was 1. Mild to moderate depression was present. Extensive work-up to exclude commonly ED reversible causes of dementia was negative. Thyroid-stimulating hormone and vitamin 12 levels were within normal range. Syphilis serology and the Mayo clinic autoimmune encephalitis panel were both PT negative (https://www.mayomedicallaboratories.com/test-catalog/Overview/48404). A brain MRI demonstrated diffuse cortical atrophy, extensive white matter hyperintensities (particul arly in posterior areas) and more than 10 strictly lobar cerebral microbleeds (CMB), qualifying for a diagnosis of probable CE CAA4 (Figure). FDG-PET showed patch y decrease uptake in the parietal lobe and diminished activity within the posterior cingulate co rtex. AC Lumbar puncture showed p-tau elevation and decreased Aβ-42 levels. During a memory clinic visit at this hospital for a second opinion in June, 2017, the patient was noted to be on dicyclomine (since December 2016) for irritable bowel syndrome. She was advised to discontinue the drug due to its anticholinergic effects. The patient’s cognitive profile subsequently improved to the point that she had regained her baseline functional independence during a follow-up visit in September 2017 (BDS was 0 and CDR was 0.5). Discussion ACCEPTED MANUSCRIPT CAA is a common age-related cerebral SVD increasingly recognized as a contributor to vascular cognitive impairment and dementia in the elderly. Recent findings suggest a pattern of widespread cognitive changes in CAA patients which affect mainly executive function and processing speed4 . The neuroradiological and neurocognitive profile of our patient is consistent with a diagnosis of probable CAA. CSF profile and FDG-PET also suggest some contribution of AD pathology in the overall clinical T picture. IP Despite clear neuroimaging evidence of CAA and AD pathology, this patient had been asymptomatic. This CR case reminds us that asymptomatic CAA and AD pathology is not uncommon 1, 5. However, in isolation the detection of these pathologies does not constitute a diagnosis of disease5 . A dramatic worsening only occurred after starting dicyclomine, a drug with anticholinergic properties. Anticholinergic drugs can US cause or worsen cognitive impairment, based on evidence from cross-sectional studies in both healthy elderly population and patients with baseline cognitive impairment or dementia 6. However, a regression AN of the cognitive symptoms after the discontinuation of the drug does not always occur 7. These studies mostly calculated the total burden of anticholinergic drugs, instead of the effect of a single drug. In the M case of dicyclomine, there have been 17 cases who experienced the side effect on cognition according to the FDA report so far ED (https://www.druginformer.com/search/side_effect_details/Dicyclomine%20Hydrochloride/cognitive%2 0disorder.html), while no formal reports are available in the literature. The cognitive deficits that have PT been related to anticholinergic drugs also varies between studies, 6, 7 likely reflect the underlying pathologic process that was already present prior to initiation of drug. One plausible explanation in our CE patient is that the underlying asymptomatic mixed CAA/AD pathology has lowered the patient’s cognitive reserve, making the patient more vulnerable to external factors. The patient’s clinical deterioration AC could have also been influenced by the occurrence of a subacute mood disorder, known to be related with cholinergic system8. In conclusion, we describe the reversal of cognitive impairment in a patient with probable CAA after dicyclomine discontinuation. Our case emphasizes the importance of detecting potentially reversible causes of cognitive impairment even in patients with known vascular and/or neurodegenerative pathologies. This case raises the question as to whether a reversible agent could be used diagnostically to identify those asymptomatic patients with underlying pathologies and low cognitive reserve who may be at increased risk to cognitively deteriorate. ACCEPTED MANUSCRIPT References: AC CE PT ED M AN US CR IP T 1. Boyle PA, Yu L, Nag S, et al. Cerebral amyloid angiopathy and cognitive outcomes in community based older persons. Neurology 2015;85:1930-1936. 2. Solomon A, Mangialasche F, Richard E, et al. Advances in the prevention of Alzheimer's disease and dementia. J Intern Med 2014;275:229-250. 3. Kivipelto M, Rovio S, Ngandu T, et al. Apolipoprotein E epsilson4 magnifies lifestyle risks for dementia: a population-based study. J Cell Mol Med 2008;12(6B):2762-2771. 4. Xiong L, Davidsdottir S, Reijmer YD, et al. Cognitive Profile and its Association with Neuroimaging Markers of Non-Demented Cerebral Amyloid Angiopathy Patients in a Stroke Unit. Journal of Alzhei mer's disease : JAD 2016;52:171-178. 5. Charidimou A, Blacker D, Viswanathan A. Context is everything: From cardiovascular disease to cerebral microbleeds. International journal of stroke : official journal of the International Stroke Society 2017:1747493017730907. 6. Swami S, Cohen RA, Kairalla JA, Manini TM. Anticholinergic Drug Use and Risk to Cognitive Performance in Older Adults with Questionable Cognitive Impairment: A Cross-Sectional Analysis. Drugs Aging 2016;33:809-818. 7. Salahudeen MS, Duffull SB, Nishtala PS. Impact of anticholinergic discontinuation on cognitive outcomes in older people: a systematic review. Drugs Aging 2014;31:185-192. 8. Pytka K, Dziubina A, Mlyniec K, et al. The role of glutamatergic, GABA-ergic, and cholinergic receptors in depression and antidepressant-like effect. Pharmacol Rep 2016;68:443-450. ACCEPTED MANUSCRIPT Figure 1 legend: Panel A: Axial FLAIR showing posterior white matter hyperintensity (arrowhead) and widening of the sulci. Panel B: Axial T2*-weighted gradient-recalled echo showing lobar cerebral microbleeds (incepts) and absence of cerebral microbleeds in deep area. Panel C: Axial FDG-PET showing patchy decreased uptake in the parietal lobe (right [arrow] greater than left). AC CE PT ED M AN US CR IP T Authors Disclosures: Marco Pasi reports no disclosures Li Xiong reports no disclosures Andreas Charidimou reports no disclosures Anand Viswanathan is supported by NIH grants R01AG047975, R01AG026484 and P50AG005134. Dr. Anand Viswanathan is a consultant for Roche M AN US CR IP T ACCEPTED MANUSCRIPT AC CE PT ED Figure 1