Iatrogenic cerebral amyloid angiopathy in older adults

Abstract Background and purpose An increasing number of cases of iatrogenic cerebral amyloid angiopathy (CAA) have now been reported worldwide. Proposed diagnostic criteria require a history of medical intervention with potential for amyloid‐β transmission, for example those using cadaveric dura mater or requiring instrumentation of the brain or spinal cord. Clinical presentation occurs after an appropriate latency (usually three or four decades); to date, most patients with iatrogenic CAA have had ‘early‐onset’ disease (compared to sporadic, age‐related, CAA), as a consequence of childhood procedures. Results We describe five cases of possible iatrogenic CAA in adults presenting in later life (aged 65 years and older); all had prior neurosurgical interventions and presented after a latency suggestive of iatrogenic disease (range 30–39 years). Use of cadaveric dura mater was confirmed in one case, and highly likely in the remainder. Conclusion The presentation of iatrogenic CAA in older adults widens the known potential spectrum of this disease and highlights the difficulties of making the diagnosis in this age group, and particularly in differentiating iatrogenic from sporadic CAA. Increased vigilance for cases presenting at an older age is essential for furthering our understanding of the clinical phenotype and broader implications of iatrogenic CAA.


INTRODUC TI ON
Iatrogenic cerebral amyloid angiopathy (CAA), that is, that occurring as a consequence of medical procedures, is now recognized as a distinct form of amyloidβ CAA.Since the first clinical reports of iatrogenic CAA in 2019 [1], more than 50 cases have been described [2][3][4][5][6][7].Iatrogenic CAA is hypothesized to occur following the transmission of amyloidβ protein during medical procedures (mainly neurosurgery), with subsequent clinical symptoms of CAA typically developing about three decades after exposure [2,3].Nearly all published reports of iatrogenic CAA to date are in patients who had childhood medical procedures, with subsequent symptomatic CAA at an age considered 'young' for sporadic CAA (typically under 55 years) [8].However, there is no biological reason why iatrogenic CAA could not occur at older ages in people who had medical procedures involving exposure to amyloidβ beyond childhood.
Here, we describe five patients presenting with possible iatrogenic CAA in later life (older than 65 years), defined using recently proposed diagnostic criteria [2].

C A S E REP ORTS
Details of the clinical features and key investigation findings for all cases are summarized in Table 1.The timeline of the clinical presentation is highlighted in Figure 1.

Case 1
A 74-year-old woman presented with a history of episodic severe bilateral headache and episodic forgetfulness for names and facts.
There was no history of hypertension.Aged 35 years (1983), she had foramen magnum decompression surgery for a Chiari I malformation (Figure 2c); the operation note confirmed that cadaveric dura mater was used to close a dural defect.
One year after presentation, the patient developed transient focal neurological episodes (TFNE), characterized by sensory disturbance (tingling and numbness) involving the right side of the mouth and right hand.Brain MRI performed 1 week later revealed a small convexity subarachnoid haemorrhage over the left central sulcus and some progression of cSS.In the 2 years after this event, she has been clinically and radiologically stable.

Case 2
A 73-year-old man was referred to the memory clinic with a 3-year history of increased forgetfulness, disorientation and apathy.He had treated hypertension and was an ex-smoker.Aged 43 years (1987), the patient suffered a traumatic subdural haematoma that was evacuated via a left craniotomy.Cadaveric dura was used routinely for this operation at the treating hospital during this period, but the operative note was unavailable to provide confirmation.
At initial assessment, the patient scored 26/30 on the Mini-Mental State Examination (MMSE) and 13/18 on the Frontal Assessment Battery.Brain MRI (blood-sensitive sequences not performed) showed extensive periventricular white matter hyperintensities (Figure 2d).Brain perfusion single photon emission computed tomography (SPECT; using r 99m Tc-ECD) revealed hypoperfusion in the posterior cingulate cortex and the precuneus.The patient was diagnosed with Alzheimer's disease.
A repeat brain MRI performed 1 year later showed a high burden of small vessel disease and bilateral exclusively lobar CMBs but no cSS (Figure 2e).
Five years after the original presentation (aged 78 years) the patient was admitted with rapidly progressive cognitive impairment, constructive and orofacial apraxia.RepeatMRI demonstrated an acute left occipital intracerebral haemorrhage (ICH) and many new CMBs (Figure 2f).Cerebrospinal fluid (CSF) analysis demonstrated reduced levels of Aβ-42 (52.5 pg/mL; normal >620 pg/mL) and reduced Aβ 42/40 ratio (0.072, normal >0.72).The patient's cognitive functions did not improve, and he was transferred to a longterm care hospital.

Case 3
A 69-year-old woman developed persistent double vision, which was fixed with prism lenses.Aged 36 (1984), she had a subtotal resection of left sphenoid meningioma.Cadaveric dura was used routinely for such operations at the treating hospital at this time, but the operation note was unavailable.The patient developed a persistent (lower) visual field defect following the procedure.There was no postoperative radiotherapy.She suffered from migraines and was not hypertensive.Neuropsychological testing revealed evidence of mild anterior/subcortical dysfunction.
A gadolinium-enhanced MRI of the brain showed slow growth of the residual meningioma over the previous 14 years (Figure 2i).T2 MRI showed enlarged CSO-EPVS (Figure 2g); susceptibility-weighted images (SWI) showed progressive cSS over both cerebral convexities (Figure 2h) and a small number of lobar CMBs (not shown).

Case 4
A 71-year-old man presented with multiple TFNE and increasing forgetfulness over 3 years.These TFNE were characterized by reduced sensation, usually involving left hand, arm and mouth.
Neuropsychological testing showed mild cognitive impairment involving verbal memory, executive function and processing speed.

Case 5
An 84-year-old man was referred with persistent diplopia.After a comprehensive clinical evaluation, the patient was diagnosed with Aged 50 (1986), the patient had an operation for a herniated intervertebral disc.The use of cadaveric dura was routine at the treating hospital during this period, but the operative note was unavailable.
In the following 3 years, repeat brain imaging showed new CMBs and progressive cSS, but the patient remained clinically stable throughout this period.

DISCUSS ION
We describe five cases of possible iatrogenic CAA, all presenting at an age older than previously reported (over 65 years).All patients had prior neurosurgery: one had confirmed and documented cadaveric dura used, whilst the remainder had procedures that were highly likely to have involved cadaveric dural grafting as standard practice in treating hospitals at the time.The latency between the index procedure and clinical presentation in all cases falls within the typical reported range of 30-40 years for iatrogenic CAA.Thus, apart from their older age of onset, these patients fulfil recently proposed diagnostic criteria for iatrogenic CAA regarding exposure, and clinical-radiological features, at an appropriate latency [2], leading us to conclude that iatrogenic CAA is likely.However, they also meet the age and clinical-radiological criteria for probable sporadic CAA [9] which is known to be prevalent in this age group.For this reason genetic causes of CAA were not systematically excluded (likely to be less relevant at later ages of presentation) and more invasive tests to demonstrate central nervous system amyloid deposition were not performed (i.e., cerebrospinal fluid, amyloid positron emission tomography, cerebral biopsy), given that amyloidβ deposition (including asymptomatic deposition) in this age group is common [9].
The clinical presentation of our cases appears to differ from younger-onset iatrogenic CAA cases reported to date, where ICH (in 83%) and seizures (in 17%) were the most common presenting symptoms [2].Three cases (1, 3 and 5) were incidentally found to have CAA after investigations for unrelated neurological symptoms (migraine, diplopia) and one of these patients (case 5) remained clinically asymptomatic from their CAA over an extended period of follow-up (over 3 years).Symptoms typical for CAA (cognitive impairment, TFNE) were observed in the remainder, although it is difficult to comment on their relative frequency compared to previously published cases, given the relatively small number of older cases.
Our cases highlight the challenges of diagnosing iatrogenic CAA in this age group (over 65 years).Genetic testing, which is important in younger cases to exclude differential causes of CAA [8], is less relevant at older ages, where the main alternative diagnosis is sporadic CAA.To date, there are no imaging or molecular biomarkers that allow definitive differentiation between late-onset iatrogenic versus sporadic CAA.Whilst it is impossible to definitively demonstrate causality, the patients reported here developed CAA at an appropriate latency after a relevant procedure associated with amyloidβ transmission.
The current diagnostic criteria for iatrogenic CAA were designed in anticipation of older-onset cases; however, their use in this group to date is limited, allowing only 'possible' diagnosis.CAA with young onset is more likely to be reported as it is unusual; it is hoped that our description of suspected iatrogenic CAA at an older age will improve awareness and lead clinicians to consider this diagnosis even in people in the typical age range for sporadic CAA.
Summary of clinical features and key investigation findings.
TA B L E 1 This series highlights the widening spectrum of iatrogenic CAA and the importance of asking about prior medical procedures in all CAA patients, regardless of age.Long-term follow-up of patients with po-Dr Panteleienko is supported in her work at the UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, by a CARA-UCL Academic Sanctuary Fellowship.Dr Banerjee is an NIHR Clinical Lecturer and also acknowledges research support from Alzheimer's Research UK and the Stroke Association.The MRC Prion Unit is core-funded by the UK Medical Research Council.Professor Yakushiji is supported in this tential amyloidβ exposure beyond childhood could help to determine whether CAA occurs more frequently than expected in later life, strengthening the hypothesis that amyloidβ transmission can occur with exposure beyond childhood.Improved understanding of the clinical phenotype in this older age group and biomarkers for iatrogenic CAA are essential for forming diagnostic criteria.AUTH O R CO NTR I B UTI O N S Larysa Panteleienko: Writing -original draft; data curation; formal analysis.Dermot Mallon: Visualization; formal analysis.Rupert Oliver: Investigation; data curation.Ahmed Toosy: Investigation; data curation.Yuki Hoshino: Investigation; data curation.Aya Murakami: Investigation; data curation.Kanishk Kaushik: Investigation; data curation.Marieke J. H. Wermer: Investigation; data curation.Hideo Hara: Investigation; data curation.Yusuke Yakushiji: Investigation; data curation.Gargi Banerjee: Conceptualization; methodology; writing -review and editing; project administration.David J. Werring: Conceptualization; methodology; writing -review and editing; project administration.ACK N OWLED G EM ENTS work by a Grants-in-Aid for Scientific Research (C), JSPS KAKENHI (Grant no.21K10510).Professor Toosy has been supported by recent grants from the MRC (MR/S026088/1), NIHR BRC (541/CAP/ OC/818837) and RoseTrees Trust (A1332 and PGL21/10079).Professor Wermer is supported by a personal grant from the Dutch Heart Foundation (2016T86).The authors would like to thank all