Acute Neuropsychiatric Decline in a Parkinson's Disease Patient with a Severe <scp> <i>GBA1</i> </scp> Mutation Following Bilateral <scp>GPi</scp> Deep Brain Stimulation

Parkinson's Disease (PD) patients who are heterozygous carriers of glucocerebrosidase (GBA1) gene pathogenic variants (PD-GBA1) are phenotypically similar to idiopathic PD (iPD) patients but may have a younger age-of-onset and earlier motor fluctuations, neuropsychiatric symptoms, and cognitive dysfunction.1 Advanced PD may be treated with deep brain stimulation (DBS), but the procedure is generally avoided in those with significant cognitive deficits and the globus pallidus internus (GPi) target is favored over subthalamic nucleus (STN) if there is concern. Genetic subtyping is not standard-of-care for DBS presurgical evaluations. However, PD-GBA1 patients may be more likely to have cognitive dysfunction after STN-DBS compared with iPD patients, with limited data regarding GPi-DBS.2, 3 In this letter, we describe the seven-year clinical course of a 65 year-old woman with asymmetric PD complicated by acute and severe neuropsychiatric decline and dementia following bilateral GPi-DBS (Fig. 1A), found to carry a pathogenic variant in the GBA1 gene. The patient presented with classic motor symptoms of PD at age 58—asymmetric left hand rest tremor, bradykinesia, and rigidity. She started carbidopa/levodopa soon after diagnosis, developed motor fluctuations after one year, and was switched to Rytary. Over the following two years, severe motor fluctuations with brittle dyskinesia and dystonia of the lower extremities emerged. At age 61, she was referred for DBS evaluation. Her MDS-UPDRS Part III score showed a 54% improvement from OFF- to ON-levodopa. Neuropsychologic evaluation revealed anxiety with history of panic attacks, and mild cognitive impairment with a Montreal Cognitive Assessment (MoCA) score of 25, impaired recent memory, and mild difficulties with language and visual perception without evidence of psychosis (Supporting Information S1). Her brain MRI was unremarkable. At age 62, she underwent uncomplicated, asleep, single-track DBS implantation using intraoperative CT in the bilateral GPi, chosen to address brittle dyskinesia and dystonia and minimize neuropsychiatric risk. Head CT revealed well-positioned leads with mild peri-lead edema. Post-operatively, she developed a two-week delirium and new-onset hallucinations, delusions, and panic attacks. Prolonged EEG and infectious, paraneoplastic, and autoimmune encephalopathy workup were unremarkable. Over the subsequent nine months, she developed progressive anxiety, psychosis, and cognitive decline. DBS was turned OFF for two weeks on two separate occasions to determine whether these new symptoms were stimulation-induced, but there was no improvement. Her motor symptoms responded well to standard monopolar GPi stimulation. Levodopa-equivalent daily dose was reduced to limit the effect of dopamine on the new-onset psychosis (73%: 1738 to 468 mg). She required titration of sertraline, gabapentin, rivastigmine, quetiapine, pimavanserin, and clozapine without improvement, but improved with aripiprazole. Neuropsychologic testing eight months post-DBS revealed significant anxiety, MoCA score of 18, and severe impairments in constructional abilities, memory, attention, language, and executive functioning, suggestive of frontoparietal dysfunction superimposed on global dysfunction, consistent with moderate dementia (Supporting Information S1). Head CT revealed global brain atrophy with frontoparietal predominance (Fig. 1B). Genetic testing obtained through the Parkinson's Foundation PD GENEration panel revealed a heterozygous severe variant in GBA1 gene (p. Leu483pro, L444P). As the incidence of PD continues to grow, many patients may ultimately require DBS surgery, and some may carry GBA1 pathogenic variants, the most common genetic risk factor for PD.4, 5 At present, there are no international guidelines or expert consensus on whether all DBS candidates should be offered pre-surgical genetic testing or how DBS neurologists should counsel patients. The L444P (p. Leu483pro) variant described in this case is one of the most common severe GBA1 mutations and is associated with a higher risk of dementia compared to mild mutations.6 Though our patient carried this severe GBA1 mutation, she also exhibited some atypical features, including rapid motor progression, high levodopa requirements, and unexpected MCI early in disease. While severe GBA1 mutations increase the risk of cognitive decline, studies have shown that in both DBS-implanted and non-implanted patients that dementia is typically observed beyond a five-year disease duration, making our patient's pre-DBS cognitive dysfunction and post-DBS subsequent dementia atypical.7, 8 This raises the question whether additional risk factors contributed to her rapid decline. The differential diagnosis for our patient should have included Dementia with Lewy Bodies (DLB), given its characteristic early neuropsychiatric symptoms and association with GBA1 variants.9 However, her asymmetric parkinsonism, levodopa-responsiveness, and aggressive dyskinesia, made a diagnosis of PD more likely than an atypical syndrome at the time. Our patient's accelerated course and brain atrophy post-DBS suggests that surgery itself hastened neurodegeneration. Brain surgery in general, post-operative delirium, and prolonged periods of anesthesia have been linked to brain atrophy and cognitive decline.10 In summary, our patient's rapid decline post-DBS may not have stemmed from the GBA1 mutation alone but rather from a confluence of risk factors. While our case highlights the potential role of genetic testing as part of the pre-DBS evaluation, it also underscores that rapid disease progression should prompt caution when pursuing DBS early in disease and we should remain hypervigilant with our differential diagnoses. Preliminary longitudinal studies have investigated the potential impact of different GBA1 variants and DBS targets on post-DBS outcomes, but replication and larger sample sizes are needed.2, 3, 7 GBA1 patients (including our patient) do benefit motorically from DBS, however, more studies are urgently needed to elucidate the factors which predict dementia in this cognitively vulnerable population.2, 3, 7 (1) Research Project: A. Conception, B. Organization, C. Execution. (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. V.G.P.: 1A, 1B, 1C, 2A, 2B G.D.P.: 1A, 1B, 1C, 2A, 2B M.A.: 1A, 1B, 1C, 2A, 2B Ethical Compliance Statement: This study was approved by the Rush University Medical Center Institutional Review Board. Written informed consent was obtained from the participant. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: The authors declare that there are no funding sources or conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: VP has had no financial disclosures to report over the last 12 months. GP is a consultant for Guidepoint, Motley RIcs, Techspert, and Health Central and serves on the Data and Safety Monitoring Board of Aspen Neuroscience. MA is a consultant for Abbott, Inc. and obtains research funding from the Parkinson's Foundation and Parkinson Study Group. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supplement S1 Neuropsychological Evaluations – (A) Pre-DBS Surgery Baseline Neuropsychological Evaluation. (B) Post-DBS Surgery Neuropsychological Evaluation (8 months post-DBS, 15 months from baseline testing). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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