Neuropathology of Perry Syndrome: Evidence of Medullary and Hypothalamic Involvement

Abstract

BackgroundBackground: Perry syndrome is a rare genetic parkinsonian disorder with TAR DNA binding protein 43 (TDP-43) pathology clinically presenting with parkinsonism, neuropsychiatric features, weight loss, and central hypoventilation. As respiratory complications are often the cause of death, studies likely show the early stage of the neurodegenerative process. Because of the rarity of this condition, few studies exist, and each case provides insight into pathological findings in this neurodegenerative condition. Objective Objective: To study the clinical and pathological correlations of an autopsy case of Perry syndrome. Methods Methods: The patient was a woman in her 50s with Perry syndrome and a DCTN1 gene mutation. Between October 2016 and July 2019, she underwent postmortem and pathological examination at University Hospital in London, Ontario, Canada. Data were obtained through clinical pathological examination. Results Results: Microscopy showed significant neuronal loss with pigmentary incontinence and gliosis in the substantia nigra. There was no atrophy elsewhere, including the frontal and cingulate cortex. Intraneuronal cytoplasmic TDP-43 inclusions and neurites were noticed in a moderate number in the substantia nigra and midbrain and were sparsely noticed in the basal ganglia, thalamus, thoracic motor neuron, posterior nucleus of the hypothalamus, and rostral ventral medulla. β-Amyloid, Lewy body, and tau pathologies were absent. Rare axonal swelling was identified at the rostral ventrolateral medulla. Conclusions and RelevanceConclusions and Relevance: This study confirms that Perry syndrome is characterized by TDP-43 pathology with absent Lewy bodies or tau pathology. These findings support the hypothesis of dysfunctional neurons in the medulla and hypothalamus, which may respectively correlate to the clinical symptoms of hypoventilation and weight loss in Perry syndrome.Perry syndrome (PS) is a rare neurodegenerative disorder with parkinsonism, neuropsychiatric features (depression/apathy), weight loss, and central hypoventilation leading to respiratory failure. 1 The causative gene is an autosomal-dominant pathogenic variant in DCTN1, which encodes dynactin subunit p150 Glued involved in axonal transport. 2 Because of the rarity of the condition, few pathological studies exist. However, it is a unique parkinsonian disorder characterized by the presence of TAR DNA binding protein 43 (TDP-43) pathology in previous studies, especially in the substantia nigra (SN). 3 Despite profound respiratory failure and weight loss in this disorder, there is no clear consensus on the clinicopathologic correlation of these symptoms. PS has been described in at least 18 families worldwide, 2,4 and we provide a pathologic study of a patient in a newly identified family to better understand the pathologic findings in PS. MethodsAt autopsy the brain was retrieved and then fixed in 10% neutral formalin for 2 weeks. After fixation, formalin-fixed paraffin embedded blocks were prepared. Blocks from the bilateral

In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use

“…A number of diseases involve TDP-43 as their primary neuropathology, in which a relevant pathogenic role has been postulated [ 4 ]. Main diseases related to TDP-43 pathology comprise most sporadic forms of ALS and about 50% of FTD (FTD-TDP), especially behavioral variant and semantic primary progressive aphasia [ 23 , 24 ] as well as cognitive impairment associated with limbic-predominant age-related TDP-43 encephalopathy [ 25 ] and Perry syndrome [ 26 ]. TDP-43 proteinopathy in skeletal muscle cells is a common finding in sporadic inclusion body myositis (IBM) [ 27 ].…”

Perry Disease: Bench to Bedside Circulation and a Team Approach

“…The pathological features of Perry disease have revealed substantial neuronal loss and gliosis, with few or no Lewy bodies or neurofibrillary tangles present in the substantia nigra [4,6,7,[17][18][19][20][21][22][23]. Neuronal loss is detected in the lentiform nucleus, the locus coeruleus, the dorsal raphe nucleus, the periaqueductal gray matter, the hypothalamus, and the brainstem, including putative respiratory neurons in the medulla [6,20,21,24]. In Perry disease patients, TDP-43 pathology is noted in the extrapyramidal system and brainstem [6,7].…”