Anatomy of disturbed sleep in pallido‐ponto‐nigral degeneration

Sleep disturbances are frequently seen in neurodegenerative conditions. They are common in tauopathies,1–3 synucleinopathies,4–8 and prion disorders.9,10 The sleep disorders in Alzheimer disease,3 Parkinson disease (PD),5,6,8,11 and fatal familial insomnia (FFI)9,10 have been well characterized. Less is known about the sleep dysfunction in progressive supranuclear palsy,12,13 Pick disease, corticobasal degeneration,14,15 and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).16 Pallido-ponto-nigral degeneration (PPND) is a familial neurodegenerative disorder pathologically characterized by the presence of 4 repeat tau deposits in neurons and glia due to an N279K mutation in the gene for the microtubule associated protein tau (MAPT).17,18 PPND belongs to a cluster of disorders collectively labeled as FTDP-17. Clinical, pathological, and neuropsychometric findings in PPND were previously published.16,18,19 Despite recent progress in the understanding of motor and cognitive symptoms, pathology, and genetics of FTDP-17, little is known about sleep disturbances in this disorder. A previous study determined that the PPND kindred demonstrated progressive, generalized slowing on electroencephalography (EEG) as the clinical severity of the disorder increased.16 Daytime recordings captured no sleep, although patients were encouraged to fall asleep. The sleep difficulties observed during the baseline EEG study prompted further polysomnographic investigation.20 Initial polysomnographic data revealed that members of this kindred did not have clinical or electrophysiological features of rapid eye movement (REM) sleep behavior disorder.21 The prevailing theory of sleep generation is a flip-flop switch that governs sleep versus arousal.22 The ascending arousal system is composed of multiple anatomically distinct groups of neurons, including the tuberomammillary nucleus (TMN), the locus ceruleus (LC), the nucleus basalis of Meynert (nbM), and the pedunculopontine tegmentum/laterodorsal tegmentum (PPN/LDT). Meanwhile, the preoptic area of the hypothalamus has been demonstrated to be responsible for generating and maintaining non-REM (NREM) sleep via efferent connections from the median preoptic nucleus (MnPN) and the ventrolateral preoptic nucleus (VLPO), respectively.23,24 These γ-aminobutyric acidergic neurons are inhibitory for the PPN/LDT and LC, thus promoting sleep. Orexin nuclei in the hypothalamus are understood to stabilize the switch via efferent connections to the LC and nbM.25,26 Pathology in the anteroventral and dorso-medial thalamus has also been implicated in sleep disorders, specifically FFI.9 Positron emission tomography (PET) studies of the PPND kindred showed decreased acetylcholinesterase activity in the thalamus,27 which may parallel underlying behavioral similarities between PPND and FFI. The goal of this study was to examine NREM and REM sleep in both affected family members and those genealogically at risk for the disease. We sought to specifically characterize the nature of the sleep disturbance in PPND and compare these findings to those in other progressive neurological illnesses. Based on the inability to sleep noted in the initial study,16 we hypothesized that the PPND patients would have impaired sleep initiation and reduced sleep efficiency. Polysomnographic findings of 6 affected and 5 at-risk individuals from the PPND family are reported. The polysomnographic results prompted further investigation by retrospective, postmortem pathological analysis of available sleep-related areas of the brain.