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Washington University Experience | NEURODEGENERATION | Progressive Supranuclear Palsy (PSP) | 7D Case 7 Denouement
Comment: The following excellent interpretation of this case, prepared by Richard Perrin, MD, PhD, demonstrates the complexity of analysis of real life degenerative disease. ---- The main neuropathologic findings of this case with relevance to the patient’s movement disorder are progressive supranuclear palsy (PSP) and Lewy body disease (LBD). Several other minor findings, likely to have contributed less to neurological impairment, include: generally mild but regionally moderate-to-severe white matter arteriolosclerosis; Alzheimer disease neuropathologic change (also consistent with primary age-related tauopathy [PART]), and mild focal aging-related tau astrogliopathy (ARTAG) noted only in the medulla. Supporting a diagnosis of PSP, this case exhibits regionally variable numbers of phospho-tau-immunoreactive neurons, oligodendroglial inclusions (coiled bodies), and astrocytes (most, with tufted morphology), predominantly in the pallidum, striatum, thalamus, hypothalamus, subthalamic nucleus, substantia nigra, dorsal midbrain, inferior olivary nucleus, reticular formation, dorsal medulla, dentate nucleus, and frontal cortex. No tau-immunoreactive ballooned neurons are present to suggest an alternative diagnosis of corticobasal degeneration. Although this case also shows Lewy body disease (the neuropathological correlate of idiopathic Parkinson disease and/or dementia with Lewy bodies discussed below), it appears likely that PSP contributed substantially to the patient’s neurological impairments. ---- In addition this case displays Lewy bodies and Lewy neurites in brainstem, olfactory bulb and medial olfactory cortex septum, a few limbic areas (nucleus basalis of Meynert, basal forebrain, amygdala, entorhinal cortex) and (to a very limited extent) other limbic and neocortical areas (anterior cingulate, middle frontal gyrus), most consistent with a stage between brainstem-predominant and limbic-predominant (transitional) Lewy body disease, according to McKeith criteria. When limbic-predominant LBD is accompanied by the modest burden of ADNC seen in this case (see discussion below), there is a high likelihood that the Lewy body pathology is responsible for any dementia with Lewy bodies (DLB) clinical syndrome; when brainstem-predominant LBD occurs in this setting, the likelihood is considered to be low; thus, given the intermediate nature of the McKeith stage of this case, it is difficult to predict what influence this LBD might have had on inducing a DLB-like syndrome. It should also be noted that this prediction may not necessarily be applicable to cases such as this with additional PSP pathology. ---- In addition to PSP and LBD, this examination finds a modest burden of beta-amyloid plaques and a very modest distribution/density of (a subset of) neurofibrillary tangles that are distributed in a neuroanatomic pattern expected to support a diagnosis of Alzheimer disease neuropathologic change (ADNC). Sufficient to support a neuropathological diagnosis of AD according to Khachaturian criteria, but the lack of neuritic plaques excludes a diagnosis of AD by the criteria of CERAD, the NIA-Reagan Institute. According to the more recent NIA-AA criteria, this case is considered consistent with low Alzheimer disease neuropathologic change (ADNC, A1B1C0). ---- An alternative diagnostic interpretation of these amyloid plaques and neurofibrillary tangles is that, whereas the plaques remain attributed to ADNC, the tangles in question might actually reflect a process of primary aging-related tauopathy (PART). Acknowledging the presence of amyloid plaques, the term 'possible' is appended to the diagnosis of PART, accompanied by Braak NFT stage I and Thal A phase 2. Irrespective of nomenclature, at this low stage of neurofibrillary tangle pathology, it is unlikely that ADNC or PART plus ADNC were of any real independent clinical consequence. ---- In addition to the features of PSP, LBD, and ADNC/PART, this case shows generally mild but focally moderate-to-severe (in the frontal lobes) white matter arteriolosclerosis. The role of arteriolosclerosis in the pathogenesis of neurodegenerative disease is incompletely understood. However, due to its relatively limited nature in this case and the participant’s reported cognitive normalcy, arteriolosclerosis likely contributed only minimally to neurological dysfunction. ---- In addition to the features of PSP, LBD, ADNC/PART, and arteriolosclerosis, this case shows tau-immunoreactive astrocytes with characteristic morphology limited to focal subpial and focal gray matter distributions (consistent with aging-related tau astrogliopathy [ARTAG]), in the lateral medulla and inferior olivary nucleus. The significance of this pathologic process to neurological dysfunction is unclear but, given the limited nature of this finding in this case, any influence on this individual’s neurological function is likely negligible
