Incipient progressive supranuclear palsy is more common than expected and may comprise clinicopathological subtypes: a forensic autopsy series

Abstract

We investigated 998 serial Japanese forensic autopsy cases (0-101 years old, mean age 61.7 ± 21.9), with no case selection, using immunohistochemistry to detect cases with progressive supranuclear palsy (PSP). Twenty-nine cases (mean age 82.3 ± 7.2 years, 11 males, 18 females) fulfilled the National Institute of Neuronal Disorders and Stroke (NINDS)-PSP pathological criteria (2.9% of all cases, 4.6% of cases over 60). All had neuronal and glial inclusions in the basal ganglia and brainstem. However, 13 cases had low tau pathology and were categorized as atypical PSP. In addition to PSP pathology, multiple types of astrocytic inclusions and comorbid proteinopathies, particularly a high prevalence of argyrophilic grain disease, were found. All cases had not been diagnosed with PSP and had preserved daily functioning prior to death. However, 14 (48.3%), 11 (37.9%), and 16 (55.2%) cases showed signs of dementia, depressive state, and gait disturbance, respectively. Sixteen accidental death cases (55.2%), including from falls and getting lost, and 11 suicide cases (37.9%) appear to have a relationship with incipient PSP pathology. Cluster analysis using the distribution and amount of 4-repeat-tau pathology classified the cases into three subgroups: Group 1 (10 cases) had typical PSP pathology and seven cases (70.0%) had dementia as the most frequent symptom; Group 2 (7 cases) had significantly higher frequency of gait disorder (6 cases, 85.7%), and less neocortical tau pathology than Group 1; Group 3 (12 cases) had relatively mild PSP pathology and high argyrophilic grain burdens. Granular-shaped astrocytes were the dominant astrocytic inclusion in all cases. We conclude that in forensic cases incipient PSP occurs with a higher prevalence than expected. If these findings can be extrapolated to other population-based cohorts, PSP may be more common than previously thought.

Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches

“…However, a study in Japan that included other PSP phenotypes in addition to PSP-RS found a total prevalence of 18 per 100,000 across all ages. 5 This higher prevalence number is consistent with estimates from autopsy series, 6 and suggests that the prevalence of the full spectrum of PSP syndromes is substantially higher than estimates based on PSP-RS alone. A cluster of PSP cases in an industrial city in France and a multicenter case-control study suggest that environmental risk factors influence PSP incidence.…”

“…24 Two similar studies found PSP pathology in 4.6% of normal elderly subjects in a healthy aging cohort 12 and 4.6% of individuals over 60 in a large forensic autopsy series in Japan. 6 These numbers are in striking contrast to the low prevalence of PSP-RS, 4 suggesting that if accurate, most individuals with presymptomatic PSP do not develop overt disease.…”

“…A wealth of evidence supports such a sequence of pathological events in Alzheimer’s disease (AD) and Parkinson’s disease (PD), 10,11 and the recent demonstration of mild asymptomatic PSP pathology in some healthy elders suggests that a similar sequence of events might occur in PSP. 6,12,13 Therefore, it is likely that PSP starts with a presymptomatic phase in which neuropathological abnormalities begin to accumulate but clinical features are absent, develops to an suggestive of PSP (soPSP) phase in which individuals develop mild or isolated symptoms, but do not meet the full research criteria for PSP, and culminates with a fully symptomatic stage that in many cases would meet the research criteria for PSP-RS or another clinical variant of PSP (vPSP; Figure 1). As the disease progresses, many vPSP syndromes eventually develop features of PSP-RS.…”

“…Currently, the presymptomatic phase can only be identified post mortem by evidence of histological changes typical of PSP pathology in individuals who are considered clinically normal. 6,12,13 Because the new MDS PSP criteria focus on clinical diagnosis, they do not include the presymptomatic PSP, but they are consistent with this concept. In one community-derived autopsy series, incipient PSP was present in five out of 233 individuals (2.1%).…”

Untangling the tauopathies: Current concepts of tau pathology and neurodegeneration

“…The proposed early brain network affected by tau pathology may shed light on the use of in vivo tau imaging as a biomarker to identify preclinical or early CBD. Neuropathological series of clinical asymptomatic cases with early PSP pathology has also emerged in the literature [25], which contributes to improve our understanding of the early disease process of 4R-tauopathies.…”