Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease.

OBJECTIVE: Alzheimer's disease neuropathologic change and alpha-synucleinopathy commonly co-exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta-amyloid compared to alpha-synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia. METHODS: We used digital histology to measure percent area-occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha-synucleinopathy, and a co-pathology group with both Alzheimer's and alpha-synuclein pathologic diagnoses. Multiple tau monoclonal antibodies were used to detect early (AT8, MC1) and mature (TauC3) epitopes of tangle progression. We used linear/logistic regression to compare groups and test the association between pathologies and clinical features. RESULTS: There were lower levels of tau pathology (ß = 1.86-2.96, p < 0.001) across all tau antibodies in the co-pathology group compared to the pure Alzheimer's pathology group. Among individuals with alpha-synucleinopathy, higher alpha-synuclein was associated with greater early tau (AT8 ß = 1.37, p < 0.001; MC1 ß = 1.2, p < 0.001) but not mature tau (TauC3 p = 0.18), whereas mature tau was associated with beta-amyloid (ß = 0.21, p = 0.01). Finally, lower tau, particularly TauC3 pathology, was associated with lower frequency of both core clinical features and categorical clinical diagnosis of dementia with Lewy bodies. INTERPRETATION: Mature tau may be more closely related to beta-amyloidosis than alpha-synucleinopathy, and pathophysiological processes of tangle maturation may influence the clinical features of dementia in mixed Lewy-Alzheimer's pathology.

Globus pallidus interna deep brain stimulation for tardive dyskinesia: case report and review of the literature.

Tardive dyskinesia (TD) can be a disabling condition and is frequently refractory to medical therapy. Over the past decade there have been many reports of TD patients experiencing significant benefit with deep brain stimulation (DBS) of the globus pallidus interna (GPi). The growing literature on this treatment option for TD consists predominantly of case reports and series. The reported benefit ranges widely, but the majority of cases experienced at least a 50% improvement in symptoms. The anatomical distribution of dyskinesias has not clearly influenced outcome, though fixed postures appear less likely to improve than phasic movements. Onset of benefit can be immediate or take months, and benefit is sustained in most cases, for at least 6 months and up to several years. A wide variety of voltages, frequencies, and pulse widths have demonstrated efficacy. A small number of reports which examined psychiatric symptoms before and after surgery did not find any decline, and in some cases revealed improvement in mood. However, these overall positive results should be interpreted with caution, as the majority of reports lacked blinded assessments, control groups, or standardized therapy parameters. Finally, we present an illustrative case of refractory tardive dyskinesia treated with GPi-DBS with 5 years of follow-up and 4 accompanying video segments.