Stages of granulovacuolar degeneration: their relation to Alzheimer's disease and chronic stress response

Granulovacuolar degeneration (GVD) is characterized by the presence of vacuolar cytoplasmic lesions in nerve cells of the medial temporal lobe. These changes occur in older non-diseased individuals as well as in patients with Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Pick's, sporadic Parkinson's (PD), and Guam diseases. We stained representative paraffin sections from all parts of the brain with anti-pTDP43, anti-CK1 delta or anti-CK1 epsilon from 14 non-demented elderly, 19 AD, 17 non-AD tauopathy, 9 sporadic PD, and 5 TDP43-proteinopathy [amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)] cases. Our results showed five stages of GVD based on its distribution pattern: GVD began in the hippocampal subfields CA1, CA2, and the subiculum. In a second stage, entorhinal cortex, and CA4 neurons exhibited GVD. Additional neurons were involved in the temporal neocortex in stage 3, whereas the affection of the amygdala and/or the hypothalamus marked stage 4. A fifth and final stage was characterized by additional GVD in the cingulate cortex and occasionally in the frontal and parietal cortices as well as in the oral raphe and pedunculopontine tegmental nuclei. The GVD stages correlated with neurofibrillary tangle stages, Consortium to Establish a Registry for AD (CERAD) scores for neuritic plaque pathology, amyloid beta-protein deposition phases, cerebral amyloid angiopathy stages, and clinical dementia rating (CDR) scores. No associations were seen between GVD stage and the presence of non-AD tauopathies, PD, ALS, or FTLD cases. In conclusion, GVD affects neurons in a hierarchical sequence that allows the distinction of five stages. The topographic distribution of GVD restricted to regions involved in response to chronic stress could indicate a link between GVD and chronically stressful influences. Moreover, the association of the GVD stages with those of AD-related pathology but not with other neurodegenerative disorders points to a possible role of GVD and the response to chronic stress in the pathogenesis of AD.