Intriguing Mixed Pathologic Features in a Case of Dementia With Lewy Bodies

Report of Case

A 74-year-old man was referred to a neurologist by his primary care physician with symptoms including frequent falls, recurrent visual hallucinations, loss of smell and taste, and panic attacks. By exclusion, the neurologist diagnosed DLB. For the next 4 years, his symptoms progressed to include gait and vision problems, increasing cognitive deficits, speech and emotional issues, and changes in sensory input. Motor changes were characterized by festinating gait, ataxia, and loss of balance. The patient's ability to read was lost, and he had frequent visual hallucinations accompanied by loss of concentration, word-finding difficulty, and agnosia. Interestingly, he could differentiate musical instruments. The patient had difficulty with verbal expression and eventually adopted a blank stare. His family reported that he could “cry at the drop of a hat” and occasionally emoted angrily. The patient had sensory problems, and he could not distinguish between hot and cold. Near the end of his life, the patient developed a heightened startle response, was unable to easily breathe through the nose, and had worsening dysphagia. Three months before his death at the age of 78 years, the patient was nonambulatory, had taken in very little nutrition, and had become increasingly withdrawn. The death certificate listed “Advanced Lewy Body Dementia” as the cause of death. Per an advance discussion and consent by the family, the postmortem brain was removed for analysis.

Neuropathologic Examination

Immunohistochemical and histochemical studies were performed on formalin-fixed paraffin-embedded brain sections, including the olfactory bulbs, prefrontal cortex, frontal cortex, amygdala, hippocampus, inferior temporal cortex, parietal cortex, occipital cortex, pons, substantia nigra, and cerebellum. All of these areas were immunopositive for α-synuclein, and prominent labeling of neuronal Lewy bodies was apparent in the amygdala and hippocampus (Figure 1A and Figure 1B). Alzheimer pathology also was found consisting of intraneuronal phosphotau immunolabeling (Figure 1C, amygdala; Figure 1D, olfactory bulb) and β-amyloid 1-42 extracellular plaque immunolabeling in multiple regions (Figure 1E, amygdala; Figure 1F, inferior temporal lobe). Dual immunolabeling for β-amyloid 1-42 and Chlamydia pneumoniae, an intracellular bacterium previously observed in AD brains,^9-11 revealed co-deposition in the amygdala and frontal cortex (Figure 1G and Figure 1H).

Figure 1.

Immunohistochemistry highlights mixed pathologic features in numerous brain regions. (A and B) Prominent α-synuclein immunoreactivity (alkaline phosphatase red–new magenta; original magnification ×10) reveals Lewy bodies in the amygdala and hippocampus; (C-F) immunolabeling (horseradish peroxidase/ 3,3’-diaminobenzidine, brown; original magnification ×10) of phosphotau in neurofibrillary tangles (C, amygdala; D, olfactory bulb) and β-amyloid 1-42 (horseradish peroxidase/DAB, brown; original magnification ×10) in extracellular plaques (E, amygdala; F, inferior temporal lobe) reveals Alzheimer disease characteristics; (G and H) dual immunolabeling for β-amyloid 1-42 (horseradish peroxidase/DAB, brown; original magnification ×10) and Chlamydia pneumoniae (alkaline phosphatase, red; original magnification ×10) reveals pathologic changes in association with infection in both the amygdala and frontal cortex.

Numerous bodies consistent with corpora amylacea were observed after examining the olfactory bulbs, optic tract and chiasm, amygdala, and hippocampus. Periodic acid-Schiff (PAS) staining was performed to evaluate the composition of these bodies, as some studies^12,13 have shown 1,4 α-glucan branching enzyme 1 gene mutations leading to polyglucosan body formation, often considered to be corpora amylacea, in the Ashkenazi Jewish population. A multitude of PAS-positive bodies were observed in the amygdala, olfactory bulbs, and the hippocampus (Figure 2). A decrease in the intensity and extent of PAS staining was observed after using amylase pretreatment on hippocampal sections followed by PAS staining (Figure 2D).

Figure 2.

Periodic acid-shift (PAS) staining of corpora amylacea/polyglucosan bodies. (A-D) PAS-positive bodies (reddish-purple; original magnification ×10) are apparent in the olfactory bulbs, amygdala, and the hippocampus; (D) amylase pretreatment on sections of the hippocampus followed by PAS staining results in a diminishment but not total loss of staining (original magnification ×10).

Discussion

The diagnosis of DLB in this case was based on the clinical history and symptoms, as well as the pathologic findings within multiple brain regions. However, the contributions of each of these findings to the initial symptoms and changes over time are more difficult to define given the varied and mixed pathologic features, including α-synuclein accumulation, β-amyloid plaques, tau tangles, C pneumoniae labeling, and PAS-positive polyglucosan bodies. The features represent later Braak stages than would be expected based simply on a diagnosis of DLB.¹⁴ Braak staging delineates the extent of Parkinson and Alzheimer disease characteristics in different brain regions. Work by others^15,16 has determined that in community settings, the cognitive deficit in DLB is most often associated with mixed structural and functional deviations, including vascular disease, AD, and DLB¹⁵; Lewy bodies, β-amyloid plaques, and tau tangles are frequently observed in postmortem DLB brains.¹⁶

One surprising finding was immunolabeling for the intracellular, respiratory pathogen C pneumoniae in the olfactory bulb, amygdala, and hippocampal sections of the brain, that had previously only been seen in AD cases.^9-11 Dual immunolabeling for amyloid and C pneumoniae is comparable to what we observed in AD brains. In DLB, AD neuropathology is often recognized.¹⁶ As the current case shows mixed pathologic features, the relationship of this dual immunolabeling may be explained. Further, DLB and AD have been shown to have comparable neuroinflammation.¹⁷ Thus, in this DLB case, the presence of C pneumoniae infection, a trigger for neuroinflammation, in conjunction with the neuropathology of β-amyloid 1-42 plaques, could further support these associations.

Another surprising finding was the large spherical structures throughout the brain that stained prominently with PAS. They could be corpora amylacea or polyglucosan bodies. Pretreatment with amylase reduced some of the PAS staining, although this was not eliminated completely. As this individual was from Ashkenazi Jewish descent, adult polyglucosan body disease could be a further confounder for the clinical presentation.¹⁸ Polyglucosan body disease can be autosomal recessive or occur sporadically, and in both occurrences there is accumulation of abnormally branched glycogen due to dysfunction of the 1,4 alpha-glucan branching enzyme 1 gene.^19,20

Individuals with adult polyglucosan body disease typically present with symptoms in a range from 40 to 60 years and can experience frontotemporal dementia, motor neuron dysfunction, and neurogenic bladder.²⁰ In comparison, individuals with a diagnosis of DLB are typically aged 70 to 85 years and present with symptoms of hallucinations, attention deficit, and late motor abnormalities.⁴

Conclusion

The rapid progression of this patient's illness was likely attributable to mixed pathologic features (DLB, AD, and polyglucosan body disease). The patient had characteristic clinical features to support the diagnosis of DLB, such as visual hallucinations and fluctuating cognition; however, analyses using single-photon emission computed tomography and positron emission tomography scans could have helped in pinpointing the disease processes. The patient's medical and social history were informative: he was a lifelong smoker with hypertension and coronary artery disease, he had a history of multiple physical traumas, and he had Ashkenazi Jewish heritage. All of these elements may have contributed to the neuropathologic changes we described. Follow-up investigation of this case will include genetic testing of tissues for GBE mutations and real-time quantitative reverse transcription–polymerase chain reaction for molecular evaluation of infection with C pneumoniae in brain tissues.