Involvement of the peripheral autonomic nervous system is a core feature of Lewy body (LB) diseases, including Parkinson disease (PD), PD with dementia, and dementia with LBs. To investigate the potential use of skin biopsy for the diagnosis of LB diseases, we assessed anti-phosphorylated alpha-synuclein immunoreactivity in peripheral nerves in samples of skin from the abdominal wall and flexor surface of the upper arm in 279 prospectively studied consecutively autopsied patients whose data were registered at the Brain Bank for Aging Research between 2002 and 2005. Positive immunoreactivity was demonstrated in the unmyelinated fibers of the dermis in 20 of 85 patients with LB pathology in the CNS and the adrenal glands, the latter representing a substitute for peripheral autonomic nervous system sympathetic ganglia; no reactivity was seen in 194 patients without CNS LB pathology. In 142 retrospectively studied patients autopsied from 1995 onward who had subclinical or clinical LB disease, the sensitivity of the positive skin immunoreactivity was 70% in PD and PD with dementia and 40% in dementia with LBs. Skin immunoreactivity was absent in cases of multiple-system atrophy, progressive nuclear palsy, and corticobasal degeneration. We demonstrate for the first time that the skin is involved and may be a highly specific and useful biopsy site for the pathological diagnosis of LB diseases.

We investigated the incidence and extent of Lewy body (LB)-related alpha-synucleinopathy (LBAS) in the olfactory bulb (OB) in 320 consecutive autopsy patients from a general geriatric hospital (mean age, 81.5 +/- 8.5 years). Paraffin sections were immunostained with anti-phosphorylated alpha-synuclein, tyrosine hydroxylase, phosphorylated tau, and amyloid beta antibodies. LBAS was found in 102 patients (31.9%) in the central nervous system, including the spinal cord; the OB was involved in 85 (26.6%). Among these 85 patients, 2 had LBAS only in the anterior olfactory nucleus, 14 in the peripheral OB only, and 69 in both areas. In 5 patients, Lewy bodies were found only in the OB by hematoxylin and eosin stain; 3 of these patients had Alzheimer disease, and all had LBAS. Very few tyrosine hydroxylase-immunoreactive periglomerular cells exhibited LBAS. All 35 LBAS patients with pigmentation loss in the substantia nigra had LBAS in the OB. LBAS in the amygdala was more strongly correlated with LBAS in the anterior olfactory nucleus than with that in the OB periphery. LBAS did not correlate with systemic tauopathy or amyloid beta amyloidosis. These results indicate a high incidence of LBAS in the aging human OB; they also suggest that LBAS extends from the periphery to the anterior olfactory nucleus and results in clinical manifestations of LB disease.

The number of people with dementia worldwide is predicted to increase to 131.5 million by 2050. When studying dementia, understanding the basis of the neuropathological background is very important. Taking Alzheimer's disease (AD) neuropathology as an example, we know that the accumulation of abnormal structures such as senile plaques and neurofibrillary tangles is a hallmark. Macroscopic atrophy affects the entorhinal area and hippocampus, amygdala, and associative regions of the neocortex. Braak advocates the spread of tau deposits from the entorhinal to associative regions of the neocortex as the disease progresses. If the AD has only tau pathology, the degree and distribution of tau deposition may be associated with clinical symptoms. However, AD is also accompanied by amyloid-β deposition and even atrophy. Although it is possible to make a neuropathological diagnosis of AD from the spread of amyloid and tau depositions, neuropathological abnormal protein accumulation cannot explain all clinical symptoms of AD. There is an ambiguity between clinical symptoms and neuropathological findings. It is important to understand neuropathological findings while understanding that this ambiguity exists. So, for the reader's help, first we briefly explain the changes in the brain with age, and then describe AD as a typical disease of dementia; finally we will describe the diseases that mimic AD for neurologists who are not experts in neuropathology.