Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68880-6.pdf

Mild cognitive impairment

Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein

The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia.

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

/pdf/national-institute-on-aging-alzheimer-s-association-5crbry24zc.pdf

National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease

We present a practical guide for the implementation of recently revised National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.

/pdf/national-institute-on-aging-alzheimer-s-association-4honfkm34a.pdf

National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach

Alpha-synuclein in Lewy bodies (LBs) is phosphorylated at Ser129. We raised monoclonal and polyclonal antibodies to this phosphorylation site (psyn) and examined 157 serial autopsy brains from a geriatric hospital. Anti-psyn immunoreactivity was observed in 40 of these cases (25.5%). Immunohistochemistry revealed 4 novel types of pathology: diffuse neuronal cytoplasmic staining (pre-LB); neuropil thread-like structures (Lewy threads); dot-like structures similar to argyrophilic grains (Lewy dots); and axons in the white matter (Lewy axons). This novel pathology was abundantly present around LBs and also involved the limbic subcortical white matter, the cerebral cortical molecular layer, and the spongiform changes of the medial temporal lobe associated with cases of dementia with LBs (DLB). The phosphorylated alpha-synuclein was limited to the temporal lobe in cases of Parkinson disease, spread from the temporal lobe to the frontal lobe in cases of DLB transitional form and further spread to the parietal and occipital lobes in DLB neocortical form. Our findings suggest that LB-related pathology initially involves the neuronal perikarya, dendrites, and axons, causes impairment of axonal transport and synaptic transmission, and later leads to the formation of LBs, a hallmark of functional disturbance long before neuronal cell death.

/pdf/accumulation-of-phosphorylated-a-synuclein-in-aging-human-1rycek8m4k.pdf

Accumulation of Phosphorylated α-Synuclein in Aging Human Brain

We have reported that the ambient gyrus is the site with the greatest accumulation of argyrophilic grains (AGs) and that the degeneration of the ambient gyrus is responsible for dementia with grains Here we analyzed 1,405 serial autopsy cases from 2 hospitals and detected AGs only in cases older than 56 years of age The distribution of AGs followed a stereotypic regional pattern Thus, we propose the following staging paradigm: stage I: AGs restricted to the ambient gyrus and its vicinity; stage II: AGs more apparent in the anterior and posterior medial temporal lobe, including the temporal pole, as well as the subiculum and entorhinal cortex; and stage III: abundant AGs in the septum, insular cortex, and anterior cingulate gyrus, accompanying spongy degeneration of the ambient gyrus Sixty-three of 65 (969%) argyrophilic grain stage III cases without other dementing pathology were classified as 05 or higher in the clinical dementia rating Forty-seven of 50 dementia with grains cases (94%) were stage III and 3 were stage II No association with apoE genotyping was detected Our study further confirms that dementia with grains is an age-associated tauopathy with relatively uniform distribution and may independently contribute to cognitive decline in the elderly

Staging of argyrophilic grains: an age-associated tauopathy.

The relationship between the indicence of cerebral infarction and the hematocrit was studied using 432 consecutive autopsied patients with the average age of 77.1 years. The incidence of cerebral infraction was higher in patients with hematocrit values of more than 46%, (the average in younger adult subjects). The increase in the frequency of cerebral infarction with high hematocrit values was more conspicuous in patients with severe cerebral atherosclerosis than in those with slight cerebral atherosclerosis. High blood pressure per se did not influence the relationship between the hematocrit value and the incidence of cerebral infarction. With hematocrit values of more than 41%, cerebral infarction occurred more frequently in patients over 78 years of age than in the younger patients, but the difference was not significant statistically. High hematocrit values are associated with a higher risk of cerebral infarction in deep subcortical structures of the brain than for cartical infarctions. The pathogenetic and preventive implications of these results are discussed in the light of blood rheology.

Importance of the hematocrit as a risk factor in cerebral infarction.

To clarify the significance of Lewy body (LB)-related alpha-synucleinopathy in aging, we investigated the incidence of LBs in 1,241 consecutive autopsy cases (663 males and 578 females). LB pathology was identified histologically in sections stained with hematoxylin and eosin and with anti-ubiquitin and anti-alpha-synuclein antibodies. Cases without LBs were classified as LB stage 0 (987 cases). Cases with LBs were classified as follows: LB stage I = incidental LBs (149 cases); LB stage II = LB-related degeneration without attributable clinical symptoms (47 cases); LB stage III = Parkinson disease without dementia (10 cases); LB stage IV = dementia with Lewy bodies (DLB) transitional (limbic) form (25 cases); and LB stage V = DLB neocortical form (23 cases). The average age at death was greater for those cases with LBs. There were no gender differences in the LB pathology. G842A polymorphism in the paraoxonase I gene was associated with men in LB stage II or above and suggests a gender-specific risk factor. LB stage V had higher stages of neurofibrillary tangle and senile plaque involvement and also had a higher frequency of apolipoprotein E epsilon4. Our findings indicate that LBs are associated with cognitive decline, either independently or synergistically with neurofibrillary tangles and senile plaques.

/pdf/lewy-body-related-alpha-synucleinopathy-in-aging-40ki1x8ft5.pdf

Lewy body-related alpha-synucleinopathy in aging.

Dementia with Lewy bodies (DLB) is characterized clinically by fluctuating cognitive impairment, visual hallucinations, and parkinsonism.1 It is the second most common neurodegenerative disease that causes dementia after AD. The pathologic hallmark of the disease is the presence of Lewy bodies in the cerebral cortex as well as in the brainstem.1 In most cases, numerous senile plaques are also observed in the cerebral cortex, similar to those in the AD brain; neocortical neurofibrillary tangles (NFTs) are rare or absent.2,3 In AD, levels of CSF amyloid β42 (Aβ42) are decreased and levels of CSF tau are increased.4 CSF Aβ42 and tau are thought to be linked with plaques and tangles in the AD brain. Thus, we hypothesized that levels of CSF Aβ42 would be decreased and levels of CSF tau would be normal in DLB. To test this hypothesis we measured levels of CSF Aβ42 …

Hiroshi Yamanouchi

Papers

Accumulation of Phosphorylated α-Synuclein in Aging Human Brain

Staging of argyrophilic grains: an age-associated tauopathy.

Importance of the hematocrit as a risk factor in cerebral infarction.

Lewy body-related alpha-synucleinopathy in aging.

Decreased CSF amyloid β42 and normal tau levels in dementia with Lewy bodies