The Existence of Primary Age-Related Tauopathy Suggests that not all the Cases with Early Braak Stages of Neurofibrillary Pathology are Alzheimer's Disease.

The distinction between Alzheimer's disease (AD) and Primary Age-Related Tauopathy (PART) is a hotly debated issue. As most lines of evidence support the tenet that tau pathology occurs downstream of amyloid-ß deposition, it seems reasonable to consider PART as a separate disease process not necessarily related to Aß and hence AD. Following this view, the early stages of neurofibrillary pathology may not always be the forerunner of diffuse neurofibrillary changes and AD. The ongoing debate further enhances the need for greater caution against any future predictions using tau cerebrospinal fluid and imaging biomarkers.

Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study.

BACKGROUND: Neurofibrillary pathology has a stereotypical progression in Alzheimer's disease (AD) that is encapsulated in the Braak staging scheme; however, some AD cases are atypical and do not fit into this scheme. We aimed to compare clinical and neuropathological features between typical and atypical AD cases. METHODS: AD cases with a Braak neurofibrillary tangle stage of more than IV were identified from a brain bank database. By use of thioflavin-S fluorescence microscopy, we assessed the density and the distribution of neurofibrillary tangles in three cortical regions and two hippocampal sectors. These data were used to construct an algorithm to classify AD cases into typical, hippocampal sparing, or limbic predominant. Classified cases were then compared for clinical, demographic, pathological, and genetic characteristics. An independent cohort of AD cases was assessed to validate findings from the initial cohort. FINDINGS: 889 cases of AD, 398 men and 491 women with age at death of 37-103 years, were classified with the algorithm as hippocampal sparing (97 cases [11%]), typical (665 [75%]), or limbic predominant (127 [14%]). By comparison with typical AD, neurofibrillary tangle counts per 0.125 mm(2) in hippocampal sparing cases were higher in cortical areas (median 13, IQR 11-16) and lower in the hippocampus (7.5, 5.2-9.5), whereas counts in limbic-predominant cases were lower in cortical areas (4.3, 3.0-5.7) and higher in the hippocampus (27, 22-35). Hippocampal sparing cases had less hippocampal atrophy than did typical and limbic-predominant cases. Patients with hippocampal sparing AD were younger at death (mean 72 years [SD 10]) and a higher proportion of them were men (61 [63%]), whereas those with limbic-predominant AD were older (mean 86 years [SD 6]) and a higher proportion of them were women (87 [69%]). Microtubule-associated protein tau (MAPT) H1H1 genotype was more common in limbic-predominant AD (54 [70%]) than in hippocampal sparing AD (24 [46%]; p=0.011), but did not differ significantly between limbic-predominant and typical AD (204 [59%]; p=0.11). Apolipoprotein E (APOE) ɛ4 allele status differed between AD subtypes only when data were stratified by age at onset. Clinical presentation, age at onset, disease duration, and rate of cognitive decline differed between the AD subtypes. These findings were confirmed in a validation cohort of 113 patients with AD. INTERPRETATION: These data support the hypothesis that AD has distinct clinicopathological subtypes. Hippocampal sparing and limbic-predominant AD subtypes might account for about 25% of cases, and hence should be considered when designing clinical, genetic, biomarker, and treatment studies in patients with AD. FUNDING: US National Institutes of Health via Mayo Alzheimer's Disease Research Center, Mayo Clinic Study on Aging, Florida Alzheimer's Disease Research Center, and Einstein Aging Study; and State of Florida Alzheimer's Disease Initiative.

The Parkinson chimera.

Although our concepts of what causes Parkinson disease (PD) are ever changing and the hunt for a reliable biomarker continues, the clinical picture remains as distinctive as when the malady was first described by James Parkinson and the neurologic Grand Masters of the nineteenth century. Hyposmia and visual hallucinations, however, can now be added as additional features of the clinical syndrome which may be helpful in distinguishing PD from atypical parkinsonism, as well as the growing list of causes of secondary parkinsonism. Selective vulnerability of catecholaminergic long axon projection neurons (part of the isodendritic core) in PD is an important, if recently somewhat neglected, fact and correlation of the severity of nigral loss with bradykinesia and rigidity is the only very reliable anatomo-clinical correlation. Although the Lewy body seems to be closely linked with our notion of PD as a clinicopathologic nosological entity, its role in the pathogenesis of the disorder is still obscure and hotly debated. Its presence in some of the long-surviving grafted neurons in fetal implants may provide important insights into its role in the disease process. Although Braak's hypothesis implicating the medulla oblongata as an obligate trigger for the subsequent spread of the pathologic process has generated much interest and encouraged more research, it seems unlikely as an explanation for the natural history of PD.

Comparative distribution of tau phosphorylated at Ser262 in pre-tangles and tangles.

The Phospho-Ser(262) epitope of phosphorylated tau, which accumulates in tangles in Alzheimer's disease (AD) brains, has been shown to have a strong disruptive effect on microtubules. Using antibodies which specifically recognize the Phospho-Ser(262) of tau, we compared the presence of this epitope in normal appearing neurons (pre-tangles) and tangles, with the presence of Phospho-Ser(199/202) (AT-8) and Phospho-Ser(396/404) (PHF-1) epitopes. All antibodies visualized lightly or darkly stained pre-tangles, neurons with immunoreactive clumps, intracellular and extracellular tangles. Pre-tangles were more abundant in control cases which showed some pathology, when compared with AD brains. Immunoreactivity for Phospho-Ser(262) was preferentially present in intracellular and extracellular tangles and was found in a significantly smaller number of pre-tangles when compared with the other epitopes. These results indicate the presence of various epitopes of Phospho-Tau in a substantial number of pre-tangles which may represent an early marker of tangle formation. The differential distribution of various epitopes suggests that the presence of the Phospho-Ser(262) epitope of tau either accelerates the transition form pre-tangle to tangle, or appears later than the other epitopes in the process of tangle formation.

Evolution of Alzheimer's disease-related cytoskeletal changes in the basal nucleus of Meynert.

This study examines the evolution of Alzheimer's disease (AD)-related pathology in a subcortical predilection site, the basal nucleus of Meynert (bnM), which is a major source of cortical cholinergic innervation. Brains of 51 autopsy cases were studied using silver techniques and immunostaining for tau-associated neurofibrillary pathology and for amyloid beta protein (Abeta) deposits. All cases are classified according to a procedure permitting differentiation of six stages of AD-related neurofibrillary changes in the cerebral cortex. Initial cytoskeletal abnormalities in the bnM are already noted in stage I of cortical neurofibrillary changes. The gradual development of the neurofibrillary pathology in the bnM parallels the progression of the AD-related stages in the cerebral cortex. A variety of morphologically distinguishable cytoskeletal alterations are observed in large nerve cells which predominate in the bnM. Based on these cellular alterations, a sequence of cytoskeletal deterioration is proposed. Initially, the abnormal tau protein is distributed diffusely throughout the cell body and the neuronal processes. Subsequently, it aggregates to form a neurofibrillary tangle, which appears as a spherical somatic inclusion. The cell processes gradually become fragmented. Finally the parent cell dies, leaving behind an extraneuronal "ghost tangle". With regard to the cortical stages of AD-related neurofibrillary changes, the initial forms of cytoskeletal changes in the bnM predominate in the transentorhinal AD stages (I and II), while "ghost tangles" preferentially occur in the neocortical stages (V and VI). The considerable morphological diversity of cytoskeletal alterations is typical of stages III and IV. These results indicate that individual neurons of the bnM enter the sequence of cytoskeletal deterioration at different times.

Entorhinal cortex of aged subjects with Down's syndrome shows severe neuronal loss caused by neurofibrillary pathology.

In Alzheimer's disease (AD), neurofibrillary degeneration of neurons starts in the transentorhinal cortex and spreads in a time-dependent manner to the entorhinal cortex, which provides a major input to the hippocampus--a key structure of the memory system. People with Down's syndrome (DS) develop neurofibrillary changes more than 30 years earlier than those with sporadic AD. To characterize AD-related pathology in the entorhinal cortex in DS, we examined seven subjects with DS of 60-74 years of age who died in the end stage of AD, and four age-matched control subjects. The volume of the entorhinal cortex in brains of subjects with DS was 42% less than that in control cases; however, the total number of neurons free of neurofibrillary changes was reduced in DS by 90%: from 9,619,000 +/- 914,000 (mean +/- standard deviation) to 932,000 +/- 504,000. The presence of 2,488,000 +/- 544,000 neurofibrillary tangles in the entorhinal cortex of people with DS, the prevalence of end-stage tangles, and the significant negative correlation between the total number of intact neurons and the percentage of neurons with neurofibrillary changes indicate that neurofibrillary degeneration is a major cause of neuronal loss in the entorhinal cortex of people with DS. The relatively low amyloid load (7 +/- 1%) and lack of correlation between the amyloid load and the volumetric or neuronal loss suggest that the contribution of beta-amyloid to neuronal loss in the entorhinal cortex is unsubstantial.

Classification of senile plaques by three-dimensional analysis.

We evaluated the number of each senile plaque subtype in Alzheimer's brain by the usual two-dimensional analysis using a single, methenamine silver stained section and three-dimensional analysis using serial section reconstruction. The number of classic plaques was underestimated due to a lack of precision in the usual evaluating procedures (two-dimensional analysis), while that of stellate deposits was overestimated. From these results, it was suggested that the three-dimensional analysis by gapless serial sections was indispensable to examine and subclassify senile plaques.