Density Of Neurofibrillary Tangles Research Articles

In vitro aggregation assays using hyperphosphorylated tau protein.

Alzheimer's disease is one of a large group of neurodegenerative disorders known as tauopathies that are manifested by the neuronal deposits of hyperphosphorylated tau protein in the form of neurofibrillary tangles (NFTs). The density of NFT correlates well with cognitive impairment and other neurodegenerative symptoms, thus prompting the endeavor of developing tau aggregation-based therapeutics. Thus far, however, tau aggregation assays use recombinant or synthetic tau that is devoid of the pathology-related phosphorylation marks. Here we describe two assays using recombinant, hyperphosphorylated tau as the subject. These assays can be scaled up for high-throughput screens for compounds that can modulate the kinetics or stability of hyperphosphorylated tau aggregates. Novel therapeutics for Alzheimer's disease and other tauopathies can potentially be discovered using hyperphosphorylated tau isoforms.

<em>In Vitro</em> Aggregation Assays Using Hyperphosphorylated Tau Protein

Alzheimer's disease is one of a large group of neurodegenerative disorders known as tauopathies that are manifested by the neuronal deposits of hyperphosphorylated tau protein in the form of neurofibrillary tangles (NFTs). The density of NFT correlates well with cognitive impairment and other neurodegenerative symptoms, thus prompting the endeavor of developing tau aggregation-based therapeutics. Thus far, however, tau aggregation assays use recombinant or synthetic tau that is devoid of the pathology-related phosphorylation marks. Here we describe two assays using recombinant, hyperphosphorylated tau as the subject. These assays can be scaled up for high-throughput screens for compounds that can modulate the kinetics or stability of hyperphosphorylated tau aggregates. Novel therapeutics for Alzheimer's disease and other tauopathies can potentially be discovered using hyperphosphorylated tau isoforms.

The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia

IntroductionThe objective of this study was to elucidate the relationship between the triggering receptor expressed on myeloid cells 2 (TREM2) risk variant, neuropathological lesions, alterations in gene and protein expression, and the severity of neuroinflammation. MethodsThe genetic association study of the R47 H TREM2 variant with Alzheimer's disease (AD), neuropathology, and changes in TREM2 and TYRO protein tyrosine kinase-binding protein (TYROBP) gene and protein expression, and neuroinflammatory markers. ResultsThe TREM2 variant is associated with: (i) AD (odds ratio: 4.76; P = .014); (ii) increased density of amyloid plaques and neurofibrillary tangles in multiple brain regions; (iii) increased TREM2 (P = .041) and TYROBP (P = .006) gene expression; (iv) decreased TREM2 protein levels (P = .016); and (v) upregulation of proinflammatory cytokines (regulated on activation, normal T cell expressed and secreted [RANTES] and interferon [IFN] gamma) (P = .003) and nominal downregulation of protective markers (α2-macroglobulin, interleukin 4 or IL-4, and ApoA1) (P = .018). DiscussionThese findings link the TREM2 missense mutation with specific molecular abnormalities and increases in neuropathological lesions in the human brain.

Neuropathology of Parkinsonism in Alzheimer's disease.

About 30 % of Alzheimer’s disease (AD) patients develop parkinsonian features, but Lewy body pathology is not always present at autopsy. So the neuropathological substrate of extrapyramidal signs in AD remains unclear. In the present study neuronal and neurofibrillary tangle (NFT) densities were counted in the substantia nigra pars compacta (SN) and in the putamen of 22 AD patients, 11 with and 11 without parkinsonism. Parkinsonism was defined as the presence of bradykinesia and at least one of resting tremor, rigidity, or gait disorders. Our results showed that parkinsonism in AD is related to a significant neuronal loss both in the SN and in the putamen, suggesting pre- and postsynaptic alterations of the nigrostriatal pathway.

Abundant kif21b is associated with accelerated progression in neurodegenerative diseases.

Kinesin family member 21b (kif21b) is one of the few multiple sclerosis (MS) risk genes with a presumed central nervous system function. Kif21b belongs to the kinesin family, proteins involved in intracellular transport of proteins and organelles. We hypothesised that kif21b is involved in the neurodegenerative component of MS and Alzheimer's (AD) disease. Post-mortem kinesin expression was assessed in 50 MS, 58 age and gender matched non-demented controls (NDC) and 50 AD. Kif21b expression was five-fold increased in AD compared to MS and NDC aged below 62 years (p = 8*10-5), three-fold between 62-72 years (p = 0.005) and not different above 72 years. No significant differences were observed between MS and NDC. In AD, kif21b expression was two-fold increased in Braak stage 6 (scoring for density of neurofibrillary tangles) compared with stage 5 (p = 0.003). In MS patients, kif21b correlated with the extent of grey matter demyelination (Spearman's rho = 0.31, p = 0.03). Abundant kif21b, defined as expression above the median, was associated with a two-fold accelerated development of the Kurtzke Expanded Disability Status Scale (EDSS) 6.0 (median time in low kif21b group 16 years vs. high kif21b 7.5 years, log-rank test p = 0.04) in MS. Given the genetic association of kif21b with MS, the results were stratified according to rs12122721[A] single nucleotide polymorphism (SNP). No association was found between kif21b expression or the time to EDSS 6 in kif21b risk SNP carriers compared to non-risk carriers. Kif21b was expressed in astrocytes in addition to neurons. Upon astrocyte activation, kif21b increased nine-fold. Abundant kif21b expression is associated with severe MS and AD pathology and with accelerated neurodegeneration independent of the kif21b risk SNP.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0144-4) contains supplementary material, which is available to authorized users.

GENOME-WIDE ASSOCIATION STUDY USING ALZHEIMER-RELATED PATHOLOGICAL BIOMARKERS

Genome-wide association study (GWAS) is a powerful technique to identify polymorphisms associated with a particular disease. However, standard case-control study can often be disappointing because no SNPs reach genome-wide significance. Another way to highlight potential disease-modifying SNPs is to perform the study with pathology-specific biomarkers. This method was applied for late-onset Alzheimer's disease (LOAD). GWAS was performed with Illumina 550-Quad BeadChip using DNA samples from Quebec Founder Population (QFP). A total of 629 French Canadians (384 LOAD patients and 245 age-matched control subjects) were recruited for the study. DNA was extracted either from blood samples or directly from available brain tissues (from the Douglas - Bell Canada Brain Bank). For a subset of post-mortem samples, the density of senile plaques (SP) and neurofibrillary tangles (NFT) were evaluated by a neuropathologist. Single nucleotide polymorphisms (SNPs) significantly associated with the disease, the age of onset or with neuropathological data will be assessed for replication in the population from the Alzheimer's Disease Neuroimaging Initiative (ADNI). With the standard case-control analysis, only four SNPs reached genome-wide significance (p< 5 x 10 -8). These four SNPs (rs429358, rs2075650, rs405509 and rs8106922) were all located on chromosome 19 near APOE gene. The strongest SNP (rs429358, p= 4.1 x 10 -24) also correlated with the age of onset (p= 2.4 x 10 -4), the density of SP in the frontal cortex (p= 6.5 x 10 -8) and in the CA1 region of the hippocampus (p= 3.6 x 10 -3), and the density of NFT in the frontal cortex (p= 7.3 x 10 -7) and in the CA1 region of the hippocampus (p= 4.6 x 10 -3). A second analysis is currently being performed in an effort to find other SNPs that correlate with pathology-related biomarkers. SNPs will be selected based on P values and the number of significant correlations with different biomarkers from our study and the ADNI database. The contribution of APOE to late-onset Alzheimer's disease has already been well established. The present study will help to identify genes never before associated with the disease.

SEARCH FOR RECESSIVE ALZHEIMER DISEASE LOCI IN AFRICAN AMERICANS BY GENOME-WIDE STUDY OF RUNS OF HOMOZYGOSITY

samples or directly from available brain tissues (from the Douglas Bell Canada Brain Bank). For a subset of post-mortem samples, the density of senile plaques (SP) and neurofibrillary tangles (NFT) were evaluated by a neuropathologist. Single nucleotide polymorphisms (SNPs) significantly associated with the disease, the age of onset or with neuropathological data will be assessed for replication in the population from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results: With the standard casecontrol analysis, only four SNPs reached genome-wide significance (p< 5 x 10 -8). These four SNPs (rs429358, rs2075650, rs405509 and rs8106922) were all located on chromosome 19 near APOE gene. The strongest SNP (rs429358, p1⁄4 4.1 x 10 -24) also correlated with the age of onset (p1⁄4 2.4 x 10 -4), the density of SP in the frontal cortex (p1⁄4 6.5 x 10 -8) and in the CA1 region of the hippocampus (p1⁄4 3.6 x 10 -3), and the density of NFT in the frontal cortex (p1⁄4 7.3 x 10 -7) and in the CA1 region of the hippocampus (p1⁄4 4.6 x 10 -3). A second analysis is currently being performed in an effort to find other SNPs that correlate with pathology-related biomarkers. SNPs will be selected based on P values and the number of significant correlations with different biomarkers from our study and the ADNI database. Conclusions: The contribution of APOE to late-onset Alzheimer’s disease has already been well established. The present study will help to identify genes never before associated with the disease.

BRAIN RESERVE IS AS IMPORTANT AS ALZHEIMER'S AND VASCULAR PATHOLOGY IN DETERMINING DEMENTIA STATUS: THE NUN STUDY

Although Alzheimer and vascular pathology are known to be strong determinants of dementia, the relative importance of brain reserve (brain volume and education) in affecting dementia status is unknown. Using data from the Nun Study, we calculated etiologic fractions for predictors of dementia at death. Predictors were determined from a factor analysis of known risk factors including educational attainment, presence of one or more apolipoprotein E-epsilon4 alleles, as well as mean densities of neurofibrillary tangles and neuritic plaques in the neocortex, presence of lacunar and large infarcts, rating of arteriosclerosis in the circle of Willis, and brain weight (excluding meninges) determined at autopsy. Three factors with Eigenvalues from 1.24-1.73 were identified [loadings indicated by L]: (1) Alzheimer's pathology (tangle [L= .82] and plaque counts [L=.75 ], and APOE4 [L=.65]); vascular pathology (atherosclerosis [L=.60], lacunar [L=.78] and large infarcts [L=.70]); and reserve (education [L=.79], brain weight [L=.73]). Factor scores were calculated and dichotomized at the median to yield high and low values for each factor. Etiologic fractions (fraction of cases attributable to each of the risk factors) for high Alzheimer, high vascular and low reserve were 38.5%, 25.6% and 39.7%, respectively. In other analyses, we found that brain weight at autopsy was most strongly related to head circumference (p<0.0001) rather than to Alzheimer (p=0.01) or vascular (p=0.67) pathology, suggesting that early brain growth plays a more important role in determining brain weight at death than brain pathology. Brain reserve plays a very strong role in determining dementia status at death, on a par with Alzheimer pathology. Higher reserve may help to explain the absence of dementia in about a third of individuals fulfilling Reagan criteria for neuropathological AD. Models predicting lifetime risk of AD need to take into account reserve and vascular lesions in addition to beta amyloid load. The findings suggest that interventions that facilitate brain growth may be very effective in preventing dementia.

Non-invasive assessment of Alzheimer’s disease neurofibrillary pathology using 18F-THK5105 PET

Non-invasive imaging of tau pathology in the living brain would be useful for accurately diagnosing Alzheimer's disease, tracking disease progression, and evaluating the treatment efficacy of disease-specific therapeutics. In this study, we evaluated the clinical usefulness of a novel tau-imaging positron emission tomography tracer 18F-THK5105 in 16 human subjects including eight patients with Alzheimer's disease (three male and five females, 66-82 years) and eight healthy elderly controls (three male and five females, 63-76 years). All participants underwent neuropsychological examination and 3D magnetic resonance imaging, as well as both 18F-THK5105 and 11C-Pittsburgh compound B positron emission tomography scans. Standard uptake value ratios at 90-100 min and 40-70 min post-injection were calculated for 18F-THK5105 and 11C-Pittsburgh compound B, respectively, using the cerebellar cortex as the reference region. As a result, significantly higher 18F-THK5105 retention was observed in the temporal, parietal, posterior cingulate, frontal and mesial temporal cortices of patients with Alzheimer's disease compared with healthy control subjects. In patients with Alzheimer's disease, the inferior temporal cortex, which is an area known to contain high densities of neurofibrillary tangles in the Alzheimer's disease brain, showed prominent 18F-THK5105 retention. Compared with high frequency (100%) of 18F-THK5105 retention in the temporal cortex of patients with Alzheimer's disease, frontal 18F-THK5105 retention was less frequent (37.5%) and was only observed in cases with moderate-to-severe Alzheimer's disease. In contrast, 11C-Pittsburgh compound B retention was highest in the posterior cingulate cortex, followed by the ventrolateral prefrontal, anterior cingulate, and superior temporal cortices, and did not correlate with 18F-THK5105 retention in the neocortex. In healthy control subjects, 18F-THK5105 retention was ∼10% higher in the mesial temporal cortex than in the neocortex. Notably, unlike 11C-Pittsburgh compound B, 18F-THK5105 retention was significantly correlated with cognitive parameters, hippocampal and whole brain grey matter volumes, which was consistent with findings from previous post-mortem studies showing significant correlations of neurofibrillary tangle density with dementia severity or neuronal loss. From these results, 18F-THK5105 positron emission tomography is considered to be useful for the non-invasive assessment of tau pathology in the living brain. This technique would be applicable to the longitudinal evaluation of tau deposition and allow a better understanding of the pathophysiology of Alzheimer's disease.

Resilience of Precuneus Neurotrophic Signaling Pathways Despite Amyloid Pathology in Prodromal Alzheimer’s Disease

BackgroundReduction of precuneus choline acetyltransferase activity co-occurs with greater beta-amyloid (Aβ) in Alzheimer’s disease (AD). Whether this cholinergic deficit is associated with alteration in nerve growth factor (NGF) signaling and its relation to Aβ plaque and neurofibrillary tangle (NFT) pathology during disease onset is unknown. MethodsPrecuneus NGF upstream and downstream signaling levels relative to Aβ and NFT pathology were evaluated using biochemistry and histochemistry in 62 subjects with a premortem diagnosis of non–cognitively impaired (NCI; n = 23), mild cognitive impairment (MCI; n = 21), and mild to moderate AD (n = 18). ResultsImmunoblots revealed increased levels of proNGF in AD subjects but not MCI subjects, whereas cognate receptors were unchanged. There were no significant differences in protein level for the downstream survival kinase-signaling proteins Erk and phospho-Erk among groups. Apoptotic phospho-JNK, phospho-JNK/JNK ratio, and Bcl-2 were significantly elevated in AD subjects. Soluble Aβ1–42 and fibrillar Aβ measured by [3H] Pittsburgh compound-B ([3H]PiB) binding were significantly higher in AD subjects compared with MCI and NCI subjects. The density of plaques showed a trend to increase, but only 6-CN-PiB–positive plaques reached significance in AD subjects. AT8-positive, TOC-1–positive, and Tau C3–positive NFT densities were unchanged, whereas only AT8-positive neuropil thread density was statistically higher in AD subjects. A negative correlation was found between proNGF, phospho-JNK, and Bcl-2 levels and phospho-JNK/JNK ratio and cognition, whereas proNGF correlated positively with 6-CN-PiB–positive plaques during disease progression. ConclusionsData indicate that precuneus neurotrophin pathways are resilient to amyloid toxicity during the onset of AD.

Amyloid deposition is decreasing in aging brains

To explore cohort effects on age- and Alzheimer disease (AD)-related neuropathologic changes. We compared amyloid deposition in autopsied cases aged 65 years and older who died between 1972 and 2006. We included consecutive cases for 1972-1975, 1980, 1985, 1990, 1995, and 2000-2006. We used linear regression models to assess period effects after adjustment for age, cognitive status, and neurofibrillary tangle (NFT) staging. We calculated amyloid/NFT stage ratios to account for possible changes in AD prevalence/severity over time. Mean amyloid stage was significantly related to year of death (p = 0.001) in the total population (1,599 cases, mean age 82 ± 8 years) and decreased 24%, from 1.88 ± 0.89 to 1.57 ± 0.81 (p < 0.0001), in 1,265 individuals without dementia. This decrease was particularly marked in the oldest age groups; people 85 years and older in 2006 had less amyloid deposition compared with those aged 75 to 84 years in 1972. Recent cohorts had lower amyloid deposition. The amyloid/NFT stage ratio decreased from 1.51 ± 0.74 to 0.99 ± 0.56 (p < 0.0001) in cases without dementia and from 0.74 ± 0.13 to 0.56 ± 0.21 (p = 0.0019) in individuals with dementia, confirming that more recent cases had less amyloid despite higher NFT densities. Cohort effects were highly significant (p < 0.0001). The strong cohort effect we describe may influence the performance of early amyloid-based AD markers. It also provides preclinical evidence supporting recently described decreases in AD incidence. This trend, if confirmed in community-based studies, may lead to new insights in our understanding of both normal and pathologic brain aging.

Modification of the Relationship of the Apolipoprotein E ε4 Allele to the Risk of Alzheimer Disease and Neurofibrillary Tangle Density by Sleep

The apolipoprotein E (APOE [GenBank, 348; OMIM, 107741]) ε4 allele is a common and well-established genetic risk factor for Alzheimer disease (AD). Sleep consolidation is also associated with AD risk, and previous work suggests that APOE genotype and sleep may interact to influence cognitive function. To determine whether better sleep consolidation attenuates the relationship of the APOE genotype to the risk of incident AD and the burden of AD pathology. A prospective longitudinal cohort study with up to 6 years of follow-up was conducted. Participants included 698 community-dwelling older adults without dementia (mean age, 81.7 years; 77% women) in the Rush Memory and Aging Project. We used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation and ascertained APOE genotype. Participants underwent annual evaluation for AD during a follow-up period of up to 6 years. Autopsies were performed on 201 participants who died, and β-amyloid (Aβ) and neurofibrillary tangles were identified by immunohistochemistry and quantified. During the follow-up period, 98 individuals developed AD. In a series of Cox proportional hazards regression models, better sleep consolidation attenuated the effect of the ε4 allele on the risk of incident AD (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .04 per allele per 1-SD increase in sleep consolidation). In a series of linear mixed-effect models, better sleep consolidation also attenuated the effect of the ε4 allele on the annual rate of cognitive decline. In individuals who died, better sleep consolidation attenuated the effect of the ε4 allele on neurofibrillary tangle density (interaction estimate, -0.42; SE = 0.17; P = .02), which accounted for the effect of sleep consolidation on the association between APOE genotype and cognition proximate to death. Better sleep consolidation attenuates the effect of APOE genotype on incident AD and development of neurofibrillary tangle pathology. Assessment of sleep consolidation may identify APOE+ individuals at high risk for incident AD, and interventions to enhance sleep consolidation should be studied as potentially useful means to reduce the risk of AD and development of neurofibrillary tangles in APOE ε4+ individuals.

Brainstem Aminergic Nuclei and Late-Life Depressive Symptoms

The neurobiologic basis of late-life depressive symptoms is not well understood. To test the hypothesis that neurodegeneration and neuronal density in brainstem aminergic nuclei are related to late-life depressive symptoms. DESIGN, SETTING, PARTICIPANTS, AND EXPOSURE: Longitudinal clinicopathological cohort study at residences of participants in the Chicago, Illinois, metropolitan area. Participants included 124 older persons without dementia in the Rush Memory and Aging Project who had annual evaluations for a mean (SD) of 5.7 (2.8) years, died, and underwent a postmortem neuropathological examination that provided estimates of the densities of Lewy bodies, neurofibrillary tangles, and aminergic neurons in the locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area. The number of depressive symptoms (mean [SD], 1.61 [1.48]; range, 0-6; skewness, 0.94) on the Center for Epidemiological Studies Depression Scale averaged across annual evaluations. Brainstem Lewy bodies were associated with depressive symptoms, and the association was attenuated in those taking antidepressant medication. Brainstem tangles were associated with more depressive symptoms in those without cognitive impairment but with fewer symptoms in those with mild cognitive impairment. Lower density of tyrosine hydroxylase-immunoreactive neurons in the ventral tegmental area was robustly associated with a higher level of depressive symptoms (mean [SE] estimate, -0.014 [0.003]; P < .001; 16.3% increase in adjusted R2). The association was not modified by medication use or cognitive impairment. Neither tyrosine hydroxlyase-immunoreactive neurons in the locus ceruleus nor tryptophan hydroxlyase-immunoreactive neurons in the dorsal raphe nucleus were related to depressive symptoms. The results suggest that the mesolimbic dopamine system, especially the ventral tegmental area, has an important role in late-life depressive symptoms.

TDP-43 pathology, cognitive decline, and dementia in old age.

Cognitive decline is a leading cause of disability and death in old age but its neurobiological bases are not well understood. To test the hypothesis that transactive response DNA-binding protein 43 (TDP-43) is related to late-life cognitive decline. Longitudinal clinical-pathologic cohort study involving more than 40 Catholic groups across the United States. A total of 130 older Catholic nuns, priests, and monks underwent annual clinical evaluations, including detailed cognitive testing, for a mean of 10.1 years prior to death. On neuropathologic examination, we collected semiquantitative measures of TDP-43 pathology, density of neuronal neurofibrillary tangles, area occupied by amyloid-beta plaques, and the presence of alpha-synuclein Lewy bodies from multiple brain regions. Gross and microscopic cerebral infarcts and hippocampal sclerosis were also identified. Annual rate of change in a previously established composite measure of global cognition during a mean of 10.1 years of annual observation before death. Transactive response DNA-binding protein 43 pathology, ranging from sparse to severe, was identified in 46% of participants and was associated with amyloid plaques, tangles, and hippocampal sclerosis but not neocortical Lewy bodies or cerebral infarcts. After controlling for amyloid plaques, tangles, and hippocampal sclerosis, TDP-43 pathology was associated with more rapid cognitive decline and accounted for nearly as much of the variability in rates of global cognitive decline as did tangles. Transactive response DNA-binding protein 43 pathology had a distinct cognitive profile that differed from other neuropathologic processes (related to decline in episodic and working memory but not in other cognitive domains), and it was elevated in those who developed dementia but not in those with mild cognitive impairment. The results suggest that TDP-43 is an important brain pathology underlying cognitive decline and dementia in old age.

In vivo parahippocampal white matter pathology as a biomarker of disease progression to Alzheimer's disease

Noninvasive diagnostic tests for Alzheimer's disease (AD) are limited. Postmortem diagnosis is based on density and distribution of neurofibrillary tangles (NFTs) and amyloid-rich neuritic plaques. In preclinical stages of AD, the cells of origin for the perforant pathway within the entorhinal cortex are among the first to display NFTs, indicating its compromise in early stages of AD. We used diffusion tensor imaging (DTI) to assess the integrity of the parahippocampal white matter in mild cognitive impairment (MCI) and AD, as a first step in developing a noninvasive tool for early diagnosis. Subjects with AD (N = 9), MCI (N = 8), or no cognitive impairment (NCI; N = 20) underwent DTI-MRI. Fractional anisotropy (FA) and mean (MD) and radial (RD) diffusivity measured from the parahippocampal white matter in AD and NCI subjects differed greatly. Discriminant analysis in the MCI cases assigned statistical membership of 38% of MCI subjects to the AD group. Preliminary data 1 year later showed that all MCI cases assigned to the AD group either met the diagnostic criteria for probable AD or showed significant cognitive decline. Voxelwise analysis in the parahippocampal white matter revealed a progressive change in the DTI patterns in MCI and AD subjects: whereas converted MCI cases showed structural changes restricted to the anterior portions of this region, in AD the pathology was generalized along the entire anterior-posterior axis. The use of DTI for in vivo assessment of the parahippocampal white matter may be useful for identifying individuals with MCI at highest risk for conversion to AD and for assessing disease progression.

Progression of Alzheimer-type Neurofibrillary Tangles is Related to the Proximodistal Segments of the Hemispheric Arteries

In Alzheimer's disease (AD), neurofibrillary degeneration in the hemispheres starts in the limbic and paralimbic regions prior to those in the isocortical ones but factors determining the progression of these changes are unknown. Previous studies have shown that migration of extracellular substances (volume transmission) driven by arterial pulse pressure waves from the cerebrospinal fluid (CSF) towards the brain parenchyma occurs earlier in these limbic and paralimbic cortices located around the basal cisterns containing the proximal segments of the main hemispheric arteries than in the isocortex. Considering this similarity, the aim of our study was to examine the relation between the proximal segments of the main hemispheric arteries and the development and spread of neurofibrillary tangles (NFTs) in limbic and early isocortical Braaks' stages. Blocks following proximosdistal levels of the anterior and middle cerebral arteries containing areas of the cingulate and insular cortices, respectively, were dissected and NFTs were counted. In both regions, the density of NFTs decreased in parallel with the proximodistal segments of the accompanying arteries. Our results show that neurofibrillary degeneration in AD is related to the proximodistal levels of the main hemispheric arteries and raise the possibility that this effect is mediated by volume transmission from the CSF into the brain.

Postmortem 3-D Brain Hemisphere Cortical Tau and Amyloid-β Pathology Mapping and Quantification as a Validation Method of Neuropathology Imaging

This work is aimed at correlating pre-mortem [18F]FDDNP positron emission tomography (PET) scan results in a patient with dementia with Lewy bodies (DLB), with cortical neuropathology distribution determined postmortem in three physical dimensions in whole brain coronal sections. Analysis of total amyloid-β (Aβ) distribution in frontal cortex and posterior cingulate gyrus confirmed its statistically significant correlation with cortical [18F]FDDNP PET binding values (distribution volume ratios, DVR) (p < 0.001, R = 0.97, R2 = 0.94). Neurofibrillary tangle (NFT) distribution correlated significantly with cortical [18F]FDDNP PET DVR in the temporal lobe (p < 0.001, R = 0.87, R2 = 0.76). Linear combination of Aβ and NFT densities was highly predictive of [18F]FDDNP PET DVR through all analyzed regions of interest (p < 0.0001, R = 0.92, R2 = 0.85), and both densities contributed significantly to the model. Lewy bodies were present at a much lower level than either Aβ or NFTs and did not significantly contribute to the in vivo signal. [18F]FDG PET scan results in this patient were consistent with the distinctive DLB pattern of hypometabolism. This work offers a mapping brain model applicable to all imaging probes for verification of imaging results with Aβ and/or tau neuropathology brain distribution using immunohistochemistry, fluorescence microscopy, and autoradiography.

Response to Sheehan, B. (2012) Assessment scales in dementia. Ther Adv Neurol Disord 5: 349-358.

I read with interest a recent review ‘Assessment scales in dementia’ by B. Sheehan published in Therapeutic Advances in Neurological Disorders [Sheehan, 2012]. The review provides important information but leaves out scales that are useful for research in advanced dementia when the subjects are mostly nonverbal. We have developed several scales for this population that may be useful for readers of the journal. Since most of the scales that measure the severity of dementia bottom out in severe stages, we developed the Bedford Alzheimer Nursing Scale – Severity (BANS-S) scale that does not have this problem [Volicer et al. 1994]. The score of this scale correlated with density of neurofibrillary tangles measured in subsequent autopsy. The scale may also be used to define the severe stage of dementia [Van der Steen et al. 2006]. Discomfort and pain are difficult to evaluate in noncommunicative individuals. We have also developed the Discomfort Scale – Dementia of the Alzheimer Type (DS-DAT) scale [Hurley et al. 1992] to measure discomfort and the Pain Assessment in Advanced Dementia (PAINAD) scale [Warden et al. 2003] to measure pain. While DS-DAT is most useful for research studies, PAINAD can be used in routine clinical practice and was translated to several languages. Behavioral symptoms are often the most disturbing symptoms of dementia. Most scales evaluating these symptoms rely on caregiver report and do not differentiate circumstances at which the symptoms occur. Direct observation can differentiate between two main behavioral symptoms, agitation and rejection of care, and we developed observational scales for both of these symptoms: the Scale for Observation of Agitation in Persons with Dementia (SOAPD) [Hurley et al. 1999] and Resistiveness to Care Scale (RTC-DAT) [Mahoney et al. 1999]. One factor that may improve quality of life of institutional persons with dementia are visits by their relatives. Improving the quality of these visits may increase their frequency and family satisfaction. Therefore, it can be useful to measure the quality of these visits using the Family Visit Scale for Dementia (FAVS-D) scale [Volicer et al. 2008]. Finally, because advanced dementia is a terminal disease, it is important to be able to evaluate end-of-life issues. We developed three scales that measure Satisfaction With Care at the End-of-life in Dementia (SWC-EOLD), Symptom Management at the End-of-life in Dementia (SM-EOLD) during the last 3 months of life, and Comfort Assessment in Dying with Dementia (CAD-EOLD) [Volicer et al. 2001]. These scales were validated [Kiely et al. 2006] and are sensitive to clinically meaningful changes of specific outcomes related to end-of-life care and quality of life among residents with end-stage advanced dementia and their healthcare providers [Kiely et al. 2012]. The psychometric characteristics of all of these scales were evaluated and they were used in multiple research studies. None of these scales is copyrighted and they are available for free use.

Glia Maturation Factor Expression in Hippocampus of Human Alzheimer’s Disease

Alzheimer's disease (AD) is characterized by the presence of neuropathological lesions containing amyloid plaques (APs) and neurofibrillary tangles (NFTs) associated with neuroinflammation and neuronal degeneration. Hippocampus is one of the earliest and severely damaged areas in AD brain. Glia maturation factor (GMF), a known proinflammatory molecule is up-regulated in AD. Here, we have investigated the expression and distribution of GMF in relation to the distribution of APs and NFTs in the hippocampus of AD brains. Our immunohistochemical results showed GMF is expressed specifically in the vicinity of high density of APs and NFTs in the hippocampus of AD patients. Moreover, reactive astrocytes and activated microglia surrounds the APs and NFTs. We further demonstrate that GMF immunoreactive glial cells were increased at the sites of Tau containing NFTs and APs of hippocampus in AD brains. In conclusion, up-regulated expression of GMF in the hippocampus, and the co-localization of GMF and thioflavin-S stained NFTs and APs suggest that GMF may play important role in the pathogenesis of AD.

Quantitative neurofibrillary tangle density and brain volumetric MRI analyses in Alzheimer’s disease presenting as logopenic progressive aphasia

Neurofibrillary tangles (NFTs) are one of the key histological lesions of Alzheimer’s disease (AD) and are associated with brain atrophy. We assessed regional NFT density in 30 patients with AD, 10 of which presented as the logopenic variant of primary progressive aphasia (lvPPA) and 20 that presented as dementia of the Alzheimer’s type (DAT). Regional grey matter volumes were measured using antemortem MRI. NFT density was significantly higher in left temporoparietal cortices in lvPPA compared to DAT, with no differences observed in hippocampus. There was a trend for the ratio of temporoparietal-to-hippocampal NFT density to be higher in lvPPA. The imaging findings mirrored the pathological findings, with smaller left temporoparietal volumes observed in lvPPA compared to DAT, and no differences observed in hippocampal volume. This study demonstrates that lvPPA is associated with a phenomenon of enhanced temporoparietal neurodegeneration, a finding that improves our understanding of the biological basis of lvPPA.