The aim of this study was to determine the frequency of ubiquitin-positive inclusions (UPI) in dementia lacking distinctive histology (DLDH), and their relationship to other pathologic features, such ...as hippocampal sclerosis (HpScl), as well as genetic factors. Routine and immunohistochemical studies were carried out in a consecutive series of 29 cases of DLDH. 83% of the cases had UPI, while HpScl was demonstrated in 76%. There was no significant correlation among pathologic features or between pathologic features and genetic factors. The high prevalence of UPI demonstrated in this study implies that DLDH is similar to motor neuron disease inclusion dementia. The high prevalence of HpScl may be the cause of some of the clinical features observed in patients with frontotemporal lobar degeneration.
To assess genetic influence on the clinical presentation of progressive supranuclear palsy (PSP), the genetic effect on disease course was examined for variants in the tau gene (MAPT) and the gene ...for apolipoprotein E (APOE) in 58 cases of pathologically confirmed PSP. Clinical indicators of disease course included age at symptomatic onset (AAO), age at death (AAD), and disease duration (DD) and the genetic effects examined included MAPT haplotypes and APOE genotypes. From linear regression analysis, the MAPT H1/H1 genotype was associated with significantly earlier AAO (
P
=
0.038). The MAPT genotype did not significantly influence DD or AAD. The APOE ɛ4 allele did not significantly influence AAO, AAD, or DD. Male sex was a predictor for earlier AAO (
P
=
0.015). The interaction between MAPT and APOE was not significant for AAD and DD, but a significant negative coefficient was found for AAO suggesting their combination does not have an additive effect. These results support the assertion that the H1/H1 genotype may contribute to the earlier occurrence of clinical symptoms.
Progressive supranuclear palsy (PSP) is a distinct clinicopathological entity characterized by neurofibrillary tangles, tufted astrocytes, threads and oligodendroglial coiled bodies. These four ...lesions are distributed in varying densities throughout subcortical and brainstem structures. There is no data regarding the relationship of disease duration to lesion burden severity in PSP. We report the results of analysis of semiquantitative data collected as part of the diagnostic evaluation on 97 cases of ‘pure’ PSP, submitted to the Society of PSP Brain Bank. Surprisingly, the data suggests that in PSP as duration of illness increases there is a decrease in oligodendroglial tau burden.
Transactive response DNA‐binding protein 43 (TDP‐43) pathological inclusions are found in frontotemporal lobar degeneration (FTLD‐TDP) and Alzheimer's disease (AD‐TDP). While clinically different, ...TDP‐43 inclusions in FTLD‐TDP and AD can have similar morphological characteristics. However, TDP‐43 colocalizing with tau and forming “apple‐bite” or “flame‐shaped” neuronal cytoplasmic inclusions (NCI) are only found in AD‐TDP. Here, we describe a case with AD and neuritic plaque‐associated TDP‐43. The patient was a 96‐year‐old right‐handed Caucasian woman who had developed a slowly progressive amnestic syndrome compatible with typical AD at age 80. Genetic testing revealed APOE ε3/ε4, GRN r5848 CT, and MAPT H1/H2 genotype. Consistent with the old age at onset and long disease duration, limbic‐predominant AD was found at autopsy, with high hippocampal yet low cortical neurofibrillary tangle (NFT) counts. Hippocampal and amygdala sclerosis were present. Immunohistochemistry for phospho‐TDP‐43 showed NCIs, dystrophic neurites, and rare neuronal intranuclear inclusions consistent with FTLD‐TDP type A, as well as tau NFT‐associated TDP‐43 inclusions. These were frequent in the amygdala, entorhinal cortex, hippocampus, occipitotemporal gyrus, and inferior temporal gyrus but sparse in the mid‐frontal cortex. Additionally, there were TDP‐43‐immunoreactive inclusions forming plaque‐like structures in the molecular layer of the dentate fascia of the hippocampus. The presence of neuritic plaques in the same region was confirmed using thioflavin‐S fluorescent microscopy and immunohistochemistry for phospho‐tau. Double labeling immunofluorescence showed colocalization of TDP‐43 and tau within neuritic plaques. Other pathologies included mild Lewy body pathology predominantly affecting the amygdala and olfactory bulb, aging‐related tau astrogliopathy, and mixed small vessel disease (arteriolosclerosis and amyloid angiopathy) with several cortical microinfarcts. In conclusion, we have identified TDP‐43 colocalizing with tau in neuritic plaques in AD, which expands the association of TDP‐43 and tau in AD beyond NFTs. The clinical correlate of this plaque‐associated TDP‐43 appears to be a slowly progressive amnestic syndrome.
OBJECTIVE To describe 3 patients with a history of transient global amnesia (TGA) who developed primary progressive aphasia (PPA). DESIGN Case series. SETTING Tertiary care center. PATIENTS The study ...included 3 patients who presented to the neurology clinic with language complaints. MAIN OUTCOME MEASURE Presence of recurrent TGA and PPA. RESULTS Three patients with a history of TGA were subsequently diagnosed as having PPA. All patients had recurrent attacks of TGA. The diagnoses of PPA were supported by speech pathology evaluations, neuropsychometric testing results, and imaging findings. Positron emission tomography revealed left posterior frontal hypometabolism in 1 patient and predominantly left temporal parietal hypometabolism in 1 patient, while single-photon emission computed tomography demonstrated decreased perfusion in the anterior left temporal and frontal lobes in the third patient. CONCLUSION There may be a relationship between recurrent TGA and the development of PPA.
Corticobasal syndrome (CBS) is a clinical phenotype characterized by asymmetric parkinsonism, rigidity, myoclonus, and apraxia. Originally believed secondary to corticobasal degeneration (CBD), ...mounting clinicopathologic studies have revealed heterogenous neuropathologies. The objectives of this study were to determine the pathologic heterogeneity of CBS, the clinicoradiologic findings associated with different underlying pathologies causing CBS, and the positive predictive value (PPV) of current diagnostic criteria for CBD among patients with a CBS.
Clinical data, brain MRI, and neuropathologic data of patients followed at Mayo Clinic and diagnosed with CBS antemortem were reviewed according to neuropathology category at autopsy.
The cohort consisted of 113 patients with CBS, 61 (54%) female patients. Mean ± SD disease duration was 7 ± 3.7 years; mean ± SD age at death was 70.5 ± 9.1 years. The primary neuropathologic diagnoses were 43 (38%) CBD, 27 (24%) progressive supranuclear palsy (PSP), 17 (15%) Alzheimer disease (AD), 10 (9%) frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein 43 (TDP) inclusions, 7 (6%) diffuse Lewy body disease (DLBD)/AD, and 9 (8%) with other diagnoses. Patients with CBS-AD or CBS-DLBD/AD were youngest at death (median interquartile range: 64 13, 64 11 years) while CBS-PSP were oldest (77 12.5 years,
= 0.024). Patients with CBS-DLBD/AD had the longest disease duration (9 6 years), while CBS-other had the shortest (3 4.25 years,
= 0.04). Posterior cortical signs and myoclonus were more characteristic of patients with CBS-AD and patients with CBS-DLBD/AD. Patients with CBS-DLBD/AD displayed more features of Lewy body dementia. Voxel-based morphometry revealed widespread cortical gray matter loss characteristic of CBS-AD, while CBS-CBD and CBS-PSP predominantly involved premotor regions with greater amount of white matter loss. Patients with CBS-DLBD/AD showed atrophy in a focal parieto-occipital region, and patients with CBS-FTLD-TDP had predominant prefrontal cortical loss. Patients with CBS-PSP had the lowest midbrain/pons ratio (
= 0.012). Of 67 cases meeting clinical criteria for possible CBD at presentation, 27 were pathology-proven CBD, yielding a PPV of 40%.
A variety of neurodegenerative disorders can be identified in patients with CBS, but clinical and regional imaging differences aid in predicting underlying neuropathology. PPV analysis of the current CBD diagnostic criteria revealed suboptimal performance. Biomarkers adequately sensitive and specific for CBD are needed.
Background
Posterior Cortical Atrophy (PCA) is one of the atypical Alzheimer’s Disease (AD) variants, characterized by predominant visuospatial and visuoperceptual deficits, with dorsal and ventral ...subtypes recognized clinically and radiographically. A third primary occipital (caudal) variant has been suggested. The objective of this study was to determine its demographics, clinical manifestations, and biomarker findings.
Method
Fifty‐two PCA patients with positive amyloid PET scans were investigated. Patients underwent neuropsychological assessment, 3T MRI imaging and FDG‐, amyloid‐ and tau‐PET scans. Regional FDG‐PET values were normalized to the pons and represented as z‐scores relative to a control population. Patients were divided into “primary occipital” and “other PCA” subgroups according to FDG‐PET defined criteria, with primary occipital defined as patients in which the z‐scores for occipital subregions were at least one standard deviation lower (i.e., more abnormal) than the z scores in all other brain regions. Global amyloid‐PET, temporoparietal FDG‐PET and temporal tau‐PET regions‐of‐interest (ROI) were calculated. Student’s T test and Fisher’s exact analyses were used to investigate differences in demographics, clinical findings, and imaging biomarkers across the two groups.
Result
Nine patients were classified as primary occipital; primary occipital patients were older (64.8±6.9 versus 59.3±6.8, p=0.034) and had more years of education (17.7±1.7 versus 15.1±2.6, p=0.007) compared to the other PCA patients. Clinical evaluation revealed worse performance for the primary occipital group on the Ishihara test for color perception (p<0.001), while the other PCA patients performed worse on the Western Aphasia Battery (WAB) praxis scale (p=0.005). Overall neuropsychiatric symptom burden as defined by the NPI‐Q was lower in the primary occipital group (p<0.001). The FDG‐PET meta‐ROI (weighted median uptake in angular gyrus, posterior cingulate, and inferior temporal ROIs, normalized to the pons and vermis) was higher in the primary occipital subtype (p=0.006), but no differences were observed in amyloid and tau‐PET.
Conclusion
Clinical and biomarker findings suggest primary occipital PCA is characterized by an older age at onset, more color perception dysfunction, less severe ideomotor apraxia and less hypometabolism in temporal‐parietal meta‐ROI compared to more established phenotypes.
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