NovoTTF treatment is an FDA approved treatment strategy for recurrent Glioblastoma multiforme (GBM) management which employs alternating electric fields to the region of the malignant tumor through probes on the patient's head which is thought to improve time to disease progression of GBM via cell cycle mitosis disruption. A patient is described with recurrent GBM who had disease progression following initial standard surgical treatment and concomitant chemo-radiotherapy and was found to have sarcomatous transformation after initiation of NovoTTF-100A electrical device therapy with bevacizumab. Upon tumor progression, less than two years after initial diagnosis, the patient underwent surgical resection which revealed transformation from a GFAP-positive WHO grade IV astrocytoma into a GFAP-negative, reticulin-positive sarcoma with rhabdomyoid features following histopathological evaluation. The possibility of a causal connection between the NovoTTF therapy and sarcomatous transformation needs to be further evaluated. No such case of sarcoma progression in the CNS following chemo-radiotherapy and/or electrical current treatment for Glioblastoma multiforme has been reported in the literature.

Introduction

The number of persons aged >90 years will grow significantly in coming decades. This group has the highest rates of dementia, most commonly Alzheimer's disease (AD).

Methods

Using The 90+ Study, we developed a statistical model for dementia risk based on brain pathologies. Intervention scenarios which reduce or eliminate AD pathology were considered, and the numbers of dementia cases among the U.S. oldest-old that could be prevented were estimated.

Results

The U.S. dementia prevalence among the oldest-old will increase from 1.35 million in 2015 to 4.72 million in 2050. If interventions eliminate AD pathology, dementia prevalence would be reduced by approximately 50%, averting nearly 2.4 million cases in 2050. However, large numbers of dementia cases would still remain.

Discussion

Reducing AD pathology would significantly decrease the public health burden of dementia. However, other interventions are needed to address the burden associated with other dementing pathologies prevalent in the oldest-old.

Introduction

We estimated the prevalence of microinfarcts and their association with dementia in a cohort of oldest-old participants.

Methods

Participants were from The 90+ Study, a population-based study of people 90 years and older. Dementia diagnoses were assigned postmortem during a consensus conference. Microinfarcts were evaluated in six brain regions.

Results

At death, the 213 participants were on average 97 years old, 69% were women, and 52% had dementia. Of the participants, 51% had microinfarcts and 17% had 3+ microinfarcts. The odds ratio (OR) for dementia was similar for 3+ microinfarcts (OR = 4.75, P < .01) and tangle stage V-VI (OR = 4.70, P < .001). Only microinfarcts in cortical regions (other than occipital) were associated to dementia.

Discussion

In this oldest-old cohort, microinfarcts are common and contribute independently and similarly in magnitude to dementia as tangles. As risk factors for microinfarcts and other dementing pathologies are likely to differ, identifying these factors is crucial to developing prevention strategies for dementia in the oldest-old.

Optune^® treatment is a US FDA-approved treatment for glioblastoma (GBM) that employs alternating electric fields. Tumor treating field (TTF) therapy can exert its effects on GBM via cell cycle mitosis disruption and cytokinesis. We describe a patient with recurrent GBM who had disease progression following standard surgical treatment and concomitant chemoradiotherapy, and was found to have sarcomatous transformation after initiation of TTF therapy with bevacizumab. Upon tumor progression, repeat surgical resection revealed transformation into a GFAP-negative, reticulin-positive sarcoma with rhabdomyoid features. The possibility of a causal connection between TTF therapy and sarcomatous transformation needs to be further evaluated. No such case of apparent sarcoma formation in the CNS following chemoradiotherapy and/or TTF treatment for GBM has been reported.

Abstract Objective: To identify the relationship between hippocampal sclerosis (HS) and other common degenerative brain pathologies and to identify neuropsychological impairments associated with HS Background: Hippocampal sclerosis of ageing is a common neuropathological finding in the oldest-old who die with dementia. HS has a strong association with dementia (5 times stronger than Alzheimer’s disease (AD)) and during life, is commonly misdiagnosed as AD. Previous studies have consistently shown a relationship between TDP-43 and HS and conflicting associations between HS and other degenerative pathologies. Design/Methods: We studied 143 participants from the 90+ study, a population based study of people aged 90 and older (the oldest-old). Neuropathology data was available for HS, Alzheimer’s disease, TDP-43, Lewy body disease (LBD), arteriolosclerosis, atherosclerosis, and infarcts. We used Neuropsychological data closest to onset of cognitive impairment or death (for cognitively normal participants). We used regression analyses to study the associations between HS and other neuropathologies and to study the effect of neuropathologies on global and domain specific cognitive measures. Results: 96% (21/22) of participants with HS had dementia at death. In the whole sample, there was no difference in demographics between those with and without HS. Logistic regressions revealed TDP-43 (OR: 20.1, p<0.001) and LBD (OR: 8.7, p=0.007) were associated with HS and arteriolosclerosis (OR: 2.65, p=0.08) trended toward significance. However, there was no association between HS and AD (OR: 1.1, p=0.6). Multiple linear regression revealed that HS, TDP-43 and AD, were independently associated with lower scores on a global cognitive measure (3MS). Linear regressions also revealed associations between HS and TDP-43 with impaired verbal memory and semantic knowledge, and between AD and construction apraxia. Conclusions: In the oldest-old, HS is associated with TDP-43 and LBD but not AD. Differential involvement of cognitive domains in HS and TDP-43 vs. AD might help diagnosing HS during life.

Cerebral microvascular disease (MVD) is an important cause of vascular cognitive impairment. MVD is heterogeneous in aetiology, ranging from universal ageing to the sporadic (hypertension, sporadic cerebral amyloid angiopathy [CAA] and chronic kidney disease) and the genetic (e.g., familial CAA, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL] and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy [CARASIL]). The brain parenchymal consequences of MVD predominantly consist of lacunar infarcts (lacunes), microinfarcts, white matter disease of ageing and microhaemorrhages. MVD is characterised by substantial arteriolar neuropathology involving ubiquitous vascular smooth muscle cell (SMC) abnormalities. Cerebral MVD is characterised by a wide variety of arteriolar injuries but only a limited number of parenchymal manifestations. We reason that the cerebral arteriole plays a dominant role in the pathogenesis of each type of MVD. Perturbations in signalling and function (i.e., changes in proliferation, apoptosis, phenotypic switch and migration of SMC) are prominent in the pathogenesis of cerebral MVD, making cerebral angiomyopathy an appropriate term to describe the spectrum of pathologic abnormalities. The evidence suggests that the cerebral arteriole acts as both source and mediator of parenchymal injury in MVD.

Primary leptomeningeal oligodendrogliomas (PLOs) are rare intracranial malignancies where tumors grow in the subarachnoid space without an obvious connection to the brain or spinal cord parenchyma. Adding to the three previously reported cases of PLO with no parenchymal involvement we report a fourth case of the same in this paper in a 50-year-old woman presenting with unrelenting headaches. CT scan of her head revealed hydrocephalus and MRI revealed diffuse enhancement of her leptomeninges throughout her brain and spine, prominent over the basilar region. Biopsy obtained using a frameless stereotactic biopsy showed sharply defined cell borders, clear cytoplasm, and rounded nuclei consistent with an oligodendroglioma. Our case suggests that PLO can mimic diffuse forms of granulomatous meningitis and should be suspected in patients that clinically and radiographically present like granulomatous meningitis but without blood or CSF markers for the same.

Background

The apolipoprotein E (APOE) epsilon2 allele has been suggested as having a protective effect and delaying the age at onset of Alzheimer disease.

Objective

To describe a dissociation between neuropathologic findings with normal cognition in a woman with severe Alzheimer disease with the APOE epsilon2/epsilon2 genotype.

Design

Case report from a community-based prospective study of persons 90 years or older (The 90+ Study).

Participant

A 92-year-old woman without dementia with the APOE epsilon2/epsilon2 genotype who lived independently without significant cognitive or functional loss and was a participant in The 90+ Study. She died in December 2004, and postmortem examination of her brain was performed.

Intervention

Neurologic examination and a battery of neuropsychological tests were performed 6 months and 1 month before death. Neuropathologic examination included Braak and Braak staging for senile plaques and neurofibrillary tangles.

Results

Neuropathologic examination of the brain revealed advanced senile plaque and neurofibrillary tangle disease consistent with a high likelihood of Alzheimer disease. At clinical evaluation, the participant demonstrated no dementia and only mild cognitive deficits.

Conclusions

The APOE genotype may have contributed to maintenance of cognition despite advanced neuropathologic findings of Alzheimer disease. This case suggests that the APOE epsilon2 isoform may have a protective effect against cognitive decline in Alzheimer disease that may be independent from senile plaques and neurofibrillary tangles.

AbstractDementia pugilistica (DP) is associated with chronic traumatic brain injury (CTBI), and leads to a “punch drunk” syndrome characterized by impairments in memory and executive function, behavioral changes, and motor signs. Microscopic features include the accumulation of neurofibrillary tangles (NFTs), beta-amyloid (Aβ), and TAR DNA binding protein 43 (TDP-43) pathology. Here we describe detailed clinical and neuropathological data about a 55-year-old retired boxer (ApoE3/4), who presented with executive dysfunction and behavioral impairments. At autopsy, significant Aβ pathology was seen, primarily in the form of diffuse plaques. Tau pathology was extensive and was determined to be of Braak and Braak stage VI. Frontal white matter showed evidence of glial tau inclusions (astrocytes and oligodendroglia). Cerebrovascular pathology was minimal with patchy amyloid angiopathy. Inflammation was another key feature, including microglial activation and significant C1q labeling of neurons, along with NFTs. TDP-43-positive pathology was also observed. Inflammation may be a key inciting as well as propagating feature of DP neuropathology.