In the Journals

Researchers identify dementia that ‘mimics’ Alzheimer’s disease

Researchers have proposed new terminology for a recently recognized late-onset form of dementia that “mimics” Alzheimer’s type dementia, according to a report published in Brain.

The report includes suggested guidelines for the autopsy evaluation and staging of this amnestic dementia, known as LATE (limbic-predominant age-related transactive response DNA binding protein of 43 kDa [TDP-43] encephalopathy), which generally affects subjects older than 80 years.

LATE is characterized by its epidemiology and fairly restricted neuroanatomical distribution of TDP-43 proteinopathy, Peter T. Nelson, MD, PhD, from Sanders-Brown Center on Aging, University of Kentucky, and colleagues explained. In previous autopsy cohorts, about 25% of brains had sufficient burden of LATE neuropathological change (LATE-NC) linked to apparent cognitive impairment, and many subjects with LATE-NC have comorbid brain pathologies.

“Given that the ‘oldest-old’ are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health,” Nelson and colleagues wrote.

To inspire research and awareness of this pathway to dementia, the researchers reported consensus-based recommendations, such as guidelines for diagnosing and staging of LATE-NC.

For all older subjects, Nelson and colleagues recommended that TDP-43 immunohistochemistry be performed in three brain areas — amygdala, mid-level hippocampus and middle frontal gyrus — as part of the neuropathological evaluation to capture possible progression of LATE-NC in the brain.

Although LATE-NC appears to affect the medial temporal lobe structures, prior neuroimaging studies showed that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex and other brain regions, according to the study.

“We emphasize that the proposed sampling for LATE-NC autopsy screening is a minimal evaluation, whereas more detailed sampling and staging should be considered for specific research settings,” Nelson and colleagues wrote.

Previous genetic evidence has yielded five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE, which indicate that LATE shares pathogenetic mechanisms with frontotemporal lobar degeneration as well as Alzheimer’s disease, the results showed.

However, LATE may have disease-specific underlying mechanisms and the researchers recommended reporting the presence or absence of LATE-NC as a separate diagnostic entity from Alzheimer’s disease neuropathological change, even when there are comorbid amyloid-beta and/or tau proteinopathies.

“For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE,” Nelson and colleagues wrote. “An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.” – by Savannah Demko

Disclosure: The authors report no relevant financial disclosures.

Researchers have proposed new terminology for a recently recognized late-onset form of dementia that “mimics” Alzheimer’s type dementia, according to a report published in Brain.

The report includes suggested guidelines for the autopsy evaluation and staging of this amnestic dementia, known as LATE (limbic-predominant age-related transactive response DNA binding protein of 43 kDa [TDP-43] encephalopathy), which generally affects subjects older than 80 years.

LATE is characterized by its epidemiology and fairly restricted neuroanatomical distribution of TDP-43 proteinopathy, Peter T. Nelson, MD, PhD, from Sanders-Brown Center on Aging, University of Kentucky, and colleagues explained. In previous autopsy cohorts, about 25% of brains had sufficient burden of LATE neuropathological change (LATE-NC) linked to apparent cognitive impairment, and many subjects with LATE-NC have comorbid brain pathologies.

“Given that the ‘oldest-old’ are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health,” Nelson and colleagues wrote.

To inspire research and awareness of this pathway to dementia, the researchers reported consensus-based recommendations, such as guidelines for diagnosing and staging of LATE-NC.

For all older subjects, Nelson and colleagues recommended that TDP-43 immunohistochemistry be performed in three brain areas — amygdala, mid-level hippocampus and middle frontal gyrus — as part of the neuropathological evaluation to capture possible progression of LATE-NC in the brain.

Although LATE-NC appears to affect the medial temporal lobe structures, prior neuroimaging studies showed that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex and other brain regions, according to the study.

“We emphasize that the proposed sampling for LATE-NC autopsy screening is a minimal evaluation, whereas more detailed sampling and staging should be considered for specific research settings,” Nelson and colleagues wrote.

Previous genetic evidence has yielded five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE, which indicate that LATE shares pathogenetic mechanisms with frontotemporal lobar degeneration as well as Alzheimer’s disease, the results showed.

However, LATE may have disease-specific underlying mechanisms and the researchers recommended reporting the presence or absence of LATE-NC as a separate diagnostic entity from Alzheimer’s disease neuropathological change, even when there are comorbid amyloid-beta and/or tau proteinopathies.

“For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE,” Nelson and colleagues wrote. “An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.” – by Savannah Demko

Disclosure: The authors report no relevant financial disclosures.