Brainstem vulnerability in AD and FTLD

Brainstem vulnerability in AD and FTLD
The Grinberg lab is developing an integrated picture of brainstem vulnerability in Alzheimer’s disease and frontotemporal lobar degeneration by using a comprehensive and pioneering network-based approach.


The most frequent neurodegenerative diseases are Alzheimer’s disease, Parkinson’s disease and frontotemporal lobar degeneration. All of them spread through functional neuronal network pathways, but feature a distinct anatomical pattern of early regional vulnerability.

Because all these diseases are clinically associated with dementia, major attention has been given to understand associated brain cortical changes. Recently it became clear that these diseases feature very long pre-symptomatic stages, in which the disease can be detected in the brain, but the brain function are still intact. Neuropathological studies from our group and others have proven that actually the brainstem, not the cortex, harbors the first detectable neurodegeneration in several of these diseases.

Since brainstem nuclei are interconnected with cortical structures, it is important to place it within an etiopathogenic context in neurodegenerative diseases. This information will complement knowledge accumulated on cortical injury and may prove relevant for deciphering early regional vulnerability, anatomical progression and possible non-cognitive symptomatology, and consequently to identify targets for effective treatment strategies.

We are developing an integrated picture of brainstem vulnerability in Alzheimer’s and frontotemporal lobar degeneration by using a comprehensive and pioneering network-based approach.

The rationale for this research is that clarifying brainstem involvement in these diseases may facilitate development of innovative biomarkers, improve diagnostic clinical criteria, and suggest novel therapeutic targets.

This study is done in collaboration with the Brain Bank of the Brazilian Aging Brain Study Group, a unique large brain bank specialized in normal brain aging.Thanks to this collection, we have access to cases of patients at pre-symptomatic stages of neurodegenerative diseases, a rarity in other brain collections.

Funding Sources

NIH Grant #R01 AG040311
John Douglas French Alzheimer Foundation

Related publications


Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer's Disease.

Journal of Alzheimer's disease
Ehrenberg AJ, Suemoto CK, de Paula França Resende E, Petersen C, Leite REP, Rodriguez RD, Ferretti-Rebustini REL, You M, Oh J, Nitrini R, Pasqualucci CA, Jacob-Filho W, Kramer JH, Gatchel JR, Grinberg LT

On the origin of tau seeding activity in Alzheimer's disease.

Acta neuropathologica
Heinsen H, Grinberg LT

Commentary: Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice.

Frontiers in neuroscience
Betts MJ, Ehrenberg AJ, Hämmerer D, Düzel E

Selective Vulnerability of Brainstem Nuclei in Distinct Tauopathies: A Postmortem Study.

Journal of neuropathology and experimental neurology
Eser RA, Ehrenberg AJ, Petersen C, Dunlop S, Mejia MB, Suemoto CK, Walsh CM, Rajana H, Oh J, Theofilas P, Seeley WW, Miller BL, Neylan TC, Heinsen H, Grinberg LT

Light at the beginning of the tunnel? Investigating early mechanistic changes in Alzheimer's disease.

Brain: a journal of neurology
Grinberg LT, Heinsen H

Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease.

Neuropathology and applied neurobiology
Ehrenberg AJ, Nguy AK, Theofilas P, Dunlop S, Suemoto CK, Di Lorenzo Alho AT, Leite RP, Diehl Rodriguez R, Mejia MB, Rüb U, Farfel JM, de Lucena Ferretti-Rebustini RE, Nascimento CF, Nitrini R, Pasquallucci CA, Jacob-Filho W, Miller B, Seeley WW, Heinsen H, Grinberg LT

Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery.

Alzheimer's & dementia: the journal of the Alzheimer's Association
Theofilas P, Ehrenberg AJ, Dunlop S, Di Lorenzo Alho AT, Nguy A, Leite REP, Rodriguez RD, Mejia MB, Suemoto CK, Ferretti-Rebustini REL, Polichiso L, Nascimento CF, Seeley WW, Nitrini R, Pasqualucci CA, Jacob Filho W, Rueb U, Neuhaus J, Heinsen H, Grinberg LT

Turning on the Light Within: Subcortical Nuclei of the Isodentritic Core and their Role in Alzheimer's Disease Pathogenesis.

Journal of Alzheimer's disease: JAD
Theofilas P, Dunlop S, Heinsen H, Grinberg LT

Brainstem: neglected locus in neurodegenerative diseases.

Frontiers in neurology
Grinberg LT, Rueb U, Heinsen H