Fronto-temporal lobar degeneration: neuropathology in 60 cases

Area of Science:

• Neuropathology
• Neurodegenerative Diseases
• Genetics

Background:

• Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of neurodegenerative disorders.
• Accurate neuropathological classification is crucial for understanding FTLD subtypes and their clinical manifestations.

Purpose of the Study:

• To neuropathologically classify a series of 60 FTLD cases.
• To correlate specific protein inclusions (TDP, FUS, TAU) with genetic mutations and clinical features, including motor neuron involvement.

Main Methods:

• Neuropathological examination of 60 FTLD cases collected over 22 years.
• Immunohistochemical labeling for TDP, FUS, and TAU proteins to identify inclusions.
• Genetic analysis for progranulin (GRN) mutations and screening for tau mutations (P301P, P301L, S305N).
• Classification of TDP-positive inclusions according to Sampathu types 1 and 2.

Main Results:

• Brain weight negatively correlated with disease duration.
• FTLD subtypes identified: 40 FTLD-TDP, 3 FTLD-FUS, 12 FTLD-TAU.
• FTLD-TDP cases included FTD-GRN (4 cases) with specific inclusions and neuronal loss, and FTD-ALS (27 cases) with familial cases showing longer survival.
• FTLD-FUS cases were associated with neuronal intermediate filament inclusion disease (NIFID), young age, and short survival.
• FTLD-TAU cases included Pick disease (5 cases) and identified tau mutations P301P, P301L, and S305N.
• The series was enriched in motor neuron disease, leading to a predominance of TDP type 2 inclusions.

Conclusions:

• The current neuropathological nomenclature effectively classifies nearly all FTLD cases.
• The prevalence of FTLD subtypes is influenced by patient recruitment, with this series showing a high rate of motor neuron disease.
• Specific genetic mutations and protein inclusions correlate with distinct FTLD subtypes and clinical outcomes.