Frontotemporal Lobar Degeneration: Clinical Features, Subtypes and Pathology Brad Boeve MD Department of Neurology Mayo Clinic Rochester, Minnesota USA

FTLD: Clinical Features, Subtypes and Pathology Objectives Review the key aspects of FTLD: Clinical features Subtypes Pathology

FTLD: Clinical Features, Subtypes and Pathology Clinical Features of Each Syndrome naPPA Nonfluent/ agrammatic variant svPPA semantic variant Behavioral Variant FTD lvPPA logopenic variant Fluent speech Decreased word comprehension and recognition of objects,people Halting speech Short phrases Grammar errors Cognitive loss Disinhibition Inflexibility Decreased insight Spontaneous but slow speech output Word retrieval problems Corticobasal Syndrome FTD -Motor Neuron Disease/ALS Cognitive loss Behavior impairment Motor symptoms Cognitive & memory loss Asymmetric rigidity Apraxia Progressive Supranuclear Palsy Motor symptoms Upper and/or lower motorneuron pathways Behavioral & cognitive loss Parkinsonism Eye movement disturbances ALS

FTLD: Clinical Features, Subtypes and Pathology Syndrome – Pathology Associations naPPA Nonfluent/ agrammatic variant svPPA semantic variant Behavioral Variant FTD lvPPA logopenic variant FTLD-Tau more than FTLD-TDP43 or AD pathology Left posterior frontal Lobe, insula FTLD-TDP43 Frontal/ventral Temporal lobe FTLD-Tau (3R) FTLD-TDP43 Prefrontal lobe Temporal lobe AD pathology more than FTLD-Tau or TDP43 Left post/supr temporal lobe & Medial parietal Corticobasal Syndrome FTD -Motor Neuron Disease/ALS FTLD-TDP43 FTLD-FUS Cortex, Motor neurons FTLD-Tau (4R) more than AD pathology Frontal, temporal lobe, Basal ganglia Progressive Supranuclear Palsy TDP43, SOD1,FUS Upper, lower MNs FTLD-Tau (4R) Basal ganglia Brainstem ALS

FTLD: Clinical Features, Subtypes and Pathology Syndrome – Pathology Associations TAU TDP FUS AD tau protein TAR DNA binding protein Fused in sarcoma protein Alzheimer’s Disease pathology

FTLD: Clinical Features, Subtypes and Pathology Behavioral Variant Frontotemporal Dementia (bvFTD) Clinical Features Apathy Loss of empathy Disinhibited behavior Mental rigidity Diminished insight Executive dysfunction

FTLD: Clinical Features, Subtypes and Pathology Behavioral Variant Frontotemporal Dementia (bvFTD) Brain-Behavioral Relationships L R L

FTLD: Clinical Features, Subtypes and Pathology Primary Progressive Aphasia – Semantic Variant Clinical Features Prominent naming difficulties Loss of word meaning

FTLD: Clinical Features, Subtypes and Pathology Primary Progressive Aphasia – Agnosia Variant Clinical Features Prominent visual agnosia (loss of visual meaning of faces or objects) Later develop naming difficulties

FTLD: Clinical Features, Subtypes and Pathology Primary Progressive Aphasia – Variant Comparison prosopagnosia/associative agnosia semantic variant PPA

FTLD: Clinical Features, Subtypes and Pathology Primary Progressive Aphasia – Nonfluent Variant Clinical Features Slow, halting speech Grammatical and articulatory errors Short phrases

FTLD: Clinical Features, Subtypes and Pathology Primary Progressive Aphasia – Logopenic Variant Clinical Features Slower speech Word retrieval problems Difficulties with repeating statements/questions

FTLD: Clinical Features, Subtypes and Pathology Primary Progressive Aphasia – Summary L naPPA TAU TDP AD lvPPA AD Tau TDP svPPA TDP Tau AD

FTLD: Clinical Features, Subtypes and Pathology ALS - Terminology Terms all mean same disorder: Amyotrophic lateral sclerosis (ALS) Motor neuron disease (MND) Lou Gehrig’s disease

FTLD: Clinical Features, Subtypes and Pathology ALS Clinical Features Altered speech Muscle weakness and atrophy Arm and/or gait difficulties Pseudobulbar affect

FTLD: Clinical Features, Subtypes and Pathology ALS Brain-Behavioral Relationships L L L

FTLD: Clinical Features, Subtypes and Pathology FTD-ALS Clinical Features FTD Apathy Loss of empathy Disinhibited behavior Mental rigidity Diminished insight Executive dysfunction ALS Altered speech Muscle weakness and atrophy Arm and/or gait difficulties Pseudobulbar affect

FTLD: Clinical Features, Subtypes and Pathology FTD-ALS Brain-Behavioral Relationships L R L

FTLD: Clinical Features, Subtypes and Pathology Corticobasal Syndrome (CBS) Distinctive Clinical Features Progressive Asymmetric Rigidity Apraxia “Cortical” Apraxia Myoclonus Cortical sensory loss Alien limb phenomenon AOS/aphasia Visuospatial deficits “Basal” Rigidity Dystonia Fisted hand

FTLD: Clinical Features, Subtypes and Pathology Corticobasal Syndrome (CBS) Topography of Degeneration L L L L R L

FTLD: Clinical Features, Subtypes and Pathology Progressive Supranuclear Palsy Syndrome/Richardson’s Syndrome Distinctive Clinical Features Parkinsonism Vision problems Gait impairment and falls Other Features Speech changes Swallowing changes Pseudobulbar palsy Executive dysfunction

FTLD: Clinical Features, Subtypes and Pathology Progressive Supranuclear Palsy Syndrome/Richardson’s Syndrome Topography of Degeneration L L L

FTLD: Clinical Features, Subtypes and Pathology Conclusions The symptoms and behaviors reflect the disease and DO NOT define the person The symptoms match the location of degeneration in the brain far better than the underlying dysfunctional protein or genetic associations This variability of symptoms and dysfunctional protein will make future treatment decisions challenging

FTLD: Clinical Features, Subtypes and Pathology Future Directions Improve ability to accurately establish a diagnosis as early as possible Improve management and quality of life for patients and families Develop better biomarkers for tau vs TDP-43 vs Alzheimer’s disease Plan for disease-modifying therapies