This study is currently recruiting participants.
Number
001642-N
Sponsoring Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Recruitment Detail
Type: Participants currently recruited/enrolled Gender: Male & Female Min Age: 18 Years Max Age: 99 Years
Referral Letter Required
No
Population Exclusion(s)
Children;Fetuses;Neonates
Keywords
Corticobasal Degeneration; Amyotrophic Lateral Sclerosis; Progressive Supranuclear Palsy; Primary Progressive Aphasia; Neurodegenerative Disorders; Frontotemporal Dementia
Recruitment Keyword(s)
None
Condition(s)
Investigational Drug(s)
Investigational Device(s)
Intervention(s)
Supporting Site
National Institute of Neurological Disorders and Stroke
Frontotemporal lobar degeneration (FTLD) is a set of disorders that cause proteins to build up in the brain and spinal cord. FTLD can develop in adults as young as 30 years old; the disease affects thinking, memory, behavior, judgment, and motor skills. FTLD symptoms always worsen over time. There are no approved treatments.
Objective:
To understand how FTLD progresses over time.
Eligibility:
People aged 18 and older with FTLD. Healthy people with a family history of FTLD are also needed. Participants must have a study partner who can provide information about their thinking and behavior.
Design:
Participants will enroll in 1 of 2 arms of this study.
In the longitudinal arm, participants will have yearly visits. At each visit, they will have a physical exam and blood tests. They will have tests of their thinking and behavior. They may have a lumbar puncture: A needle will be inserted into their back to draw a sample of fluid from around the spinal cord. They may have an imaging scan of their brain.
Study partners in this arm will be asked to fill in questionnaires yearly for up to 5 years.
In the biofluid arm, participants will have one visit. They will have a physical exam and blood tests. They may have a lumbar puncture. They may complete surveys remotely for up to 5 years. Study partners in this arm will fill in questionnaires. They will answer questions about the participant s thinking and behavior and how the participant s disease affects them. They may complete short surveys remotely.
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INCLUSION CRITERIA: General Inclusion Criteria: 1. Referring diagnosis of an FTLD clinical syndrome (see below) or a member of a family with a strong medical history of an FTLD syndrome. 2. Age 18 years of age or greater (preferably at least 30 because symptoms rarely develop before then). 3. Have a reliable study partner who can provide general information about behavior and feelings/emotions, and an independent evaluation of functioning. 4. Must, in the opinion of the site investigator, be able to complete a majority of study procedures. Longitudinal Arm Inclusion Criteria: All longitudinal arm participants must speak English or Spanish (consents will be translated) as a primary language. Many of the clinical and neuropsychological scales required for ALLFTD are unvalidated in languages other than English or Spanish, rendering the data unusable for cross-sectional comparisons. Familial FTLD participants 1) members of families in whom at least one member has a known disease-associated mutation in one of the major genes that cause f-FTLD: MAPT, GRN, C9orf72 (or other rare genes) OR 2) an autosomal dominant family history of a FTLD syndrome (without a known gene) verified by medical record review or well-documented family history including family members with a medical history consistent with FTLD or a related disorder. Participants will be enrolled based on membership in these families and not individual genotype status, and knowledge of personal genotype status (in families with known mutations) is not required for participation. Each center will evaluate the eligibility of candidates prior to enrollment through a phone interviewing process, or via direct contact with the center or laboratory including establishing symptom severity (this may be conducted by phone interview for screening purposes). All familial enrollees will be made aware that they are being enrolled because of family history and/or because of a known mutation in the family; no participant has to be aware of their own genetic status to participate. Familial participants may be asymptomatic or symptomatic; all assessments are the same regardless of the presence or absence of symptoms. Because genetically-mediated FTLD syndromes may manifest in heterogeneous and diverse ways, participants do not have to meet research criteria for a known FTLD syndrome to be included. Sporadic FTLD participants Sporadic participants should be symptomatic with no known family history or genetic mutation to indicate f-FTLD. All sporadic participants must have an FTLD syndrome as a referring diagnosis; those determined by ALLFTD clinicians to have non-FTLD diagnoses will be excluded from longitudinal visits, but their baseline visit will be included in comparative datasets. For inclusion in the longitudinal followup, participants should meet research criteria for one of the following FTLD syndromes: -Progressive Supranuclear Palsy: Inclusion criteria for progressive supranuclear palsy are based upon the 2017 Movement Disorders Society Consensus Criteria (full criteria can be found in the Manual of Procedures). These criteria for probable or possible PSP of either typical (Richardson s) or variant syndromes are defined based on criteria plus 2 or 3 features below: Core Features: 1) History of postural instability 2) Ocular motor deficits (supranuclear gaze palsy) 3) Akinesia 4) Cognitive dysfunction and/or a speech/language disorder -Semantic variant Primary Progressive Aphasia (svPPA): The core features of svPPA include 1) a language disorder characterized by progressive, fluent, empty spontaneous speech, and semantic paraphasias; 2) selective impairment of semantic memory causing anomia, impaired spoken and written single word comprehension, and an impoverished fund of general information; 3) relative sparing of syntax and phonology; and 4) normal visuospatial abilities. -Corticobasal Syndrome (CBS). Inclusion criteria for CBS are based on the probable or possible CBD criteria by Armstrong et al. 1) for probable CBS: insidious onset after age 50, at least a 12 month history of symptoms: Asymmetric presentation of at least 2 of the following: limb rigidity or akinesia, limb dystonia, limb myoclonus, plus 2 of: orobuccal or limb apraxia, alien limb phenomenon, cortical sensory loss 2) insidious onset with no minimum age; at least one year history of at least one of: limb rigidity or akinesia, limb dystonia, limb myoclonus, plus 2 of: orobuccal or limb apraxia, alien limb phenomenon, cortical sensory loss. Symptoms may be symmetric. -Behavioral variant Frontotemporal dementia (bvFTD). Inclusion criteria for bvFTD are based on consensus criteria. The primary features are early decline in regulation of personal and social and interpersonal conduct, emotional blunting, and loss of insight. Specifically, early presentation (first six months) must be characterized by at least five of the following: loss of insight, disinhibition, restlessness, distractibility, emotional lability, reduced empathy or unconcern for others, lack of foresight and planning, impulsivity, social withdrawal, apathy or lack of spontaneity, poor self-care, reduced verbal output, verbal stereotypies or echolalia, perseveration, overeating or excessive fluid intake, and sexual hyperactivity. -Nonfluent variant Primary Progressive Aphasia (nfvPPA) subtype: The primary clinical features in nfvPPA are non-fluent spontaneous speech with agrammatism, phonemic paraphasias, and anomia. Other features include problems with speech initiation, and finding and sequencing of articulatory movements. Comprehension is relatively well preserved, although difficulty following syntactically complex commands may be present. -Frontotemporal Dementia with Amyotrophic Lateral Sclerosis (FTD/ALS): A diagnosis of FTD-ALS relies on meeting diagnostic criteria for possible bvFTD or PPA plus clear evidence of ALS on physical examination, such as weakness, muscle atrophy, fasciculations, and elevated reflexes as described in the El Escorial diagnostic criteria for ALS, but not necessarily meeting probable ALS criteria. EMG is not required for diagnosis. Biofluid-Focused Arm Inclusion Criteria: Participants enrolled in the biofluid arm may be either f-FTLD or s-FTLD. All general inclusion criteria apply. Participants should meet research criteria (as specified above) for any FTLD syndrome or meet familial FTLD inclusion criteria. Because the biofluid arm participants do not undergo the same detailed clinical and functional assessments required for the longitudinal arm, participants may be included regardless of primary language, as long as an appropriately translated consent is available. EXCLUSION CRITERIA: Exclusion criteria are evaluated at the site investigator s discretion; if the site investigator believes that the participant s symptoms are due to FTLD despite the presence of an exclusionary condition, the investigator may overrule the exclusion. 1. Known presence of a structural brain lesion (e.g. tumor, cortical infarct) that could reasonably explain symptoms in a symptomatic participant. 2. Known presence of an Alzheimer s disease causing mutation in PSEN1, PSEN2 or APP; or biomarker evidence for Alzheimer s disease as a cause of the clinical syndrome. 3. A previous history of Korsakoff encephalopathy, severe alcohol dependence (within 5 years of onset of dementia), frequent alcohol or other substance intoxication, or other neurological disorder. 4. Evidence through history or laboratory testing of uncorrected B12 deficiency (B12 < 95% of local laboratory s normal value), unregulated hypothyroidism (TSH >150% of normal), HIV positive, renal failure (creatinine > 2), liver failure (ALT or AST > two times normal), respiratory failure that requires supplemental oxygen, large confluent white matter lesions, significant systemic medical illnesses such as deteriorating cardiovascular disease. 5. Current medication likely to affect CNS functions in the opinion of the site PI. 6. In the site investigator s opinion, the participant cannot complete sufficient key study procedures. The participant may be enrolled into the biofluid-focused arm if they can tolerate a blood draw and short clinical exam, but must be able to complete at least 75% of study procedures for enrollment into the longitudinal arm.
General Inclusion Criteria:
1. Referring diagnosis of an FTLD clinical syndrome (see below) or a member of a family with a strong medical history of an FTLD syndrome.
2. Age 18 years of age or greater (preferably at least 30 because symptoms rarely develop before then).
3. Have a reliable study partner who can provide general information about behavior and feelings/emotions, and an independent evaluation of functioning.
4. Must, in the opinion of the site investigator, be able to complete a majority of study procedures.
Longitudinal Arm Inclusion Criteria:
All longitudinal arm participants must speak English or Spanish (consents will be translated) as a primary language. Many of the clinical and neuropsychological scales required for ALLFTD are unvalidated in languages other than English or Spanish, rendering the data unusable for cross-sectional comparisons.
Familial FTLD participants
1) members of families in whom at least one member has a known disease-associated mutation in one of the major genes that cause f-FTLD: MAPT, GRN, C9orf72 (or other rare genes)
OR
2) an autosomal dominant family history of a FTLD syndrome (without a known gene) verified by medical record review or well-documented family history including family members with a medical history consistent with FTLD or a related disorder.
Participants will be enrolled based on membership in these families and not individual genotype status, and knowledge of personal genotype status (in families with known mutations) is not required for participation.
Each center will evaluate the eligibility of candidates prior to enrollment through a phone interviewing process, or via direct contact with the center or laboratory including establishing symptom severity (this may be conducted by phone interview for screening purposes). All familial enrollees will be made aware that they are being enrolled because of family history and/or because of a known mutation in the family; no participant has to be aware of their own genetic status to participate.
Familial participants may be asymptomatic or symptomatic; all assessments are the same regardless of the presence or absence of symptoms. Because genetically-mediated FTLD syndromes may manifest in heterogeneous and diverse ways, participants do not have to meet research criteria for a known FTLD syndrome to be included.
Sporadic FTLD participants
Sporadic participants should be symptomatic with no known family history or genetic mutation to indicate f-FTLD. All sporadic participants must have an FTLD syndrome as a referring diagnosis; those determined by ALLFTD clinicians to have non-FTLD diagnoses will be excluded from longitudinal visits, but their baseline visit will be included in comparative datasets. For inclusion in the longitudinal followup, participants should meet research criteria for one of the following FTLD syndromes:
-Progressive Supranuclear Palsy: Inclusion criteria for progressive supranuclear palsy are based upon the 2017 Movement Disorders Society Consensus Criteria (full criteria can be found in the Manual of Procedures). These criteria for probable or possible PSP of either typical (Richardson s) or variant syndromes are defined based on criteria plus 2 or 3 features below:
Core Features:
1) History of postural instability
2) Ocular motor deficits (supranuclear gaze palsy)
3) Akinesia
4) Cognitive dysfunction and/or a speech/language disorder
-Semantic variant Primary Progressive Aphasia (svPPA): The core features of svPPA include
1) a language disorder characterized by progressive, fluent, empty spontaneous speech, and semantic paraphasias;
2) selective impairment of semantic memory causing anomia, impaired spoken and written single word comprehension, and an impoverished fund of general information;
3) relative sparing of syntax and phonology; and
4) normal visuospatial abilities.
-Corticobasal Syndrome (CBS). Inclusion criteria for CBS are based on the probable or possible CBD criteria by Armstrong et al.
1) for probable CBS: insidious onset after age 50, at least a 12 month history of symptoms: Asymmetric presentation of at least 2 of the following: limb rigidity or akinesia, limb dystonia, limb myoclonus, plus 2 of: orobuccal or limb apraxia, alien limb phenomenon, cortical sensory loss
2) insidious onset with no minimum age; at least one year history of at least one of: limb rigidity or akinesia, limb dystonia, limb myoclonus, plus 2 of: orobuccal or limb apraxia, alien limb phenomenon, cortical sensory loss. Symptoms may be symmetric.
-Behavioral variant Frontotemporal dementia (bvFTD). Inclusion criteria for bvFTD are based on consensus criteria. The primary features are early decline in regulation of personal and social and interpersonal conduct, emotional blunting, and loss of insight. Specifically, early presentation (first six months) must be characterized by at least five of the following: loss of insight, disinhibition, restlessness, distractibility, emotional lability, reduced empathy or unconcern for others, lack of foresight and planning, impulsivity, social withdrawal, apathy or lack of spontaneity, poor self-care, reduced verbal output, verbal stereotypies or echolalia, perseveration, overeating or excessive fluid intake, and sexual hyperactivity.
-Nonfluent variant Primary Progressive Aphasia (nfvPPA) subtype: The primary clinical features in nfvPPA are non-fluent spontaneous speech with agrammatism, phonemic paraphasias, and anomia. Other features include problems with speech initiation, and finding and sequencing of articulatory movements. Comprehension is relatively well preserved, although difficulty following syntactically complex commands may be present.
-Frontotemporal Dementia with Amyotrophic Lateral Sclerosis (FTD/ALS): A diagnosis of FTD-ALS relies on meeting diagnostic criteria for possible bvFTD or PPA plus clear evidence of ALS on physical examination, such as weakness, muscle atrophy, fasciculations, and elevated reflexes as described in the El Escorial diagnostic criteria for ALS, but not necessarily meeting probable ALS criteria. EMG is not required for diagnosis.
Biofluid-Focused Arm Inclusion Criteria:
Participants enrolled in the biofluid arm may be either f-FTLD or s-FTLD. All general inclusion criteria apply. Participants should meet research criteria (as specified above) for any FTLD syndrome or meet familial FTLD inclusion criteria. Because the biofluid arm participants do not undergo the same detailed clinical and functional assessments required for the longitudinal arm, participants may be included regardless of primary language, as long as an appropriately translated consent is available.
EXCLUSION CRITERIA:
Exclusion criteria are evaluated at the site investigator s discretion; if the site investigator believes that the participant s symptoms are due to FTLD despite the presence of an exclusionary condition, the investigator may overrule the exclusion.
1. Known presence of a structural brain lesion (e.g. tumor, cortical infarct) that could reasonably explain symptoms in a symptomatic participant.
2. Known presence of an Alzheimer s disease causing mutation in PSEN1, PSEN2 or APP; or biomarker evidence for Alzheimer s disease as a cause of the clinical syndrome.
3. A previous history of Korsakoff encephalopathy, severe alcohol dependence (within 5 years of onset of dementia), frequent alcohol or other substance intoxication, or other neurological disorder.
4. Evidence through history or laboratory testing of uncorrected B12 deficiency (B12 < 95% of local laboratory s normal value), unregulated hypothyroidism (TSH >150% of normal), HIV positive, renal failure (creatinine > 2), liver failure (ALT or AST > two times normal), respiratory failure that requires supplemental oxygen, large confluent white matter lesions, significant systemic medical illnesses such as deteriorating cardiovascular disease.
5. Current medication likely to affect CNS functions in the opinion of the site PI.
6. In the site investigator s opinion, the participant cannot complete sufficient key study procedures. The participant may be enrolled into the biofluid-focused arm if they can tolerate a blood draw and short clinical exam, but must be able to complete at least 75% of study procedures for enrollment into the longitudinal arm.
Principal Investigator
Referral Contact
For more information: