Jaime Toro, MD, Saúl Reyes, MD, Lisseth Burbano, MD, William T. Hu, MD, PhD, Kelly D. Watts, MS, Se Min Heo, BSc, Thomas S. Wingo, MD, Gonazalo Ucrós, MD and Manuel Yepes, MD
Jaime Toro, MD, Saúl Reyes, MD, Lisseth Burbano, MD, William T. Hu, MD, PhD, Kelly D. Watts, MS, Se Min Heo, BSc, Thomas S. Wingo, MD, Gonazalo Ucrós, MD and Manuel Yepes, MD
Jaime Toro, MD, Saúl Reyes, MD, Lisseth Burbano, MD, William T. Hu, MD, PhD, Kelly D. Watts, MS, Se Min Heo, BSc, Thomas S. Wingo, MD, Gonazalo Ucrós, MD and Manuel Yepes, MD
December 2, 2014
Topics
The final diagnosis and a discussion
The 53-year-old woman presenting with cognitive decline and apraxia (see NEJM JW Neurol Nov 7 2014 and NEJM JW Neurol Nov 18 2014) underwent positron emission tomography (PET) scan using 18F-fluorodeoxyglucose (FDG). The scans showed bilateral frontal and parietal hypometabolism, most prominent on the right side, with normal glucose metabolism in the basal ganglia (see ). (PET amyloid imaging was unavailable.)
Cerebrospinal fluid (CSF) analysis for 14-3-3 protein was negative. Total tau (t-tau) protein was 92.38 ng/mL and phosphorylated tau181 (p-tau) was 66.82 ng/mL. The CSF level of the 42–amino acid form of amyloid-β (αβ42) was 55.33 ng/mL, and the t-tau/αβ42 ratio was 1.67. Thus, with a low CSF αβ42 and elevated t-tau and p-tau (NEJM JW Neurol Feb 14 2012), the patient was ultimately diagnosed as having a corticobasal syndrome (CBS) with underlying Alzheimer disease (AD) pathology.
Blood samples for sequencing were obtained from the proband and five first-degree relatives. Sanger sequencing — performed for the last three coding exons of amyloid precursor protein (APP) and all coding exons of presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes (primer sequences available upon request) — identified no pathogenic mutations.
Physical, occupational, and speech therapy were initiated. The patient did not continue on cholinesterase inhibitors due to a lack of clinical response. At follow-up 6 months later, she continued to have progressive neurological deterioration, with severe dependence in basic activities of daily living.
Comment
In this patient, cognitive impairment with marked executive, language, and behavior disturbances accompanied by parkinsonian signs and myoclonus were suggestive of a neurodegenerative condition.
CBS characteristically presents with dementia, asymmetric parkinsonism, dystonia, and apraxia. It was initially proposed to characterize the pathognomonic features of corticobasal degeneration (CBD). However, it has been reported with different underlying pathologies, including AD, progressive supranuclear palsy, frontotemporal dementia, dementia with Lewy bodies, and Creutzfeldt-Jakob disease.
Predicting AD pathology in CBS is challenging, particularly because histopathology is the gold standard in confirming the diagnosis of CBD, and differentiating AD from CBD based solely on clinical features is not possible. However, some clinical characteristics in association with biomarkers can be useful to predict the underlying pathology. A younger age at onset, the presence of memory impairment, dressing apraxia, and myoclonus are associated with AD pathology (Expert Rev Neurother 2011; 11:1569). Also, a characteristic AD CSF profile, as seen in our patient, makes a diagnosis of a CBS with AD pathology more likely.
When evaluating a patient with early-onset dementia, treatable conditions such as inflammatory disorders, infectious diseases, metabolic abnormalities (e.g., vitamin B12 deficiency), and normal-pressure hydrocephalus should also be considered.
Patients with early-onset dementia present with an atypical clinical course consisting of rapid progression and early myoclonus, accompanied by compromise of multiple cognitive domains such as language, visuospatial, and executive function. The diagnosis can be challenging. Although AD is still the most common neurodegenerative etiology of dementia in this group of patients, it represents only one third of cases with early-onset cognitive decline, so other conditions should be ruled out (Semin Neurol 2013; 33:365).
Autosomal-dominant inheritance of AD is rare, with about 10% of families showing autosomal-dominant transmission (Am J Hum Genet 1999; 65:664). In most cases (about 90%), young-onset AD does not have an apparent autosomal-dominant transmission, and recessive causes have been hypothesized (Arch Neurol 2012; 69:59). For dominantly transmitted AD, most disease-causing mutations are found in PSEN1, followed by APP and PSEN2. For patients with dominant mutations, myoclonus and seizures are more common than in patients without disease-causing mutations. Certain mutations are also associated with spastic paraparesis, extrapyramidal signs, or cerebellar ataxia (Pract Neurol 2012; 12:358). Whether the patient in this case had a classic pattern of dominant inheritance is unclear, given a paucity of information on her father. Like most individuals with young-onset AD, she harbored no known AD-causing mutation in PSEN1, PSEN2, or APP. Even in families with apparent autosomal-dominant transmission, a known disease-causing mutation is identified only 70% of the time.
AD dementia criteria were revised a few years ago (NEJM JW Neurol May 17 2011). Although AD is fundamentally a clinical diagnosis, biomarkers are now included in the criteria to improve the detection of early AD and aid in the differential diagnosis of dementia in research settings. Biomarkers in AD can be classified into two categories: markers of brain αβ protein accumulation and markers of downstream neuronal degeneration or injury.
The CSF biomarker signature of AD is decreased αβ42, increased t-tau, and increased p-tau. The ratio of αβ42 to t-tau or p-tau is the best measurement to support the diagnosis of AD; sensitivity and specificity are each about 85% to 90% (Neurobiol Aging 2011; 32:S4). The use of biomarkers can aid in the differential diagnosis of dementia; however, these still require further validation and standardization to become widely used in clinical practice.
We must acknowledge our readers for following this case so closely. Many readers submitted a diagnosis of corticobasal degeneration, which is very close to the final diagnosis. Corticobasal syndrome has been reported with different underlying pathologies, including Alzheimer disease, which makes this the most likely diagnosis after testing CSF biomarkers. Many other readers made a diagnosis of Creutzfeldt-Jakob disease or frontotemporal dementia, which may also be underlying pathologies of CBS. Many thanks to all for their very active participation.
Comment
In this patient, cognitive impairment with marked executive, language, and behavior disturbances accompanied by parkinsonian signs and myoclonus were suggestive of a neurodegenerative condition.
CBS characteristically presents with dementia, asymmetric parkinsonism, dystonia, and apraxia. It was initially proposed to characterize the pathognomonic features of corticobasal degeneration (CBD). However, it has been reported with different underlying pathologies, including AD, progressive supranuclear palsy, frontotemporal dementia, dementia with Lewy bodies, and Creutzfeldt-Jakob disease.
Predicting AD pathology in CBS is challenging, particularly because histopathology is the gold standard in confirming the diagnosis of CBD, and differentiating AD from CBD based solely on clinical features is not possible. However, some clinical characteristics in association with biomarkers can be useful to predict the underlying pathology. A younger age at onset, the presence of memory impairment, dressing apraxia, and myoclonus are associated with AD pathology (Expert Rev Neurother 2011; 11:1569). Also, a characteristic AD CSF profile, as seen in our patient, makes a diagnosis of a CBS with AD pathology more likely.
When evaluating a patient with early-onset dementia, treatable conditions such as inflammatory disorders, infectious diseases, metabolic abnormalities (e.g., vitamin B12 deficiency), and normal-pressure hydrocephalus should also be considered.
Patients with early-onset dementia present with an atypical clinical course consisting of rapid progression and early myoclonus, accompanied by compromise of multiple cognitive domains such as language, visuospatial, and executive function. The diagnosis can be challenging. Although AD is still the most common neurodegenerative etiology of dementia in this group of patients, it represents only one third of cases with early-onset cognitive decline, so other conditions should be ruled out (Semin Neurol 2013; 33:365).
Autosomal-dominant inheritance of AD is rare, with about 10% of families showing autosomal-dominant transmission (Am J Hum Genet 1999; 65:664). In most cases (about 90%), young-onset AD does not have an apparent autosomal-dominant transmission, and recessive causes have been hypothesized (Arch Neurol 2012; 69:59). For dominantly transmitted AD, most disease-causing mutations are found in PSEN1, followed by APP and PSEN2. For patients with dominant mutations, myoclonus and seizures are more common than in patients without disease-causing mutations. Certain mutations are also associated with spastic paraparesis, extrapyramidal signs, or cerebellar ataxia (Pract Neurol 2012; 12:358). Whether the patient in this case had a classic pattern of dominant inheritance is unclear, given a paucity of information on her father. Like most individuals with young-onset AD, she harbored no known AD-causing mutation in PSEN1, PSEN2, or APP. Even in families with apparent autosomal-dominant transmission, a known disease-causing mutation is identified only 70% of the time.
AD dementia criteria were revised a few years ago (NEJM JW Neurol May 17 2011). Although AD is fundamentally a clinical diagnosis, biomarkers are now included in the criteria to improve the detection of early AD and aid in the differential diagnosis of dementia in research settings. Biomarkers in AD can be classified into two categories: markers of brain αβ protein accumulation and markers of downstream neuronal degeneration or injury.
The CSF biomarker signature of AD is decreased αβ42, increased t-tau, and increased p-tau. The ratio of αβ42 to t-tau or p-tau is the best measurement to support the diagnosis of AD; sensitivity and specificity are each about 85% to 90% (Neurobiol Aging 2011; 32:S4). The use of biomarkers can aid in the differential diagnosis of dementia; however, these still require further validation and standardization to become widely used in clinical practice.
We must acknowledge our readers for following this case so closely. Many readers submitted a diagnosis of corticobasal degeneration, which is very close to the final diagnosis. Corticobasal syndrome has been reported with different underlying pathologies, including Alzheimer disease, which makes this the most likely diagnosis after testing CSF biomarkers. Many other readers made a diagnosis of Creutzfeldt-Jakob disease or frontotemporal dementia, which may also be underlying pathologies of CBS. Many thanks to all for their very active participation.