Chapter 10
Corticobasal Degeneration

HistoryIn 1968, Rebeiz et al. reported corticobasal degeneration (CBD) as a clinicopathologically independent disease.
Pathologically, CBD manifests strong asymmetric cerebral cortical atrophy in the frontoparietal lobe, together withdegeneration in the basal ganglia and substantia nigra. Histologically, accumulation of abnormal phosphorylated tau isobserved in neurons and glial cells. CBD is characterized by astrocytic plaque, and is classified as 4-repeat tauopathy (4RT),
like progressive supranuclear palsy (PSP).
The typical clinical features of CBD are cerebral cortical signs including progressive and asymmetric apraxia, as well as
extrapyramidal signs including muscle stiffness. Currently, these signs are referred to as corticobasal syndrome (CBS).
Recently, CBD is used when the disease is pathologically diagnosed, and CBS is used when the disease is clinically diagnosed.

Diagnosis
In the diagnostic criteria of Armstrong et al. (2013), clinical symptoms of CBD were extracted from brain banks andpublished articles reporting at least 5 pathologically proven cases, and four clinical phenotypes associated with CBDpathology were proposed (CQ10-1). Furthermore, the four clinical phenotypes and other features were combined to create
clinical research criteria for “probable sporadic CBD” that corresponds to pure CBD, and clinical criteria for “possible CBD”
that includes tauopathy other than CBD (CQ10-1). However, subsequent validation study shows that the sensitivity of the
new classification is not different from the conventional diagnostic criteria. Furthermore, the specificity is not high. Therefore,
search for clinical diagnostic criteria with higher sensitivity and specificity or biomarkers will be a challenge for future
research. The definitive diagnosis of CBD is pathological diagnosis.

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CQ 10-1

What are the features of cognitive impairment in corticobasal degeneration(CBD), and what are the test methods?
AnswerIn CBD, cognitive impairment often appears, and impaired executive function, behavioral and personality changes
such as disinhibition, visuospatial disorder, and non-fluent aphasia are observed. A useful test for differentiating CBDfrom other diseases has not been established.DComments and evidence

1. Features of cognitive impairment in CBD
The clinical phenotypes of CBD proposed in the clinical diagnostic criteria of CBD by Armstrong et al. 1) in 2013 consistof the following: (1) corticobasal syndrome (CBS), (2) frontal behavioral-spatial syndrome (FBS), (3) non-fluent/agrammatic
variant of primary progressive aphasia (naPPA), and (4) progressive supranuclear palsy syndrome (PSPS). Apart from thesetypes, cases with a clinical picture resembling Alzheimer’s disease dementia have also been reported. Among the clinicalsymptoms of pathologically confirmed CBD cases, general cognitive impairment is the most frequently seen cerebral corticalsymptom, and is found in 52% of the patients at onset and in 70% during the course of disease 1). Among the four CBDphenotypes, FBS manifests impaired executive function, behavioral/personality changes such as disinhibition, andvisuospatial deficit. Moreover, naPPA manifests effortful, non-fluent speech, and apraxia of speech with distorted speech
production and agrammatism. These symptoms appear before onset of dementia 1).
Lee et al. 2) studied 18 patients with histopathologically confirmed CBD, and found 4 clinical syndromes: progressive nonfluent aphasia (5 patients), behavioral variant frontotemporal dementia (5 patients), executive-motor (7 patients), and posteriorcortical atrophy (1 patient). They reported that behavioral or cognitive problems were the initial symptoms in 15 of 18 patients.

2. Methods for assessing cognitive impairment in CBD
Scales used to assess cognitive impairment in CBD include Mini Mental State Examination (MMSE), Addenbrooke’s
Cognitive Examination (ACE) 3), Dementia Rating Scale (DRS), Frontal Assessment Battery (FAB) 4), and NeuropsychiatricInventory (NPI). A meta-analysis examined whether several higher brain function tests were useful in differentiating
parkinsonian disorders, but evaluation of these tests was difficult due to inadequate sample size 5).

▪ References
1) Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013; 80(5): 496-503.
2) Lee SE, Rabinovici GD, Mayo MC, Clinicopathological correlations in corticobasal degeneration. Ann Neurol. 2011; 70(2): 327-340.
3) Rittman T, Ghosh BC, McColgan P, et al. e Addenbrooke’s Cognitive Examination for the differential diagnosis and longitudinal assessment ofpatients with parkinsonian disorders. J Neurol Neurosurg Psychiatry. 2013; 84(5): 544-551.
4) Marconi R, Antonini A, Barone P, et al. Frontal assessment battery scores and non-motor symptoms in parkinsonian disorders. Neurol Sci. 2012;33(3): 585-593.
5) Lee W, Williams DR, Storey E. Cognitive testing in the diagnosis of parkinsonian disorders: a critical appraisal of the literature. Mov Disord. 2012;27(10): 1243-1254.

▪ Search formula

PubMed search: June 23, 2015 (Tuesday), July 7, 2015 (Tuesday), July 13, 2015 (Monday), August 12, 2015 (Monday)#1 ((“Dementia/diagnosis” [Mesh] OR (dementia [TI] AND (diagnosis [TI] OR diagnostic [TI])) OR “Cognition Disorders/diagnosis” [Mesh] OR(“cognition disorder*” [TI] AND (diagnosis [TI] OR diagnostic [TI]))) AND “corticobasal degeneration”) OR ((corticobasal [TI] OR (“Basal Ganglia/pathology” [Mesh] AND “Cerebral Cortex/ pathology” [Mesh] AND “Neurodegenerative Diseases/pathology” [Mesh]) OR “Primary Progressive
Nonfluent Aphasia” [Majr] OR “progressive nonfluent aphasia” [TI]) AND (“Cognition Disorders/etiology” [Majr] OR “Cognition” [Majr] ORcognition [TI] OR cognitive feature* OR behavioral feature* OR cognitive mechanism* OR “emotion processing” OR “Emotions” [Majr]))
Ichushi search: June 23, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI) AND(corticobasal degeneration/TH OR corticobasal degeneration/TI) AND ((SH = Diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis,
radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI)

Chapter 10191

CQ 10-2

Are there effective pharmacological and non-pharmacological therapies
for cognitive impairment in corticobasal degeneration (CBD)?
Recommendation

No pharmacological and no non-pharmacological therapies have been confirmed to be effective for treating cognitive
impairment in CBD. When Alzheimer’s disease is considered to be the underlying pathology for CBS, cholinesteraseinhibitor or N-methyl-D-aspartate (NMDA) receptor antagonist may be tried. Rehabilitation is recommended for
language disorders, behavioral disorders, and visuospatial deficits.
2D

Comments and evidence

1. Pharmacotherapy for cognitive impairment
Regarding pharmacotherapy for cognitive impairment in CBD, no effective drugs with an adequate level of evidence havebeen reported. For CBS, cholinesterase inhibitors have been tried based on the personal opinions of experts 1, 2). The effect ofNMDA receptor antagonist is unknown.

2. Pharmacotherapy for behavioral and psychological disorders
There is little evidence of pharmacotherapy for behavioral and psychological symptoms in CBD. Sertraline hydrochloride,
which is a selective serotonin reuptake inhibitor (SSRI) may be effective for depression 1). Cholinesterase inhibitors are used
for apathy and anxiety, but these symptoms are difficult to treat 1).

3. Non-pharmacological therapies
Although evidence of a certain level is lacking, physiotherapy, occupational therapy, and speech therapy may be effective
for cognitive impairment in CBD 1, 2). Cognitive behavioral therapy may be effective in some cases of depression in CBD,according to expert opinion 2).

▪ References
1) Armstrong MJ. Diagnosis and treatment of corticobasal degeneration. Curr Treat Options Neurol. 2014; 16(3): 282.
2) Boeve BF, Josephs KA, Drubach DA. Current and future management of the corticobasal syndrome and corticobasal degeneration. Handb Clin
Neurol 2008; 89: 533-548.

▪ Search formula

Pharmacotherapy
PubMed search: June 23, 2015 (Tuesday), August 12, 2015 (Monday)#1 (“Dementia/drug therapy” [Mesh] OR (dementia [TI] AND (“drug therapy” OR chemotherapy)) OR “Cognition Disorders/drug therapy”[Mesh] OR (“cognition disorder*” [TI] AND (“drug therapy” OR chemotherapy))) AND (“corticobasal degeneration” OR ((“Basal Ganglia”[Mesh] OR “Basal Ganglia Diseases” [Mesh]) AND “Neurodegenerative Diseases” [Mesh]))Ichushi search: June 23, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI) AND(corticobasal degeneration/TH OR corticobasal degeneration/TI) AND ((SH = Pharmacotherapy) OR Pharmacotherapy/TH OR Drug treatment/
TI OR Pharmacotherapy/TI OR Therapeutic drug/TI)
Non-pharmacological therapies
PubMed search: June 23, 2015 (Tuesday), August 12, 2015 (Monday)#1 (“Dementia/therapy” [Mesh] OR (dementia [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI])) OR “Cognition Disorders/therapy” [Mesh] OR (“cognition disorder*” [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI]))) AND (“corticobasal degeneration”
OR ((“Basal Ganglia” [Mesh] OR “Basal Ganglia Diseases” [Mesh]) AND “Neurodegenerative Diseases” [Mesh])) NOT (“Dementia/drug therapy”[Mesh] OR (dementia [TI] AND (“drug therapy” OR chemotherapy)) OR “Cognition Disorders/drug therapy” [Mesh] OR (“cognition disorder*”[TI] AND (“drug therapy” OR chemotherapy)))
Ichushi search: June 23, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI) AND(corticobasal degeneration/TH OR corticobasal degeneration/TI) AND (Treatment/TH OR Treatment/TI OR Therapy/TI OR (SH = Therapeuticuse, treatment, drug treatment, surgical treatment, transplantation, dietary treatment, psychiatric treatment, radiologic treatment)) NOT ((SH =Pharmacotherapy) OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/TI OR Therapeutic drug/TI)

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