Method: Collection of all the pre-clinical and clinical findings carried out investigating the effects of CBD alone, not in combination with other substances, in the neurological arena with the exclusion of studies on neuropsychiatric disorders.
Conclusion: Pre-clinical evidence largely shows that CBD can produce beneficial effects in AD, PD and MS patients, but its employment for these disorders needs further confirmation from well designed clinical studies. CBD pre-clinical demonstration of antiepileptic activity is supported by recent clinical studies in human epileptic subjects resistant to standard antiepileptic drugs showing its potential use in children and young adults affected by refractory epilepsy. Evidence for use of CBD in PD is still not supported by sufficient data whereas only a few studies including a small number of patients are available.
Objective: The aim of the present review was to describe the state of art about the pre-clinical research, the potential use and, when existing, the clinical evidence related to CBD in the neurological field.
Background: Cannabidiol (CBD) is among the major secondary metabolites of Cannabis devoid of the delta-9-tetra-hydrocannabinol psychoactive effects. It is a resorcinol-based compound with a broad spectrum of potential therapeutic properties, including neuroprotective effects in numerous pathological conditions. CBD neuroprotection is due to its antioxidant and antiinflammatory activities and the modulation of a large number of brain biological targets (receptors, channels) involved in the development and maintenance of neurodegenerative diseases.
Results: Laboratory and clinical studies on the potential role of CBD in Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), Huntington’s disease (HD), amyotrophic lateral sclerosis ALS), cerebral ischemia, were examined.
Keywords: Cannabidiol; neurodegenerative diseases; neurological; neurology; neuroprotection.
Studies comparing the different CBD phenotypes are described in the supplemental text. No study conclusively identified clinical features or imaging characteristics distinguishing CBD from other pathologies. Potential differentiating features are described in the supplemental text but require validation with larger sample sizes.
While tau mutations are allowed for p-CBD, GRN, TDP-43, or FUS mutations are exclusions for both sets of criteria. Because emerging research suggests that amyloid imaging and CSF Aβ42/tau ratio may be useful in diagnosing AD and these biomarkers have been incorporated into the 2011 AD diagnostic criteria, 59 results suggestive of AD on these studies are exclusion criteria for CBD, acknowledging that we lack confirmation of the ability of these tests to distinguish AD from CBD. Mutations known to be associated with AD are also exclusion criteria. Similarly, imaging studies suggestive of other pathologies (e.g., CJD) are exclusions for CBD diagnoses, but CBD-supportive imaging is not included as a criterion given the need for further validation.
Previous CBD clinical diagnostic criteria were reviewed. Invited international specialists in behavioral neurology, neuropsychology, and movement disorders met on October 14–15, 2009, and based on participants’ experience and literature reviews, clinical phenotypes were identified and CBD criteria were drafted.
Neuroimaging and laboratory markers
Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.
When first described, “corticodentatonigral degeneration with neuronal achromasia” was considered a distinct clinicopathologic entity, 1 eventually termed corticobasal degeneration (CBD). 2 Clinicopathologic studies have since revealed that the originally described clinical features of CBD, now called corticobasal syndrome (CBS), are often due to other pathologies. As a pathologic diagnosis, CBD is characterized by widespread deposition of hyperphosphorylated 4-repeat tau in neurons and glia, the latter as astrocytic plaques, in specific topographic areas. 3 Despite various clinical diagnostic criteria (table e-1 on the Neurology® Web site at www.neurology.org), 4 – 10 the pathology of CBD is predicted antemortem in only 25% to 56% of cases. 11 – 17 Additionally, while these clinical criteria continue to be widely applied and cited, they reflect CBS alone and not the more recently recognized behavioral presentations of CBD.
Frequency of motor features in available brain banks and studies with ≥5 pathologically confirmed corticobasal degeneration cases a
In the 129 patients in the brain banks and literature 12 , 16 , 21 , 49 , 50 with initial clinical diagnoses described, CBS was the most common presenting diagnosis (27.1%, 35/129), followed by FTD and PD or atypical PD (each 15.5%, 20/129), aphasia (14.7%, 19/129), AD/dementia (9.3%, 12/129), and PSPS (6.2%, 8/129). The finding of PD as an early clinical diagnosis and the difference in frequency between early and late clinical diagnoses underscores the challenge in making an accurate early diagnosis and the changing phenomenology over time.
Both sets of criteria require insidious onset and gradual progression with symptom duration of at least 1 year to exclude rapidly progressive conditions more likely to represent other pathologies (e.g., CJD). Age at onset ≥50 years is required for cr-CBD given that this will identify 98% of patients with CBD and exclude pathologies with younger age at onset (e.g., FTLD). No age minimum is set for p-CBD, allowing for young-onset familial cases of CBD related to tau mutations. In addition, a family history (>1 relative) of a similar neurodegenerative disease is an exclusion criterion for cr-CBD but not p-CBD.