Kate Dawson

The prevalence of frontotemporal dementia

Objective To estimate the prevalence of frontotemporal dementia (FTD) and other degenerative early-onset dementias in a geographically defined population. Background Early-onset dementia (at age <65 years) results in high psychiatric morbidity and caregiver burden. Prevalence figures are available for early-onset AD but not for FTD, a dementia that is almost invariably of early onset. Methods Case ascertainment was by review of case records of three specialist clinic databases and inpatient admissions at a university hospital in Cambridge, United Kingdom, for patients with dementia who were <65 years of age, living in Cambridge City or East or South Cambridgeshire (population 326,019) on May 30, 2000. All the relevant health services in the area were also contacted for potential cases. Diagnosis of various dementias was based on published criteria. All patients with potential FTD were examined by the study investigators and underwent structural neuroimaging. The 1998 population estimates for the area were used to calculate age and sex prevalence with confidence intervals for AD, FTD, and other causes of dementia. Results A total of 108 patients (66 men and 42 women) with dementia with onset before they were 65 years of age were identified, of whom 60 were <65 years on the census date, giving an overall prevalence of 81 (95% CI, 62.8 to 104.5) per 100,000 in the 45- to 64-year age group. The prevalences of early-onset FTD and AD were the same: 15 per 100,000 (8.4 to 27.0) in the 45- to 64-year-old population. The mean age at onset of FTD was 52.8 years and there was a striking male preponderance (14:3). It is possible case ascertainment methods resulted in a relative underrepresentation of some forms of dementia. Conclusions Frontotemporal dementia is a more common cause of early-onset dementia than previously recognized and appears to be more common in men.

Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway

Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of experimental autoimmune encephalomyelitis, preventive or therapeutic application of dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of dimethylfumarate led to stabilization of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of NADP(H) quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of dimethylfumarate, monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2, Kelch-like ECH-associated protein 1, at cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced protein nitrosylation were detected in the central nervous sytem of dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with multiple sclerosis. In dimethylfumarate-treated mice suffering from experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the dimethylfumarate mediated beneficial effects on clinical course, axon preservation and astrocyte activation were almost completely abolished thus proving the functional relevance of this transcription factor for the neuroprotective mechanism of action. We conclude that the ability of dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural antioxidant responses in multiple sclerosis tissue and is not yet targeted by other multiple sclerosis therapies.

Semantic dementia: demography, familial factors and survival in a consecutive series of 100 cases

A great deal has been written about cognitive aspects of semantic dementia but little is known about the demography or prognosis. We describe these features in a consecutive series of 100 patients seen over a 17-year period; all cases were assessed and followed up in a specialist clinic. The mean age at diagnosis was 64.2 (+/-7.1) range 40-79 years, but 46 presented after age 65 and 7 after 75; a higher proportion than the existing literature might predict. Fifteen had a first-degree relative with dementia, but in seven this was almost certainly unrelated. Only two had relatives with young-onset dementia. There were no families with more than two affected members. The familial rate was estimated at between 2% and 7% (95% confidence interval 0-12%). Kaplan-Meier analyses indicated a 50% survival of 12.8 years (95% confidence interval 11.9-13.7); a more benign course than suggested by neuropathologically based studies. We were unable to identify any factors influencing survival. Of the 100, 34 have died, with pathological confirmation in 24; 18 had frontotemporal lobar degeneration with ubiquitin-positive inclusions (13 of 13 confirmed TAR DNA binding protein-43 positive), and 3 had classic tau-positive Pick bodies and 3 had Alzheimers pathology. The age at diagnosis or death across the pathological subgroups was equivalent. Although semantic dementia has a strong statistical association with ubiquitin-positive pathology, it does not have the signature of familial frontotemporal lobar degeneration with ubiquitin-positive inclusions, notably the presence of intranuclear lentiform TAR DNA binding protein-43 inclusions. The age of onset is older than predicted and the course more slowly progressive than suggested by earlier studies of small groups of subjects.

Naming and Knowing in Dementia of Alzheimer's Type

We studied the relationship between naming and the integrity of physical and associative knowledge in a group of patients with dementia of the Alzheimer type (DAT) and matched normal controls. All subjects named 48 line drawings and later generated verbal definitions in response to the names of a subset of the 48 items, which included a minimum of six definitions for correctly named objects and six definitions for items that the subject failed to name. A comprehensive scoring system was designed for the definitions, including physical and associative features of a general and a specific type, a superordinate label, the core concept, and various categories of errors. The definitions generated by the DAT patients, even those in the minimal group, contained significantly less correct information than those of normal subjects, and definitions corresponding to unnamed items were more impoverished than those for named items. Particularly striking was the loss of core concept for unnamed items. There was also a disproportionate reduction in physical information on unnamed compared to named items. We conclude that quantitative assessment of verbal definitions is a sensitive index of semantic memory breakdown. Our findings offer some support for the hypothesis that successful naming depends upon integrity of the subset of semantic knowledge comprising physical features.

Activities of daily living in frontotemporal dementia and Alzheimer disease.

Objective: To evaluate activities of daily living (ADLs) in three clinical variants of frontotemporal dementia and the relationship to cognitive dysfunction. Methods: Fifty-nine patients and caregivers participated in this cross-sectional study: behavioral variant frontotemporal dementia (bv-FTD, n = 15), progressive nonfluent aphasia (PNFA, n = 10), semantic dementia (n = 15), and Alzheimer disease (AD, n = 19). Caregivers were interviewed with the Disability Assessment for Dementia (DAD) to provide two outcome measures about ADLs: basic and instrumental ADLs (BADLs, IADL). In addition, patients were rated on the Clinical Dementia Rating Scale (CDR), and performance on cognitive measures (Addenbrookes Cognitive Examination Revised [ACE-R]) was assessed. Results: On the DAD, the bv-FTD group was most affected (56% of normal), whereas PNFA and semantic dementia patients were least impaired (83% and 85%); AD was intermediate (76%). The opposite pattern was seen on the ACE-R, where PNFA and semantic dementia groups were most affected, and bv-FTD showed least impairment; AD was again intermediate. Scores on the DAD did not correlate with cognitive measures, CDR, or disease duration. We further analyzed which aspect of ADLs was most affected, and a unique pattern of deficits emerged for the bv-FTD group (initiation affected > planning > execution for BADLs). Conclusion: Frontotemporal dementia has a devastating effect on activities of daily living, which is of considerable importance to caregivers and not captured by bedside cognitive tests.

Self administered cognitive screening test (TYM) for detection of Alzheimer’s disease: cross sectional study

Objective To evaluate a cognitive test, the TYM (“test your memory”), in the detection of Alzheimer’s disease. Design Cross sectional study. Setting Outpatient departments in three hospitals, including a memory clinic. Participants 540 control participants aged 18-95 and 139 patients attending a memory clinic with dementia/amnestic mild cognitive impairment. Intervention Cognitive test designed to use minimal operator time and to be suitable for non-specialist use. Main outcome measures Performance of normal controls on the TYM. Performance of patients with Alzheimer’s disease on the TYM compared with age matched controls. Validation of the TYM with two standard tests (the mini-mental state examination (MMSE) and the Addenbrooke’s cognitive examination-revised (ACE-R)). Sensitivity and specificity of the TYM in the detection of Alzheimer’s disease. Results Control participants completed the TYM with an average score of 47/50. Patients with Alzheimer’s disease scored an average of 33/50. The TYM score shows excellent correlation with the two standard tests. A score of ≤42/50 had a sensitivity of 93% and specificity of 86% in the diagnosis of Alzheimer’s disease. The TYM was more sensitive in detection of Alzheimer’s disease than the mini-mental examination, detecting 93% of patients compared with 52% for the mini-mental state exxamination. The negative and positive predictive values of the TYM with the cut off of ≤42 were 99% and 42% with a prevalence of Alzheimer’s disease of 10%. Thirty one patients with non-Alzheimer dementias scored an average of 39/50. Conclusions The TYM can be completed quickly and accurately by normal controls. It is a powerful and valid screening test for the detection of Alzheimer’s disease.

A study of stereotypic behaviours in Alzheimer’s disease and frontal and temporal variant frontotemporal dementia

Objective: To document the prevalence and pattern of stereotypic behaviour in patients with Alzheimer’s dementia and frontal and temporal variants of frontotemporal dementia. Secondly, to examine the relationship between stereotypic and other neuropsychiatric behaviours. Methods: Patients with the following were studied; Alzheimer’s disease (n=28), frontal variant frontotemporal dementia (fvFTD, n=18), and semantic dementia—the temporal lobe variant of FTD (n=13). All patients were assessed using the Neuropsychiatric Inventory (NPI), the Mini-Mental State Examination, Addenbrooke’s Cognitive Examination, and the Clinical Dementia Rating scale. Patients were also rated on the newly devised Stereotypic and Ritualistic Behaviour (SRB) subscale, which was designed as an addendum to the NPI. Results: There was no significant difference across diagnostic groups in terms of age, sex, or severity of cognitive deficits. The overall NPI was significantly higher in patients with fvFTD compared with the other two groups, but fvFTD and semantic dementia showed a similar, and significantly increased, prevalence of stereotypic behaviours on the SRB subscale. Within the FTD group as a whole these behaviours were more likely to be complex, whereas in Alzheimer’s disease, when present, such behaviours tended to be more simple stereotypies or stimulus bound repetitive behaviours. Stereotypic behaviours were not correlated with either disease severity or the extent of cognitive impairment in the fvFTD group, but were in the other two diagnostic groups. Conclusion: Complex stereotypic behaviours are a core feature of the dementing syndrome in FTD and may reflect early and specific deficits in orbitofrontal circuitry and basal ganglia involvement.

Incidence of early-onset dementias in Cambridgeshire, United Kingdom

Objective: To estimate the incidence of early-onset dementias in a defined area of Cambridgeshire served by Addenbrooke’s Hospital. Methods: The area selected for the study was that covered by the local authority areas of Cambridge City, East Cambridgeshire, and South Cambridgeshire. Cases were identified from the specialist memory and dementia clinics held at Addenbrooke’s Hospital and were defined as those patients resident in the target area at the time of diagnosis, who were diagnosed with dementia before the age of 65 years between June 1, 2000, and May 31, 2006. Results: No obvious pattern by sex was present. The incidence for all cases of primary dementia for the age range 45–64 years was estimated to be 11.5 cases per 100,000 person-years (95% CI 8.6–15.0). The incidence of frontotemporal dementia for the age range 45–64 years was estimated to be 3.5 cases per 100,000 person-years (95% CI 2.0–5.7); for Alzheimer disease the incidence for the same group was 4.2 (95% CI 2.5–6.6) and for Huntington disease the incidence rate of cases becoming affected (with or without dementia) was 0.8 (95% CI 0.2–2.3). Conclusion: If the incidence rates were extrapolated across England and Wales, in the region of 460 new cases of frontotemporal dementia and 550 new cases of Alzheimer disease could be expected each year in the 45–64 years age group.

Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes

Objectives: To estimate the lifetime risk, prevalence, incidence, and mortality of the principal clinical syndromes associated with frontotemporal lobar degeneration (FTLD) using revised diagnostic criteria and including intermediate clinical phenotypes. Methods: Multisource referral over 2 years to identify all diagnosed or suspected cases of frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS) in 2 UK counties (population 1.69 million). Diagnostic confirmation used current consensus diagnostic criteria after interview and reexamination. Results were adjusted to the 2013 European standard population. Results: The prevalence of FTD, PSP, and CBS was 10.8/100,000. The incidence and mortality were very similar, at 1.61/100,000 and 1.56/100,000 person-years, respectively. The estimated lifetime risk is 1 in 742. Survival following diagnosis varied widely: from PSP 2.9 years to semantic variant FTD 9.1 years. Age-adjusted prevalence peaked between 65 and 69 years at 42.6/100,000: the age-adjusted prevalence for persons older than 65 years is double the prevalence for those between 40 and 64 years. Fifteen percent of those screened had a relevant genetic mutation. Conclusions: Key features of this study include the revised diagnostic criteria with improved specificity and sensitivity, an unrestricted age range, and simultaneous assessment of multiple FTLD syndromes. The prevalence of FTD, PSP, and CBS increases beyond 65 years, with frequent genetic causes. The time from onset to diagnosis and from diagnosis to death varies widely among syndromes, emphasizing the challenge and importance of accurate and timely diagnosis. A high index of suspicion for FTLD syndromes is required by clinicians, even for older patients.

Determinants of survival in behavioral variant frontotemporal dementia

Background: Behavioral variant frontotemporal dementia (bvFTD) is a common cause of younger onset dementia. Little is known about its rate of progression but a recently identified subgroup seems to have an excellent prognosis. Other determinants of survival are unclear. Methods: We analyzed survival in a large group of clinically diagnosed bvFTD patients (n = 91) with particular attention to demographic and clinical features at presentation. Of the 91 cases, 50 have died, with pathologic confirmation in 28. Results: Median survival in the whole group was 9.0 years from symptom onset, and 5.4 years from diagnosis. After the exclusion of 24 “phenocopy” cases, the analysis was repeated in a subgroup of 67 patients. The mean age at symptom onset of the pathologic group was 58.5 years and 16% had a positive family history. Their median survival was 7.6 years (95% confidence interval [CI] 6.6–8.6) from symptom onset and 4.2 years (95% CI 3.4–5.0) from diagnosis. The only factor associated with shorter survival was the presence of language impairment at diagnosis. Conclusions: Patients with definite frontotemporal dementia have a poor prognosis which is worse if language deficits are also present. This contrasts with the extremely good outcome in those with the phenocopy syndrome: of our 24 patients only 1 has died (of coincident pathology) despite, in some cases, many years of follow-up.