Slowly progressive dementia caused by MAPT R406W mutations: longitudinal report on a new kindred and systematic review.

BACKGROUND: The MAPT c.1216C > T (p.Arg406Trp; R406W) mutation is a known cause of frontotemporal dementia with Parkinsonism linked to chromosome 17 tau with Alzheimer's disease-like clinical features. METHODS: We compiled clinical data from a new Swedish kindred with R406W mutation. Seven family members were followed longitudinally for up to 22 years. Radiological examinations were performed in six family members and neuropathological examinations in three. We systematically reviewed the literature and compiled clinical, radiological, and neuropathological data on 63 previously described R406W heterozygotes and 3 homozygotes. RESULTS: For all cases combined, the median age of onset was 56 years and the median disease duration was 13 years. Memory impairment was the most frequent symptom, behavioral disturbance and language impairment were less common, and Parkinsonism was rare. Disease progression was most often slow. The most frequent clinical diagnosis was Alzheimer's disease. R406W homozygotes had an earlier age at onset and a higher frequency of behavioral symptoms and Parkinsonism than heterozygotes. In the new Swedish kindred, a consistent imaging finding was ventromedial temporal lobe atrophy, which was evident also in early disease stages as a widening of the collateral sulcus with ensuing atrophy of the parahippocampal gyrus. Unlike previously published R406W carriers, all three autopsied patients from the novel family showed neuropathological similarities with progressive supranuclear palsy, with predominant four-repeat (exon 10+) tau isoform (4R) tauopathy and neurofibrillary tangles accentuated in the basal-medial temporal lobe. Amyloid-ß pathology was absent. CONCLUSIONS: Dominance of 4R over three-repeat (exon 10-) tau isoforms contrasts with earlier reports of R406W patients and was not sufficiently explained by the presence of H1/H2 haplotypes in two of the autopsied patients. R406W patients often show a long course of disease with marked memory deficits. Both our neuropathological results and our imaging findings revealed that the ventromedial temporal lobes were extensively affected in the disease. We suggest that this area may represent the point of origin of tau deposition in this disease with relatively isolated tauopathy.

A long-term longitudinal follow-up of depressed patients treated with ECT with special focus on development of dementia.

BACKGROUND: In this study, the long term effects of ECT on patients with depression were investigated through repeated rCBF and EEG measures as well as clinical characteristics over several years. The aim of the investigation was to establish an association with the eventual development of dementia. METHOD: A cohort of forty-nine patients (21 men and 28 women) with a mean age of 61 years underwent ECT. A subsequent evaluation from medical records and three rating-scales for diagnosis of Alzheimer´s disease (AD), fronto-temporal dementia (FTD), and for vascular dementia (VaD), revealed that 17 patients (8 men and 9 women), had developed dementia. These cases were compared to the 32 patients (13 men and 19 women), who had not developed dementia. RESULT: Initially, the dementia group, compared to those without dementia, showed a lower hemispheric CBF (left side; p=.029, right side; p=.033), and a lower mean occipital EEG frequency (p=.048). After the first ECT-series, an increase in general disorientation (p=.015), personal disorientation (p=.009), and subsequently, spatial disorientation (p=.021), were seen in the dementia group. There were no differences in the clinical response or remissions after treatment in the groups. LIMITATIONS: The small sample-size, which did not allow for the comparison of characteristics between different dementias. CONCLUSION: Depressed older patients who later developed dementia showed lower hemispheric mean level of CBF and EEG mean frequency before ECT and higher personal and spatial disorientation following ECT.

Rapid Optical Cavity PCR.

Recent outbreaks of deadly infectious diseases, such as Ebola and Middle East respiratory syndrome coronavirus, have motivated the research for accurate, rapid diagnostics that can be administered at the point of care. Nucleic acid biomarkers for these diseases can be amplified and quantified via polymerase chain reaction (PCR). In order to solve the problems of conventional PCR--speed, uniform heating and cooling, and massive metal heating blocks--an innovative optofluidic cavity PCR method using light-emitting diodes (LEDs) is accomplished. Using this device, 30 thermal cycles between 94 °C and 68 °C can be accomplished in 4 min for 1.3 µL (10 min for 10 µL). Simulation results show that temperature differences across the 750 µm thick cavity are less than 2 °C and 0.2 °C, respectively, at 94 °C and 68 °C. Nucleic acid concentrations as low as 10(-8) ng µL(-1) (2 DNA copies per µL) can be amplified with 40 PCR thermal cycles. This simple, ultrafast, precise, robust, and low-cost optofluidic cavity PCR is favorable for advanced molecular diagnostics and precision medicine. It is especially important for the development of lightweight, point-of-care devices for use in both developing and developed countries.

Psychotic symptoms in frontotemporal dementia: a diagnostic dilemma?

BACKGROUND: Frontotemporal dementia (FTD) constitutes a spectrum of neurodegenerative disorders associated with degeneration of, predominantly, the frontal and temporal lobes. The clinical heterogeneity is evident, and early diagnosis is a challenge. The primary objectives were to characterize psychotic symptoms, initial clinical diagnoses and family history in neuropathologically verified FTD-patients and to analyze possible correlations with different neuropathological findings. METHODS: The medical records of 97 consecutive patients with a neuropathological diagnosis of frontotemporal lobar degeneration (FTLD) were reevaluated. Psychotic symptoms (hallucinations, delusions, paranoid ideas), initial diagnosis and family history for psychiatric disorders were analyzed. RESULTS: Psychotic symptoms were present in 31 patients (32%). There were no significant differences in age at onset, disease duration or gender between patients with and without psychotic symptoms. Paranoid ideas were seen in 20.6%, and hallucinations and delusions in 17.5% in equal measure. Apart from a strong correlation between psychotic symptoms and predominantly right-sided brain degeneration, the majority of patients (77.4%) were tau-negative. Only 14.4% of the patients were initially diagnosed as FTD, while other types of dementia were seen in 34%, other psychiatric disorders in 42%, and 9.2% with other cognitive/neurological disorders. The patients who were initially diagnosed with a psychiatric disorder were significantly younger than the patients with other initial clinical diagnoses. A positive heredity for dementia or other psychiatric disorder was seen in 42% and 26% of the patients respectively. CONCLUSIONS: Psychotic symptoms, not covered by current diagnostic criteria, are common and may lead to clinical misdiagnosis in FTD.

CYP2B6 genotype, but not rifampicin-based anti-TB cotreatments, explains variability in long-term efavirenz plasma exposure.

AIM: We investigated the effects of rifampicin-based anti-TB treatment on plasma efavirenz exposure and the implications of CYP2B6 genotype. PATIENTS & METHODS: Antiretroviral therapy-naive Ugandan HIV patients without (n = 157) or with TB coinfection (n = 106) were enrolled and treated with efavirenz-based highly active antiretroviral therapy alone or with rifampicin-based anti-TB therapy, respectively. Efavirenz plasma concentration was determined on day 3 and weeks 1, 2, 8, 12, 16, 20, 24, 28 and 32. RESULTS: Rifampicin-based anti-TB cotreatment reduced plasma efavirenz exposure during the first 2 weeks (p < 0.05), but no significant effect was observed afterwards. Although not significant, rifampicin-based anti-TB cotreatment inconsistently increased efavirenz exposure over time, which was reduced immediately after completing anti-TB therapy. CYP2B6*6, *11 and ABCB1 c.4036A>G genotypes were significant predictors of efavirenz plasma exposure. CONCLUSION: Plasma efavirenz exposure is mainly influenced by CYP2B6 genotype, but not by rifampicin cotreatment. Therefore, no efavirenz dosage adjustment during rifampicin cotreatment is required in Ugandans.

Somatic complaints in frontotemporal dementia.

Frontotemporal dementia (FTD) is associated with a broad spectrum of clinical characteristics. The objective of this study was to analyze the prevalence of unexplained somatic complaints in neuropathologically verified FTD. We also examined whether the somatic presentations correlated with protein pathology or regional brain pathology and if the patients with these somatic features showed more depressive traits. Ninety-seven consecutively neuropathologically verified FTLD patients were selected. All 97 patients were part of a longitudinal study of FTD and all medical records were systematically reviewed. The somatic complaints focused on were headache, musculoskeletal, gastro/urogenital and abnormal pain response. Symptoms of somatic character (either somatic complaints and/or abnormal pain response) were found in 40.2%. These patients did not differ from the total group with regard to gender, age at onset or duration. Six patients showed exaggerated reactions to sensory stimuli, whereas three patients showed reduced response to pain. Depressive traits were present in 38% and did not correlate with somatic complaints. Suicidal behavior was present in 17 patients, in 10 of these suicidal behavior was concurrent with somatic complaints. No clear correlation between somatic complaints and brain protein pathology, regional pathology or asymmetric hemispherical atrophy was found. Our results show that many FTD patients suffer from unexplained somatic complaints before and/or during dementia where no clear correlation can be found with protein pathology or regional degeneration. Somatic complaints are not covered by current diagnostic criteria for FTD, but need to be considered in diagnostics and care. The need for prospective studies with neuropathological follow up must be stressed as these phenomena remain unexplained, misinterpreted, bizarre and, in many cases, excruciating.

A long-term follow-up of clinical response and regional cerebral blood flow changes in depressed patients treated with ECT.

BACKGROUND: Depression is the leading cause of disability worldwide and electroconvulsive therapy (ECT) is the most potent therapy. We investigated the clinical response and regional cerebral blood flow changes in depressed in patients treated with (ECT) in a repeated longitudinal study. METHOD: Forty-nine patients (21 men and 28 women) with a mean age 61 years underwent ECT. Forty-one patients grading improvement after the initial ECT-series (responder group) were compared with eight, grading no improvement (non-responder group). The patients underwent neuropsychiatric ratings, measure of clinical response (defined as ≥50% reduction of pre-treatment depression score) and measure of regional cerebral blood flow (rCBF). RESULTS: The responder group had an initial 60-82%, and the non-responder group a 30-64% clinical response throughout the follow-up. The non-responder group showed more reported depression (p=.003), and vegetative anxiety (p=.024), with a generally higher left temporal rCBF (p=.045). LIMITATIONS: The retrospective approach and the small sample-size. CONCLUSION: Patients with no subjective improvement after ECT had lesser objective clinical response, more sustained reported depression with anxiety features, and higher left temporal rCBF.

Frontotemporal dementia with a C9ORF72 expansion in a Swedish family: clinical and neuropathological characteristics.

BACKGROUND: In 2011 the C9ORF72 repeat expansion was identified as the most frequent genetic mutation underlying FTD and ALS. The main aim of this study was to investigate clinical characteristics in a large C9ORF72-positive FTD family, and to compare these with the neuropathological findings. METHODS: The clinical records of 12 related FTD patients were thoroughly evaluated. The five neuropathologically examined cases were revised using additional TDP-43 immuno-stainings. Four cases were screened for the C9ORF72 expansion. RESULTS: All 12 patients fulfilled the criteria for bvFTD. Restlessness and social neglect were often among the first reported symptoms. Psychotic symptoms were reported in 8 patients. Somatic complaints were seen in 7 cases. All the neuropathologically examined cases were TDP-43 positive. CONCLUSIONS: The phenotype of this C9ORF72 hexanucleotide expansion carrier family was bvFTD. The clinical symptom profile was strikingly homogenous. Psychotic symptoms and somatic complaints were observed in most of the cases.

Benefits of extra-pair mating may depend on environmental conditions-an experimental study in the blue tit (Cyanistes caeruleus).

Extra-pair mating constitutes a relatively common reproductive strategy in many socially monogamous bird species. This strategy may considerably improve reproductive success of males, but female benefits from extra-pair matings still remain unclear and empirical evidence is scarce. This may be because genetic benefits of extra-pair mating are not always revealed. It is possible that they are shown only in unfavourable environmental conditions and hence problems arise with detecting differences between within- and extra-pair offspring whose performance is measured under favourable conditions. In order to test this prediction, we manipulated environmental conditions by altering brood sizes of blue tits and compared phenotypic characteristics of within- and extra-pair offspring in mixed-paternity broods. We found that extra-pair young exhibited a higher response to phytohemagglutinin in comparison to within-pair young, but this was only observed among nestlings from experimentally enlarged broods. These results indicate that genetic benefits may interact with the environment, and thus benefits of extra-pair mating are likely to become visible only when conditions are relatively unfavourable.

Elevated plasma homocysteine level in vascular dementia reflects the vascular disease process.

BACKGROUND: Patients with vascular dementia (VaD) exhibit particularly elevated levels of plasma total homocysteine (tHcy) compared to patients with other psychogeriatric diseases. METHODS: We investigated the main determinants (age, renal impairment, cobalamin/folate status and presence of extracerebral vascular disease) of plasma tHcy in 525 patients with VaD. Furthermore, 270 patients with depression were used as a reference group to reveal the potential specificity of elevated plasma tHcy in patients with VaD. RESULTS: Elevated plasma tHcy levels in patients with VaD could only partly be attributed to cobalamin/folate deficiency or renal impairment. Plasma tHcy might also be related to the vascular disease process since patients with depression and vascular disease exhibited similar plasma tHcy levels to patients with VaD. CONCLUSION: Our findings suggest that elevated plasma tHcy might be a sensitive marker for the vascular disease process in patients with VaD and that the level also is a reflection of changes in the other main determinants of plasma tHcy.

Publications on dementia in Medline 1974-2009: a quantitative bibliometric study.

OBJECT: The aim is to describe the development of the scientific literature on dementia. METHODS: We present a quantitative, bibliometric study of the literature on dementia, based on Medline, covering 36 years (1974-2009). Two samples of references to dementia papers were retrieved: The main sample based on the MeSH term Dementia holds more than 88,500 references. We have compared the annual additions of references on dementia with the addition to total Medline. Changes of 'the Dementia to Medline ratio' (%) give the best information on the development. RESULTS: Publications on dementia increased 5.6 times faster than Medline. Most of this relative acceleration took place during 1980-1997, when the references on dementia increased from 0.17 to 0.78%. During the recent 12 years, the publications on dementia have been keeping pace with Medline and have stabilized around 0.8%. CONCLUSIONS: We have shown a large increase of the literature on dementia, relative both to the development of all medical research and to all psychiatric research. The bibliometric approach may be questioned as quantitative methods treat articles as being of equal value, what is not true. If, for example, during a certain period, the research output is 'inflated' by a great number of repetitive papers, the quantitative method will give an unfair picture of the development. Our relative method, however, will give relevant results as, at each point of time, the proportion of 'valuable research' ought to be about the same in the dementia group as in total Medline.

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in adult psychiatry. A 20-year register study.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are increasingly recognized in adults. This study aimed to assess trends in diagnostic practice, diagnostic delay and comorbidity regarding ADHD and ASD in adult psychiatric patients. METHODS: Individuals with diagnosed ADHD or ASD were identified in an adult psychiatry register comprising 56,462 patients. RESULTS: ADHD was diagnosed in up to 2.7% and ASD in 1.3% of the patients. Most cases were diagnosed within 2 years of first contact with adult psychiatry, but some patients were treated for 10 years or more before being diagnosed with ADHD or ASD. Seventy per cent of ADHD and 56% of ASD patients were treated as outpatients only. Other psychiatric diagnoses were registered in about 60%. Affective disorders were common in patients with ADHD. Psychoses and intellectual disability were more common in ASD patients. Psychoactive substance use-related disorders were considerably more common in those with ADHD. Concomitant ADHD and ASD were seldom diagnosed in this clinical material. CONCLUSION: ADHD and ASD were probably much underdiagnosed in the studied group of psychiatric patients. Other psychiatric diagnoses were common, but not ADHD with concomitant ASD.

History of depression prior to Alzheimer's disease and vascular dementia verified post-mortem.

The aim of this study was to analyze the medical history, with regards to previous remote depression, in patients with neuropathologically verified Alzheimer's disease (AD), vascular dementia (VaD) and mixed AD/VaD. The 201 patients included (115 AD, 44 VaD and 42 mixed AD/VaD) had been referred to the Psychogeriatric/Psychiatric Department, Lund University Hospital, for psychogeriatric investigation and were followed-up with clinical records and detailed information on psychiatric history prior to the onset of dementia. Depression was considered to exist when the patient had consulted a psychiatrist or physician and had been diagnosed with a "depressive episode" or "depression" and when anti-depressants and/or other specific treatments had been prescribed. Twenty patients (10%) had suffered from depression earlier in life well before the onset of dementia. Eight of the 9 AD patients with a previous diagnosis of depression had suffered from only one depressive episode and all had responded well to treatment, with complete recovery. In the VaD group, 8 out of 9 patients suffered two or more depressive episodes and only two recovered completely. Events with a possible significant relationship to depression were seen in 8 of the 9 AD patients but in only 1 of the 9 VaD patients. Psychotic symptoms were more common in VaD than in the AD group. The treatment modality of depression was similar in the groups. In conclusion, a history of depression prior to dementia is more common and more therapy-resistant in VaD than in AD.

Elevated plasma homocysteine level is not primarily related to Alzheimer's disease.

BACKGROUND: A moderate elevation of plasma total homocysteine (tHcy) is considered a potential risk factor for Alzheimer's disease (AD). METHODS: We have investigated the main determinants (age, renal impairment, cobalamin/folate status and the presence of vascular disease) of plasma tHcy in 326 patients with AD, and also in 281 patients with mild cognitive impairment (MCI), since about half of these patients develop AD during the first 5 years. RESULTS: Elevated plasma tHcy in patients with AD could mainly be attributed to cobalamin/folate deficiency or renal impairment. Younger patients (below 75 years) with AD and patients with MCI without cobalamin/folate deficiency or renal impairment showed normal levels of plasma tHcy. CONCLUSION: Our findings suggest that plasma tHcy is not primarily involved in the pathogenesis of AD but rather a reflection of changes of the main determinants of plasma tHcy in AD patients.

Familial Lund frontotemporal dementia caused by C9ORF72 hexanucleotide expansion.

Frontotemporal dementia (FTD) as an important clinical entity was rediscovered in Lund and Manchester in the early 1990s. Here we show that the large Lund pedigree with behavioral variant of frontotemporal dementia previously described with this disorder has an expansion in the recently described C9ORF72 locus on chromosome 9.

The use of N-terminal pro-brain natriuretic Peptide to evaluate vascular disease in elderly patients with mental illness.

BACKGROUND: Serum N-terminal pro-brain natriuretic peptide (NT-proBNP) is regarded as a sensitive marker of cardiovascular disease. Vascular disease plays an important role in cognitive impairment. METHOD: In 447 elderly patients with mental illness, serum NT-proBNP level and the presence or absence of vascular disease according to the medical record were used to categorize patients in different subgroups of vascular disease. RESULTS AND CONCLUSION: Patients with vascular disease and elevated serum NT-proBNP level had a lower cognition level, shorter survival time, lower renal function and a higher percentage of pathological brain imaging than patients with vascular disease and normal NT-proBNP level. Thus, elevated serum NT-proBNP level might be helpful to detect patients who have a more severe cardiovascular disease.

Plasma homocysteine, brain imaging and cognition in older patients with mental illness.

BACKGROUND: Total plasma homocysteine (tHcy) concentration is elevated in older patients with mental illness, and patients with vascular disease have higher plasma tHcy concentration than patients without vascular disease. Plasma tHcy has been reported to be associated with cognitive functions. The mechanism by which plasma tHcy may influence cognitive functions is not clear. METHOD: We have investigated the relation between plasma tHcy, brain imaging findings (computer tomography scan [CT]) and cognition, measured as Mini mental state examination (MMSE), in 395 consecutively enrolled older patients with mental illness. RESULTS: Age and plasma tHcy were significant predictors of MMSE score, whereas pathological CT findings, indicating cerebrovascular disease, showed no prediction of MMSE score. CONCLUSION: The relation between plasma tHcy and cognition is not mediated by cerebrovascular disease as evaluated by pathological CT findings.

C-reactive protein level is decreased in patients with Alzheimer's disease and related to cognitive function and survival time.

BACKGROUND: Previous studies have observed decreased serum CRP levels in patients with established Alzheimer's disease (AD) compared to controls or other diagnostic groups of elderly patients with mental illness. METHODS: We have investigated the relation between CRP level and the severity of AD as assessed by cognitive function, brain imaging and survival time. RESULTS: Patients with AD showed overall lower CRP levels than other patients with mental illness, but elevated CRP levels in these patients were associated with lower cognitive function and shorter survival time. CONCLUSION: The reason for an overall low CRP level is not obvious. Elevated CRP level in patients with AD suggests the presence of inflammatory activity in this subgroup of patients that may benefit from anti-inflammatory administration.

The birth and early evolution of the frontotemporal dementia (FTD) concept.

An historical overview of the development of the concept of frontotemporal dementia is presented, regarding the last 30 years, using as a backbone the conferences held on this theme, with a start in 1986 in Lund, Sweden. Since then, a dramatic increase in research activities and publications has rapidly expanded our knowledge in this field, a step necessary for the ultimate goal to find an effective treatment of this devastating disorder.

Survival in a large elderly population of patients with dementia and other forms of psychogeriatric diseases.

BACKGROUND: Dementia and other psychogeriatric diseases in elderly patients bring an increased risk of death. Better knowledge of prognosis in elderly patients affected by dementia or mental illness should be of great importance in order to improve care plans and assist in medical decisions. METHODS: We have investigated the survival time in 2,112 patients with dementia and other forms of psychogeriatric diseases, enrolled during 1990 to 2005 and followed up until 2009, and the influence of diagnoses, plasma homocysteine level, presence of vascular disease and renal impairment. RESULTS: The survival time after diagnosis in most diagnostic groups is about a third compared to an average population of similar age and sex. Age was the main predictor of survival time in all patients. CONCLUSIONS: All diagnoses, except in patients with subjective cognitive impairments, showed an increased mortality. These estimates can be used for prognosis and planning for patients, carers, service providers and policy makers.