Somatic comorbidities and Alzheimer's disease treatment.

Therapeutic strategies in Alzheimer's disease (AD) must take into account the characteristics of elderly people, who often have somatic comorbidities. Moreover, demented patients are more frequently frailer than older people. They have a higher number of admissions to hospital, a greater prevalence of complications and an increased risk of death. Therapeutic decisions for these patients have to be approached cautiously: aging, a more elevated comorbidity/polytherapy index and frailty contribute to enhance the risk of pharmacological adverse events and drug interactions. The aim of the present study was to focus on risk-benefit profile of pharmacological therapy for AD in relation to somatic comorbidities that often affect these patients. A Medline search (from 2001 to 2012) was performed using as key words dementia, Alzheimer's disease, drug treatment, somatic comorbidities, side effects/adverse events and elderly. Cholinesterase inhibitors (ChEIs) and memantine represent the main pharmacological strategies effective in reducing the progression of cognitive decline and functional loss in AD. Many conditions very common in the elderly may restrict the use of ChEIs and/or treatment efficacy in AD patients. Memantine has a good efficacy and tolerability profile with better safety in pulmonary, cardiovascular and central nervous system comorbidities compared to ChEIs. Drug interactions with memantine are also more favorable since they concern mostly drugs not commonly used in the elderly. Only a careful evaluation of the associated somatic diseases, taking into account different drugs safety indexes and tolerability, can lead to personalized treatment management, in order to maximize drug efficacy and optimize quality of life.

Ischemic Stroke and Provoked Seizure as a Manifestation of Brugmansia suaveolens (Angel's Trumpet) Acute Intoxication: A Detailed Clinical, Electroencephalogram, and Magnetic Resonance Imaging Description and 5-Month Follow-up.

METHODS: We present a detailed clinical, laboratory, electroencephalogram/magnetic resonance imaging description and a 4-month follow-up of a case of stroke and provoked seizures as manifestation of angel's trumpet intoxication. RESULTS/DISCUSSION: A 76-year-old woman presented with stuporous state evolving in 48 hours in bilateral mydriasis, vomiting, global aphasia, confusion, and stereotyped movement. An interictal electroencephalogram, performed 72 hours later, showed frequent generalized epileptiform discharges, and a brain magnetic resonance imaging revealed 2 small subcortical lesions in the right frontal lobe on diffusion weighted imaging sequences. When completely recovered, she could tell that she had mistaken angel's trumpet flowers for pumpkin flowers, so she had eaten them. CONCLUSIONS: Angel's trumpet intoxication is a neurological emergency that deserves attention of both the media in matter of plant poisoning and the scientific forums because of the high lethal potential to better choose the diagnostic and therapeutic process.

Preliminary evidences of a NOS2A protective effect from relapsing-remitting multiple sclerosis.

The gene encoding the inducible form of Nitric Oxide Synthase (NOS2A) has been considered with interest in the evaluation of the genetic predisposition to Multiple Sclerosis (MS). The aim of the present study was to address the possible contribution of two microsatellites repeats of the NOS2A promoter region - (CCTTT)(n) and (AAAT)(n) - to MS susceptibility. One hundred and thirteen Italian patients with clinically definite RRMS and 237 age and sex matched healthy controls from Calabria (South Italy) were studied. The distribution analysis of the markers frequencies showed that the (CCTTT)(14) allele was found in 11.5% of the RRMS patients and in 25.3% of the healthy subjects, with a statistically significant difference (chi(2)=8.843, p=0.003). This data seems to confer a significant protection against MS (OR=0.348; 95% CI=0.174-0.693, corrected for age and gender). No association with MS susceptibility was observed for the bi-allelic (AAAT)(n) microsatellite. In conclusion, we found that the NOS2A (CCTTT)(14) allele was detected more frequently in the control group than in the RRMS patients, thus confirming the scientific interest on this marker.

Impact of individual cognitive profile on visuo-motor reorganization in relapsing-remitting multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), relationships between disease-related MRI changes, cognitive function and brain responses are complex and still unclear. This study addresses the relative effects of cognitive impairment and brain atrophy on the cortical reorganization associated with a visuo-motor task. METHODS: Multivariate analysis was applied to compare functional MRI brain responses of 28 relapsing-remitting (RR) MS patients (16 cognitively preserved and 12 cognitively impaired) to that of 35 matched healthy controls during the execution of visuo-motor integration task. Regression analysis was performed to test for linear effects of structural variables (grey matter (GM) and white matter (WM) volumes) and cognitive profiles--and their combined effect--on the same response. RESULTS: Compared to preserved MS patients or normal controls, cognitively impaired MS patients showed significant decreases of brain parenchymal and GM volumes, but only a trend for lower WM volume. Multivariate analysis showed that cognitive profile, GM and WM atrophy independently contributed to the activation of parieto-premotor cortices. Baseline cognition predicted the greatest response of the entire network, whereas WM and GM losses predicted selective responses of parietal and premotor regions. CONCLUSIONS: Visuo-motor function in MS is associated with altered patterns of brain activation that vary as a function of cognitive decline. This is confirmed by a larger effect size of the individual cognitive profile compared to the structural damage. Both effects contribute in an additive way to cortical reorganization, which is primarily driven by such a cognitive gradient in RR-MS patients.

Short-Term Response is not Predictive of Long-Term Response to Acetylcholinesterase Inhibitors in Old Age Subjects with Alzheimer's Disease: A "Real World" Study.

BACKGROUND: Most of clinical guidelines recommend discontinuing treatment with cholinesterase inhibitors (ChEIs) in patients with Alzheimer's disease (AD) who do not show an initial response to therapy as evaluated with the Mini-Mental State Examination (MMSE) scale. However, understanding the relationship between the initial response to ChEI treatment and the subsequent course of the disease is extremely important in clinical practice, but evidence is limited, particularly in the old-old population. OBJECTIVE: We aimed at investigating the relationship between short-term and long-term response to ChEI therapy in old age subjects with AD in a "real life" setting. METHODS: This is a retrospective longitudinal study of 628 old age subjects (≥65 years old) with AD and treated with ChEIs over three year follow-up. The sample was divided into "young-old" (≤75 years) and "old-old" (≥76 years) according to age, and as "responder" and "non-responder" according to the initial (i.e., after three months) response to treatment. Cognitive and functional evaluation was performed by means of MMSE and ADL/IADL, respectively. RESULTS: In the long run, subjects considered as non-responders showed a lower rate of cognitive decline as compared with responders, with a mean annual decline at MMSE of 1.0 point versus 1.6 points (p < 0.0001), respectively. Old-old non-responders had a slower rate of cognitive (p < 0.0001) and functional decline (p < 0.0001) as compared with responders after three years of observation. CONCLUSION: Discontinuing ChEI treatment solely for the absence of an initial response is not appropriate, especially in old-old subjects.

Role of Niemann-Pick Type C Disease Mutations in Dementia.

BACKGROUND: Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance. OBJECTIVE: To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus. METHODS: We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients. RESULTS: Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2. CONCLUSIONS: Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.

Adaptive cortical changes and the functional correlates of visuo-motor integration in relapsing-remitting multiple sclerosis.

Cortical reorganization has been demonstrated during performance of a motor task in patients with multiple sclerosis. Converging evidence suggests that changes in gray matter volume represent an early hallmark of the disease. We used functional MRI to investigate the role of cortical adaptive mechanisms in maintaining visuo-motor function in the face of structural damage. Two cohorts of patients with clinically definite relapsing-remitting multiple sclerosis were compared with healthy controls matched for demographic, motor and cognitive characteristics during the performance of a visuo-motor integration task. Direct comparison between the two groups demonstrated a greater response of the contralateral dorsal premotor cortex and of the ipsilateral superior parietal cortex in relapsing-remitting multiple sclerosis patients. The functional MRI changes in these areas were strongly correlated with decreased gray matter volumes and increased lesion burden, respectively. Our study demonstrated a selective involvement of the parieto-premotor circuitry in a relatively early stage of the disease, which was not influenced by clinical, motor or cognitive variables. Moreover these results confirm the potential for functional recovery and the adaptive role of these areas in the motor reorganization of multiple sclerosis patients.

An adenovirus carrying the rat protein tyrosine phosphatase eta suppresses the growth of human thyroid carcinoma cell lines in vitro and in vivo.

We demonstrated previously that rat tyrosine phosphatase r-PTPeta expression was suppressed in rat and human thyroid neoplastic cells, and that restoration of r-PTPeta expression reverted the malignant phenotype. To investigate the potential of this gene for cancer therapy, we generated an adenovirus carrying the r-PTPeta cDNA (Ad-r-PTPeta). This virus infected human thyroid carcinoma cells and overexpressed the r-PTPeta protein. Overexpression of r-PTPeta significantly inhibited the growth of four thyroid carcinoma cell lines. Cell growth inhibition was associated with down-regulation of extracellular signal-regulated kinase 1/2 activity, with increased levels of the cell-cycle inhibitor p27(kip1) protein and with dephosphorylation of PLCgamma1, a substrate of DEP-1, the human homologue of r-PTPeta. Finally, the growth of xenograft tumors induced in athymic mice by anaplastic thyroid carcinoma ARO cells transduced with the Ad-r-PTPeta virus was drastically reduced. These data suggest that gene therapy based on restoration of PTPeta function has potential in the treatment of human thyroid malignant neoplasias.

Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family.

OBJECTIVE: To report, for the first time, a large autosomal dominant Alzheimer disease (AD) family in which the APP A713T mutation is present in the homozygous and heterozygous state. To date, the mutation has been reported as dominant, and in the heterozygous state associated with familial AD and cerebrovascular lesions. METHODS: The family described here has been genealogically reconstructed over 6 generations dating back to the 19th century. Plasma ß-amyloid peptide was measured. Sequencing of causative AD genes was performed. RESULTS: Twenty-one individuals, all but 1 born from 2 consanguineous unions, were studied: 8 were described as affected through history, 5 were studied clinically and genetically, and 8 were asymptomatic at-risk subjects. The A713T mutation was detected in the homozygous state in 3 patients and in the heterozygous state in 8 subjects (6 asymptomatic and 2 affected). CONCLUSIONS: Our findings, also supported by the ß-amyloid plasma assay, confirm (1) the pathogenic role of the APP A713T mutation, (2) the specific phenotype (AD with cerebrovascular lesions) associated with this mutation, and (3) the large span of age at onset, not influenced by APOE, TOMM40, and TREM2 genes. No substantial differences concerning clinical phenotype were evidenced between heterozygous and homozygous patients, in line with the classic definition of dominance. Therefore, in this study, AD followed the classic definition of a dominant disease, contrary to that reported in a previously described AD family with recessive APP mutation. This confirms that genetic AD may be considered a disease with dominant and recessive traits of inheritance.

Identification of three novel LRRK2 mutations associated with Parkinson's disease in a Calabrian population.

BACKGROUND: LRRK2 mutations are common in familial and sporadic Parkinson's disease (PD) cases. OBJECTIVE: We present a screening of the most frequently mutated exons of LRRK2 in Calabrian population. METHODS: Eighty-eight PD patients diagnosed according to standard criteria, underwent screening for LRRK2 mutations in exons 19, 21, 24, 25, 27, 29, 31, 32, 33, 35, 38, 40, 41, and 48. RESULTS: Eight LRRK2 variations were identified in nine patients affected by PD, including three novel missense variations (p.Phe1227Leu, p.Gly1520Ala, p.Ile2020Ser) and five previously identified mutations (p.Ala1151Thr, IVS31+3A>G, p.Arg1514Gln, p.Gly2019Ser, p.Thr2356Ile). LRRK2 frequency mutations were approximately 10.2% in all PD patients, 12% in familial, 8% in sporadic cases. The p.Gly2019Ser mutation was found in 2.3% of the total cohort and in 3.2% of sporadic cases. The clinical features of LRRK2-associated with PD in our patients were similar to those of idiopathic PD although most LRRK2 mutated patients presented with bradykinesia instead of tremor; 33.3% developed dementia. CONCLUSIONS: We identified three novel LRRK2 mutations and reported a higher frequency in Calabria compared to previously reported data possibly due to the relative genetic isolation of the Calabrian population. These findings contribute to the understanding of the role of LRKK2 variations in PD and provide additional genetic insight into this disease.

Novel N-terminal domain mutation in prion protein detected in 2 patients diagnosed with frontotemporal lobar degeneration syndrome.

Prion protein gene mutations have been associated with clinical pictures mimicking neurodegenerative diseases different from inherited prion diseases (IPD). We report a novel missense P39L mutation in the N-terminal domain of prion protein in 2 patients affected by frontotemporal lobar degeneration syndrome, negative for mutations in genes causative of dementia. Neither the first carrier, a 67-year-old male in which the onset was a progressive non-fluent aphasia, nor the second carrier, a 78-year-old male affected by frontotemporal dementia and parkinsonism, showed any clinical or instrumental findings suggestive of IPD. Genetic screening of healthy controls and in silico analysis provide support for the potential pathogenicity of this variant. Patient phenotypes, unclassifiable as prion disease, may depend on the location of the mutation in the N-terminal domain, outside the amyloid core of pathologic prion protein, although further functional studies are required to determine whether and how this mutation exerts its pathogenic effect. However, genetic screening of prion protein gene becomes relevant in familial degenerative dementia, particularly in geographical areas with high IPD prevalence.

Role of TOMM40 rs10524523 polymorphism in onset of alzheimer's disease caused by the PSEN1 M146L mutation.

We investigated the association between TOMM40 rs10524523, age of onset, and memory performance in patients with the PSEN1 M146L mutation in a large familial Alzheimer's disease Calabrian kindred, with a wide variability of onset not attributable to APOE. APOE33/TOMM40VL/VL patients showed a tendency for an earlier age at onset compared to those with APOE33/TOMM40VL/S and APOE33/TOMM40S/S. Moreover, TOMM40VL/VL patients had better memory performance, when compared to TOMM40S/S but not to TOMM40VL/S patients, so there is not a dose-dependent effect. Our results suggest that, in the presence of the PSEN1 mutation, the slight difference in age of onset together with memory performance could be influenced by TOMM40 genotypes.

Autosomal dominant frontotemporal lobar degeneration due to the C9ORF72 hexanucleotide repeat expansion: late-onset psychotic clinical presentation.

BACKGROUND: A hexanucleotide repeat expansion in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis or frontotemporal lobar degeneration (FTLD). Atypical presentations have been described, particularly psychosis. METHODS: We determined the frequency of the hexanucleotide repeat expansions in a population of 651 FTLD patients and compared the clinical characteristics of carriers and noncarriers. In addition, we genotyped 21 patients with corticobasal syndrome, 31 patients with progressive supranuclear palsy, and 222 control subjects. RESULTS: The pathogenic repeat expansion was detected in 39 (6%) patients with FTLD (17 male and 22 female subjects); however, it was not detected in any corticobasal syndrome and progressive supranuclear palsy patients or controls. Twenty-four of 39 carriers had positive family history for dementia and/or amyotrophic lateral sclerosis (61.5%), whereas only 145 of 612 noncarriers had positive family history (23.7%; p<.000001). Clinical phenotypes of carriers included 29 patients with the behavioral variant frontotemporal dementia (bvFTD; 5.2% of all bvFTD cases), 8 with bvFTD/motor neuron disease (32% bvFTD/motor neuron disease cases), 2 with semantic dementia (5.9% of patients with semantic dementia), and none with progressive nonfluent aphasia. The presentation with late-onset psychosis (median age = 63 years) was more frequent in carriers than noncarriers (10/33 vs. 3/37, p = .029), as well as the presence of cognitive impairment at onset (15/33 vs. 5/37; p = .0039). CONCLUSIONS: The repeat expansion in C9ORF72 is a common cause of FTLD and often presents with late-onset psychosis or memory impairment.

Epidemiology and genetics of frontotemporal dementia: a door-to-door survey in southern Italy.

The objectives of this study were to estimate frontotemporal dementia (FTD) prevalence, identify FTD-related mutations, and correlate FTD phenotype with mutations in a southern Italian population. The study population consisted of subjects ≥ 50 years of age residing in the Community of Biv. on January 1, 2004, and a door-to-door 2-phase design was used. Genetic and biochemical analyses were done on samples collected from 32 patients. Prevalence rates were 0.6 for Alzheimer's disease, 0.4 for vascular dementia (VD), 3.5 for FTD, 0.2 for Parkinson dementia, and 1.2 for unspecified dementia. Three GRN (1 known and 2 novel) mutations with reduced plasma protein levels were found associated to 3 distinct phenotypes (behavioral, affective, and delirious type). We report an unusually high FTD prevalence in the investigated population, but a low prevalence of Alzheimer's disease. We confirm the heterogeneity of FTD phenotype associated with different GRN mutations.

PSEN1 and PRNP gene mutations: co-occurrence makes onset very early in a family with FTD phenotype.

Prion protein (PRNP) gene mutations have recently been associated with clinical pictures resembling Frontotemporal dementia (FTD). We describe a novel seven extra-repeat insertional mutation in the PRNP gene in a family affected by early-onset autosomal dominant FTD previously reported as caused by a PSEN1 mutation in which there was inconsistency between clinical picture and genotype. Both mutations were pathogenic and showed a variable penetrance when present separately; when occurring together, the onset was very early, within the third decade of life. Genetic screening of the PRNP gene becomes of major importance in early onset autosomal dominant dementia.

A novel pathogenic PSEN1 mutation in a family with Alzheimer's disease: phenotypical and neuropathological features.

We report a novel presenilin1 (PSEN1) gene mutation (I143 V) in a four-generation family with Alzheimer's disease. Clinical, molecular, and neuropathological examinations were performed on index patient; thirteen affected subjects were also identified. The index patient presented at 55 with personality changes, apathy, reduction of verbal fluency, and temporal and spatial disorientation. At 68, she showed visual hallucinations; blurred language, and rigidity. She became bedridden and died at 75. A novel mutation at codon 143 was found in PSEN1 gene, changing isoleucine to valine. The brain showed severe atrophy of the frontal and temporal lobes. Parenchymal amyloid-ß (Aß) deposits were abundant, diffuse to grey structures and contained Aß42, but very few Aß40. Amyloid angiopathy was absent. Neurofibrillary changes were severe. Our study confirms that PSEN1 mutations can be associated with unusual phenotypes. The peculiarity of the age at onset (not very early), the long course, and the frontal involvement, together with the rather complete absence of Aß40 and of amyloid angiopathy, widen the spectrum of PSEN1-linked phenotypes.