Neuropsychiatric or Behavioral and Psychological Symptoms of Dementia (BPSD): Focus on Prevalence and Natural History in Alzheimer's Disease and Frontotemporal Dementia.

Neuropsychiatric or behavioral and psychological symptoms of dementia (BPSD) represent a heterogeneous group of non-cognitive symptoms that are virtually present in all patients during the course of their disease. The aim of this study is to examine the prevalence and natural history of BPSD in a large cohort of patients with behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) in three stages: (i) pre-T0 (before the onset of the disease); (ii) T0 or manifested disease (from the onset to 5 years); (iii) T1 or advanced (from 5 years onwards). Six hundred seventy-four clinical records of patients with bvFTD and 1925 with AD, from 2006 to 2018, were studied. Symptoms have been extracted from Neuropsychiatric Inventory (NPI) and from a checklist of BPSD for all periods observed. In our population, BPSD affect up to 90% of all dementia subjects over the course of their illness. BPSD profiles of the two dementia groups were similar but not identical. The most represented symptoms were apathy, irritability/affective lability, and agitation/aggression. Considering the order of appearance of neuropsychiatric symptoms in AD and bvFTD, mood disorders (depression, anxiety) come first than the other BPSD, with the same prevalence. This means that they could be an important "red flag" in detection of dementia. With the increase of disease severity, aberrant motor behavior and wandering were significantly more present in both groups. Differences between BPSD in AD and bvFTD resulted only in prevalence: Systematically, in bvFTD, all the symptoms were more represented than in AD, except for hallucinations, depression, anxiety, and irritability. Given their high frequency and impact on management and overall health care resources, BPSD should not be underestimated and considered as an additional important diagnostic and therapeutic target both in patients with AD and bvFTD.

A Comparison of Behavioral and Psychological Symptoms of Dementia (BPSD) and BPSD Sub-Syndromes in Early-Onset and Late-Onset Alzheimer's Disease.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) have a large impact on the quality of life of patients with Alzheimer's disease (AD). Few studies have compared BPSD between early-onset (EOAD) and late-onset (LOAD) patients, finding conflicting results. OBJECTIVE: The aims of this study were to: 1) characterize the presence, overall prevalence, and time of occurrence of BPSD in EOAD versus LOAD; 2) estimate the prevalence over time and severity of each BPSD in EOAD versus LOAD in three stages: pre-T0 (before the onset of the disease), T0 (from onset to 5 years), and T1 (from 5 years onwards); 3) track the manifestation of BPSD sub-syndromes (i.e., hyperactivity, psychosis, affective, and apathy) in EOAD versus LOAD at T0 and T1. METHODS: The sample includes 1,538 LOAD and 387 EOAD diagnosed from 1996 to 2018. Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment and at different follow-up period. RESULTS: The overall prevalence for the most of BPSD was significantly higher in EOAD compared to LOAD whereas most BPSD appeared significantly later in EOAD patients. Between the two groups, from pre-T0 to T1 we recorded a different pattern of BPSD prevalence over time as well as for BPSD sub-syndromes at T0 and T1. Results on severity of BPSD did not show significant differences. CONCLUSION: EOAD and LOAD represent two different forms of a single entity not only from a neuropathological, cognitive, and functional level but also from a psychiatric point of view.

A Novel Mutation (D395A) in Valosin-Containing Protein Gene Is Associated With Early Onset Frontotemporal Dementia in an Italian Family.

Inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and/or frontotemporal dementia (FTD) (IBMPFD) was recently identified as rare autosomal dominant disorder due to mutations in VCP gene. However, VCP mutations have also been documented in patients with amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth type 2 (CMT2) disease, and hereditary spastic paraplegia (HSP), underlining the heterogeneity of the phenotypes due to VCP mutations. In this study, we reported a novel missense heterozygous variant c.1184A > C (p.D395A) in exon 10 of VCP gene identified in three patients (two sisters and one brother) belonging to an Italian family. The patients underwent a detailed clinical evaluation including medical history, neurological examination, and neuropsychological assessment. Brain's morphologic and functional analysis was also performed. The whole picture was consistent with the criteria of behavioral variant frontotemporal dementia (bvFTD) without IBM and PBD. Our report confirms the high degree of heterogeneity of VCP disease. A VCP analysis should be considered for the genetic screening of familial bvFTD with an early onset also in absence of IBM or PDB signs.

Frequency of Cardiovascular Genetic Risk Factors in a Calabrian Population and Their Effects on Dementia.

BACKGROUND: Several genetic variants playing a key role in cholesterol levels, blood pressure, and vascular dysfunction influence the risk of Alzheimer's disease (AD) and vascular dementia (VaD). The many meta-analysis studies carried out on large numbers of samples in different populations have not provided clear results to date, because a trans-ethnic shift of risk genotypes in different populations is often observed. OBJECTIVES: To determine genotypes allele frequencies of the polymorphisms most frequently identified to be correlated with cardio-cerebrovascular disease and AD in a Southern Italy population and to investigate their possible association with dementia. METHODS: The genotype and allele frequencies of 13 cardio-cerebrovascular risk polymorphisms were assessed and their possible association with dementia was investigated in a case-control study, including 221 consecutive unrelated subjects diagnosed with dementia (120 subjects affected by AD, 55 by frontotemporal dementia, and 33 by vascular dementia) and 218 matched controls of Calabrian origin. RESULTS: Carriers of at least one APOEɛ4 allele resulted to be at higher risk of AD [OR(95% CI) = 2.721(1.477-5.011)] and VaD [OR(95% CI) = 6.205(2.356-16.342)] compared to non-carriers. Individuals with the IV genotype of the CETP polymorphism were more likely to have AD [OR(95% CI) = 2.427(1.364-4.319)] and VaD [OR(95% CI) = 3.649(1.455-9.152)] compared to subjects with the II-VV genotypes. CONCLUSION: CETP I405V polymorphism is likely a risk factor for AD and VaD in our cohort, independent of APOEɛ4 status. Unmodifiable genetic risk factors should be taken into account to promote a healthy lifestyle to prevent dementia.

The novel PSEN1 M84V mutation associated to frontal dysexecutive syndrome, spastic paraparesis, and cerebellar atrophy in a dominant Alzheimer's disease family.

We identified the novel PSEN1 pathogenic mutation M84V in 3 patients belonging to a large kindred affected by autosomal dominant Alzheimer's disease (AD). The clinical phenotype was characterized by early onset dementia in 14 affected subjects over 3 generations. Detailed clinical, imaging and genetic assessment was performed. We highlighted the presence of unusual symptoms such as frontal executive syndrome, psychosis and spastic paraparesis in these patients. Spastic paraparesis has been reported in other PSEN1 mutations in adjacent codons, suggesting that the position of the genetic defect may affect the clinical expression, although this phenotype can occur in mutations throughout the whole PSEN1 gene. Brain magnetic resonance imaging showed diffuse cortical atrophy, but also atrophy of cerebellar lobules, mainly involving Crus I, in 2 patients without cerebellar motor deficits. These neuroimaging results were consistent with recent findings about the association between sporadic AD and distinct and circumscribed cerebellar atrophy. The present work acknowledged the novel PSEN1 pathogenic mutation M84V and might contribute to the ongoing debate about the involvement of cerebellum in AD.

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.

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.

Influence of controlled encoding and retrieval facilitation on memory performance in patients with different profiles of mild cognitive impairment.

Memory tests able to differentiate encoding and retrieval processes from the memoranda storing ones should be used to differentiate patients in a very early phase of AD. In fact, individuals with mild cognitive impairment (MCI) can be characterized by two different memory profiles: a pure amnestic one (with poor learning and retrieval and poor improvement when encoding is assisted and retrieval is facilitated) and a dysexecutive one (with inefficient encoding and/or poor retrieval strategies and improvement with assisted encoding and retrieval). The amnestic profile characterizes subjects affected by medio-temporal atrophy typical of AD. In this study, a Grober-Buschke memory procedure was used to evaluate normal controls and MCI patients with different cognitive profiles: pure amnestic (aMCIsd), amnestic plus other cognitive impairments (aMCImd) and non-amnestic (naMCI). An index of sensitivity of cueing (ISC) measured the advantage passing from free to cued recall. Results showed that both strategic and consolidation abilities were impaired in the aMCIsd and aMCImd groups and were preserved in the naMCI group. aMCImd, however, compensated the memory deficit with assisted encoding and retrieval, but aMCIsd performed very poorly. When MCI subjects were defined according to the ISC value, subjects with poor ISC were primarily in the aMCIsd group and, to a lesser extent, in the aMCImd group and the naMCI group. Finally, patients with a poor ISC showed cerebral atrophy documented in the precocious phase of AD and the retrosplenial cerebral areas seemed to be the most useful areas for identifying patients in the early phase of AD.

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.

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.

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.

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.

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.

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.

Compound heterozygosity of 2 novel MAPT mutations in frontotemporal dementia.

Intronic MAPT mutations altering exon 10 splicing lead mainly to an increase of 4Rtau. The objective of this study is to report clinical, genetic, and neuropathological data of an apparently sporadic early onset frontotemporal dementia (FTD) case associated with 2 novel intronic MAPT gene mutations IVS10+4A > C and IVS9-15T > C that increase 3Rtau. Methods and subjects used are clinical, neuroradiological, and neuropathological examination; molecular genetics of MAPT, PGRN, and other relevant genes. Exon 10 splicing tested with minigene constructs. Tau deposits detected by immunohistochemistry. Sarkosyl-insoluble and soluble tau investigated by immunoblotting. Two novel MAPT mutations IVS10+4A > C and the IVS9-15T > C transmitted by the unaffected parents were identified. Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) analyses on minigenes and in brain tissue showed that both mutations cause an increase of tau mRNA (messenger ribonucleic acid) transcripts lacking exon 10 only in the patient. Immunohistochemistry and immunoblotting of the patient's brain revealed tau deposits composed mostly of 3Rtau isoforms with a predominance of the shorter 3Rtau isoforms. The compound heterozygosity of the patient increasing 3Rtau seems to be responsible for the disease and furthermore suggests that sporadic cases can be caused by genetic mutations.

MAPT V363I variation in a sporadic case of frontotemporal dementia: variable penetrant mutation or rare polymorphism?

The V363I mutation of the microtubule-associated protein tau gene has previously been associated with a case of primary progressive nonfluent aphasia with variable penetrance. Herein, we report the finding of the V363I variation in a sporadic early onset frontotemporal dementia patient and in several members of her family. The V363I variation was associated with frontotemporal dementia only in the proband which was also homozygous for the A allele of the progranulin single-nucleotide polymorphism rs9897526 and for methionine at codon 129 of the prion protein gene. The microtubule-associated protein tau V363I variation could be considered either an incomplete penetrant mutation or a rare polymorphism; although its pathogenicity has yet to be clearly demonstrated, modifier genetic factors seem to contribute to the pathogenic effects observed in the patient underlining the great complexity existing in neurodegenerative diseases and questioning so-called sporadic cases that can potentially be caused by gene mutation.

Novel MAPT Val75Ala mutation and PSEN2 Arg62Hys in two siblings with frontotemporal dementia.

A clinical and molecular overlap between Alzheimer's disease (AD) and frontotemporal dementia (FTD) has been reported. Presenilins have been associated with FTD or with FTD-like phenotype, while mutations in the MAPT gene have been linked to a clinical phenotype of AD. We performed a clinical and genetic examination in two FTD siblings and their family tree has been reconstructed. We identified a novel Val75Ala MAPT mutation in one patient and in the other the Arg62His Presenilin2 mutation. The DNA variations identified, defined mutations by frequency, per se are not causative of the disease. These mutations, possibly in association with other unknown environmental and genetic factors, may contribute to neurodegeneration. In this family, the disease might result from a genetically interconnected spectrum of altered pathways that could link most neurodegenerative disorders. Moreover, the novel mutation identified merits further functional studies that would contribute to the unravelling of such a complex field.

AbetaPP A713T mutation in late onset Alzheimer's disease with cerebrovascular lesions.

Mutations in the amyloid-beta protein precursor (AbetaPP) gene can cause autosomal dominant early-onset Alzheimer's disease, or Alzheimer's disease (AD) associated with cerebral amyloid angiopathy (CAA), cerebral hemorrhage, or both. We have previously reported that the AbetaPP A713T mutation is associated with AD and subcortical ischemic lesions at magnetic resonance imaging in a large family which neuropathology confirmed CAA, stroke, and AD lesions. The objective of this clinical and molecular study was to investigate AbetaPP gene mutations in 59 patients affected by AD with cerebrovascular lesions (CVLs) and a family history of dementia. We identified three affected subjects with the AbetaPP A713T mutation. Since the prevalence of this mutation worldwide is very low, a common founder could exist in southern Italy. The pathogenicity of this mutation was confirmed and the clinical AD phenotype with CVLs seems to be a distinctive feature in the southern Italian population. The identification of these patients suggests that genetic epidemiology in large cohorts of familial late onset AD with CVLs would increase the probability of identifying AbetaPP mutations.

Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia.

BACKGROUND: Frontotemporal dementia is a clinically and genetically heterogeneous syndrome. Mutations in two genes, Microtubule Associated Protein Tau (MAPT) and Progranulin (PGRN), and rarely Presenilin mutations, have been causally linked to this disorder. OBJECTIVE: To investigate the presence of PGRN, PSEN1, PSEN2 and APP mutations in a group of familial early-onset frontotemporal dementia (f-EOFTD) patients negative for MAPT gene mutations. SUBJECTS AND METHODS: We prospectively studied 17 unrelated subjects diagnosed with f-EOFTD (one case neuropathologically confirmed as FTD-Ub+). Among these subjects eight belonged to eight autosomal dominant families unrelated to each other, and nine had at least one first degree relative affected by dementia. RESULTS: We identified two novel heterozygous mutations in two unrelated patients, Cys139Arg in the PGRN gene and Val412Ile in the PSEN1 gene. CONCLUSIONS: Early-onset f-FTD remains a heterogeneous disorder from a genetic point of view. PGRN mutation frequency was low in our sample. The presence of a novel PSEN1 mutation suggests that presenilin molecular studies should be performed when screening for MAPT and PGRN genes is negative.