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Neurological Sciences

, Volume 39, Issue 4, pp 615–627 | Cite as

The diagnosis of dementias: a practical tool not to miss rare causes

  • Camilla FerrariEmail author
  • Benedetta Nacmias
  • Sandro Sorbi
Review Article

Abstract

Dementia represents one of the most diffuse disorders of our Era. Alzheimer’s disease is the principle cause of dementia worldwide. Metabolic, infectious, autoimmune, inflammatory, and genetic dementias represent a not negligible number of disorders, with increasing numbers in younger subjects. Due to the heterogeneity of patients and disorders, the diagnosis of dementia is challenging. In the present article, we propose a practical diagnostic approach following the two-step investigation procedure. The first step includes basic blood tests and brain neuroimaging, performed on all patients. After this first-line investigation, it is then possible to rule out metabolic causes of dementia and to identify three main subgroups in dementia: predominant gray matter atrophy, white matter disease, basal ganglia pathologies. The predominant gray matter atrophy subgroup includes neurodegenerative causes of dementia and some lysosomal storage disorders. The white matter subgroup indicates a comprehensive list of vascular dementia causes, mitochondrial diseases, and leukodystrophies. Whereas, the basal ganglia alterations are due to metal accumulation pathologies, such as iron, copper, or calcium. Each category has specific clinical hallmarks, accurately reported in the article, and requires specific second-line investigation. Thus, we indicate the distinct second diagnostic step of each disease. The proposed diagnostic flow-chart follows the clinical reasoning and helps clinicians through the differential diagnosis of dementia.

Keywords

Dementia Uncommon dementia Rare dementia Differential diagnosis Practical tool 

Introduction

Dementia is an epidemic phenomenon affecting 44 million individuals worldwide. The prevalence increases with age, from 1% among 65 years old to more than 22% among subjects older than 85 years [1]. Young-onset dementia is not negligible since it represents around 4–10% of all dementias [2]. The etiologies of dementia differ according to the age of disease onset [3]. Nevertheless, neurodegenerative disorders are the leading causes of cognitive decline with a frequency of 80–90% among older patients [4], and 30–34% among patients younger than 45 years [3, 5]. Metabolic, autoimmune, inflammatory, and infective dementias, even if singularly are uncommon, represent around 20% of the young onset cases [5]. Epidemiological data among the elderly population are not available and based only on single case reports. The European Dementia Guidelines [6, 7] already suggest specific approach for each dementia and neurologist are aware of peculiar investigation in different dementia subtype, however, due to the heterogeneity and rarity of diseases, the diagnosis of dementia is challenging, and 20 to 40% of younger patients had no cause identified [2]. The aim of the present article is to provide a practical tool that guides clinicians through the differential diagnosis of dementia. Following the typical first- and second-line investigation procedure, we propose a flow-chart that takes into account all dementia causes. In the paper, we highlight the clinical hallmarks of each disorder that are helpful for the diagnostic suspicion and the differential diagnosis. The diagnosis of rapid progressive dementia is also included. A detailed description of each disorder is beyond the scope of the present article.

Dementia classification

Dementia includes a broad variety of etiology and could be associated with many disorders. Many authors have attempted to provide [3, 8, 9] a comprehensive list of dementia causes, but in our opinion a complete dementia classification is lacking.

Table 1 shows a proposal of common and uncommon dementias classification following etiological and radiological criteria. Among neurodegenerative causes, we select two subgroups of disorders based on clinical features:
  • Neurodegenerative dementia with peculiar cognitive profile, that includes Alzheimer’s disease (AD), fronto-temporal lobar degeneration spectrum (FTLD) corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Lewy body dementia spectrum (LBD); and

  • Other neurodegenerative diseases, in which dementia is non-specific or with prominent frontal dysfunction.

Table 1

Classification of dementias

Neurodegenerative diseases

 (a) Specific cognitive profile: Alzheimer disease, Fronto-temporal lobar dementia, Lewy Body Dementia, Corticobasal Degeneration, Progressive Supranucelar Palsy

 (b) Other neurodegenerative dementia whit prominent frontal symptoms: Huntington disease, Autosomal Dominant Spino-Cerebellar Ataxia, Hereditary Spastic Paraparesis, FTAX

Vascular dementia

 (a) Large vessel disease

 (b) Small vessel diseases (hypertensive, sporadic cerebral amyloid angiopathy)

Familial cause of vascular Dementia

CADASIL, CARASIL, COL4A1, RVCL, genetic form of cerebral amyloid angiopathy

Adult-onset Leukodystrophy

Adrenoleukodystrophy, Adult-onset leukoencephalopathy with axonal spheroid and pigmented glia, ovario-leukodystrophy, Cerebrotendinous Xanthomatosis, Pelizaeus-Merzbacher Disease, Alexander disease, Adult polyglucosan body disease, Vanishing white matter disease

Lysosomal storage disorders

 (a) with mainly primary neuronal dysfunction: Gaucher’s disease, Niemann-Pick Type C, Kuf’s disorder (Neuronal ceroid lipofuscinosis), Tay-Sachs disease

 (b) with primary glial dysfunction and leukoencephalopathy: Krabbe disease Metachromatic leukodystrophy

 (c) with vascular dysfunction: Fabry disease

Mitochondrial pathologies

MELAS, MERFF, Kearn-Sayre Syndrome

Basal Ganglia pathologies

 (a) Degeneration: Wilson disease; Neuroacanthocytoses (Chorea-Acanthocytosis, McLeod Syndrome, HD-like syndrome)

 (b) Accumulation pathologies: Neurodegeneration with iron accumulation (Pantothenate kinase-associated neurodegeneration, PLA2G6, Kufor-Rakeb, Neuropherritinopathy, Aceruloplasminemia), Fahr disease

Infective dementia

HIV, Syphilis, Borrelia, Herpes Simplex, VZV, Prion diseases

Metabolic dementia

hypo and hyperthyroidism, vitamin deficits, hyponatremia, hepatic encephalopathy, uremic encephalopathy

Autoimmune dementia

Multiple Sclerosis, Vasculitis, Limbic Encephalitis, Hashimoto encephalopathy, NMDAR encephalitis

Neurosurgical causes

Neoplasm, Normal Pressure Hydrocephalus, Subdural Hematoma

Two new categories are also suggested: Basal ganglia pathologies and neurosurgical dementia. In the present paper, basal ganglia pathologies are defined by the presence of altered signal in basal ganglia detected by conventional magnetic resonance imaging (MRI): T2 hyperintensity in case of degeneration and T2 hypointensity in case of metal accumulation. We decide to group under the category neurosurgical dementia a heterogeneous group of diseases characterized by structural brain damage that can be surgically treated. This group includes brain tumor, subdural hematoma, and normal pressure hydrocephalus.

First diagnostic step

After the first visit, as suggested by EFNS guidelines [6, 7], neurologists request basic blood test and neuroimaging exams from each patient. Basic blood tests include complete blood counts, serum electrolytes, liver and thyroid function tests, vitamin B12 and folate, cholesterol and triglycerides, glucose, urea, and serum creatinine. Metabolic causes of dementia (hypo and hyperthyroidism, vitamin deficits, hyponatremia, hepatic encephalopathy, uremic encephalopathy) can be immediately ruled out. Then, neuroimaging is necessary to exclude tumor, subdural hematoma, normal-pressure hydrocephalus or major cerebral lesion as in case of previous stroke [6]. To this purpose, computed tomography scan (CT) is sufficient, but magnetic resonance imaging (MRI) is more sensitive and is required in the diagnostic work up of dementia [6, 7].

Once the MRI is performed, we suggested three principle patterns: predominant gray matter atrophy, predominant white matter involvement, presence of peculiar basal ganglia alteration. When atrophy is the principal MRI feature, differential diagnosis is between Neurodegenerative diseases and some Lysosomal storage disorders. White matter disease is associated to a wider number of disorders: vascular dementia, familial form of vascular dementia, leukodystrophy, mitochondrial disease. Infective and autoimmune dementia can present characteristic white matter lesions [10, 11]. Basal ganglia alteration can be caused by neurodegeneration or by metal accumulation. Once a subgroup is identified, it is possible to proceed to the second diagnostic step, which is different in each category (Fig. 1).
Fig. 1

Flow-chart. The first diagnostic step of the diagnostic procedure of dementias

Second diagnostic step (Tables 2, 3, 4, 5)

Neurosurgical dementia: tumor, subdural hematoma, normal pressure hydrocephalus

Normal pressure hydrocephalus (NPH) should be suspected in older patients, when the enlargement of the cerebral ventricles is associated with gait disturbance, urinary incontinence and dementia [53]. However, in the elderly, those symptoms are common and to differentiate normal pressure hydrocephalus from brain atrophy can be challenging. According to diagnostic criteria [54], MRI or CT must show an Evan’s index (maximal ventricular width divided by the largest biparietal distance between the inner tables of the skull) of at least 0.3. Measurement of cerebrospinal fluid (CSF) flow by phase-contrast MRI can support diagnostic suspicion but is insufficient [6, 55] in predicting response to shunting. The CSF tap test, which involves the removal of 30–50 ml of CSF, is useful for the diagnosis and in predicting shunt effectiveness [56]. The diagnosis of NPH is important since around 59% of patients ameliorate after the treatment [54].
Table 2

Clinical features, MRI pattern, and specific second step investigations among the predominant gray matter atrophy subgroup. Neurodegenerative diseases with peculiar cognitive profile

Diseases

Diagnostic criteria and cognitive profile

MRI

Second diagnostic step (sensibility, specificity)

Alzheimer’s disease

McKhann 2011 [12]

[13, 14] Amnestic: bilateral hippocampal atrophy

Frontal: temporo-parietal and inferior and superior frontal region

LPA: left temporo-parietal cortex

PCA temporo-parietal-occipital bilateral atrophy

FDG-PET (85–95%) Amyloid-PET (70–97%) [15]

CSF abeta, tau, ph-tau (85–95%) [16]

Genetic: APOE, PSEN1, PSEN2, APP

Fronto-temporal dementia

Rasckovsky 2011 [17]

Gorno-Tempini 2011 [18]

bvFTD: (50% normal) frontal cortex and anterior temporal lobe [19]

nvPPA: anterior peri-Sylvian cortices, prominently asymmetric (left)

svPPA: asymmetric antero-inferior temporal lobe atrophy [20]

FDG-PET

Genetic: C9ORF72, MAPT, PGRN, VCP, TARDBP, CHMP2B, FUS [21]

Lewy body dementia

McKeith IG 2017 [22]

Relative preservation of medial temporal lobe, parieto-occipital atrophy [22]

DATSCAN SPECT (78%, 90%)

123iodine-MIBG myocardial scintigraphy (69%, 87%)

Polysomnography (70–95%, 70–95%)

FDG-PET (70%, 74%) [22]

Cortico-basal degeneration

Armstrong MJ, 2013 [23]

Asymmetrical parietal atrophy [24]

DATSCAN SPECT

FDG-PET

Progressive supranuclear palsy

Hoglinger GU 2017 [25]

Midbrain and superior cerebellar peduncle atrophy [24]

DATSCAN SPECT

FDG-PET

FDG-PET 18-fluorodeoxyglucose positron emission tomography, DATSCAN SPECT dopamine transporters single-photon emission computed tomography, APOE apolipoprotein E, PSEN1 presenilin 1, PSNE2 presenilin 2, APP amyloid precursor protein, C9ORF chromosome 9 open reading frame 72, MAPT microtubule associated protein tau, PGRN progranulin, VCP valosin containing protein, TARDBP TAR DNA binding protein, CHMP2B charged multivesicular body protein 2b, FUS fused in sarcoma

Table 3

Clinical features, MRI pattern, and specific second step investigations among the predominant gray matter atrophy subgroup. Other neurodegenerative dementia and Lysosomal storage disorders

Diseases

Clinical features associated with dementia

MRI

Second diagnostic step

Other neurodegenerative dementia

 Huntington disease [26, 27]

Choreiform movements

Psychiatric symptoms juvenile variant (i.e., Westphal variant) [27]

Late-onset [26]

atrophy of the head of caudate, putamen, and frontal lobes

Genetic: CAG repeats in the huntingtin gene on chromosome 4.

 Autosomal dominant cerebellar ataxia [28, 29]

ataxia pyramidal, extrapyramidal signs

Cerebellar atrophy

Genetic: DRPLA, SCA17, SCA 8, SCA 13

 Hereditary spastic paraparesis [30]

slowly progressive spasticity and weakness of lower limb

Non-specific alteration in structural MRI

Spinal cord MRI

MEP

Genetic: SPG 4

 Myotonic dystrophy [31]

weakness, myotonia, cataracts, cardiac conduction defects, Insulin resistance, respiratory failure

Bilateral frontal, temporal and parietal atrophy

EMG

Cardiological evaluation

Opthalmologist evaluation

Genetic: CTG trinucleotide repeats expansion

Lysosomal storage disorders (primary neuronal dysfunction)

 Gaucher’s disease type 3 [32]

Supranuclear horizontal gaze palsy

Akinetic-rigid syndrome,

Hepatosplenomegaly

Normal, or cortical, basal ganglia

Abdominal ultrasound

Glucocerebrisdase enzyme activity

Genetic: GBA

 Niemann-Pick type C [33]

Supranuclear vertical gaze palsy

Ataxia

Splenomegaly

Normal or Unspecific cortical or cerebellar atrophy

Abdominal ultrasound

Skin biopsy: Accumulation of unsterified cholesterol in fibroblasts

Genetic: NPC1 and NPC2

 Tay-Sachs type 3 [34]

Ataxia or Progressive muscle atrophy

Cerebellar atrophy

Hexosaminidase A enzyme activity

Genetic: HEXA

 Kuf’s disease [35]

Facial Dyskinesia

cerebral (hippocampus), cerebellar, basal ganglia atrophy, callosal thinning

Uncertain

Skin biopsy: granular osmiophilic deposits, −fingerprint profiles, −curvilinear profiles, or rectilinear complexes

Genetic: CLN6, CTSF, DNAJC5, GRN, and PPT1

MEP motor evoked potentials, EMG electroneuromyography, GBA glucocerebrosidase, NPC1 and NPC2 NPC intracellular cholesterol transporter 1 and 2, HEXA hexosaminidase subunit alfa, CLN6 transmembran ER protein, CTSF cathepsin F, DNAJC5 DNA J heat shock protein, GRN granulin precursor, PPT1 palmitoyl-protein thioesterase 1

Table 4

Clinical features, MRI pattern, and specific second step investigations among White Matter Diseases subgroup

Diseases

Clinical features associated with dementia/diagnostic criteria

MRI characteristics

Second diagnostic step

Vascular dementia

Hypertensive small vessel disease

NINDS-AIREN [36]

SVID [37]

Lacunar stroke.

Microbleeds

Periventricular WMH

visible perivascular spaces

Screening for vascular risk factors

Cerebral amyloid angiopathy [38]

Processing speed, language skills and episodic memory, visuospatial skills.

Lacunar stroke, lobar hemorrhage, lobar microbleeds, predominant posterior WMH, siderosis visible perivascular spaces

Boston criteria [39]

T2 gradient Echo MRI

Amyloid-PET [38]

CSF: increased levels of anti-Aβ autoantibodies decreased Aβ40 and Aβ42 levels [38]

Familial form of Vascular dementia

 CADASIL

CADASIL Scale [40]

Stroke/TIA, Migraine, Esternal capsule and temporal lobe

Lacunar stroke basal ganglia, brain stem; WM in external capsule and temporal pole

Genetic: NOTCH3

Skin biopsy (granular deposits in the basal lamina of small blood vessels)

 CARASIL [41, 42]

CARASIL = acute lumbago, spondylosis deformans, premature alopecia

Diffuse WM alteration

Genetic: HTRA1

X-Ray of the spine

 COL4A1 [41, 42]

Cerebral poroencephalic cystis

Renal cysts

Migraine, retinal hemorrhage, ocular malformation muscle cramps, Reynaud phenomenon, cardiac arrhythmias, glomerulopathy

Lacunar infart, poroencephalic cysts, predominant posterior WM alteration

Nephrological studies and renal ecographia

Ophthalmologist evaluation

Electrocardiogram

Genetic:COL4A1

 RVCL [41, 42]

Progressive visual loss, stroke, seizure, migraine, kidney dysfunction

Subcortical contrast-enhancing lesion with edema, mainly fronto-parietal

Genetic: TREX1

Abdominal ultrasound

Adult-onset leukodystrophies

 Adrenoleukodystrophy [41, 42]

Spastic paraparesis

Autonomic dysfunction

Sensory ataxia

Addison diseases

Frontal and parieto-occipital WM alteration

EMG

Spinal cord MRI

VLCFA high level

 Adult-onset leukoencephalopathy with axonal spheroid and pigmented glia [42]

Spastic paraparesis, ataxia

Bilateral patchyWM alteration

Genetic: CSF1R

 Ovario-leukodystrophy [43]

Spastic paraparesis, ataxia

Ovarian failure

asymmetric fronto-parietal and periventricular WMH, white matter rarefaction,

Gynecologic evaluation

Genetic: AARS2

 Cerebrotendinous xanthomatosis [41, 42]

Pyramidal signs, Ataxia

Juvenile ocular cataracts tendon xanthomata

Liver abnormalities

Periventricular WMH

Cholestenol plasma level increased

 Pelizaeus-Merzbacher disease [41, 42]

Spastic paraparesis, ataxia

WM tigroid appearance

Genetic: PLP

 Alexander disease [41, 42]

Palatal myoclonus

Spastic paraparesis, ataxia

Ocular motor abnormalities

Neuroimaging criteria [44]

Frontal WM, contrast enhancement of ventricular lining, tumor-like lesion

Genetic: GFAP

 Adult polyglucosan body disease

Neurogenic bladder, tetraparesis, sensory neuropathy

Occipital WMH

Spinal cord MRI

EMG

GBE1 activity on skin fibroblasts or muscle decreased

 Vanishing white matter disease

Episodes of rapid neurological deterioration

Neuroimaging criteria [45]

Bilateral degeneration of hemispheric WM

Genetic: EIF2B

Lysosomal storage disorders (leukoecephalopathy, vascular dysfunction)

 Krabbe disease [41, 42]

Spastic tetraparesis, cerebellar ataxia

Blindness, Deafness

Symmetric or asymmetric WM of corticospinal tract, parieto-occipital regions, and splenium

Ophthalmologist evaluation

Audiological evaluation

ß-galactocerebrosidase low activity in leukocytes

 Metachromatic leukodystrophy [41, 42]

Spastic paraparesis, cerebellar ataxia

Bilateral diffuse WM alteration (more periventricular), tigroid aspect

Arylsulfatase A decreased activity

 Fabry disease [41, 42]

Stroke small fiber neuropathy renal and cardiac disorders, angiokeratoma, hypohidrosis, corneal and lenticular opacities male patients

Predominant lacunar posterior stroke, diffuse WMH

EMG

Cardiological evaluation

Abdominal ultrasound

Ophthalmologist evaluation

galactosidase A enzyme decreased activity

Mitochondrial diseases

 MELAS

Diagnostic criteria [46]

Stroke-like episodes (headache, seizure, hemiplegia, ..)

Short stature, hearing loss, cardiomyopathy

Diffuse WMH, cortical posterior lesions without vascular territory

Lactate level in plasma and CSF increased

Mitochondrial enzyme activities decreased

EMG

Cardiologic evaluation

Audiological evaluation

Muscle biopsy

Genetic: mitochondrial DNA mutation

 MERRF [41, 42]

Myoclonic epilepsy, myopathy, ataxia, hearing loss

Diffuse WMH

EEG

EMG

Audiological evaluation

Muscle biopsy

Genetic: mitochondrial DNA

Neurodegenerative diseases

 FTAX [41, 42]

Tremor/cerebellar ataxia

Radiological features (WM) [47]

WMH in middle cerebellar peduncles and surrounding dentate nuclei

Genetic: CGG expansion on FMR1, X-chromosome

Infective dementia

 HIV-dementia [48]

General in known HIV-patient (rare first symptom)

HIV dementia scale (multidomain deficits) [10]

Spastic paraparesis

Behavioral disease (depression, apathy, anxiety, mania)

Diffuse and symmetric WMH

Spinal MRI

HIV management.

(antiretroviral therapy)

Autoimmune dementia  Vasculitis [49]

Meningoencephalitis, stroke, headache, psychiatric symptoms

Multiple juxtacortical WM lesions, leptomeningeal enhancement

Blood: autoimmune screening

Skin examination

Skeletal X-ray

Lung, kidney CT scan

Cerebral FDG-PET

CSF: oligoclonal bands, pleiocitosis

Therapy: corticosteroid, other immunosuppressants

 MS

Retrobulbar optic neuritis, ataxia, spastic paraparesis

WM lesion: juxtacortical periventicular, posterior fossa, spinal cord

Criteria McDonald [50]

Spinal MRI

PEV

CSF: oligoclonal bands

MS management

Microgliopathy

 Nasu-Hakola [51]

Repeated bone fractures

Diffuse atrophy of gray and white matter

Bone-X rays

Genetic: TREM2, DAP12

NINDS-AIREN National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences, WMH white matter hyperintensity, CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CARASIL cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, NOTCH3 NOTCH3, HTRA1 HtrA serine peptidase 1, COL4A1 collagen type IV alpha 1 chain, RVCL retinal vasculopathy with cerebral leukodystrophy, TREX 1 three prime repair exonuclease 1, VLCFA very long chain fatty acid, CSF1R colony-stimulating factor 1 receptor, AARS2 Alanyl t-RNA Synthetase 2; proteolipid protein 1; GFAP glial fibrillary acidic protein, GBE1 1,4-Alpha-Glucan Branching Enzyme 1, EIF2B eukaryotic translation initiation factor 2B subunit beta, MELAS mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke, MERFF myoclonus epilepsy associated with ragged red fibers, FMR1 fragile X mental retardation 1, MS multiple sclerosis, TREM2 triggering receptor expressed on myeloid cells 2, DAP12 DNAX-Activation Protein 12

Table 5

Clinical features and specific second step investigations in the basal ganglia pathologies subgroup

Diseases

Clinical features associated with dementia

Second diagnostic step

Neuroacanthocytosis (NA)

 Corea-Achantocitosis [41]

Orobuccal chorea, psychiatric symptoms

Blood acanthocytes, reduced chorein on red blood cells

Genetic: VPS13A

 Mc Leod Syndrome [41]

Psychiatric symptoms, choreic movements

Myopathy, cardiomyopahty

Elevated Creatin Kinase

Blood acanthocytes

EMG

Cardiological evaluation

Genetic: XK

Copper accumulation

 Wilson disease [41]

Parkinsonism, dystonia, psychiatric symptoms

Hepatic dysfunction

osteoartrithis

Ophthalmologist evaluation: Kaiser-Flash ring of the cornea

Abdominal ultrasound

Ceruloplasmin plasma low level

Urinary copper increased

Genetic: ATP7B

Iron accumulation (NBIA)

 Hallevorden- Spatz syndrome [41]

Facial dystonia, psychiatric symptoms

Genetic: PANK2

 PLA2G6 [41]

Subacute dystonia-parkinson, psychiatric symptoms

Genetic: PLA2G6

 Kufor Rakeb disease [41]

Oculogyric dystonic spasms, facial-finger mini-myoclonus, supranuclear gaze palsy, psychiatric symptoms

Genetic: ATP13A2

 Neuropherritinopathy [41]

Chorea, oro-facial action-specific dystonia

Low ferritin plasma level

Genetic: FTL

 Aceruloplasminemia [41]

Parkinsonism, ataxia

Retinal degeneration

Hepatic iron accumulation

Ceruloplasmina serum level undetectable, elevated ferritin, iron low level

Abdominal ultrasound

Genetic: CP

Calcium accumulation

 Fahr disease [41]

Parkinsonism, ataxia

Calcium metabolism (secondary causes hypo or hyper parathyroidism)

Genetic: SLC20A2, PDGFRB, PDGFB, XPR1 [52]

VPS13A vacuolar protein sorting 13 homolog A, XK X-linked Kx blood group, ATP7B ATPase copper transporting beta, PANK2 pantothenate kinase 2, PLA2G6 phospholipase A2 group VI, ATP13A2 ATPase 13A2, FTL ferritin light chain, CP ceruloplasmin SLC20A2 solute carrier family 20 member 2, PDGFRB platelet-derived growth factor receptor, beta, PDGFB platelet-derived growth factor, beta polypeptide, XPR1 xenotropic and polytropic retrovirus receptor

Predominant gray matter atrophy

Neurodegenerative disease (Table 2) with specific cognitive profile: Alzheimer’s disease (AD),Fronto temporal dementia (FTD), Lewy body dementia (LBD), Cortico basal degeneration (CBD), Progressive supranuclear palsy (PSP)

Each of these diseases presents a peculiar neuropsychological profile, neurological signs, and pattern of cerebral atrophy. In the typical clinical presentation, the diagnosis can be done following diagnostic criteria [12, 17, 18, 22, 23, 25].

Alzheimer’s disease is the most common type of dementia in the general population. It is usually the disorder of the medial temporal lobe, with its first symptoms as memory loss. However, more than 15% of cases [57] have a different focal presentation; language variant, frontal variant (or executive dysfunction), and posterior variant (or visuospatial) [22, 58, 59, 60]. AD non-amnestic subtypes are more often present in younger subjects. Each subtype has been well characterized by clinical and radiological criteria [18, 61]. However, sometimes the first-line investigation is not sufficient in distinguishing AD between the other neurodegenerative diseases. The language variant phenotype overlaps with the FTD, CBD, and PSP spectrum, while the visuospatial variant with LBD. In these cases amyloid biomarkers, CSF or amyloid-PET, are required to confirm AD pathology [12]. In the presence of extrapyramidal signs, LBD, PSP, or CBD should be suspected. The principle hallmarks of each disease are rapid eye movements-behavioral disorders [22, 24] and early hallucination in LBD, supranuclear vertical palsy and falls in PSP [24, 25], and apraxic-dystonic limb in CBD [23, 24]. Neuroimaging atrophic pattern is also helpful, i.e., FTD languages variant, AD language variant, and CBD usually show an asymmetric atrophy [24] (Table 2). A genetic form of AD (10%) and FTD (20%) should be suspected in case of positive family history for dementia, early or atypical clinical presentation. It is important to note that AD-genetic mutations can be often associated with atypical frontal-cognitive phenotype and with myoclonus, cerebellar ataxia, or spastic paraparesis [5, 62].

Other neurodegenerative diseases (Table 3): Huntington disease (HD), autosomal dominant cerebellar ataxia (SCA), hereditary spastic paraparesis (HSP), myotonic dystrophies

This group includes autosomal dominant diseases, and the diagnosis is always based on genetic mutation. Besides dementia, that is usually of the frontal type, choreiform movements and psychiatric symptoms are the hallmarks of HD, SCA 17, and Dentato-Pallido-Rubro-Luysian atrophy (DPRL) [26, 27, 28, 29]. They share part of the pathogenetic mechanism being polyglutamate disorders. To guide clinicians in differential diagnosis, we highlight that SCA 17 and DPRL present a more catastrophic clinical picture, with seizures. More than are very rare and mostly described in Japanese families [28, 29]. Furthermore, on MRI imaging HD is characterized by atrophy of the head of the caudate nucleus, while SCAs has atrophy of the cerebellum. Dementia and cerebellar ataxia are the main feature of SCA 8 and SCA 13 [29]. Dementia has not been described in the other SCAs, and is present only in the hereditary spastic paraparesis associated with the SPG4 mutation [30].

Lysosomal storage disorders with mainly primary neuronal dysfunctions (Table 3): Niemann Pick, Kuf’s disease, Tay–Sachs disease, Gaucher disease

The above diseases are autosomal recessive disorders with clinical onset in infancy and with systemic involvement, but sometimes are responsible for dementia syndrome among young-adult subjects (20–60 years). Typical clinical symptoms are reported in Table 3. The second diagnostic step includes the amount of specific enzyme activity. Supranuclear gaze palsy is typical of Gaucher type 3 and Niemann-Pick type C, horizontal and vertical palsy respectively [32, 33]. Akinetic-rigid syndrome, poorly responsive to dopa therapy, is described in Gaucher type 3 cases, while cerebellar ataxia is present in Niemann-Pick type C, Tay-Sachs and Kuf’s disease [32, 33, 34, 35]. Kuf’s disease presents variable motor signs and is characterized by facial dyskinesia [35]. The adult onset form of Tay-Sachs could be phenotypical as an ataxia Friedreich-like syndrome or a progressive spinal amyotrophy [34]. Hepatosplenomegaly should be investigated in Gaucher and Niemann Pick Disorders.

To summarize:
  • Language disorders: AD, FTD, CBD, PSP

  • Visuospatial deficit: AD, LBD

  • Apraxia: AD, CBD, PSP

  • Parkinsonian symptoms: LBD, CBD, PSP, Gaucher syndrome

  • Gaze palsy: Vertical PSP and Niemann-Pick type C, Horizontal Gaucher syndrome

  • Chorea/dyskinesia/psychiatric disorders: HD, SCA 17, DPRLA, Kuf’s disease

  • Cerebellar ataxia: SCA8, SCA13, Niemann-Pick type C, Tay-Sachs disease, genetic-AD (PSEN1)

  • Spastic-paraparesis: SPG4, genetic-AD (PSEN1),

  • Muscle-weakness: Tay-Sachs, Myotonic Dystrophy

White matter disease (Table 4)

Smal vessels diseases: hypertensive small vessel disease, cerebral amyloid angiopathy (CAA). Neuroimaging findings in this group include, along with white matter hyperintensities, lacunar or small subcortical infarcts or hemorrhages, visible perivascular spaces, micro bleeds, and brain atrophy [63]. The distribution of each radiological feature differs between pathologies (Table 4). Subcortical ischemic vascular dementia [37] is the most frequent vascular cause of cognitive decline in elderly persons.

Clinically, in elderly with small vessel diseases or sporadic CAA, cognitive deficits concern attentive functions, information processing, working memory, language, mood and motivation [64]. Visuospatial skills are also characteristically impaired in CAA. Gait disturbance, urinary incontinence, and behavioral changes are also frequently present [37].

Familial cause of vascular dementia should be suspected in younger subjects with more specific clinical and radiological profile and often with positive family history for the disorder (Table 4).

The differential diagnosis of dementia associated with white matter lesions includes a wide number of inherited leukoencephalopathies [41]: adult-onset leukodystrophies, mitochondrial diseases, lysosomal storage disorders with primary glial dysfunction and leukoencephalopathy or with vascular dysfunctions, and Fragile-X associated tremor/ataxia (FTAX) among neurodegenerative disease. Infective dementia (HIV-related dementia) and autoimmune dementias such as in case of cerebral vasculitis or multiple sclerosis (MS) are also included in this subgroup. Distinctive clinical and neuroimaging features are described in Table 4 [42].

To summarize:
  • Young onset of stroke or stroke-like symptoms: CADASIL (in presence of autosomal dominant inheritance), CARASIL, RVCL, Fabry’s disease; MELAS

  • Migraine: CADASIL (in presence of autosomal dominant inheritance), COL4A, RVCL, MELAS, Vasculitis

  • Spastic paraparesis: All leukodystrophies, HIV-dementia, MS

  • Ataxia: all leukodystrophies, FTAX, MS

The Nasu–Hakola disease, which is difficult to classify, has recently been given the term microgliopathy. Nasu-Hakola is a unique disease characterized by an early onset with personality changes, memory disorder, apraxia, and seizures, along with a history of repeated bone fractures. Bone X-rays show multiple cystic lesions in the epiphyses of long bones. It is associated with homozygous mutations in the TREM2 gene. Brain neuroimaging shows diffuse atrophy and white matter diseases [51].

The concurrent presence of gray matter atrophy with white matter hyperintensity is also frequent in elderly AD patients [65] and in some genetic case of FTD [66].

Basal ganglia pathologies (Table 5)

  • Basal ganglia degeneration: neuroacanthocytosis (NA), Wilson’s disease,

  • Basal ganglia accumulation pathologies: neurodegeneration with iron accumulation (NBIA), Fahr’s disease

This group includes disorders characterized by chorea/dystonic/parkinsonian symptoms and psychiatric features as obsessive-compulsive disorders, schizophrenic-like psychosis.

NA [41] and Wilson’s disease [41] present a T2 basal ganglia hyperintensity. While in the NBIA [41], iron is visualized as hypointense in T2 MRI. Calcium accumulation is well characterized with computed tomography (CT) scans in Fahr’s disease [6]. Chorea movements, especially in the facial regions, are typical for NA and are in differential diagnosis with HD. NA can be associated with blood acanthocytes and, differently from HD, have no autosomal dominant inheritance [41]. Dystonia and parkinsonian symptoms are the hallmarks of NBIA. Dystonia usually affects the facial region, with characteristic of oculogyric dystonic spasm in the Kufor Rakeb disease, oro-facial action-specific dystonia in neuropherritinopathy, or mouth and neck dystonia in the Hallevorden-Spatz syndrome. PLA2G6, aceruloplasminemia, Kufor-Rakeb, and neuropherritinopathy present Parkinsonian symptoms partially L-DOPA responsive. Among all these disorders, neuroferritinopathy is the only one with autosomal dominant inheritance and with older age at onset (> 40 years). In this subgroup, systemic involvement includes the liver, joints, and eyes, due to the metal accumulation [41].

Subacute dementias

By definition, dementia usually presents a gradual worsening of cognitive performance over years. However, in some cases, patients move from normal status to severe cognitive decline in just a few months. Rapidly progressive dementias can be treatable and therefore it is paramount to diagnose these patients immediately. Thus, in cases of subacute dementia, we suggest to proceed immediately with a complete first-line investigation for all patients. We recommend, beyond the basic blood tests, a urine analysis, a brain MRI, and an electroencephalogram (EEG) and CSF examination (Fig. 2). In case of rapid alteration of cognitive status, especially among the elderly, the diagnosis of delirium [67] should be ruled out, and/or concurrent urinary or systemic infectious, liver and renal dysfunction, alteration of serum electrolytes. Brain neuroimaging is of great importance as it helps to exclude chronic or subacute subdural hematoma, brain tumor or vascular alterations. It has been found that prion disease represents a large portion of rapid progressive dementias [68]. Patients experience cerebellar ataxia, pyramidal or extrapyramidal signs, sometimes psychiatric disturbances and myoclonus. Death occurs generally within 6 months and not longer than 2 years from the onset of the disease. Brain MRI reveals an unusual T2 basal ganglia hyperintensity, while the EEG can show a pseudo-periodic pattern [69]. However, recently, the real-time quaking-induced conversion test, is indicate as a sensitive (82%) and specific (99%) approach in detecting prions on the CSF [70]. Diagnosis is important for the repercussion on family members but also for the Public Health, as the disease can be transmitted and no treatment to cure it is available. On the other hand, infective, metabolic and autoimmune subacute dementias can be treatable. Hashimoto’s Encephalopathy, can have a similar presentation to prion disorders, but is a steroid-responsive disease associated with autoimmune thyroiditis. A prompt treatment usually determines a good prognosis [71]. Investigations can be non-specific, thus the diagnosis sometimes is based on the exclusion of the other causes [70]. The clinical presentation of Limbic Encephalitis is the classic triad: memory deficits, behavioral changes and temporal epilepsy. The paraneoplastic etiology should always be investigated and in cases of negative results the search of primary tumor should continue up to 5 years. Plasmapheresis or tumor specific treatment ameliorates cognitive status [72]. An abrupt psychiatric presentation (typically psychosis) in isolation [11, 73], is characteristic for NMDAR encephalitis, usually in young females often associated with an underlying teratoma (usually ovarian) [73]. The picture evolves with rapid progressive dementia, oromandibular dyskinesia and myoclonus. A timely treatment is important for prognosis and consists in tumor identification and treatment or immunosuppressant therapy.
Fig. 2

The diagnostic approach to subacute dementias

The acute onset of Wernicke Encephalopathy requires thiamine and magnesium replacement. Wernicke Encephalopathy is characterized by psychosis, ataxia and ophthalmoplegia. Around 20% of Wernicke Encephalopathy cases results in death [74]. To prevent such cases, this disease should be suspected in patients who are malnourished, who have pathology that can reduce vitamin absorption (anorexia and gastric resection) and have a history of alcoholism (Fig. 2). After the exclusion of treatable causes of dementia, it is important to remember that an atypical rapid progression can be seen even in primitive neurodegenerative dementias, especially in genetic case. A recent study revealed that more than 20% of cases where patients were referred to various national prion centers were affected by Alzheimer’s disease [68].

Conclusion

Dementia is a generic term that indicates the progressive loss of intellectual functioning. Alzheimer’s disease has been for decades the emblem of dementia, and until recently, diagnostic criteria for dementia required the presence of memory deficits. However, in clinical practice, this definition has always been limited and many patients with cognitive impairment never reached a diagnosis. In the last years, thanks to technology, especially in the genetic field, clinicians had the possibility to identify previous unknown disorders and sometimes to cure dementia. In this picture, the diagnosis of dementia has become challenging. In our opinion, the proposed diagnostic flow-chart will support clinicians during clinical practice, suggesting differential diagnosis and guiding the appropriate use of investigation options.

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2017

Authors and Affiliations

  1. 1.IRCCS Don GnocchiFlorenceItaly
  2. 2.Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA)University of FlorenceFlorenceItaly

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